NUCLEOSIDE DERIVATIVES FOR THE TREATMENT OF CANCER

DERIVES DE NUCLEOSIDES POUR LE TRAITEMENT DU CANCER

English Abstract

Provided herein are compounds, compositions, and methods for the treatment of cancer, including leukemia. In one embodiment, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-cancer agents.

French Abstract

L'invention concerne des composés, des compositions et des méthodes pour le traitement du cancer, y compris de la leucémie. Dans un mode de réalisation, l'invention concerne des composés et des compositions de dérivés de nucléosides qui peuvent être administrés soit seuls, soit en combinaison avec d'autres agents anticancéreux.

Claims

What is claimed is:
1. A compound of Formula I:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
<IMG>

<IMG> , p-NO2PhCH2O¨, ¨NHCH2Ph, ¨N(CH3)CH2Ph, ¨NHR2,
¨NH(CH2)5N(CH3)2, -BH3, <IMG>
<IMG>
R z is H or C(O)Z where Z is a fatty acid chain selected from palmitoleic,
oleic,
linoleic, or arachidonic acid;
W is NH2, halo, OMe or OH;
T is NH2, F, Cl or halogen;
R1 is hydrogen, halo, OH, protected OH, cyano or alkynyl;
Q is OR3;
E is CR4R5;

L is H, p-Me, p-OMe, p-C1, or 3,4-Cl;
n is 1;
m is 1 or 2;
p is absent or O;
R y is alkyl, alkenyl, alkynyl, alkoxycarbonyl, or hydroxyalkyl, each
independently
optionally substituted;
R2 is hydrogen or alkyl;
R3 is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl or aralkyl;
R4 and R5 are selected from:
i) R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl, or alkylheteroaryl,
wherein the alkyl is
optionally substituted by alkoxy; or
ii) R4 and R5 together with the carbon atom to which they are attached form a
3-7
membered cycloalkyl ring;
R6 is hydrogen, <IMG> or
R6 with one of X and Y, together with the atoms to which they are attached,
combine to form a six-membered heterocyclic ring where R6 and the one of X and
Y together
represent a single divalent ¨O¨; or
R6 with one of X and Y, together with the atoms to which they are attached,
combine to form a 7-12-membered heterocyclic ring;

wherein, when R is <IMG>, and X and Y both are <IMG> ,
then at least one R y is
other than alkyl.
2. The compound of claim 1, wherein R1 is OH or F.
3. The compound of claim 1 or claim 2, wherein:
X is , ¨NHCH2Ph, Y is selected from OH,
<IMG>
4. The compound of any one of claims 1 or 2 haying the Formula IId:
<IMG>
(IId)
or a pharmaceutically acceptable salt thereof
5. The compound of claim 1 or claim 2 haying the Formula IIe:
<IMG>

(IIe)
or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen; R3 is alkyl; R4 is hydrogen and R5 is alkyl, or cycloalkyl; or
R4 is alkyl or
cycloalkyl, and R5 is hydrogen.
6. The compound of claim 1 or claim 2 having the Formula IIf:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen; R3 is alkyl; R4 is hydrogen and R5 is alkyl, or cycloalkyl; or
R4 is alkyl or
cycloalkyl, and R5 is hydrogen.
7. The compound of claim 1 or claim 2 having the Formula IIg:
<IMG>
or a pharmaceutically acceptable salt thereof
8. The compound of claim 1 or claim 2 having the Formula IIh:

<IMG>
(IIh)
or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen; R3 is alkyl; R4 is hydrogen and R5 is alkyl, or R4 is alkyl
and R5 is
hydrogen.
9. The compound of claim 1 or claim 2 having one of the following Formulas:
<IMG>
10. The compound of claim 1 or claim 2 having one of the following
Formulas:

<IMG>
11. The compound
of claim 1 or claim 2 having one of the following Formulas:
<IMG>

12. The compound of claim 1 or claim 2 having one of the following
Formulas:
<IMG>
13. The compound of claim 1 or claim 2 having one of the following
Formulas:
<IMG>
14. The compound of claim 1 or claim 2 having the Formula:

<IMG>
15. A compound of Formula Ha:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
<IMG>
R z is H or C(O)Z where Z is a fatty acid chain selected from palmitoleic,
oleic, linoleic,
or arachidonic acid;
W is NH2, Cl, or OMe;
T is NH2, F, or Cl;
1Z1 is hydrogen, OH, or F;

R2 is hydrogen or alkyl;
Q is OR3;
E is CR4R5;
n is 1;
R3 is hydrogen, alkyl, alkenyl, or alkynyl;
R4 and R5 are selected from:
i) R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
aralkyl,
cycloalkyl, cycloalkenyl, alkylheterocyclyl, or alkylheteroaryl, wherein the
alkyl is optionally
substituted by alkoxy; or
ii) R4 and R5 together with the carbon atom to which they are attached form a
3-7
membered cycloalkyl ring;
R7 is alkyl, alkenyl, or alkynyl, each independently optionally substituted.
16. The compound of claim 15 haying the Formula:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen; R3 is alkyl; R4 is hydrogen and R5 is alkyl, or cycloalkyl; or
R4 is alkyl or
cycloalkyl, and R5 is hydrogen.
17. The compound of any one of claims 15 or 16 haying one of the following
Formulas:

<IMG>
18. The compound of any one of claims 15 or 16 haying one of the following
Formulas:
<IMG>
19. A compound of Formula IIb:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
Y is OH, <IMG> , or OR7;

<IMG>
Rz is H or C(O)Z where Z is a fatty acid chain selected from palmitoleic,
oleic,
linoleic, or arachidonic acid;
R2 is hydrogen or alkyl;
Q is OR3;
E is CR4R5;
n is 1;
R3 is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;
R4 and R5 are selected from:
i) R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl,
wherein the alkyl is
optionally substituted by alkoxy; or
ii) R4 and R5 together with the carbon atom to which they are attached form a
3-7
membered cycloalkyl ring;
R7 is alkyl, alkenyl, or alkynyl, each independently optionally substituted.
20. The compound of claim 19 having the Formula:
<IMG>

or a pharmaceutically acceptable salt thereof, wherein:
R2is hydrogen; R3 is alkyl; R4 is hydrogen and R5 is alkyl, or cycloalkyl; or
R4 is alkyl or
cycloalkyl, and R5 is hydrogen.
21. The compound of any one of claims 19 or 20 having the Formula:
<IMG>
22. A compound selected from:
ethyl ((4aR,6R,7S,7aR)-6-(6-amino-2-chloro-9H-purin-9-yl)-7-fluoro-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)-L-alaninate,
ethyl ((4aR,6R,7S,7aR)-6-(6-amino-2-chloro-9H-purin-9-yl)-7-fluoro-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)-L-alaninate,
((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-
hydroxytetrahydrofuran-2-yl)methyl hydrogen benzylphosphoramidate,
((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-
hydroxytetrahydrofuran-2-yl)methyl di(((3-hydroxy-2,2-
dimethylpropanoyl)thio)ethyl) phosphate,
S-(2-(((((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-
hydroxytetrahydrofuran-2-yl)methoxy)(benzylamino)phosphoryl)oxy)ethyl) 3-
hydroxy-2,2-dimethylpropanethioate,
S-(2-(((((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-
hydroxytetrahydrofuran-2-yl)methoxy)(benzylamino)phosphoryl)oxy)ethyl) 3-
hydroxy-2,2-dimethylpropanethioate,
methyl ((((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-
hydroxytetrahydrofuran-2-yl)methoxy)(2-methoxy-2-oxoethoxy)phosphoryl)-L-

leucinate,
methyl ((((2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-3-
hydroxytetrahydrofuran-2-yl)methoxy)(2-methoxy-2-oxoethoxy)phosphoryl)-L-
leucinate,
((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methyl hydrogen benzylphosphoramidate,
((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methyl ((1-methyl-2-nitro-1H-imidazol-5-
yl)methyl) benzylphosphoramidate,
((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methyl ((1-methyl-2-nitro-1H-imidazol-5-
yl)methyl) benzylphosphoramidate,
methyl ((((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(2-methoxy-2-oxoethoxy)phosphoryl)-L-
leucinate,
ethyl ((((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(2-ethoxy-2-oxoethoxy)phosphoryl)-L-
leucinate,
ethyl ((((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(2-ethoxy-2-oxoethoxy)phosphoryl)-L-
leucinate,
S-(2-(((((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(benzylamino)phosphoryl)oxy)ethyl) 3-
hydroxy-2,2-dimethylpropanethioate,
methyl (2S)-((((2R,3S,4S,5R)-3,4-dihydroxy-5-(4-((E)-octadec-9-enamido)-2-
oxopyrimidin-1 (2H)-yl)tetrahydrofuran-2-yl)methoxy)(((S)- 1 -methoxy-4-methyl-
1-oxopentan-2-yl)amino)phosphoryl)-L-leucinate,
((2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methyl hydrogen benzylphosphoramidate,
((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methyl ((1-methyl-2-nitro-1H-imidazol-5-

yl)methyl) benzylphosphoramidate,
ethyl ((4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-9H-purin-9-yl)-7-hydroxy-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)-L-leucinate,
ethyl ((4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-9H-purin-9-yl)-7-hydroxy-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)-L-leucinate,
isopropyl ((((2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate,
S-(2-(((((2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(benzylamino)phosphoryl)oxy)ethyl) 3-
hydroxy-2,2-dimethylpropanethioate,
ethyl ((((2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(2-((3-hydroxy-2,2-
dimethylpropanoyl)thio)ethoxy)phosphoryl)-L-leucinate,
(4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-9H-purin-9-yl)-7-hydroxy-2-
isopropoxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine 2-oxide,
(4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-9H-purin-9-yl)-7-hydroxy-2-
isopropoxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinine 2-oxide,
ethyl ((((2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)-L-leucinate,
ethyl ((((2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(2-ethoxy-2-oxoethoxy)phosphoryl)-L-
leucinate,
methyl ((((2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(2S-1-methoxy-1-oxo-4-methylpent-2-
ylamino)phosphoryl)-L-leucinate,
methyl ((((2R,3R,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-4-
(((benzyloxy)carbonyl)oxy)-3-hydroxytetrahydrofuran-2-yl)methoxy)(2-methoxy-
2-oxoethoxy)phosphoryl)-L-leucinate,
methyl ((((2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(2-methoxy-2-oxoethoxy)phosphoryl)-L-
leucinate,

(2S)-2-4(4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-9H-purin-9-yl)-7-hydroxy-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)amino)propyl
propionate,
(2S)-2-4(4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-9H-purin-9-yl)-7-hydroxy-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)amino)propyl
propionate,
ethyl ((4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-9H-purin-9-yl)-7-hydroxy-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)-L-alaninate,
ethyl ((4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-9H-purin-9-yl)-7-hydroxy-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)-L-alaninate,
ethyl ((4aR,6R,7S,7aS)-6-(2-amino-6-methoxy-9H-purin-9-yl)-7-hydroxy-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)-L-alaninate,
ethyl ((4aR,6R,7S,7aS)-6-(2-amino-6-methoxy-9H-purin-9-yl)-7-hydroxy-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)-L-alaninate,
(2S)-2-4(4aR,6R,7S,7aS)-6-(2-amino-6-methoxy-9H-purin-9-yl)-7-hydroxy-2-
oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)amino)propyl
propionate,
S-(2-(((((2R,3S,4S,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methoxy)(benzylamino)phosphoryl)oxy)ethyl) 3-
hydroxy-2,2-dimethylpropanethioate, or
((2R,3S,4S,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)methyl hydrogen benzylphosphoramidate,
or a pharmaceutically acceptable salt thereof
23. A compound selected from:
ethyl (2S)-2-[[(4aR,6R,7S,7aR)-6-(6-amino-2-chloro-purin-9-yl)-7-fluoro-2-oxo-
4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-
yl]amino]propanoate (diastereomer 1 and 2);
[(2R,3S,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-
2-yl]methoxy-N-benzyl-phosphonamidic acid;

4-amino-1-[(2R,3S,4S,5R)-5-[[(benzylamino)-[(3-methyl-2-nitro-imidazol-4-
yl)methoxy]phosphoryl]oxymethyl]-3,4-dihydroxy-tetrahydrofuran-2-
yl]pyrimidin-2-one (diastereomer 1 and 2);
[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydroxy-
tetrahydrofuran-2-yl]methyl bis[(2-nitrothiazol-5-yl)methyl] phosphate;
[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydroxy-
tetrahydrofuran-2-yl]methyl (3-methyl-2-
nitro-imidazol-4-yl)methyl (2-
nitrothiazol-5-yl)methyl phosphate;
4-amino-1-[(2R,3S,4S,5R)-5-[[(benzylamino)-[(5-nitro-2-
thienyl)methoxy]phosphoryl]oxymethyl]-3,4-dihydroxy-tetrahydrofuran-2-
yl]pyrimidin-2-one (diastereomer 1 and 2);
[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydroxy-
tetrahydrofuran-2-yl]methyl bis[(5-nitro-2-furyl)methyl] phosphate;
benzyl (2S)-2-[[[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydroxy
tetrahydrofuran-2-yl]methoxy-[(5-nitro-2-
thienyl)methoxy]phosphoryl]amino]propanoate (diastereomer 1 and 2);
4-amino-1-[(2R,3S,4S,5R)-5-[[(benzylamino)-[(5-nitro-2-
furyl)methoxy]phosphoryl]oxymethyl]-3,4-dihydroxy-tetrahydrofuran-2-
yl]pyrimidin-2-one(diastereomer 1 and 2);
benzyl (2S)-2-
[[(4aR,6R,7S,7aR)-6-(6-amino-2-chloro-purin-9-yl)-7-fluoro-2-
oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-
yl]amino]propanoate (diastereomer 1 and 2); and
ethyl (2S)-2-
[[(4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-purin-9-yl)-7-hydroxy-2-
oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-
yl]amino]propanoate (diastereomer 1 and 2);
Methyl (2S)-2-[[[(2R,3S,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-3,4-dihydroxy-
tetrahydrofuran-2-yl]methoxy-(2-methoxy-2-oxo-ethoxy)phosphoryl]amino]-4-
methyl-pentanoate;
or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound of any one of claims
1-23,
or a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable excipient,
carrier, or diluents.
25. The pharmaceutical composition of claim 24, wherein the composition is
an oral
formulation.
26. A method for the treatment of a blood cancer comprising administering
an
effective treatment amount of a compound of any of claims 1-23, or a
pharmaceutically
acceptable salt thereof or a composition of claim 24 or 25.
27. The method of claim 26, wherein the blood cancer is a leukemia cancer.
28. The method of claim 27, wherein the leukemia is acute myelogenous
leukemia
(AML).
29. The method of claim 26, wherein said compound or composition is
administered
in combination or alternation with a second chemotherapeutic agent.
30. A combination comprising a compound of any one of claims 1-23, or a
pharmaceutically acceptable salt thereof and one, two, three or more other
therapeutic agents.

Description

CA 02947939 2016-11-03
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NUCLEOSIDE DERIVATIVES FOR THE TREATMENT OF CANCER
FIELD
Provided herein are nucleoside derivatives, pharmaceutical compositions
comprising the
compounds, processes of preparation thereof, and methods of use thereof for
treating
cancer.
BACKGROUND
Cancer is a disease characterized primarily by an uncontrolled divisions of
abnormal cells
derived from a given normal tissue and the invasion of adjacent tissues by
these malignant
cells. Blood or lymphatic transportation can spread cancer cells to other
parts of the body
leading to regional lymph nodes and to distant sites (metastasis). Cancer is a
complex,
multistep process that begins with minor preneoplastic changes, which may
under certain
conditions progress to neoplasia. There are more than 100 different types of
cancer,
which can be grouped into broader categories. The main categories include:
carcinoma,
sarcoma, leukemia, lymphoma and myeloma, and central nervous system cancers.
The
incidence of cancer continues to climb as the general population ages, as new
cancers
develop, and as susceptible populations (e.g., people infected with AIDS or
excessively
exposed to sunlight) grow. A tremendous demand therefore exists for new
methods and
compositions that can be used to treat patients with cancer.
Hematologic or hematopoietic malignancies are cancers of the blood or bone
marrow,
including leukemia and lymphoma. Leukemia is a type of cancer of the blood
characterized by abnormal accumulation of immature white blood cells. There
are four
types of leukemia: acute lymphocytic leukemia (ALL), acute myelogenous
leukemia
(AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia
(CIVIL). Acute leukemia is a rapidly progressing disease that results in the
accumulation
of immature, functionless cells in the marrow and blood. The marrow often
stops
producing enough normal red cells, white cells and platelets. On the other
hand, chronic
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leukemia progresses more slowly and allows greater numbers of more mature,
functional
cells to be made.
Leukemia can affect people at any age. The cause of most cases of leukemia is
not
known. Extraordinary doses of radiation and certain cancer therapies are
possible causes.
About 90% of leukemia are diagnosed in adults. In 2000 approximately 256,000
children
and adults around the world developed some form of leukemia, and 209,000 died
from it.
Cases of Chronic leukemia account for 4.5 percent more cases than acute
leukemia. The
most common types of leukemia in adults are acute myelogenous leukemia (AML),
with
estimated 14,590 new cases in 2013, and chronic lymphocytic leukemia (CLL),
with
about 15,680 new cases in 2013. Chronic myelogenous leukemia (CIVIL) was
estimated
to affect about 5,920 persons in 2013 (data from the Leukemia and Lymphoma
Society,
Facts 2013, August 2013).
The dramatic improvement in blood cancer treatment in the latter part of the
20th century
is largely the result of chemotherapy. In addition, there are more than 50
drugs
individually used to treat these disorders and a number of potential new
therapies are
under investigation in clinical trials. While current chemotherapy can result
in complete
remissions, the long term disease-free survival rate for leukemia, in
particular AML, is
low. For example, the overall relative survival rate for AML was estimated to
be about
59% from 2003 to 2009. Therefore, there is a clear and unmet need for
effective
therapeutics for treatment of blood cancers, including leukemia.
SUMMARY OF THE DISCLOSURE
Derivatives, in one embodiment phosphoramidate derivatives and cyclic
phosphate
derivatives, of a variety of therapeutic agents are provided, as well as
pharmaceutical
compositions and methods of treatment of a variety of cancer including
hematopoietic
malignancies. The therapeutic agent is, for example, an anti-cancer agent that
includes, or
has been derivatized to include, a reactive group, such as a hydroxyl, for
attachment of the
phosphoroamidate and cyclic phosphate moiety. Such therapeutic agents include,
but are
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not limited to nucleosides and nucleoside analogs including acyclic
nucleosides. A
nucleoside analog refers to a structurally modified nucleoside. In one
embodiment, the
nucleosides or nucleoside analogs are derivitized at the 5'- and/or the 3'-
position by
removal of a hydrogen from an hydroxyl group to incorporate a phosphoramidate
and
cyclic phosphate group. In one embodiment, the nucleosides or nucleoside
analogs are
derivitized at the 5'- and/or the 2'-position by removal of a hydrogen from an
hydroxyl
group to incorporate a phosphoramidate and cyclic phosphate group. In one
embodiment,
phosphorodiamidates of nucleosides and nucleoside analogs are provided. In
other
embodiments, the compound is a S-pivaloy1-2-thioethyl phosphoroamidate or S-
hydroxypivaloy1-2-thioethyl phosphoroamidate. In another embodiment, S-
pivaloy1-2-
thioethyl disulfide phosphoroamidate or S-2,2-dimethy1-3-oxopropanoate 2-
thioethyl
benzyl phosphoroamidate or benzylphosphoramidate of nucleosides and nucleoside
analogs are provided. In other embodiments, the derivative is 1-methy1-2-nitro-
1H-
imidazol-5-methoxymethyl N- benzylphosphoramidate or 5-nitrofuran-2-
methoxymethyl
N-benzyl phosphoramidate. In one embodiment the derivative is a 3', 5'-cyclic
phosphate.
In another embodiment the derivative is a 2', 5'-cyclic phosphate.
Phosphoroamidate and cyclic phosphate compounds of a variety of anti-cancer
agents are
provided. The anti-cancer agents include, but are not limited to, modified
nucleosides. In
another embodiment, the anti-cancer agent is clofarabine, cytarabine,
isocladribine,
cladribine, fludarabine or nelarabine. In another embodiment, the anti-cancer
agent is
clofarabine, cytarabine, isocladribine, cladribine or fludarabine. In another
embodiment,
the anti-cancer agent is clofarabine or cytarabine.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
To facilitate understanding of the disclosure set forth herein, a number of
terms are
defined below.
Generally, the nomenclature used herein and the laboratory procedures in
organic
chemistry, medicinal chemistry, and pharmacology described herein are those
well known
and commonly employed in the art. Unless defined otherwise, all technical and
scientific
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terms used herein generally have the same meaning as commonly understood by
one of
ordinary skill in the art to which this disclosure belongs.
The term "alkyl", as used herein, unless otherwise specified, refers to a
saturated straight
or branched hydrocarbon. In one embodiment, the alkyl group is a primary,
secondary, or
tertiary hydrocarbon. In one embodiment, the alkyl group includes one to ten
carbon
atoms, i.e., Ci to Cio alkyl. In one embodiment, the alkyl group is methyl,
CF3, CC13,
CFC12, CF2C1, ethyl, CH2CF3, CF2CF3, propyl, isopropyl, butyl, isobutyl, sec-
butyl, t-
butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-
dimethylbutyl, or
2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl
groups,
including halogenated alkyl groups, preferably unsubstituted or halogenated
alkyl groups.
In one embodiment, the alkyl group is a fluorinated alkyl group. Non-limiting
examples
of moieties with which the alkyl group can be substituted include halogen
(fluoro, chloro,
bromo, or iodo), oxo, hydroxyl, amino, alkylamino, arylamino, alkylarylamino,
alkoxy,
aryloxy, thioalkoxy, thioaroxyl, alkyldisulfanyl, acyl, hydroxylcarbonyl,
alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl,
alkylarylaminocarbonyl, acyloxy, acylthio, nitro, cyano, sulfonic acid,
sulfate, phosphonic
acid, phosphate, or phosphonate, either unprotected, or protected as
necessary, as known
to those skilled in the art, for example, as taught in Greene, et aL,
Protective Groups in
Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby
incorporated by
reference.
The term "lower alkyl", as used herein, and unless otherwise specified, refers
to a
saturated straight or branched hydrocarbon having one to six carbon atoms,
i.e., Ci to C6
alkyl. In one embodiment, the lower alkyl group is a primary, secondary, or
tertiary
hydrocarbon. The term includes both substituted and unsubstituted moieties,
preferably
unsubstituted
The term "cycloalkyl", as used herein, unless otherwise specified, refers to a
saturated
cyclic hydrocarbon. In one embodiment, the cycloalkyl group may be a
saturated, and/or
bridged, and/or non-bridged, and/or a fused bicyclic group. In one embodiment,
the
cycloalkyl group includes three to ten carbon atoms, i.e., C3 to C10
cycloalkyl. In some
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embodiments, the cycloalkyl has from 3 to 15 (C3_15), from 3 to 10 (C3_10), or
from 3 to 7
(C3_7) carbon atoms. In one embodiment, the cycloalkyl group is cyclopropyl,
cyclobutyl,
cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cycloheptyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl. The term
includes both
substituted and unsubstituted cycloalkyl groups, including halogenated
cycloalkyl groups.
Non-limiting examples of moieties with which the cycloalkyl group can be
substituted
include halogen (fluoro, chloro, bromo, or iodo), oxo, hydroxyl, amino,
alkylamino,
arylamino, alkylarylamino, alkoxy, aryloxy, thioalkoxy, thioaroxyl,
alkyldisulfanyl, acyl,
hydroxylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylaminocarbonyl,
arylaminocarbonyl, alkylarylaminocarbonyl, acyloxy, acylthio, nitro, cyano,
sulfonic acid,
sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or
protected as
necessary, as known to those skilled in the art, for example, as taught in
Greene, et al.,
Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition,
1991,
hereby incorporated by reference. In preferred embodiments, the cycloalkyl
is
unsubstituted or substituted with one or more halogens.
"Alkenyl" refers to monovalent olefinically unsaturated hydrocarbon groups, in
certain
embodiment, having up to about 11 carbon atoms, from 2 to 8 carbon atoms, or
from 2 to
6 carbon atoms, which can be straight-chained or branched and having at least
1 or from 1
to 2 sites of olefinic unsaturation. The term "alkenyl" embraces radicals
having a "cis" or
"trans" configuration or a mixture thereof, or alternatively, a "Z" or "E"
configuration or a
mixture thereof, as appreciated by those of ordinary skill in the art. For
example, C2-6
alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to
6 carbon
atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6
carbon atoms.
In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical
of 2 to 20
(C2_20), 2 to 15 (C2_15), 2 to 10 (C2_10), or 2 to 6 (C2_6) carbon atoms, or a
branched
monovalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C3_15), 3 to 10
(C3_10), or 3 to 6
(C3_6) carbon atoms. Examples of alkenyl groups include, but are not limited
to, ethenyl,
propen-1 -yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl. The term
includes both
substituted and unsubstituted alkenylene groups, including halogenated
cycloalkyl groups,
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preferably unsubstituted or halogenated cycloalkyl. Non-limiting examples of
moieties
with which the alkenylene group can be substituted include halogen (fluoro,
chloro,
bromo, or iodo), oxo, hydroxyl, amino, alkylamino, arylamino, alkylarylamino,
alkoxy,
aryloxy, thioalkoxy, thioaroxyl, alkyldisulfanyl, acyl, hydroxylcarbonyl,
alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl,
alkylaminocarbonyl, arylaminocarbonyl,
alkylarylaminocarbonyl, acyloxy, acylthio, nitro, cyano, sulfonic acid,
sulfate, phosphonic
acid, phosphate, or phosphonate, either unprotected, or protected as
necessary, as known
to those skilled in the art, for example, as taught in Greene, et al.,
Protective Groups in
Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby
incorporated by
reference.
The term "cycloalkenyl", as used herein, unless otherwise specified, refers to
an
unsaturated cyclic hydrocarbon and includes both substituted and unsubstituted
cycloalkenyl groups, preferably unsubstituted. Non-limiting examples of
moieties with
which the cycloalkenyl group can be substituted include halogen (fluoro,
chloro, bromo, or
iodo), oxo, hydroxyl, amino, alkylamino, arylamino, alkylarylamino, alkoxy,
aryloxy,
thioalkoxy, thioaroxyl, alkyldisulfanyl, acyl, hydroxylcarbonyl,
alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl,
alkylarylaminocarbonyl, acyloxy, acylthio, nitro, cyano, sulfonic acid,
sulfate, phosphonic
acid, phosphate, or phosphonate, either unprotected, or protected as
necessary, as known
to those skilled in the art, for example, as taught in Greene, et al.,
Protective Groups in
Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby
incorporated by
reference.
The term "alkenylene" refers to a linear or branched divalent hydrocarbon
radical, which
contains one or more, in one embodiment, one, two, three, four, or five, in
another
embodiment, one or two, carbon-carbon double bond(s). The term "alkenylene"
embraces
radicals having a "cis" or "trans" configuration or a mixture thereof, or
alternatively, a "Z"
or "E" configuration or a mixture thereof, as appreciated by those of ordinary
skill in the
art. For example, C2-6 alkenylene refers to a linear unsaturated divalent
hydrocarbon
radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon
radical of 3
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to 6 carbon atoms. In certain embodiments, the alkenylene is a linear divalent
hydrocarbon radical of 2 to 20 (C2_20), 2 to 15 (C2_15), 2 to 10 (C2_10), or 2
to 6 (C2_6) carbon
atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15
(C3_15), 3 to 10
(C3_10), or 3 to 6 (C3_6) carbon atoms. Examples of alkenylene groups include,
but are not
limited to, ethenylene, allylene, propenylene, butenylene, and 4-
methylbutenylene. The
term includes both substituted and unsubstituted groups, including halogenated
groups,
preferably unsubstituted. Non-limiting examples of moieties with which the
alkenylene
group can be substituted include halogen (fluoro, chloro, bromo, or iodo),
oxo, hydroxyl,
amino, alkylamino, arylamino, alkylarylamino, alkoxy, aryloxy, thioalkoxy,
thioaroxyl,
alkyldisulfanyl, acyl, hydroxylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl,
alkylaminocarbonyl, arylaminocarbonyl, alkylarylaminocarbonyl, acyloxy,
acylthio, nitro,
cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,
either
unprotected, or protected as necessary, as known to those skilled in the art,
for example, as
taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley
and Sons,
Second Edition, 1991, hereby incorporated by reference.
"Alkynyl" refers to acetylenically unsaturated hydrocarbon groups, in certain
embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms
which can
be straight-chained or branched and having at least 1 or from 1 to 2 sites of
alkynyl
unsaturation. Non-limiting examples of alkynyl groups include acetylenic,
ethynyl (-
CCH), propargyl (-CH2CCH), and the like. The term also includes both
substituted and
unsubstituted alkynyl groups, preferably unsubstituted. Non-limiting examples
of
moieties with which the alkynyl group can be substituted include halogen
(fluoro, chloro,
bromo, or iodo), oxo, hydroxyl, amino, alkylamino, arylamino, alkylarylamino,
alkoxy,
aryloxy, thioalkoxy, thioaroxyl, alkyldisulfanyl, acyl, hydroxylcarbonyl,
alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl,
alkylarylaminocarbonyl, acyloxy, acylthio, nitro, cyano, sulfonic acid,
sulfate, phosphonic
acid, phosphate, or phosphonate, either unprotected, or protected as
necessary, as known
to those skilled in the art, for example, as taught in Greene, et al.,
Protective Groups in
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Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby
incorporated by
reference.
The term "aryl", as used herein, and unless otherwise specified, refers to
phenyl, biphenyl,
or naphthyl. The term includes both substituted and unsubstituted moieties. An
aryl group
can be substituted with any described moiety, including, but not limited to,
one or more
moieties selected from halogen (fluoro, chloro, bromo, or iodo), alkyl,
haloalkyl, alkenyl,
alkynyl, cycloalkyl, cycloakenyl, hydroxyl, amino, alkylamino, arylamino,
alkylarylamino, alkoxy, aryloxy, thioalkoxy, thioaroxyl, alkyldisulfanyl,
acyl,
hydroxylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylaminocarbonyl,
arylaminocarbonyl, alkylarylaminocarbonyl, acyloxy, acylthio, nitro, cyano,
sulfonic acid,
sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or
protected as
necessary, as known to those skilled in the art, for example, as taught in
Greene, et al.,
Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition,
1991.
"Alkoxy" refers to the group ¨OR' where R' is alkyl or cycloalkyl where alkyl
and
cycloalkyl are as defined herein. Alkoxy groups include, by way of example,
methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-
hexoxy,
1,2-dimethylbutoxy, and the like.
"Aryloxy" refers to the group ¨OR' where R' is aryl or heteroaryl where aryl
and
heteroaryl are as defined herein.
"Alkoxycarbonyl" refers to a radical -C(0)-alkoxy where alkoxy is as defined
herein.
"Amino" refers to the radical ¨NH2.
"Carboxyl" or "carboxy" refers to the radical ¨C(0)0H. "Carbonyl" refers to
the radical ¨
C(0)¨.
The term "alkylamino," "arylamino," or "alkylarylamino" refers to an amino
group that
has one or two alkyl substituents (¨NEM' or ¨NR'R', where R' is alkyl as
defined herein),
one or two aryl substituents (¨NEM' or ¨ NR'R', where R' is aryl as defined
herein), or
one alkyl substituent and one aryl substituent (¨NR'R", where one of R' and R"
is alkyl as
defined herein and the other is aryl as defined herein), respectively. In one
embodiment,
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the alkyl substituent is lower alkyl. In another embodiment, the alkyl or
lower alkyl is
unsubstituted.
"Halogen" or "halo" refers to fluoro, chloro, bromo, or iodo.
"Oxo" refers to =0 or
"Thioalkoxy" refers to the group ¨SR' where R' is alkyl or cycloalkyl each of
which is as
defined herein. "Thioaryloxy" refers to the group ¨SR' where R' is aryl or
heteroaryl each
of which is as defined herein.
"Alkyldisulfanyl" refers to the group R'¨S¨S¨, where R' is alkyl or cycloalkyl
each of
which is as defined herein.
The term "heterocyclyl" or "heterocyclic" refers to a monovalent monocyclic
non-
aromatic ring system and/or multicyclic ring system that contains at least one
non-
aromatic ring, wherein one or more of the non-aromatic ring atoms are
heteroatoms
independently selected from 0, S, or N; and the remaining ring atoms are
carbon atoms.
In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to
20, from 3 to
15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
Heterocyclyl groups
are bonded to the rest of the molecule through the non-aromatic ring. In
certain
embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or
tetracyclic ring
system, which may include a fused or bridged ring system, and in which the
nitrogen or
sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally
quaternized, and some rings may be partially or fully saturated, or aromatic.
The
heterocyclyl may be attached to the main structure at any heteroatom or carbon
atom
which results in the creation of a stable compound. Examples of such
heterocyclic
radicals include, but are not limited to, azepinyl, benzodioxanyl,
benzodioxolyl,
benzofuranonyl, benzopyranonyl, benzopyranyl,
benzotetrahydrofuranyl,
benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, P-carbolinyl,
chromanyl,
chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,
dihydrobenzisothiazinyl,
dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl,
dihydropyranyl,
dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,
dihydropyrimidinyl,
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dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl,
imidazolinyl,
indolinyl, is ob enzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isochromanyl,
isocoumarinyl, isoindolinyl, isothiazolidinyl, is
oxazolidinyl, morpholinyl,
octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl,
piperazinyl,
piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,
pyrrolinyl,
quinuclidinyl, tetrahydrofuryl, tetrahy dro is o quino linyl,
tetrahydropyranyl,
tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and
1,3,5-
trithianyl. The term also includes both substituted and unsubstituted
heterocyclyl groups.
Non-limiting examples of moieties with which the heterocyclyl group can be
substituted
include halogen (fluoro, chloro, bromo, or iodo), oxo, hydroxyl, amino,
alkylamino,
arylamino, alkylarylamino, alkoxy, aryloxy, thioalkoxy, thioaroxyl,
alkyldisulfanyl, acyl,
hydroxylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylaminocarbonyl,
arylaminocarbonyl, alkylarylaminocarbonyl, acyloxy, acylthio, nitro, cyano,
sulfonic acid,
sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or
protected as
necessary, as known to those skilled in the art, for example, as taught in
Greene, et al.,
Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition,
1991,
hereby incorporated by reference.
The term "heteroaryl" refers to a monovalent monocyclic aromatic group and/or
multicyclic aromatic group that contain at least one aromatic ring, wherein at
least one
aromatic ring contains one or more heteroatoms independently selected from 0,
S, and N
in the ring. Heteroaryl groups are bonded to the rest of the molecule through
the aromatic
ring. Each ring of a heteroaryl group can contain one or two 0 atoms, one or
two S atoms,
and/or one to four N atoms, provided that the total number of heteroatoms in
each ring is
four or less and each ring contains at least one carbon atom. In certain
embodiments, the
heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
Examples of
monocyclic heteroaryl groups include, but are not limited to, furanyl,
imidazolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl,
pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl,
tetrazolyl,
triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but
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to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl,
benzothiadiazolyl,
benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,
imidazopyridinyl,
imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl,
isobenzothienyl,
isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl,
phthalazinyl,
pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl,
quinazolinyl,
thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl
groups include,
but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl,
perimidinyl,
phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, and xanthenyl. A heteroaryl group can be substituted with any
described
moiety, including, but not limited to, one or more moieties selected from
halogen (fluoro,
chloro, bromo, or iodo), oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,
cycloakenyl,
hydroxyl, amino, alkylamino, arylamino, alkylarylamino, alkoxy, aryloxy,
thioalkoxy,
thioaryloxy, alkyldisulfanyl, acyl, hydroxylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl,
aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylarylaminocarbonyl,
acyloxy, acylthio, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,
phosphate, or
phosphonate, either unprotected, or protected as necessary, as known to those
skilled in the
art, for example, as taught in Greene, et al., Protective Groups in Organic
Synthesis, John
Wiley and Sons, Second Edition, 1991.
The term "alkylaryl" refers to an aryl group with an alkyl substituent. The
term "aralkyl"
or "arylalkyl" includes an alkyl group with an aryl substituent.
The term "alkylheterocycly1" refers to a heterocyclyl group with an alkyl
substituent. The
term "alkylheterocycly1" includes an alkyl group with a heterocyclyl
substituent.
The term "alkylheteroaryl" refers to a heteroaryl group with an alkyl
substituent. The term
"alkylheteroaryl" includes an alkyl group with a heteroaryl substituent.
The term "protecting group" as used herein and unless otherwise defined refers
to a group
that is added to an oxygen, nitrogen, or phosphorus atom to prevent its
further reaction or
for other purposes. A wide variety of oxygen and nitrogen protecting groups
are known to
those skilled in the art of organic synthesis.
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"Pharmaceutically acceptable salt" refers to any salt of a compound provided
herein which
retains its biological properties and which is not toxic or otherwise
undesirable for
pharmaceutical use. Such salts may be derived from a variety of organic and
inorganic
counter-ions well known in the art. Such salts include, but are not limited
to: (1) acid
addition salts formed with organic or inorganic acids such as hydrochloric,
hydrobromic,
sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic,
trichloroacetic, propionic,
hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic,
succinic,
sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-
hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric,
methanesulfonic,
ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic,
benzenesulfonic, 4-
chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-to luenesulfoni c,
camphoric,
camphorsulfonic, 4-methylbicyclo [2.2. 2]-oct-2-ene-1 -carboxylic,
glucoheptonic, 3 -
phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic,
benzoic,
glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic,
muconic acid
and the like acids; or (2) salts formed when an acidic proton present in the
parent
compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an
alkaline earth
ion or an aluminum ion, or alkali metal or alkaline earth metal hydroxides,
such as sodium,
potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide,
ammonia, or (b) coordinates with an organic base, such as aliphatic,
alicyclic, or aromatic
organic amines, such as ammonia, methylamine, dimethylamine, diethylamine,
picoline,
ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine,
arginine,
ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine,
diethanolamine,
procaine, N-benzylphenethylamine, N-methylglucamine piperazine,
tris(hydroxymethyl)-
aminomethane, tetramethylammonium hydroxide, and the like.
Pharmaceutically acceptable salts further include, by way of example only and
without
limitation, sodium, potassium, calcium, magnesium, ammonium,
tetraalkylammonium,
and the like, and when the compound contains a basic functionality, salts of
non-toxic
organic or inorganic acids, such as hydrohalides, e.g. hydrochloride and
hydrobromide,
sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate,
trichloroacetate, propionate,
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hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate,
malonate,
succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate,
benzoate, 3-(4-
hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate,
methanesulfonate (mesylate), ethanesulfonate,
1,2-ethane-disulfonate, 2-
hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate,
2-
naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-
methy lb icyclo [2. 2.2] -oct-2 -ene-1 -carboxylate,
glucoheptonate, 3 -phenylpropionate,
trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate,
glutamate,
hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate,
muconate, and the
like.
The term "purine" or "pyrimidine" base refers to, but is not limited to,
adenine, guanine,
adenine, hypoxanthine, 7-deazaguanine, 7-deazaadenine, 2,6-diaminopurine, 6-
chloropurine, N6-alkylpurines, N6-acylpurines (wherein acyl is C(0)(alkyl,
aryl, alkylaryl,
or arylalkyl), N6-benzylpurine, 6-halopurine, N6-vinylpurine, N6-acetylenic
purine, N6-
purine, N6-alkylaminopurine, N6-thioalkyl purine, N2-alkylpurines, N2-alky1-
6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-
azapyrimidine,
including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil,
including
5-fluorouracil, C5-alkylpyrimidines, C5-benzylpyrimidines, C5-halopyrimidines,
C5-
vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl
purine,
C5-amidopyrimidine, C5-cyanopyrimidine, C5-iodopyrimidine, C6-iodo-pyrimidine,
C5-Br-
vinyl pyrimidine, C6-Br-vinyl pyrimidine, C5-nitropyrimidine, C5-amino-
pyrimidine, 5-
azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,
pyrrolopyrimidinyl, and
pyrazolopyrimidinyl. Functional oxygen and nitrogen groups on the base can be
protected
as necessary or desired. Suitable protecting groups are well known to those
skilled in the
art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and
t-
butyldiphenylsilyl, trityl, alkyl groups, acyl groups such as acetyl and
propionyl,
methanesulfonyl, and p-toluenesulfonyl.
The term "acyl" or "0-linked ester" refers to a group of the formula -0
C(0)R', wherein
R' is alkyl or cycloalkyl (including lower alkyl), carboxylate reside of amino
acid, aryl
13

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including phenyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including
methoxymethyl, aryloxyalkyl such as phenoxymethyl. For example, R' can be
substituted
alkyl (including lower alkyl), aryl including phenyl optionally substituted
with chloro,
bromo, fluoro, iodo, Ci to C4 alkyl or Ci to C4 alkoxy, sulfonate esters such
as alkyl or
arylalkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate
ester, trityl or
monomethoxy-trityl, substituted benzyl, alkaryl, arylalkyl including benzyl,
alkoxyalkyl
including methoxymethyl, aryloxyalkyl such as phenoxymethyl. Aryl groups in
the esters
optimally comprise a phenyl group. In
particular, acyl groups include acetyl,
trifluoroacetyl, methylacetyl, cyclpropylacetyl, propionyl, butyryl, hexanoyl,
heptanoyl,
octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl,
diphenylacetyl, a-
methoxy-a-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-
chloro-
benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl,
trimethylacetyl,
chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl,
methoxyacetyl,
2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl,
tert-
butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, 7H-
dodecafluoro-
heptanoyl, perfluoro-heptanoyl, 7H-dodeca-fluoroheptanoyl, 7-
chlorododecafluoro-
heptanoyl, 7-chloro-dodecafluoro-heptanoyl, 7H-dodecafluoroheptanoyl, 7H-
dodeca-
fluoroheptanoyl, nona-fluoro-3,6-dioxa-heptanoyl,
nonafluoro-3 ,6-di oxaheptanoyl,
perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-
carboxyl, 3,6-
di chloro-2-methoxy-benzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-
propi onyl,
omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-
propionyl, 1-
benzene-carboxyl, 0-acetylmandelyl, pivaloyl acetyl, 1-adamantane-carboxyl,
cyclohexane-carboxyl, 2,6-pyridinedicarboxyl, cyclopropane-carboxyl,
cyclobutane-
carboxyl, perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl
isoxazolyl
carbonyl, perfluorocyclohexyl carboxyl, crotonyl, 1-methyl-1H-indazole-3 -
carbonyl, 2-
propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4-phenylbenzoyl.
The term "amino acid" refers to naturally occurring and synthetic a, (3, y, or
6 amino acids,
and includes but is not limited to, amino acids found in proteins, i.e.
glycine, alanine,
valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline,
serine,
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threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate,
lysine, arginine
and histidine. In one embodiment, the amino acid is in the L-configuration.
Alternatively,
the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleuccinyl,
prolinyl,
phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl,
cysteinyl,
tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl,
histidinyl, (3-
alanyl, f3-valinyl, f3-leucinyl, f3-isoleuccinyl, f3-prolinyl, f3-
phenylalaninyl, f3-tryptophanyl,
f3-methioninyl, f3-glycinyl, f3-serinyl, f3-threoninyl, f3-cysteinyl, f3-
tyrosinyl, f3-asparaginyl,
f3-glutaminyl, f3-aspartoyl, f3-glutaroyl, f3-lysinyl, f3-argininyl, or f3-
histidinyl.
The term "substantially free of' or "substantially in the absence of' with
respect to a
nucleoside composition refers to a nucleoside composition that includes at
least 85 or 90%
by weight, in certain embodiments 95%, 98 % , 99%, or 100% by weight, of the
designated nucleoside, the designated diastereomer of such nucleoside, or the
designated
enantiomer of such nucleoside. In one embodiment, in the methods and compounds
provided herein, the compounds are substantially free of other compounds,
other
nucleosides, other diastereomers, or other enantiomers that are not
designated.
Similarly, the term "isolated" with respect to a nucleoside composition refers
to a
nucleoside composition that includes at least 85, 90%, 95%, 98%, 99%, to 100%
by
weight, of the nucleoside, the remainder comprising other chemical species or
enantiomers.
"Solvate" refers to a compound provided herein or a salt thereof, that further
includes a
stoichiometric or non-stoichiometric amount of solvent bound by non-covalent
intermolecular forces. Where the solvent is water, the solvate is a hydrate.
"Isotopic composition" refers to the amount of each isotope present for a
given atom, and
"natural isotopic composition" refers to the naturally occuring isotopic
composition or
abundance for a given atom. Atoms containing their natural isotopic
composition may
also be referred to herein as "non-enriched" atoms. Unless otherwise
designated, the
atoms of the compounds recited herein are meant to represent any stable
isotope of that
atom. For example, unless otherwise stated, when a position is designated
specifically as

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"H" or "hydrogen", the position is understood to have hydrogen at its natural
isotopic
composition.
"Isotopic enrichment" refers to the percentage of incorporation of an amount
of a specific
isotope at a given atom in a molecule in the place of that atom's natural
isotopic
abundance. For example, deuterium enrichment of 1% at a given position means
that 1%
of the molecules in a given sample contain deuterium at the specified
position. Because
the naturally occurring distribution of deuterium is about 0.0156%, deuterium
enrichment
at any position in a compound synthesized using non-enriched starting
materials is about
0.0156%. The isotopic enrichment of the compounds provided herein can be
determined
using conventional analytical methods known to one of ordinary skill in the
art, including
mass spectrometry and nuclear magnetic resonance spectroscopy.
"Isotopically enriched" refers to an atom having an isotopic composition other
than the
natural isotopic composition of that atom. "Isotopically enriched" may also
refer to a
compound containing at least one atom having an isotopic composition other
than the
natural isotopic composition of that atom.
As used herein, "alkyl," "cycloalkyl," "alkenyl," "cycloalkenyl," "alkynyl,"
"aryl,"
"alkoxy," "alkoxycarbonyl," "amino," "carboxyl," "alkylamino," "arylamino,"
"thioalkyoxy," "heterocyclyl," "heteroaryl," "alkylheterocyclyl,"
"alkylheteroaryl,"
cc
acyl," "aralkyl," "alkaryl," "purine," "pyrimidine," "carboxyl," and "amino
acid" groups
optionally comprise deuterium at one or more positions where hydrogen atoms
are present,
and wherein the deuterium composition of the atom or atoms is other than the
natural
isotopic composition.
Also as used herein, "alkyl," "cycloalkyl," "alkenyl," "cycloalkenyl,"
"alkynyl," "aryl,"
"alkoxy," "alkoxycarbonyl," "carboxyl," "alkylamino," "arylamino,"
"thioalkyoxy,"
"heterocyclyl," "heteroaryl," "alkylheterocyclyl," "alkylheteroaryl," "acyl,"
"aralkyl,"
"alkaryl," "purine," "pyrimidine," "carboxyl," and "amino acid" groups
optionally
comprise carbon-13 at an amount other than the natural isotopic composition.
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Further, "alkyl," "cycloalkyl," "alkenyl," "cycloalkenyl," "alkynyl," "aryl,"
"heterocyclyl," and "heteroaryl" groups that are included as examples of
moieties with
which a certain functional group can be substituted can further be
substituted.
The term "proliferative disorder or disease" refers to unwanted cell
proliferation of one or
more subset of cells in a multicellular organism resulting in harm (i.e.,
discomfort or
decreased life expectancy) to the multicellular organisms. A proliferative
disorder or
disease can occur in different types of animals and humans. For example, as
used herein,
"proliferative disorder or disease" includes neoplastic disorders and other
proliferative
disorders.
The term "neoplastic disorder or disease" or "cancer" refers to a tumor
resulting from
abnormal or uncontrolled cellular growth. Examples of neoplastic disorders
include, but
are not limited to, hematopoietic disorders, such as the myeloproliferative
disorders,
thrombocythemia, essential thrombocytosis (ET), angiogenic myeloid metaplasia,
myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM), chronic
idiopathic
myelofibrosis (IMF), polycythemia vera (PV), the cytopenias, and pre-malignant
myelodysplastic syndromes; cancers, such as glioma cancers, lung cancers,
breast cancers,
colorectal cancers, prostate cancers, gastric cancers, esophageal cancers,
colon cancers,
pancreatic cancers, ovarian cancers, and hematologic malignancies.
The term "hematologic malignancy" refers to cancer of the body's blood-forming
and
immune system-the bone marrow and lymphatic tissue. Examples of hematological
malignancies include, for instance, myelodysplasia, lymphomas, leukemias,
lymphomas
(non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma),
and
myeloma, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia
(AML),
acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),
chronic
myeloid leukemia (CIVIL), chronic neutrophilic leukemia (CNL), acute
undifferentiated
leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia
(PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with
trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL),
17

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myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and
multiple
myeloma (MM).
The term "leukemia" refers to malignant neoplasms of the blood-forming
tissues,
including, but not limited to, chronic lymphocytic leukemia, chronic
myelocytic leukemia,
acute lymphoblastic leukemia, acute myeloid leukemia and acute myeloblastic
leukemia.
The leukemia can be relapsed, refractory, or resistant to conventional
therapy.
The term "relapsed" refers to a situation where a subject or a mammal, who has
had a
remission of cancer after therapy, has a return of cancer cells.
The term "refractory or resistant" refers to a circumstance where a subject or
a mammal,
even after intensive treatment, has residual cancer cells in his body.
The term "drug resistance" refers to the condition when a disease does not
respond to the
treatment of a drug or drugs. Drug resistance can be either intrinsic, which
means the
disease has never been responsive to the drug or drugs, or it can be acquired,
which means
the disease ceases responding to a drug or drugs that the disease had
previously responded
to. In certain embodiments, drug resistance is intrinsic. In certain
embodiments, the drug
resistance is acquired.
As used herein, the term "EC50" refers to a dosage, concentration or amount of
a
particular test compound that elicits a dose-dependent response at 50% of
maximal
expression of a particular response that is induced, provoked or potentiated
by the
particular test compound.
As used herein, the term "Emax" refers to an amount, concentration or dosage
of a
particular test compound that achieves a 100% inhibition of a maximal response
in an
assay that measures such response.
As used herein, the term "Eo" refers to an amount, concentration or dosage of
a particular
test compound that achieves a 0% inhibition of a maximal response in an assay
that
measures such response.
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As used herein, the terms "subject" and "patient" are used interchangeably
herein. The
terms "subject" and "subjects" refer to an animal, such as a mammal including
a non-
primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate
(e.g., a monkey
such as a cynomolgous monkey, a chimpanzee and a human), and for example, a
human.
In another embodiment, the subject is a farm animal (e.g., a horse, a cow, a
pig, etc.) or a
pet (e.g., a dog or a cat). In one embodiment, the subject is a human.
As used herein, the terms "drug," "therapeutic agent," and "chemotherapeutic
agent" refer
to any agent(s), compound, or pharmaceutical composition thereof, which can be
used in
the treatment or prevention of a disorder or one or more symptoms thereof. In
certain
embodiments, the term "therapeutic agent" includes a compound provided herein.
In one
embodiment, a therapeutic agent is an agent which is known to be useful for,
or has been
or is currently being used for the treatment or prevention of a disorder or
one or more
symptoms thereof
"Therapeutically effective amount" refers to an amount of a compound or
composition
that, when administered to a subject for treating a disease, is sufficient to
effect such
treatment for the disease. A "therapeutically effective amount" can vary
depending on,
inter alia, the compound, the disease and its severity, and the age, weight,
etc., of the
subject to be treated.
"Treating" or "treatment" of any disease or disorder refers, in one
embodiment, to
ameliorating a disease or disorder that exists in a subject. In another
embodiment,
"treating" or "treatment" includes ameliorating at least one physical
parameter, which may
be indiscernible by the subject. In yet another embodiment, "treating" or
"treatment"
includes modulating the disease or disorder, either physically (e.g.,
stabilization of a
discernible symptom) or physiologically (e.g., stabilization of a physical
parameter) or
both. In yet another embodiment, "treating" or "treatment" includes delaying
the onset of
the disease or disorder.
As used herein, the terms "prophylactic agent" and "prophylactic agents" as
used refer to
any agent(s) which can be used in the prevention of a disorder or one or more
symptoms
thereof In certain embodiments, the term "prophylactic agent" includes a
compound
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provided herein. In certain other embodiments, the term "prophylactic agent"
does not
refer to a compound provided herein. For example, a prophylactic agent is an
agent which
is known to be useful for, or has been or is currently being used to prevent
or impede the
onset, development, progression and/or severity of a disorder.
As used herein, the phrase "prophylactically effective amount" refers to the
amount of a
therapy (e.g., prophylactic agent) which is sufficient to result in the
prevention or
reduction of the development, recurrence or onset of one or more symptoms
associated
with a disorder or to enhance or improve the prophylactic effect(s) of another
therapy
(e.g., another prophylactic agent).
Compounds
Prodrug compounds of a variety of therapeutic agents can be formed using
methods
available in the art and those disclosed herein. The therapeutic agent can be
derivatized to
include a reactive group for attachment of the phosphate moiety. Such
therapeutic agent
includes but is not limited to nucleosides and nucleoside analogues including
acyclic
nucleosides.
As used herein, a "phosphoramidate or cyclic phosphate compound of a
therapeutic agent"
includes a therapeutic agent derivatized to include a phosphoramidate or
cyclic phosphate
group. The therapeutic agent is, for example, an anti-cancer agent that
includes, or has
been derivatized to include, a reactive group, such as a hydroxyl, for
attachment of the
phosphoroamidate and cyclic phosphate moiety. Such therapeutic agents include,
but are
not limited to nucleosides and nucleoside analogs including acyclic
nucleosides. A
nucleoside analog refers to a structurally modified nucleoside. In one
embodiment, the
nucleosides or nucleoside analogs are derivitized at the 5'- and/or the 3'-
position by
removal of a hydrogen from an hydroxyl group to include a phosphate moiety
comprising
a phosphoramidate and a cyclic phosphate group. In another embodiment, the
nucleosides
or nucleoside analogs are derivitized at the 5'- and/or the 2'-position by
removal of a
hydrogen from an hydroxyl group to include a phosphate moiety comprising a
phosphoramidate and a cyclic phosphate group.

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Modified phosphate derivatives comprising phosphoramidate and cyclic phosphate
derivatives of nucleoside analogues comprising natural and non-natural
nucleosides
described herein can be formed as described herein and used for the treatment
of cancer.
In one embodiment, the derivative moiety can be at the 3' position. In another
embodiment, the derivative moiety can be at the 5' position. In another
embodiment, the
derivative moiety can be at the 3', 5' positions linked together to form a
cyclic derivative.
In one embodiment, the prodrug moiety can be at the 2', 5' positions linked
together to
form a cyclic derivative.
In one embodiment, provided herein is a compound of Formula I:
0
11
R
R1
X
R66
(I)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric,
tautomeric, or polymorphic form thereof, wherein
each of X and Y is independently hydrogen, ¨01V, ¨NRaRb, an N-linked or 0-
linked amino acid residue, or an N-linked or 0-linked residue of an amino acid
derivative;
where Ra and Rb at each occurrence is independently hydrogen, alkyl,
aryl, arylalkyl, or heteroarylalkyl;
R is a nucleobase;
Rl is hydrogen, halo, cyano, alkynyl or ¨0R6; and
R6 is hydrogen, alkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aroxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, or
alkylarylaminocarbonyl.
In one embodiment Rl is hydrogen, halo or ¨0R6.
In one embodiment, when one of X and Y is hydroxyl, the other is other
than hydroxyl.
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In one embodiment, provided herein is a compound of Formula I:
0
I I0,,R
Y¨P-0\c La
1 R1
X
R6O7- :III
(I)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric, or
polymorphic form thereof, wherein
R2\
N¨
(E) o o
Q 0 (:)
¨CI y j..( 0,,sss >S,s0,s cl)...0,, y y
c.o.,
m ss'
Y is 0 R S 0 ,
)¨NN '----"\o A `N. o o - ----\o 0"---\oA
02N \ ON , ON Q sc)
p-NO2PhCH20¨, ¨NHCH2Ph, ¨N(CH3)CH2Ph, ¨NI-IR2, ¨NH(CH2)5N(CH3)2, ¨BH3,
I I X
NH
T T 1-11\1 HN
HN HN HN ( )rn -vt,
)
/ HN N m
HN N HN (CH2)3
1 __
0 LN, -....;-- *
P, =P OR3 I-12N OH .
or
Nr-----\ A
,--s
02N .
,
22

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R2õ
N¨
(E) 0 0
m ,
X is OH, OR3, 0 , RYS V
N---\0A \
Q 0 (:) ..----\0
T 0
002N \ 02N , ON
0 0
Q)S V
, p-NO2PhCH20¨, NHCH2Ph, ¨N(CH3)CH2Ph, ¨NEIR2,
I 1
7 T HN HN
( ) m
HN
HN
/
-{. HN" HN
1
1\1
0 , i
= ,
L N
,
¨NH(CH2)5N(CH3)2, ¨BH3, OR' ,
c`ss\F
NH
)1.1-
HN)
HN N m
0H2)3
N '-----"N A .
)--s
HN OH
, or ;
' 02N
0 NH2 0
IN NHRz
N /- N
N-..../N -)1\1 1 NH )LNH
1 t0 1
......, ,
-N T N
NI Thl 0 N1 0 N 0
/ 1
R is,
'
'Ilw , 'T's ,
0
)Li NH
N 0
,
Rz is H or C(0)Z where Z is a fatty acid chain selected from palmitoleic,
oleic,
linoleic, or arachidonic acid;
23

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W is NH2, halo, OMe, or OH;
T is NH2, F, Cl or hydrogen;
Rl is hydrogen, halo, OH, protected OH, cyano or alkynyl;
Q is OR3;
E is CR4R5;
L is H, p-Me, p-OMe, p-C1, or 3,4-Cl;
n is 1;
m is 1 or 2;
p is absent or 0;
RY is alkyl, alkenyl, alkynyl, alkoxycarbonyl, or hydroxyalkyl, each
independently
optionally substituted;
R2 is hydrogen or alkyl;
R3 is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl or aralkyl;
R4 and R5 are selected from:
i) R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl, or alkylheteroaryl,
wherein the alkyl is
optionally substituted by alkoxy; or
ii) R4 and R5 together with the carbon atom to which they are attached form
a 3-7 membered cycloalkyl ring;
0
R6 is hydrogen, , or
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R6 with one of X and Y, together with the atoms to which they are attached,
combine to form a six-membered heterocyclic ring where R6 and the one of X and
Y
together represent a single divalent ¨0¨; or
R6 with one of X and Y, together with the atoms to which they are attached,
combine to form a 7-12-membered heterocyclic ring;
N
N
0
N 0
y
wherein, when R is , and X and Y both are R S ,
then at least one
RY is other than alkyl.
In one embodiment, provided herein is a compound of Formula I:
0
I I
Y¨P-0
R1
X
R66
(I)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric, or
polymorphic form thereof, wherein
R2µ
N¨
Y is 1
Q
0_ _s
RYiLsCV Q)-4 'sss' y
0 0
0 0
0\0A
0 1¨S
02N \ 02N , 02N QS
p-NO2PhCH20¨, ¨NHCH2Ph, ¨N(CH3)CH2Ph,
¨NH(CH2)5N(CH3)2, ¨BH3,

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I I
r\SS-NH
7 T 1-11\1 HN
7"-
HN 1-11\1 ( )rn ,,,,,, HN
/)
HN N m
HN N HN (CH2)3
I
0 L DN, * __________________ 0
P P DR I-12N OH =
, or
N'----\ A
)\--s
o2N
;
R2,
iv-1
¨CI RS,
X is OH, 0 Q/
m ,
,
1\l'---\0A
Q 0 (:)s ---\(:)
Y y
0 ON \ ON , ON
0 0
Q)S(:))ss
, p-NO2PhCH20¨, NHCH2Ph, ¨N(CH3)CH2Ph, ¨NEIR2,
I 1
T T HN. HN
HN HN /
HN" HN
1
40e
L 0, I .
¨NH(CH2)5N(CH3)2, ¨BH3, p, P , OR3 ,
15.5cH
)11"
HN,)
HN N m
(CH2)3
,0 Nr----"N A
)\--s
H2N OH 02N
, or . =
26

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0 NH 2 0
NHRz
N
NH NN
I L NO T 0
N 0 NO
R is
0
NH
NO
or ;
Rz is H or C(0)Z where Z is a fatty acid chain selected from palmitoleic,
oleic,
linoleic, or arachidonic acid;
W is NH2, Cl, OMe or OH;
T is NH2, F, Cl or hydrogen;
Rl is hydrogen, OH, F, cyano or alkynyl;
Q is OR3;
E is independently CR4R5;
L is H, p-Me, p-OMe, p-C1, or 3,4-Cl;
n is 1;
m is 1 or 2;
p is absent or 0
RY is alkyl, alkenyl, alkynyl, alkoxycarbonyl, or hydroxyalkyl, each
independently
optionally substituted;
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R2 is hydrogen or alkyl;
R3 is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;
R4 and R5 are selected from:
i) R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
aralkyl,
cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, wherein alkyl
is optionally
substituted by alkoxy; or
ii) R4 and R5 together with the carbon atom to which they are attached form a
3-7
membered cycloalkyl ring;
NHIRz
0
N 0
wherein, when Rl is , and X and Y both are R S , then at
least
one RY is other than alkyl.
In an embodiment of each one of the above embodiments,
s\s.
NH
HN N )m
N
)LS
=
Y is not or 02N =
c=s<
NH
HN N )m
A
)Ls
x is not C)2N or =
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0 NH2 0 0
FNH N
)NH
NH
NO 0 0 0 0
R is not, 'ffr , or =
T is not hydrogen;
W is not OH;
Rl is not cyano or alkynyl; and
R3 is not aralkyl.
The variables X, Y, Z, E, L, Q, W, T, n, m, p, R, RY, Rz, Ri, R2, R3, R4, R5,
and R6 as provided herein are defined as follows. All combinations of such
embodiments
are within the scope of this disclosure.
In one embodiment, RY is alkyl, alkenyl, or alkynyl. In one embodiment, RY
is alkyl.
In one embodiment, RY is alkenyl. In one embodiment, RY is alkynyl. In
one embodiment, RY is hydroxyalkyl. In one embodiment, RY is 2-
hydroxylmethylprop-2-
yl.
In one embodiment, Q is OR3, wherein R3 is as defined herein. In one
embodiment Q is
OCH3, OCH2CH3, OCH(CH3)2 or OCH2phenyl. In one embodiment Q is OCH3,
OCH2CH3, or OCH(CH3)2.
In one embodiment, Rz is hydrogen.
In one embodiment, R3 is CH3, CH2CH3, CH(CH3)2 or CH2phenyl.
In one embodiment, E is CR4R5, wherein R4 and R5 are each as defined
herein. In one embodiment, R4 or R5 is hydrogen. In one embodiment, R4 or R5
is alkyl or
cycloalkyl. In one embodiment, R4 or R5 is lower alkyl. In one embodiment, R4
or R5 is
methyl. In one embodiment, R4 or R5 is isobutyl. In one embodiment, R4 or R5
is C3-05
cycloalkyl. In one embodiment, R4 or R5 is cyclopentyl. In one embodiment, one
of R4
29

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and R5 is hydrogen and the other is alkyl or cycloalkyl. In one embodiment,
one of R4 and
R5 is hydrogen and the other is lower alkyl. In one embodiment, one of R4 and
R5 is
hydrogen and the other is methyl. In one embodiment, one of R4 and R5 is
hydrogen and
the other is isobutyl. In one embodiment, one of R4 and R5 is hydrogen and the
other is
C3-05 cycloalkyl. In one embodiment, one of R4 and R5 is hydrogen and the
other is
cyclopentyl.
In one embodiment, Z is an oleic acid chain.
In one embodiment, W is NH2 and T is Cl or F. In one embodiment, W is Cl
or OMe and T is NH2. In one embodiment, W is OMe and T is NH2. In one
embodiment,
W is Cl and T is NH2.
In one embodiment, Rl is hydroxyl or fluoro. In one embodiment, Rl is
hydroxyl. In one embodiment, Rl is fluoro.
In one embodiment, R2 is hydrogen or alkyl. In one embodiment, R2 is
lower alkyl. In one embodiment, R2 is methyl. In one embodiment, R2 is
hydrogen.
In one embodiment, R6 is hydrogen.
NHRz NHRz NHRz
NHIRz
(L11
0
0 õ,
N 0
Dy0
Jvw
When R is -I- it is any one of
and
NHRz
0

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NHRz
HN
H 0
In one embodiment, R is I,
In certain embodiments, the compound of formula (I) is selected such that when
R is
NHIRz
0
N 0
, X and Y are both R then , then RY is other than alkyl.
In certain embodiments, the compound of formula (I) is selected such that when
X and Y
0
0õs
are both RY S , then RY is other than alkyl.
In certain embodiments, the compound of formula (I) is selected such that when
R is
NHIRz
)N 0
tNO
; at least one of X or Y is other than
R2,
(E),
In one embodiment, when X is OH, Y is 0 .
0
In one embodiment, when X is OH, Y is RA S
>õ.S õs 0
In one embodiment, when X is OH, Y is
jt(õyo
In one embodiment, when X is OH, Y is
m
Q 0 0,
osc
In one embodiment, when X is OH, Y is o
31

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)\---N -
In one embodiment, when X is OH, Y is 02N \
NO)1/4
0
In one embodiment, when X is OH, Y is 02N
In one embodiment, when X is OH, Y is 02N
0 0
In one embodiment, when X is OH, Y is
In one embodiment, when X is OH, Y is p-NO2PhCH20¨.
In one embodiment, when X is OH, Y is ¨NHCH2Ph.
In one embodiment, when X is OH, Y is ¨N(CH3)CH2Ph.
In one embodiment, when X is OH, Y is ¨NEIR2.
In one embodiment, when X is OH, Y is ¨NH(CH2)5N(CH3)2.
In one embodiment, when X is OH, Y is ¨BH3.
HN
L
In one embodiment when X is OH, Y is
HN
In one embodiment when X is OH, Y is P=
HN
In one embodiment, when X is OH, Y is .
32

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HN
HN X
In one embodiment, when X is OH, Y is
HN
In one embodiment, when X is OH, Y is 0R3.
HN
In one embodiment, when X is OH, Y is oR3
HN
In one embodiment, when X is OH, Y is 0R3.
HN
CH2)3
i<0
In one embodiment, when X is OH, Y is H2N OH
)11-
HN
CH2)3
! 0
)II
In one embodiment, when X is OH, Y is H2N OH
HN
(CH2)3
1<0
In one embodiment, when X is OH, Y is H2N OH
(E), 0
In one embodiment when X is 0 y is RY
33

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R2,
(E),
0
In one embodiment when X is 0 , Y is
R2,
(E),
In one embodiment, when X is 0 y is 02N \
R2,
'(E
)-0 -
In one embodiment, when X is 0 y is 02N
R2,
(E),
In one embodiment, when X is 0 y is 02N
R2, ,
In one embodiment when X is 0 , Y is
R2,
(E),
In one embodiment, when X is 0 , Y is p-NO2PhCH20¨.
R2, ,
(E),
In one embodiment, when X is 0 , Y is ¨NHCH2Ph.
R2, ,
(E),
In one embodiment, when X is 0 , Y is ¨N(CH3)CH2Ph.
R2,
(E),
In one embodiment when X is 0 , Y is ¨NHR2.
34

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R2,
(E),
In one embodiment, when X is 0 , Y is ¨NH(CH2)5NICH3/2.
R2,
(E),
In one embodiment, when X is 0 , Y is ¨BH3.
R2, HN
(E),
L
In one embodiment when X is 0 , Y is
R HN
HN
(E),
In one embodiment, when X is 0 , Y is
HN
R2,
(E),
In one embodiment, when X is 0 , Y is P .
HN
R2,
HN X
(E),
In one embodiment, when X is 0 , Y is
HN
(E),
In one embodiment, when X is 0 , y is oR3.
R2,
HN
(E),
In one embodiment, when X is 0 , y is 01R3

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R2,
,N1¨ HN/
(E),
In one embodiment, when X is 0 , y is oR3 .
R HN
HN
,NI¨ (CH2)3
(E), 0
¨CI 'I(
In one embodiment, when X is 0 , y is H2N OH .
R2, HN
,N-1 (CH2)3
¨CI
In one embodiment, when X is 0 , y is H2N OH .
R2, HN
,N-1 (CH2)3
(E),44, 0
¨CI
In one embodiment, when X is 0 , y is H2N OH .
0
JL (:),õ.., .
In one embodiment, when X is RY S Y is
, .
0
0
JL0
..--...õ,ss
In one embodiment, when Xis RY S 0 i
, Y s =
O Q 0y 0s
J.L .,,õ . H c3-
In one embodiment, when X is RY S (:) Y is 0
, =
O Nr----No)z.z.
)\--N -
JL)'s, \
In one embodiment, when X is RY S C) y is 02N .
O
-----.\,,,\
' 0 -
jLV,
In one embodiment, when X is RY s y is 02N .
O 0
-IL ,,,
In one embodiment, when Xis RY s 0
'. cs- , y is 02N .
36

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0 0 0
Q)LSC)'S
In one embodiment, when X is RY S , Y is
0
In one embodiment, when X is RY S , Y is p-NO2PhCH20¨.
0
In one embodiment, when X is RY S , Y is ¨NHCH2Ph.
0
In one embodiment, when X is RY S Y is ¨N(CH3)CH2Ph.
0
In one embodiment, when X is RY s Y is -NER2.
In one embodiment, when X is RY , Y is ¨NH(CH2)5N(CH3)2.
0
In one embodiment, when X is RY s cs- , Y is ¨BEL.
HN
0
L
In one embodiment, when X is RY s , Y is
1-11\1
0
In one embodiment, when X is RY s i
, Y s P.
HN
0
In one embodiment, when Xis RY s cc" , Y is .
37

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HN
( lrn
HN N
0
In one embodiment when X is RY SC)V, Y is II .
snow
HN
0
In one embodiment, when X is RY S V, Y is 0R3.
74'
HN
0
In one embodiment, when X is RY S Y, Y is 0R3
HN
0
In one embodiment, when X is RY S cc- , Y is 0R3.
HN
(sCH2)3
0 /<0
In one embodiment, when X is RY S y is H2N OH
HN
(sCH2)3
0 ! 0
/<
In one embodiment, when X is RYjLscV, y is H2N OH
HN
(CH2)3
0
0
In one embodiment, when X is RY S 'Y is H2N OH
In one embodiment when X is , Y is
38

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0
0
y
Q)LH.0,õ
In one embodiment when X is , Y is m
0
Q 0 0,
In one embodiment, when X is , Y is 0
)\--N
In one embodiment, when X is , Y is ON
IX0 0)'/*
In one embodiment, when X is , Y is O2N
In one embodiment, when X is , Y is 02N
0 0
- ay
In one embodiment when X is Y is
In one embodiment, when X is , Y is p-NO2PhCH20¨.
In one embodiment, when X is , Y is ¨NHCH2Ph.
>,s,s0,csss
In one embodiment, when X is , Y is ¨N(CH3)CH2Ph.
0
y
In one embodiment, when X is , Y is ¨NE1R2.
In one embodiment, when X is , Y is ¨NH(CH2)5MCH312.
0
In one embodiment, when X is , Y is ¨BH3.
HN
0
õcos
L
In one embodiment when X is Y is
39

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HN
0
y
In one embodiment when X is Y is
1
HN
0
y
In one embodiment, when X is , Y is P .
1
HN
)rn
HN N
0
y
In one embodiment when X is Y is
HN
In one embodiment, when X is , Y is 0R3.
HN
0
y
In one embodiment when X is , Y is 0R3
HN
0
y
In one embodiment, when X is y is oR3.
HN
CH2)3
In one embodiment when X is y is H2N OH

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)11-
HN
H2)3
! 0
õS
)
In one embodiment, when X is y is H2N OH .
H N
(C H2)3
õS
0
In one embodiment, when X is y is H2N OH .
O 0
)t0 c,
In one embodiment, when X is m Y is m
0
Jt 0 0 0 0, , risc
In one embodiment, when X is m Y is 0
O N \ A
J0
t(õ).0 )\--N
In one embodiment when X is
m s' y is 02N \
0
oA
0)-L(õ).0
In one embodiment when X is
m y is 02N
0
\OA
J-L(.0
In one embodiment when X is
m y is 02N
O 0 0
0 .,..ss
QSO
In one embodiment, when X is m Y is
0
In one embodiment, when X is (:))4m , Y is p-NO2PhCH20¨.
0
In one embodiment, when X is (:)).m , Y is ¨NHCH2Ph.
0
In one embodiment, when X is m , Y is ¨N(CH3)CH2Ph.
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0
In one embodiment, when X is m Y is ¨NEM2.
0
0).LH-oy
In one embodiment, when X is m , Y is ¨NH(CH2)5N(CH3)2.
In one embodiment, when X is m QLO e , Y is ¨BEL.
HN
0
cl)tH.0 L
In one embodiment when X is m Y is
HN
cl)tH2O,ss
In one embodiment, when X is m Y is P.
HN
0)-LH.O.ss
In one embodiment, when X is m e Y is P .
HN
( lm
0 HN N
In one embodiment, when X is m Y is
HN
0
0)-LH.0
In one embodiment, when X is sse
m Y is 0R3.
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7"
HN
0
Q
In one embodiment, when X is m Y is 0R3
=
HN
0
cl)-LH.Os
In one embodiment when X is m Y is 0R3.
HN
CH2)3
0
In one embodiment when X is m e- ^ y is H2N OH .
76,
HN
CH2)3
0 ! 0
)
In one embodiment when X is m ^ y is H2N OH .
HN
(CH2)3
0 0
Q)O
1
In one embodiment when X is
m y is H2N OH .
Q010/ Q IrOy0s
In one embodiment, when X is 0 , Y is 0
N
Q010,
In one embodiment, when X is 0 y is 02N \
=
Ql.royoy 0
In one embodiment, when X is 0 y is 02N
=
In one embodiment, when X is 0 y is 02N
43

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0 0
Q( 0J
y cl)ys
In one embodiment when X is 0 Y is .
0yoyoy
In one embodiment, when X is 0 , Y is p-NO2PhCH20¨.
0yoyoy
In one embodiment, when X is 0 , Y is ¨NHCH2Ph.
01royoy
In one embodiment, when X is 0 , Y is ¨N(CH3)CH2Ph.
Qy0y0,,,
In one embodiment, when X is 0 , Y is ¨NE1R2.
0yoyoy
In one embodiment, when X is 0 , Y is ¨NH(CH2)5N(CH3)2.
0yoyoy
In one embodiment, when X is 0 , Y is ¨BH3.
HN
Q1(0y0y
0 L
In one embodiment when X is 0 Y is .
,
7
HINI,
Q1(0 yOy
N,
In one embodiment, when X is 0 , Y is P.
7
hini
Ql.r010,,, I\J
i
In one embodiment, when X is 0 , Y is P .
44

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HN
( )rn
HN N
In one embodiment when X is 0 , Y is II .
HN
Q 0 0,
In one embodiment, when X is 0 , Y is 0R3.
HN
Q
In one embodiment, when X is 0 , Y is 0R3.
HN
Q010
In one embodiment, when X is 0 , Y is 0R3.
HN
CH2)3
In one embodiment when X is 0 y is H2N OH
HN
CH2)3
! 0
Q 1.(00y
In one embodiment when X is 0 I , Y is H2N OH
HN
(CH2)3
QOyOi<0
In one embodiment when X is 0 I , Y is H2N OH
-
In one embodiment, when X is 02N \ y is 02N \

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In one embodiment, when X is 2N y is 02N
A \O>L
In one embodiment, when X is 2N y is o2N
Qlroyoy.
In one embodiment, when X is 02N \ , Y is 0
)\¨N -
In one embodiment, when X is 02N \ , Y is p-NO2PhCH20¨.
A
)\--N
In one embodiment, when X is 02N \ , Y is ¨NHCH2Ph.
)\--N -
In one embodiment, when X is 02N \ , Y is ¨N(CH3)CH2Ph.
)\--N -
In one embodiment, when X is 02N \ , Y is ¨NE1R2.
)\--N -
In one embodiment, when X is 02N \ , Y is ¨NH(CH2)5N(CH3)2.
A
)\--N
In one embodiment, when X is 02N \ , Y is ¨BH3.
HN
A
L
In one embodiment, when X is 02N \ , Y is
46

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HN
N
)¨N
In one embodiment, when X is 02N \
, Y is P
1
HN
Nr--"NrIA
)¨N
In one embodiment, when X is 02N \ , Y is P .
1
HN
lrn
N HN N
)¨N -
In one embodiment when X is 02N \ ,y is =
N HN
)¨N
In one embodiment, when X is 02N \ , Y is 0R3.
'7"
N HN
)--N
In one embodiment, when X is 02N \ , Y is 0R3.
HN
)¨N
In one embodiment, when X is 02N \ , Y is 0R3.
HN
(CH2)3
N
)--N
In one embodiment, when X is 02N \ y is H2N OH
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HN
CH2 )3
A 0
)\--N ) __ /<
In one embodiment, when X is 02N \ y is H2N OH .
HN
(CH2)3
0
)\--N
In one embodiment, when X is 02N \ y is H2N OH .
0 0
In one embodiment, when X is 02N y is ON
=
iS
0
0
In one embodiment, when X is 02N y is 02N
0 0
0
QSC)1
In one embodiment when X is 02N , Y is
0
In one embodiment, when X is 02N , Y is p-NO2PhCH20¨.
0
In one embodiment, when X is 02N , Y is ¨NHCH2Ph.
0
In one embodiment, when X is 02N , Y is ¨N(CH3)CH2Ph.
0
In one embodiment, when X is 02N , Y is ¨NEIR2.
In one embodiment, when X is 02N , Y is ¨NH(CH2)5MCH3/2.
48

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0
In one embodiment, when X is 02N , Y is ¨BH3.
HN
0 110 L
In one embodiment, when X is 02N Y is
HN
In one embodiment, when X is 2N Y is
HN
0
In one embodiment, when X is 02N , Y is P .
HN
( 6
HN N
0
In one embodiment, when X is 02N Y is
HN
0
In one embodiment, when X is 02N , Y is 0R3
"r"
HN
0
In one embodiment, when X is 02N , Y is 0R3.
HN
In one embodiment, when X is 02N , Y is 0R3
49

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)11-
HN
CH2)3
0 l<0
In one embodiment, when X is 02N y is H2N OH .
71/4.
HN
CH2)3
0 )
In one embodiment, when X is 02N y is H2N OH .
"µ'=
HN
CH2)3
0
In one embodiment, when X is 02N y is H2N OH .
In one embodiment, when X is 02N y is 02N
0 0
0 s
In one embodiment when X is 2N , Y is
In one embodiment, when X is 02N , Y is p-NO2PhCH20¨.
In one embodiment, when X is 02N , Y is ¨NHCH2Ph.
In one embodiment, when X is 02N , Y is ¨N(CH3)CH2Ph.
In one embodiment, when X is 02N , Y is ¨NEIR2.
In one embodiment, when X is 02N , Y is ¨NH(CH2)5N(CH3)2.

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In one embodiment, when X is 02N , Y is ¨BH3.
HN
O'oA
= L
In one embodiment, when X is 02N Y is
1-11\1
In one embodiment, when X is 2N Y is
HN
In one embodiment, when X is 02N , Y is P .
HN
6
HN N
0-MA
In one embodiment, when X is 02N Y is
HN
In one embodiment, when X is 02N , Y is 0R3.
"7""
HN
In one embodiment, when X is 02N , Y is 0R3.
HN
In one embodiment, when X is 02N , Y is 0R3.
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HN
CH2)3
l<0
In one embodiment, when X is 02N y is H2N OH
)11-
HN
CH2)3
! 0
In one embodiment, when X is 02N y is H2N OH
HN
CH2)3
In one embodiment, when X is 02N y is H2N OH
O 0 0 0
Q)Y(SCV QLSO
In one embodiment, when X is Y is
O 0
Q)L/sc)',
In one embodiment, when X is , Y is p-NO2PhCH20¨.
O 0
Q)Y(sc)',/
In one embodiment, when X is , Y is ¨NHCH2Ph.
O 0
Q)Lsc)',1
In one embodiment, when X is , Y is ¨N(CH3)CH2Ph.
O 0
QLSO
In one embodiment, when X is , Y is ¨NE1R2.
O 0
QSO
In one embodiment, when X is , Y ls ¨NEI(CE12)5N1CH312.
O 0
C2)LSCV
In one embodiment, when X is , Y is ¨BH3.
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HN
O 0
SC))ss L
In one embodiment when X is c))L , Y is
HN
O 0
1111 o II
In one embodiment when X is , Y is P .
1
HN
O 0
Q).LSCV
In one embodiment, when X is , Y is P .
1
HN
H
0 0 N N
Q)y(sc)
In one embodiment, when X is , Y is 41.
HN
O 0
(:))L/Lsc)Y
In one embodiment when X is , Y is 0R3.
HN
O 0
Q)Lsc)',
In one embodiment when X is , Y is 0R3.
.,õ.,
HN
O 0
QSO
In one embodiment when X is , Y is 0R3.
)1r-
HN
CH2)3
In one embodiment, when X is y is H2N 0H
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HN
CH2)3
c1)00 ,0
In one embodiment when X is y is H2N OH
HN
(CH2)3
Q)0 0 0
In one embodiment, when X is y is H2N OH
In one embodiment, when X is p-NO2PhCH20¨, Y is p-NO2PhCH20¨.
In one embodiment, when X is p-NO2PhCH20¨, Y is ¨NHCH2Ph.
In one embodiment, when X is p-NO2PhCH20¨, Y is ¨N(CH3)CH2Ph.
In one embodiment, when X is p-NO2PhCH20¨, Y is ¨NFIR2.
In one embodiment, when X is p-NO2PhCH20¨, Y is ¨NH(CH2)5N(CH3)2.
In one embodiment, when X is p-NO2PhCH20¨, Y is ¨BH3.
HN
L
In one embodiment, when X is p-NO2PhCH20¨, Y is
HN
I
In one embodiment, when X is p-NO2PhCH20¨, Y is P .
HN
In one embodiment, when X is p-NO2PhCH20¨, Y is .
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HN
(
HN N
In one embodiment, when X is p-NO2PhCH20¨, Y is I/ .
HN
In one embodiment, when X is p-NO2PhCH20¨, Y is OR3 .
HN
In one embodiment, when X is p-NO2PhCH20¨, Y is OR3
HN
In one embodiment, when X is p-NO2PhCH20¨, Y is OR3 .
)11-
HN
CH2)3
i<0
In one embodiment, when X is p-NO2PhCH20¨, Y is H2 N OH .
)11-
HN
CH2)3
! 0
-..
<
In one embodiment, when X is p-NO2PhCH20¨, Y is H2N% OH
HN
(CH2)3
/<0
In one embodiment, when X is p-NO2PhCH20¨, Y is H2N OH .
In one embodiment, when X is ¨NHCH2Ph, Y is ¨NHCH2Ph.
In one embodiment, when X is ¨NHCH2Ph, Y is ¨N(CH3)CH2Ph.
In one embodiment, when X is ¨NHCH2Ph, Y is ¨NE1R2.

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In one embodiment, when X is ¨NHCH2Ph, Y is ¨NH(CH2)5NICH3/2.
In one embodiment, when X is ¨NHCH2Ph, Y is ¨BH3.
HN
In one embodiment, when X is ¨NHCH2Ph, Y is L
HN
QN
In one embodiment, when X is ¨NHCH2Ph, Y is P.
HN
In one embodiment, when X is ¨NHCH2Ph, Y is P .
HN
( Im
HN N
In one embodiment, when X is ¨NHCH2Ph, Y is
HN
In one embodiment, when X is ¨NHCH2Ph, Y is 0R3.
HN
In one embodiment, when X is ¨NHCH2Ph, Y is 0R3.
=NIA,
HN
In one embodiment, when X is ¨NHCH2Ph, Y is 0R3.
56

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HN
CH2)3
i<0
In one embodiment, when X is ¨NHCH2Ph, Y is H2N OH
HN
CH2)3
! 0
I<
)
In one embodiment, when X is ¨NHCH2Ph, Y is H2N OH
HN
CH2)3
_4()
In one embodiment, when X is ¨NHCH2Ph, Y is H2N OH
0
In one embodiment, when X is ¨NHCH2Ph, Y is selected from OH, RY S ,
\IDA
ON , ON , ON , or
0 0
(:))Lsc)i
0
y 0õs
In one embodiment, when X is ¨NHCH2Ph, Y is " e
, and RY is alkyl. In
one embodiment, RY is hydroxyalkyl. In
one embodiment, RY is
2-hydroxylmethylprop-2-yl.
0 0
QSO
In one embodiment, when X is ¨NHCH2Ph, Y is , and Q
is OR3. In
one embodiment, R3 is alkyl. In one embodiment, Q is OCH3, OCH2CH3, or
OCH(CH3)2.
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is ¨N(CH3)CH2Ph.
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is ¨NEIR2.
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is ¨NH(CH2)5MCH3/2.
57

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In one embodiment, when X is ¨N(CH3)CH2Ph, Y is ¨BH3.
HN
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is 110 L
HN
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is
HN
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is P .
HN
( ),õ
HN N
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is
HN
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is OR3
HN
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is 0R3.
HN
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is 0R3
58

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)11-
HN
CH2)3
l<0
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is H2N OH
711-
HN
CH2)3
! 0
) ________________________________________________ I<
OH
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is H2N
HN
CH2)3
In one embodiment, when X is ¨N(CH3)CH2Ph, Y is H2N OH
In one embodiment, when X is ¨NEIR2, Y is ¨NEIR2.
In one embodiment, when X is ¨NEIR2, Y is ¨NH(CH2)5N(CH3)2.
In one embodiment, when X is ¨NEIR2, Y is ¨BH3.
HN
= L
In one embodiment when X is ¨NEIR2, Y is
HN
In one embodiment, when X is ¨NEIR2, Y is P
=
HN
In one embodiment, when X is ¨NEIR2, Y is .
59

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HN
(
HN N
In one embodiment, when X is ¨NEIR2, Y is II .
HN
In one embodiment, when X is ¨NEIR2, Y is 0R3.
HN
In one embodiment, when X is ¨NEIR2, Y is 0R3.
HN
In one embodiment, when X is ¨NEIR2, Y is 0R3.
HN
CH2)3
i<0
In one embodiment, when X is ¨NEIR2, Y is H2 N OH
HN
CH2)3
! 0
/
)
In one embodiment, when X is ¨NEIR2, Y is H2N OH
HN
(CH2)3
/<0
In one embodiment, when X is ¨NEIR2, Y is H2N OH
In one embodiment, when X is ¨NH(CH2)5N(CH3)2, Y is ¨NH(CH2)5N(CH3)2.
In one embodiment, when X is ¨NH(CH2)5N(CH3)2, Y is ¨BH3.

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HN
L
In one embodiment, when X is ¨NH(CH2)5N(CH3)2, Y is
HN
In one embodiment, when X is ¨NH(CH2)5N(CH3)2, Y is
HN
C
In one embodiment, when X is ¨NH(CH2)5N(CH3)2, Y is P
HN
( ),
HN N
In one embodiment, when X is ¨N1-1(CH2)5N(CH3)2, Y is
HN
In one embodiment, when X is ¨NEI(CH2)5N(CH3)2, Y is OR3 .
7v
HN
In one embodiment, when X is ¨N1-1(CH2)5N(CH3)2, Y is 0R3.
HN
In one embodiment, when X is ¨NH(CH2)5N(CH3)2, Y is 0R3.
HN
CH2)3
/<0
In one embodiment, when X is ¨NH(CH2)5N(CH3)2, Y is H2N OH
61

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)11-
HN
CH2)3
! 0
/<
)
In one embodiment, when X is ¨NH(CH2)5N(CH3)2, Y is H2N OH
HN
CH2)3
/<0
In one embodiment, when X is ¨NH(CH2)5N(CH3)2, Y is H2N OH
In one embodiment, when X is ¨BH3, Y is ¨BH3.
HN
L
In one embodiment, when X is ¨BH3, Y is
HN
In one embodiment, when X is ¨BH3, Y is
HN
1\1
In one embodiment, when X is ¨BH3, Y is P .
HN
( lm
HN X
In one embodiment, when X is ¨BH3, Y is II .
HN
In one embodiment, when X is ¨BH3, Y is 0R3.
62

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.7"
HN
In one embodiment, when X is ¨BH3, y is oR3.
HN
In one embodiment, when X is ¨BH3, Y is 0R3.
76,
HN
CH2)3
In one embodiment, when X is ¨BH3, Y is H2N OH
HN
CH2)3
! 0
)
In one embodiment, when X is ¨BH3, Y is H2N OH
HN
(CH2)3
In one embodiment, when X is ¨BH3, Y is H2N OH
HN HN
=L y is L
In one embodiment when X is
HN HN
In one embodiment when X is LY is
63

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HN
HN
In one embodiment, when X is L
Y is P .
HN
lm
HN
HN N
In one embodiment, when X is = L
Y is
HN
HN
L
In one embodiment when X is y is 0R3.
HN
HN
In one embodiment, when X is L
Y is 0R3.
HN
HN
L
In one embodiment when X is Y is 0R3.
HN HN
CH2)3
In one embodiment, when X is L
y is HN OH .
HN HN
CH2)3
,0
In one embodiment when X is L
y is H2N OH .
64

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7
HN HN
(cH2)3
In one embodiment when X is L i<0
Y is H2N OH
HN HN
In one embodiment, when X is Y is
HN HN
L
In one embodiment, when X is P, Y is
=
HN
HN ( lm
HN N
In one embodiment, when Xis Y is 4*.
HN
HN ( lm
HN N
In one embodiment when X is P, Y is .
7
HN osn.,
HN
In one embodiment when X is P, Y is 0R3.
7
HN
HN
N
In one embodiment when X is 'P, Y is 0R3.

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HN
HN
In one embodiment when X is P , Y is 0R3.
HN HN
CH2)3
0
In one embodiment, when X is y is H2N OH .
HN HN
CH2)3
In one embodiment when X is P y is H2N OH .
HN HN
CH2)3
0
In one embodiment, when Xis y is H2N OH .
~IV
1
HN HN
In one embodiment, when X is P , Y is P .
1 1
HN HN
( )rn
HN
In one embodiment when X is P , Y is
HN
HN/
The
In one embodiment, when X is P , Y is 0R3
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HN
7"
HN
The
In one embodiment, when X is P , Y is 0R3.
HN
HN
In one embodiment, when X is P , Y is 0R3
HN )11-
HN
(CH)3
In one embodiment, when X is p y is H2N OH
HN
HN
(CH)3
! 0
1\1
In one embodiment, when X is p y is H2N OH
HN
HN
(CH)3
In one embodiment, when X is p y is H2N OH
HN HN
( )rn (
HNN HN N
In one embodiment, when X is =, Y is
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1
HN
( )rn
HNN HN
In one embodiment, when X is =, Y is 0R3.
HN
( )rn
HN N HN
In one embodiment, when X is ,Y is 0R3.
HN
( ),õ
HN N HN
In one embodiment when X is 40 , Y is 0R3.
HN
HN
HN N (CH2)3
In one embodiment when X is y is H2N OH .
1
HN
( ),õHN
HN N (CH2)3
!, 0
=5 In one embodiment when X is y is H2N OH
.
1
HN
( )rn HN
HN N .(CH2)3
In one embodiment, when X is y is H2N OH .
HN/
HN/
In one embodiment, when X is 01R3, y is 0R3.
68

69
ST uatIm
Inatumociwo auo uj
= HO NH s! A HO NH
c(zHo) c(zHO)
NH NH
ST uatIm
Inatumociwo auo uj
= HO NH s! A HO NH
0 2
c(zHo) c(zHO)
NH NH
ST uatIm
Inatumociwo auo uj
= HO NH s! A HO NH
c(zHo) c(zHO)
NH NH
= HO NH JO HO NH s! A
ci() s! X uatIm Inatumociwo auo uj c
0 2
c(zHo) c(zHO) NH NH
NH NH
,4n
= HO NH s! A
s! X ualm Inawmociwo auo UJ
O
c(zHo) NH
NH
= s! A Eic) s! X uatIm Inawmociwo auo UJ
NH NH
= Ei() s! A 'clo s! X uatIm Inawmociwo auo UJ
NH NH
=o s! A 'clo s!
X uatIm Inawmociwo auo UJ
NH NH
Li6000/SIOZEII/I3d
tZ9I8I/SIOZ OM
0-TT-9TOZ 66L.V6Z0 YD

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HN HN
CH2)3 (CH2)3
k 0
In one embodiment, when X is H2N OH , y is H2N OH
7"-
HN HN
CH2)3 (CH2)3
0
)
In one embodiment, when X is H2N OH , y is H2N OH
R2 R2
1\1-1
(E) (E),,
In one embodiment, when X is 0 , Y is 0 .
R2õ R2õ
(E) (E),,
In one embodiment, when X is 0 , Y is 0 ,
and Q is OR3, wherein n, R2, R3, R4,
R5, R6, and all other variables are as described elsewhere herein. In one
embodiment, Q is
OCH3, OCH2CH3, or OCH(CH3)2.
R2 R2
1\1-1
(E),,
In one embodiment, when X is 0 , Y is 0 ,
R2 is hydrogen, R4 or R5 is
hydrogen. In one embodiment, R4 or R5 is alkyl or cycloalkyl. In one
embodiment, R4 or
R5 is isobutyl. In one embodiment, R4 or R5 is C3-05 cycloalkyl. In one
embodiment, R4
or R5 is cyclopentyl. In one embodiment, Q is OR3, wherein R3 and all other
variables are
as described elsewhere herein.
R2õ R2õ
(E) (E),,
In one embodiment, when X is 0 , Y is 0 ,
R2 is hydrogen, R4 or R5 is
hydrogen. In one embodiment, R4 or R5 is alkyl. In one embodiment, R4 or R5 is
isobutyl.

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In one embodiment, Q is OR3. In one embodiment, R3 is alkyl. In one embodiment
Q, is
OCH3, OCH2CH3, or OCH(CH3)2.
R2, 5
O (E)
In one embodiment, when X is m Y is 0
R2, 5
O (
In one embodiment, when X is m Y is 0 , m is 1, and Q is OR3,
wherein n,
R2 R3 R4 R5 R6 and all other variables are as described elsewhere herein. In
one
embodiment, Q is OCH3, OCH2CH3, or OCH(CH3)2.
$
O (E),,
In one embodiment, when X is m Y is 0 , m is 1, R2 is hydrogen, R4
or R5
is hydrogen. In one embodiment, R4 or R5 is alkyl or cycloalkyl. In one
embodiment, R4
or R5 is isobutyl. In one embodiment, R4 or R5 is C3-05 cycloalkyl. In one
embodiment,
R4 or R5 iscyclopentyl. In one embodiment, Q is OR3, wherein R3 and all other
variables
are as described elsewhere herein.
R2, 5
Qjt(,40"
In one embodiment, when Xis m Y is 0 , m is 1, R2 is hydrogen, R4
or R5
is hydrogen. In one embodiment, R4 or R5 is alkyl. In one embodiment, R4 or R5
is
isobutyl. In one embodiment, Q is OR3. In one embodiment, R3 is alkyl. In one
embodiment Q, is OCH3, OCH2CH3, or OCH(CH3)2.
0 0
,y 0 ES y
In one embodiment when X is rc y is R S
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NHIRz
0
N
In one embodiment, when R is ; X and Y both are R S
cr, then at least
one RY is other than alkyl, and other variables are as described elsewhere
herein.
NHIRz
tNL0 0
In one embodiment, when R is -I- ; X and Y both are R S RY
is
hydroxyalkyl. In one embodiment, RY is 2-hydroxylmethylprop-2-yl, and other
variables
are as described elsewhere herein.
R2, 5
(E ),,
Ql.r0y0y
In one embodiment, when X is 0 , Y is 0
R2, 5
(E ),,
Qi0TO>ss
In one embodiment, when X is 0 , Y is 0 ,
and Q is OR3, wherein n, R2,
R3, R4, R5, R6 and all other variables are as described elsewhere herein. In
one
embodiment, Q is OCH3, OCH2CH3, or OCH(CH3)2.
R2, 5
(E ),,
Qir0y0s
In one embodiment, when X is 0 , Y is 0 , R2 is
hydrogen, R4 or R5 is
hydrogen. In one embodiment, R4 or R5 is alkyl or cycloalkyl. In one
embodiment, R4 or
R5 is methyl. In one embodiment, R4 or R5 is C3-05 cycloalkyl. In one
embodiment, R4 or
R5 is cyclopentyl. In one embodiment, Q is OR3, wherein R3 and all other
variables are as
described elsewhere herein.
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R2õ
(E)
Qy0y0y
In one embodiment, when X is 0 , Y is 0 ,
R2 is hydrogen, R4 or R5 is
hydrogen. In one embodiment, R4 or R5 is alkyl. In one embodiment, R4 or R5 is
methyl.
In one embodiment, Q is OR3. In one embodiment, R3 is alkyl. In one embodiment
Q, is
OCH3, OCH2CH3, or ocH(cH3)2.
HN
\ \N 0 Ao
L
In one embodiment, when X is y is 02N \ 02N
, or
02N . In one embodiment, L is hydrogen.
HN
L
In one embodiment, when X is y is 02N \ .
In one embodiment, L is
hydrogen.
HN
oi1/4
L
In one embodiment, when X is y is 02N .
In one embodiment, L is
hydrogen.
HN
0
L
In one embodiment, when X is y is 02N .
In one embodiment, L is
hydrogen.
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A A
In one embodiment, when X is 02N y is 02N
=
A Nr----"N A
In one embodiment, when X is C)2N y is 02N
In one embodiment, L is hydrogen.
In some embodiments, when the phosphoramidate is substituted with at least one
amino
acid group, the amino acid is in the L-configuration. In one embodiment, the
amino acid
is alanine. In one embodiment, the amino acid is leucine.
In some embodiments, the phosphoramidate compound provided herein possesses a
chiral
phosphorous center. In some embodiments, the phosphoramidate is
diastereomerically
enriched.
In some embodiments, provided herein are:
(a) compounds as described herein, e.g., of Formula I and pharmaceutically
acceptable
salts and compositions thereof;
(b) compounds as described herein, e.g., of Formula I and pharmaceutically
acceptable
salts and compositions thereof for use in therapy;
(c) compounds as described herein, e.g., of Formula I and pharmaceutically
acceptable
salts and compositions thereof for use in the treatment and/or prophylaxis of
cancer
including leukemia;
(d)
processes for the preparation of compounds as described herein, e.g., of
Formula I
as described in more detail elsewhere herein;
(e) pharmaceutical compositions comprising a compound as described herein,
e.g., of
Formula I or a pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable carrier, diluents or excipient;
(f) a
method for the treatment and/or prophylaxis of cancer, in one embodiment,
leukemia, comprising the administration of an effective amount of a compound
as
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described herein, e.g., of Formulas I its pharmaceutically acceptable salt or
composition.
(g) combinations comprising an effective amount of a compound as
described herein,
e.g., of Formulas I or its pharmaceutically acceptable salt, and one, two,
three or
more other therapeutic agents, e.g. anti-cancer agents.
In one embodiment, provided herein is a compound of Formula Ha:
0 R
Cr-CZ
-p_R1
0- $ 0 A
(Ha)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric, or
polymorphic form thereof, wherein
R2, 5
Y is OH, 0 , or OR7;
IN NHRz
N3CLN
NNT N
Ris , or .µv,A, =
Rz is H or C(0)Z where Z is a fatty acid chain selected from palmitoleic,
oleic,
linoleic, or arachidonic acid;
W is NH2, halo, or OMe;
T is NH2, F, or Cl;
Rl is hydrogen, halo, OH, or protected OH;
Q is OR3;
E is CR4R5;
nisi;
R7 is alkyl, alkenyl, or alkynyl, each of which is optionally substituted;
R3 is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;

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R4 and R5 are selected from:
i) R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
aralkyl,
cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, wherein the
alkyl is
optionally substituted by alkoxy; or
ii) R4 and R5 together with the carbon atom to which they are attached form a
3-7
membered cycloalkyl ring.
In one embodiment, R3 is not aralkyl.
In one embodiment, provided herein is a compound of Formula Ha:
0
Cr:Ps 1.11 Ri
(Ha)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric, or
polymorphic form thereof, wherein
(E ),,
Y is OH, 0 , or OR7;
NHRZ
NI)N
NNT NO
R is '. or
Rz is H or C(0)Z where Z is a fatty acid chain selected from palmitoleic,
oleic,
linoleic, or arachidonic acid;
W is NH2 or Cl;
T is NH2, F or Cl;
Rl is hydrogen, OH or F;
Q is OR3;
E is CR4R5;
n is 1;
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R7 is alkyl, alkenyl, or alkynyl, each of which is optionally substituted;
R3 is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;
R4 and R5 are selected as follows:
i) R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
aralkyl,
cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, wherein alkyl
is optionally
substituted by alkoxy; or
ii) R4 and R5 together with the carbon atom to which they are attached form a
3-7
membered cycloalkyl ring.
In one embodiment R3 is not aralkyl.
The variables X, Y, Z, E, Q, W, T, n, R, RY, Rz, Rl, R2, R3, R4, R5, and R7 as
provided
herein are defined as herein.
In one embodiment, E is CR4R5, wherein R4 and R5 are each as defined herein.
In one
embodiment, R4 or R5 is hydrogen. In one embodiment, R4 or R5 is alkyl, or
cycloalkyl.
In one embodiment, R4 or R5 is lower alkyl. In one embodiment, R4 or R5 is
methyl. In
one embodiment, R4 or R5 is isobutyl. In one embodiment, R4 or R5 is C3-05
cycloalkyl.
In one embodiment, R4 or R5 is cyclopentyl. In one embodiment, one of R4 and
R5 is
hydrogen and the other is alkyl or cycloalkyl. In one embodiment, one of R4
and R5 is
hydrogen and the other is lower alkyl. In one embodiment, one of R4 and R5 is
hydrogen
and the other is methyl. In one embodiment, one of Wand R5 is hydrogen and the
other is
isobutyl. In one embodiment, one of R4 and R5 is hydrogen and the other is C3-
05
cycloalkyl. In one embodiment, one of R4 and R5 is hydrogen and the other is
cyclopentyl.
In one embodiment, Z is an oleic acid chain.
In one embodiment, W is NH2, T is Cl or F. In one embodiment, W is Cl, T is
NH2. In
one embodiment, W is OMe, T is NH2.
In one embodiment, Rl is hydrogen. In one embodiment, Rl is hydroxy or halo.
In one
embodiment Rl is fluoro.
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In one embodiment, R2 is hydrogen or alkyl. In one embodiment, R2 is lower
alkyl. In
one embodiment, R2 is methyl. In one embodiment, R2 is hydrogen.
In one embodiment, R3 is CH3, CH2CH3, CH(CH3)2 or CH2phenyl.
R2\ 5
(E/),,
Q
In one embodiment, Y is 0 .
In one embodiment Y is OR7, wherein R7 is as defined
herein. In one embodiment Y is OCH3, OCH2CH3, or OCH(CH3)2. In one embodiment
Q
is OCH(CH3)2. In one embodiment Q is OCH2CH3 or OCH2phenyl.
In some embodiments, when the phosphoramidate is substituted with an amino
acid group,
the amino acid is in the L-configuration. In one embodiment, the amino acid is
alanine. In
one embodiment, the amino acid is leucine.
In some embodiments, the phosphoramidate compound provided herein possesses a
chiral
phosphorous center. In some embodiments, the phosphoramidate is
diastereomerically
enriched.
In one embodiment, provided herein is a compound of Formula Ilb:
0
p _ 0
0' \ OH
(Ilb)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric, or
polymorphic form thereof, wherein
R2\ 5
(E/),,
Y is OH, 0 , or OR7;
NHRZ
N 0
R is ¨ =
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Rz is H or C(0)Z where Z is a fatty acid chain selected from palmitoleic,
oleic, linoleic, or
arachidonic acid;
Q is OR3;
E is CR4R5;
nisi;
R7 is alkyl, alkenyl, or alkynyl, each of which is optionally substituted;
R3 is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;
R4 and R5 are selected from:
i) R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
aralkyl,
cycloalkyl, cycloalkenyl, alkylheterocyclyl, or alkylheteroaryl, wherein alkyl
is optionally
substituted by alkoxy; or
ii) R4 and R5 together with the carbon atom to which they are attached form a
3-7
membered cycloalkyl ring.
In one embodiment R3 is not aralkyl.
The variables X, Y, Z, E, Q, W, T, n, R, RY, Rz, Rl, R2, R3, R4, R5, and R7 as
provided
herein are defined as herein.
In one embodiment, E is CR4R5, wherein R4 and R5 are each as defined herein.
In one
embodiment, R4 or R5 is hydrogen. In one embodiment, R4 or R5 is alkyl, or
cycloalkyl. In
one embodiment, R4 or R5 is lower alkyl. In one embodiment, R4 or R5 is
methyl. In one
embodiment, R4 or R5 is isobutyl. In one embodiment, R4 or R5 is C3-05
cycloalkyl. In one
embodiment, R4 or R5 is cyclopentyl. In one embodiment, one of R4 and R5 is
hydrogen and
the other is alkyl or cycloalkyl. In one embodiment, one of R4 andR5 is
hydrogen and the
other is lower alkyl. In one embodiment, one of R4 and R5 is hydrogen and the
other is
methyl. In one embodiment, one of Wand R5 is hydrogen and the other is
isobutyl. In one
embodiment, one of R4 and R5 is hydrogen and the other is C3-05 cycloalkyl. In
one
embodiment, one of R4 and R5 is hydrogen and the other is cyclopentyl.
In one embodiment, Z is an oleic acid chain.
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In one embodiment, R2 is hydrogen or alkyl. In one embodiment, R2 is lower
alkyl. In one
embodiment, R2 is methyl. In one embodiment, R2 is hydrogen.
In one embodiment, R3 is CH3, CH2CH3, CH(CH3)2 or CH2phenyl.
R2, 5
N¨$
(E/),,
Q
In one embodiment, Y is 0 . In one embodiment Y is OR7, wherein R7 is as
defined
herein. In one embodiment, Y is OCH3, OCH2CH3, or OCH(CH3)2. In one embodiment
Q
is OCH(CH3)2. In one embodiment Q is OCH2CH3 or OCH2phenyl.
In one embodiment, provided herein is a compound of Formula IIc:
0
Os
Y'fs17 R1
d
0
(TIc)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric, or
polymorphic form thereof, wherein
R2, 5
(E ),,
Y is OH, 0 , or OR7;
NHRZ
)N
0
Ris .""V
Rz is H or C(0)Z where Z is a fatty acid chain selected from palmitoleic,
oleic, linoleic, or
arachidonic acid;
Q is OR3;
E is CR4R5;

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n is 1;
R7 is alkyl, alkenyl, or alkynyl, each of which is optionally substituted;
R3 is hydrogen, alkyl, alkenyl, alkynyl or aralkyl;
R4 and R5 are selected from:
i) R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,
aralkyl,
cycloalkyl, cycloalkenyl, alkylheterocyclyl, or alkylheteroaryl, wherein alkyl
is optionally
substituted by alkoxy; or
ii) R4 and R5 together with the carbon atom to which they are attached form a
3-7
membered cycloalkyl ring.
In one embodiment R3 is not aralkyl.
The variables X, Y, Z, E, Q, W, T, n, R, RY, Rz, Rl, R2, R3, R4, R5, and R7 as
provided
herein are defined as herein.
In one embodiment, E is CR4R5, wherein R4 and R5 are each as defined herein.
In one
embodiment, R4 or R5 is hydrogen. In one embodiment, R4 or R5 is alkyl, or
cycloalkyl. In
one embodiment, R4 or R5 is lower alkyl. In one embodiment, R4 or R5 is
methyl. In one
embodiment, R4 or R5 is isobutyl. In one embodiment, R4 or R5 is C3-05
cycloalkyl. In one
embodiment, R4 or R5 is cyclopentyl. In one embodiment, one of R4 and R5 is
hydrogen
and the other is alkyl or cycloalkyl. In one embodiment, one of R4 andR5 is
hydrogen and
the other is lower alkyl. In one embodiment, one of Wand R5 is hydrogen and
the other is
methyl. In one embodiment, one of Wand R5 is hydrogen and the other is
isobutyl. In one
embodiment, one of R4 and R5 is hydrogen and the other is C3-05 cycloalkyl. In
one
embodiment, one of R4 and R5 is hydrogen and the other is cyclopentyl.
In one embodiment, Z is an oleic acid chain.
In one embodiment, R2 is hydrogen or alkyl. In one embodiment, R2 is lower
alkyl. In one
embodiment, R2 is methyl. In one embodiment, R2 is hydrogen.
In one embodiment, R3 is CH3, CH2CH3, CH(CH3)2 or CH2phenyl
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R2, 5
(E/),,
In one embodiment, Y is 0 . In one embodiment Y is OR7, wherein R7 is as
defined
herein. In one embodiment, Y is OCH3, OCH2CH3, or OCH(CH3)2. In one embodiment
Q
is OCH(CH3)2. In one embodiment, Q is OCH2CH3 or OCH2phenyl.
In some embodiments, when the phosphoramidate is substituted with an amino
acid group,
the amino acid is in the L-configuration. In one embodiment, the amino acid is
alanine. In
one embodiment, the amino acid is leucine.
In some embodiments, the phosphoramidate compound provided herein possesses a
chiral
phosphorous center. In some embodiments, the phosphoramidate is
diastereomerically
enriched.
In one embodiment, provided herein is a compound of Formula lid:
0
HOrS
O-P-0¨ R1
0 HN
OH H
(lid)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric,
or polymorphic form thereof, wherein R and Ware as defined herein.
In one embodiment, provided herein is a compound of Formula He:
R2 0
\ I I R1
N¨p--0 __________ IccLI
(
N-R2
0 w (On OR6 H
0
(He)
82

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or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric,
or polymorphic form thereof, wherein R, R2, R6, E, n, and Q are as defined
herein.
In one embodiment, R2 is hydrogen; R3 is alkyl; R4 is hydrogen and R5 is alkyl
or
cycloalkyl; or R4 is alkyl or cycloalkyl, and R5 is hydrogen.
In one embodiment, provided herein is a compound of Formula
R2 0
\ I I R1
(
0
OC) )m OR6 H
0
(llf)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric,
or polymorphic form thereof, wherein R, R2, R6, E, m, n, and Q are as
defined herein.
In one embodiment, R2 is hydrogen; R3 is alkyl; R4 is hydrogen and R5 is alkyl
or
cycloalkyl; or R4 is alkyl or cycloalkyl, and R5 is hydrogen.
In one embodiment, provided herein is a compound of Formula IIg:
0
HOr R1
0
oR6 H
0
OH
(IIg)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric,
or polymorphic form thereof, wherein R, and R6 are as defined herein.
In one embodiment, provided herein is a compound of Formula IIh:
83

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R2 0
\ II n _________________ R1
(EtiN---P- cL/R
OAQ OR6 H
0--
Q
(IIh)
or a pharmaceutically acceptable salt, or solvate thereof, or a
stereoisomeric, tautomeric,
or polymorphic form thereof, wherein R, Rl, R2, R6, E, n, and Q are as defined
herein.
In one embodiment, R2 is hydrogen; R3 is alkyl; R4 is hydrogen and R5 is
alkyl, or R4 is
alkyl and R5 is hydrogen.
In one embodiment, the compound provided herein is a compound of one of the
following
Formulas:
H,Rz
N
NH2
)N N--...)
I NI'
R20 t R2 0
\ II OH N 0 \ II c(LF/N--N CI
N-----P--0 ______________ c_13/ \ N¨p--0
(Eln \ (Eln
,N-R2 6 N-R2
0 Q (E)n OR H 0 Q (E) OR- H
Q Q
0 0
NH2 0
N...._)N N..-..)N
I
1
R2 0
R2 0 OH
N^.N"...- F \N !......0 OH N----N
NH2
\N ili.......0 0
0
(EL \ (E' \
N-R2 6 p-R2 6
0 Q ( E% OR 0 Q (E )n OR H
,:::-CI
,:::-CI
1 0
wherein E, Q, n, Rz, R2, and R6 are as described in Formula I.
84

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In another embodiment, the compound provided herein is a compound of one of
the
following Formulas:
HN-Rz NH2
N....._AN
AN I 1
0 t 0 NF N 'CI
RY S II HO ON RY S II
y 0-F1-0¨L____ 4/0
)--r y
1
0 HN 0 HN
OR6 H OR6 H
40 el
NH2 (:)
N ....,/iN
N.....)N
I 1
0 N...-Nr NH2
RY S II
y o00H N N"-- F Ry s 9,
y o-15-o 0 OH
0 HIV 0 HN
OR6 H OR6 H
0 I.
wherein RY, Rz, and R6 are as described in Formula I.
In another embodiment, the compound provided herein is a compound of one of
the
following Formulas:
H,Rz
N
NH2
A NN//
I 11 \ I
R2 0
\II_0_ ?/OH N 0 \ II R2 0 N----NCI
N¨p¨o-4./F
(EL \ (EL \
o o
o Q OR6 H 0 Q OR6 H
Q

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NH2 o
N.,.,)
1\1 NN
R2 0 I R2 0 I
\ II OH N'''''N1" I=,1_0_0H NN NI-12
N¨ ¨
P-031 F \N____I
(Eln \
0 0 (
0 Q OR6 H 0 Q OR6 H
Q Q
0 0
wherein E, Q, R2, Rz, and R6 are as described in Formula I.
In another embodiment, the compound provided herein is a compound of one of
the
following Formulas:
HN,Rz
NH2
1 11 N....N
R2R2 0 I
\ II ¨
\ II F N..--Nr CI
N¨po¨
(EL N (On \
o Q 0 H 0 Q
0 H
NH2 (:)
R2 0 1
R2 0 I
\N__pII___OOH N.---N F \ II OH N ---- Nr NH2
(Eln N ,N¨P-0 0
(E )n
0 Q 0 H 0 Q 0 H
wherein E, Q, R2, and Rz are as described in Formula II.
In another embodiment, the compound provided herein is a compound of one of
the
following Formulas:
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,Rz
HN
NH2
AN N......)
0 trA 0 I
II OH - n - II NNCI
0-P-a 0-PN-07cLyF
Q N Q N
0 0 H 0 0 H
NH2 o
N....../LN N.......LN
0 I 0 I
031N-070H F (0-PIIN-a
_lcH
Q N Q N
0 0 H 0 0 H
wherein Q and Rz are as described in Formula II.
In another embodiment, the compound provided herein is a compound of one of
the
following Formulas:
,Rz
HN NH2
N ....,/L N
A
1 X
R2 0 R 1 ),
2 0
\ II 0 Th\I 0 \N____11,_____õovjy-) N----N CI
N¨P---'--- 0
(EL ( Eln
0 Q OH H 0 Q OH H
NH2 o
N.,..LN N....,)N
R2 0 R2 0
N N FN N NH2
\N¨Iliy \N-11:!--'-' W)
0
( Eln ( On
0 Q OH H 0 Q OH H
wherein E, Q, R2, and Rz are as described in Formula IIb.
In another embodiment, the compound provided herein is a compound of one of
the
following Formulas:
87

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HN-Rz
NH2
N-..,)N
00 el
N N CI
0
Q Q
0 OH H 0 OH H
o
NH2
NN/, N....../LN
0 \ I 1 0 I
F
Q Q
0 OH H 0 OH H
wherein Q, and Rz are as described in Formula IIb.
In one embodiment, the nucleosides that can be derivatized to include a
phosphoramidate,
e.g., at the 5' position, include:
NH2 NH2
t 1
1\1---NCI
OH N 0 _________________________
HO¨L:),./ HO _ICLF?/
OH H OH H
NH2 NH2
N--AN N-.....AN
I
....-
N N CI NNF
HO HO
OH OH .
In one embodiment, the compound provided herein is a compound of one of the
following
Formulas:
88

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NH2
NH2
N....,,/L
0 F OH N-C) -----c,. n 1 ji\IL
L
N---.1\1 -CI
r..-0 I-1 I
/ 0 _.-0 H I
OH H 0
OH H
0
0 0
) 0
\ ,
,
NH2
NH2
1 0 ,
0
_ )---- II N
I
OH i\j'LO
N¨ 0
H N 0 0 HN¨P --n /
_IC27 I
,.0 H I 0
0 OH H
,.
OH H 0 0
i
0
0 , (:)
\ I
,
NH2
--I\ N ...,/LN
I 1
0 0 m ---
N¨P¨
N F
Nr0 H I
0
OH H
lz)0
\, or
0
---k N.õ.)Ni
I *L
0 0 OH N N NH2
Yo H !
OH H
(:)0
\ .
89

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In one embodiment, the compound provided herein is a compound of one of the
following
Formulas:
NH2 NH2
)11\1 N--..)N
0 t 0 I
OH N 0 I I F N.----1\r CI
4
HO-A-0- /
HN
OH H 0OH H
401
ONH2
N,........):-.N NI-...õ):-. N
9I
OH N---N F 0
I II
OH N----Nr NH2
HO-P-0 HO-P-0
41 -24/ 1
HN
OH H OH H
0 , or 0
=
In one embodiment, the compound provided herein is a compound of one of the
following
Formulas:

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NH2
ej
0
HOrS
0 00H N
0
CIC:71/H
OH
NH2
N
0 I
HO(S00N NCI
0
OH H
OH
NH2
0 I NI
HOSO-112'-0
OH N F
0 0
OH H
OH or
NN
0 I
HOrSO-P-0F NH2
0
OH H
S)
OH
In one embodiment, the compound provided herein is a compound of one of the
following
Formulas:
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NH2 NH2
el\I (ILI
0 0
11 (-) 01-11\1 0 11 r) OH N 0
lot HN-P\-----K HN-P\-----1:7
0 . 0
OH H OH H
/
----N1
N NO2 NO2
NH2 NH2
e1,1 N....,),N
0 0 , 1
õ r) __________________ 01-11\10 Ny-----\ 11 0
o_pc -21 FIKN--N CI
. HN-PC IL:).,?/ \\
j-N
0 02N \ NH
OH H OH H
K.LNO2 41
,
NH2
N--.)N
0 I
04 ________________________ " I
k,_--,
------\___c) 0 F N-, CI
' 0 \
02N NH
OH H
41 ,
NH2
N.,--LN
0 I I
..),,F/N---NCI
02N NH
OH H
,=
92

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NH2
N
0 <II
o KOH F
02N \
NH
OH H
NH2
N
0
0j--0 0 OH N N F
0
02N
NH
OH H
NH2
0 I NI'
F
S
02N NH
OH H
0
N3CLN
0o I
N NH2
02N \ NH
OH H
93

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0
NN
0 I *L
N---1\1 NH2
)\--0 . -P¨C)-4H
02N NH
OH H
or
0
NN
0 I
II OHN-N NH2
a-\X
02N NH
OH H
In one embodiment, the compound provided herein is a compound of one of the
following
Formulas:
94

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NH2 NH2
-----( N
t ----(N-
.._)N
=0 1
0 ::-. OH N 0 0 : Z N--Th\r CI
,/ \N-FIC)¨Ic_IC/
,0 H I ,0 H I
HN HN
=y0OH H oOH H
.......- 0 0
NH2
-----(
N-,...--jo-.. N
0 F 0 _--
OH N -N F
I 740
)---C) H HN
OH H
hr
,
/
0
------
NN
=0
0 = OH N N NH2
NI\I-1
I
r ----I40
NO H HN
,,s=y OH H
0
, or
0
HN
-----( )1\1
=0 t
0 = HN
,0 H I
HN
H
0
=

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In one embodiment, the compound provided herein is a compound of one of the
following
Formulas:
NH2
N
0 t
HOS0-11=L0 ,/-1) ?
OH N 0
0 HN
OH H
0 ,
NH2
N1AN
I
0
HOrSO4_0_4N N CI
0 HN
OH H
0 ,
NH2 NH2
N N
0 >( tm Lr_l 0 tr\in
s,So_ig_0_4H - - 01(\cS0_pii_07c, ?./
OH - -
1 1
HN 0 0 HN
OH H OH H
0 lei
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NH2
NN
HOrs, OH N -1\1
0 HN
OH H
or
0
HO NN
OHN---1\r NH2
0 HN
OH H
=
In one embodiment, the compound provided herein is a compound of one of the
following
Formulas:
NH2
11
N 0
a-5 0 A
NH
NH2
NH2
NI)N
N/0 N N CI
OH
FNH
0- 1/4-/ H
NH
0
0
0
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NH2
NIA N
1
--13 (r.,,,..:t_<N1-12 N N F
0 N \N q ---L
___________________ /0/I 0
X _p_0 s' H
:_ OH
00
0 HN-P , N--(--
- $
6 0-- A OH F NH
r01
0
0 7-'0
NH2 1:)
NN
-....A N.-----L,N
I 1
, oN/N--"N"-- -F _ , /0 N---NI NH2
0/ 0---L4
%
,p_e :. OH -p ,' - OH
u- 5 H 0- $_ 0 A
NH NH
0
0
NI''''''',. m NH2 NH2
1
NXJ:,=Ki AN
N N NH2 1 )µ1 1
N 0
07-----(1: N N F
A cr¨C_
NH
A 0,1:_oss A OH
0 ......../0 .,..../0
NH2 NH2
N--../ AN
I I t NO
---.... _
o
N N CI
A 0' 5 OH
\
,or ----- .
Optically Active Compounds
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It is appreciated that compounds provided herein have several chiral centers
and may exist
in and be isolated in optically active and racemic forms. Some compounds may
exhibit
polymorphism. It is to be understood that any racemic, optically-active,
diastereomeric,
polymorphic, or stereoisomeric form, or mixtures thereof, of a compound
provided herein,
which possess the useful properties described herein is within the scope of
the invention. It
is well known in the art how to prepare optically active forms (for example,
by resolution
of the racemic form by recrystallization techniques, by synthesis from
optically-active
starting materials, by chiral synthesis, or by chromatographic separation
using a chiral
stationary phase).
In particular, since the 1' and 4' carbons of a nucleoside are chiral, their
nonhydrogen
substituents (the base and the CHOR groups, respectively) can be either cis
(on the same
side) or trans (on opposite sides) with respect to the sugar ring system. The
four optical
isomers therefore are represented by the following configurations (when
orienting the sugar
moiety in a horizontal plane such that the oxygen atom is in the back): cis
(with both
groups "up", which corresponds to the configuration of naturally occurring 13-
D
nucleosides), cis (with both groups "down", which is a nonnaturally occurring
13-L
configuration), trans (with the C2' substituent "up" and the C4' substituent
"down"), and
trans (with the C2' substituent "down" and the C4' substituent "up"). The "D-
nucleosides"
are cis nucleosides in a natural configuration and the "L-nucleosides" are cis
nucleosides in
the non-naturally occurring configuration.
Likewise, most amino acids are chiral (designated as L or D, wherein the L
enantiomer is
the naturally occurring configuration) and can exist as separate enantiomers.
Examples of methods to obtain optically active materials are known in the art,
and include
at least the following.
i) physical separation of crystals - a technique whereby macroscopic
crystals of the individual enantiomers are manually separated. This
technique can be used if crystals of the separate enantiomers exist,
i.e., the material is a conglomerate, and the crystals are visually
distinct;
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ii) simultaneous crystallization - a technique whereby the
individual
enantiomers are separately crystallized from a solution of the
racemate, possible only if the latter is a conglomerate in the solid
state;
iii) enzymatic resolutions - a technique whereby partial or complete
separation of a racemate by virtue of differing rates of reaction for
the enantiomers with an enzyme;
iv) enzymatic asymmetric synthesis - a synthetic technique whereby at
least one step of the synthesis uses an enzymatic reaction to obtain
an enantiomerically pure or enriched synthetic precursor of the
desired enantiomer;
v) chemical asymmetric synthesis - a synthetic technique whereby the
desired enantiomer is synthesized from an achiral precursor under
conditions that produce asymmetry (i.e., chirality) in the product,
which may be achieved using chiral catalysts or chiral auxiliaries;
vi) diastereomer separations - a technique whereby a racemic compound
is reacted with an enantiomerically pure reagent (the chiral auxiliary)
that converts the individual enantiomers to diastereomers. The
resulting diastereomers are then separated by chromatography or
crystallization by virtue of their now more distinct structural
differences and the chiral auxiliary later removed to obtain the
desired enantiomer;
vii) first- and second-order asymmetric transformations - a technique
whereby diastereomers from the racemate equilibrate to yield a
preponderance in solution of the diastereomer from the desired
enantiomer or where preferential crystallization of the diastereomer
from the desired enantiomer perturbs the equilibrium such that
eventually in principle all the material is converted to the crystalline
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diastereomer from the desired enantiomer. The desired enantiomer is
then released from the diastereomer;
viii) kinetic resolutions - this technique refers to the achievement of
partial or complete resolution of a racemate (or of a further
resolution of a partially resolved compound) by virtue of unequal
reaction rates of the enantiomers with a chiral, non-racemic reagent
or catalyst under kinetic conditions;
ix) enantiospecific synthesis from non-racemic precursors - a synthetic
technique whereby the desired enantiomer is obtained from non-
chiral starting materials and where the stereochemical integrity is not
or is only minimally compromised over the course of the synthesis;
x) chiral liquid chromatography - a technique whereby the enantiomers
of a racemate are separated in a liquid mobile phase by virtue of their
differing interactions with a stationary phase. The stationary phase
can be made of chiral material or the mobile phase can contain an
additional chiral material to provoke the differing interactions;
xi) chiral gas chromatography - a technique whereby the racemate is
volatilized and enantiomers are separated by virtue of their differing
interactions in the gaseous mobile phase with a column containing a
fixed non-racemic chiral adsorbent phase;
xii) extraction with chiral solvents - a technique whereby the enantiomers
are separated by virtue of preferential dissolution of one enantiomer
into a particular chiral solvent;
xii) transport across chiral membranes - a technique whereby
a racemate
is placed in contact with a thin membrane barrier. The barrier
typically separates two miscible fluids, one containing the racemate,
and a driving force such as concentration or pressure differential
causes preferential transport across the membrane barrier.
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Separation occurs as a result of the non-racemic chiral nature of the
membrane which allows only one enantiomer of the racemate to pass
through.
In some embodiments, compositions of the present disclosure are provided that
are
substantially free of an undesignated enantiomer of a nucleoside or nucleoside
derivative.
In one embodiment, in the methods and compounds of this invention, the
compounds are
substantially free of undesignated enantiomers. In some embodiments, the
composition
includes a compound that is at least 85 %, 90%, 95%, 98%, 99%, to 100% by
weight of
the designated compound, the remainder comprising other chemical species or
enantiomers.
Isotopically Enriched Compounds
Also provided herein are isotopically enriched compounds, including but not
limited to
isotopically enriched nucleoside derivatives.
Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve
pharmacokinetics ("PK"), pharmacodynamics ("PD"), and toxicity profiles, has
been
demonstrated previously with some classes of drugs. See, for example, Lijinsky
et. al.,
Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst.,
69: 1127
(1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug
Metab.
Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et.
al.,1 Nucl.
Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).
Isotopic enrichment of a drug can be used, for example, to (1) reduce or
eliminate
unwanted metabolites, (2) increase the half-life of the parent drug, (3)
decrease the number
of doses needed to achieve a desired effect, (4) decrease the amount of a dose
necessary to
achieve a desired effect, (5) increase the formation of active metabolites, if
any are
formed, and/or (6) decrese the production of deleterious metabolites in
specific tissues
and/or create a more effective drug and/or a safer drug for combination
therapy, whether
the combination therapy is intentional or not.
102

CA 02947939 2016-11-03
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Replacement of an atom for one of its isotopes often will result in a change
in the reaction
rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope
Effect
("KIE"). For example, if a C¨H bond is broken during a rate-determining step
in a
chemical reaction (i.e. the step with the highest transition state energy),
substitution of a
deuterium for that hydrogen will cause a decrease in the reaction rate and the
process will
slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect
("DKIE"). (See, e.g, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985);
Kushner et aL,
Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).
The magnitude of the DKIE can be expressed as the ratio between the rates of a
given
reaction in which a C¨H bond is broken, and the same reaction where deuterium
is
substituted for hydrogen. The DKIE can range from about 1 (no isotope effect)
to very
large numbers, such as 50 or more, meaning that the reaction can be fifty, or
more, times
slower when deuterium is substituted for hydrogen. Without being limited to a
particular
theory, high DKIE values may be due in part to a phenomenon known as
tunneling, which
is a consequence of the uncertainty principle. Tunneling is ascribed to the
small mass of a
hydrogen atom, and occurs because transition states involving a proton can
sometimes
form in the absence of the required activation energy. Because deuterium has
more mass
than hydrogen, it statistically has a much lower probability of undergoing
this
phenomenon.
Tritium ("T") is a radioactive isotope of hydrogen, used in research, fusion
reactors,
neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that
has 2
neutrons in the nucleus and has an atomic weight close to 3. It occurs
naturally in the
environment in very low concentrations, most commonly found as T20. Tritium
decays
slowly (half-life = 12.3 years) and emits a low energy beta particle that
cannot penetrate
the outer layer of human skin. Internal exposure is the main hazard associated
with this
isotope, yet it must be ingested in large amounts to pose a significant health
risk. As
compared with deuterium, a lesser amount of tritium must be consumed before it
reaches a
hazardous level. Substitution of tritium ("T") for hydrogen results in yet a
stronger bond
than deuterium and gives numerically larger isotope effects. Similarly,
substitution of
103

CA 02947939 2016-11-03
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isotopes for other elements, including, but not limited to, "C or 14C for
carbon, "S, 34, or
36
S for sulfur, 15N for nitrogen, and 170 or 180 for oxygen, may lead to a
similar kinetic
isotope effect.
For example, the DKIE was used to decrease the hepatotoxicity of halothane by
presumably limiting the production of reactive species such as trifluoroacetyl
chloride.
However, this method may not be applicable to all drug classes. For example,
deuterium
incorporation can lead to metabolic switching. The concept of metabolic
switching asserts
that xenogens, when sequestered by Phase I enzymes, may bind transiently and
re-bind in
a variety of conformations prior to the chemical reaction (e.g., oxidation).
This hypothesis
is supported by the relatively vast size of binding pockets in many Phase I
enzymes and
the promiscuous nature of many metabolic reactions. Metabolic switching can
potentially
lead to different proportions of known metabolites as well as altogether new
metabolites.
This new metabolic profile may impart more or less toxicity.
The animal body expresses a variety of enzymes for the purpose of eliminating
foreign
substances, such as therapeutic agents, from its circulation system. Examples
of such
enzymes include the cytochrome P450 enzymes ("CYPs"), esterases, proteases,
reductases, dehydrogenases, and monoamine oxidases, to react with and convert
these
foreign substances to more polar intermediates or metabolites for renal
excretion. Some of
the most common metabolic reactions of pharmaceutical compounds involve the
oxidation
of a carbon-hydrogen (C¨H) bond to either a carbon-oxygen (C-0) or carbon-
carbon (C¨
C) pi-bond. The resultant metabolites may be stable or unstable under
physiological
conditions, and can have substantially different pharmacokinetic,
pharmacodynamic, and
acute and long-term toxicity profiles relative to the parent compounds. For
many drugs,
such oxidations are rapid. These drugs therefore often require the
administration of
multiple or high daily doses.
Therefore, isotopic enrichment at certain positions of a compound provided
herein will
produce a detectable KIE that will affect the pharmacokinetic, pharmacologic,
and/or
toxicological profiles of a compound provided herein in comparison with a
similar
compound having a natural isotopic composition.
104

CA 02947939 2016-11-03
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Preparation of Compounds
The compounds provided herein can be, in some instances, prepared, isolated,
or obtained
by any method apparent to those of skill in the art. Those skilled in the art
will recognize
that compounds provided herein may be designed or prepared by reaction, e.g.,
at a
hydroxy group of said anti-cancer drug, for example, via condensation or
dehydration.
In other instances, compounds provided herein can be prepared according to the
Exemplary Preparation Schemes provided below. In certain embodiments,
compounds
provided herein can be prepared according to Schemes 1-6. Reaction conditions,
steps,
and reactants not provided in the Exemplary Preparation Schemes would be
apparent to,
and known by, those skilled in the art and, thus, are within the scope of this
disclosure.
105

Scheme 1
2a: R= B0cNHCH2C(CH3)2C(0)S(CH2)2-
0
n.)
2b: R= TrOCH2C(CH3)2C(0)S(CH2)2-
o
1-,
0, N
un
2c: R= N.---(/
cc
n.)
0
R0 .6.
0 // \ //
// Benzylamine
0-p Et3N1-1 2-)P\
ChP\
HO-0,B/ = \
R H 0
2 R H 0-
HO- o 13 CCI4
NH 0--..,0 )13(
\ __ hip,X ______ 7 -'N( :)( CH2Cl2
7
: =
Hu
PivCI =:-.
HO
HO
Pyridine
1 3
4
la: X= F and B= B1 3a: X= F, B= B1 and R=
4a: X= F, B= B1 and R= B0cNHCH2C(CH3)2C(0)S(CH2)2-
1b: X= OH and B= B2 B0CNHCH2C(C1-13)2C(0)S(CH2)2- 4b:
X= F, B= B1 and R= TrOCH2C(CH3)2C(0)S(CH2)2-
3b: X= F, B= B1 and R= TrOCH2C(CH3)2C(0)S(CH02-
4c: X= -OH, B= 62 and R=
TrOCH2C(CH3)2C(0)S(CH02- P
with B1= 2-chloro-6-aminopurine
3c: X= OH, B= B2 and R= TrOCH2C(CH3)2C(0)S(C1-102- .
N,
NHdMTr
u,
B2= 4d: X= OH, B= B2
and R= 0, N1 .
,
CC/ -<Nk5.z
,--,
I J\ -R N
3d: X= OH, B= B2 and R= = /
IV
Ip --
.
1-
I 0 N
1
1-
i
R /P
T
.
b -P'
,..
Acetyl chloride / \
Ethanol NHO--,,x13
= -:.
1-11CI
5a: X= F, B= 131 and R= -H
5b1: X= F, B= B1 and R= HOCH2C(CH3)2C(0)S(C1-12)2- (diastereoisomer 1)
5b2: X= F, B= B1 and R= HOCH2C(CH3)2C(0)S(C1-12)2- (diastereoisomer 2)
IV
n
5c: X= -OH, B= cytosine and R= HOCH2C(CH3)2C(0)S(C1-12)2- (diastereoisomer 1)
5
-0 N
N
5d1: X= OH, B= cytosine and R= (diastereoisomer 1)
o
1-,
5d2: X= OH, B= cytosine and R= e N '
un
i (27
o
-0
=
\ N
un
11.--___
C( N--... j2s (diastereoisomer 2)
/

Scheme 2
0¨R1
yi H¨Cl
Et3N
0\_____ 5?
0=P¨C1 NH
= 2
CH2Cl2 HO-N(IDB
0--p--0 . 0
NO2
I
I N
mns
R HO---").r 'Ri
4\1H =
1¨,
0 =::: un
0 HO
q 1¨,
oe
,,,,2 R = -CH3 or -CH2CH3
R1 = -CH3 or -CH2CH3 1¨,
1
---ar R cA
n.)
6
.6.
6a: R= -CH3 and R1= -CH3
with B1= 2-chloro-6-aminopurine 6b: R= -CH2CH3 and R1= -CH2CH3
NHdMTr
B2=
N
0
0¨Ri 0¨Ri
C) 0ic, 0
P
tBuMgC1 \____ F3CCO2H
,
0¨p---0 B ---0--p-0
_,.
THF I 0 CH2C12 I4\1H -11µc _,...
pH
L.
8' ,
.
-_1 0 H8 0 HO
,õ
0
,
'Or IR ----01- 'IR
.
,
,
,
,
0
7 8
L.
7a: X= -OH, B= B2, R= -CH3 and R1= -CH3 8a1: X= -OH, B= cytosine, R= -CH3
and R1= -CH3 (diastereomer 1)
7b: X= -OH, B= B2, R= -CH2CH3 and R1= -CH2CH3 8a2: X= -OH, B= cytosine, R= -
CH3 and R1= -CH3 (diastereomer 2)
7c: X= -F, B= B1, R= -CH3 and R1= -CH3 8b1: X= -OH, B= cytosine, R= -CH2CH3
and R1= -CH2CH3 (diastereomer 1)
8b2: X= -OH, B= cytosine, R= -CH2CH3 and R1= -CH2CH3 (diastereomer 2)
8c1: X= -F, B= B1, R= -CH3 and R1= -CH3 (diastereomer 1)
8c2: X= -F, B= B1, R= -CH3 and R1= -CH3 (diastereomer 2)
IV
n
,¨i
,4
-
u,
7:-,--,
,.,
u,
-4

ht4,
Scheme
NO2 1), 1
NH2 0
"" \Ili: 1=47="-N", IP
1) POCb
N ,s. b.)
*,
1 N o
I-.
EtIN NO4' la
N -A,
EL.0 0, p THF
0 I.-"\Cy.14 N CI oc
I-.
P
HO * 02 ________________________ ow ti,
r. F cr.
t.)
2) Et3Ni--* N W
2)
N ct
U
.., '',..õ
',,.
4.
CI-ECI2 0--A( H iik ci.N
.c.-H
.--. Rai 0 3) CH2C12
...
__I¨N142 NO2
10
9
K
RI¨ ---0 Peel
Rt= Ethyl. tlastereolsomei 2
11: 124= Ethyl. dastereoisomer 1
26a: Rt= Beryl: dasterecismner 1
26b: Rt-= Beryl: dasterearsomer 2
0
0
.
..1
to
8'C.
00
.
.
.
.
.
.
.0
c -5
E
o
us
,
o
o
o
us
...,1

N H2
Scheme 3bis
e...1)N1
NO2 1)
0 HO¨\ 1ocszN F N H2 N H2
0
1) POCI3
<Nx...-LN eNlx-LN N
0
1¨,
H 0
Pd/C
H2,
CA
Et3N
-..1.
Et20 Os p THF 0 IA0,4 N F
Et0H %/
(DA Ot N F
pe
H = 41 NO2 _______ > ... si¨ 0 =,- OCBz
P
_______________________________________________________________________________
______ ==== p 0 H
CA
2 " N /
===....., : / \ , t.)
CH2Cl2 /0--CH 0
CH3CN
..,.cH 0
.r
H
0
) Et3N 2) DBU
.6.
I's IR4 0 3) CH2Cl2
/0____(- N H2 NO2 '1-) 0 Cr-1/4
I 0
CI 9 R4
R4
R4 0 hr 27: Ret= Ethyl:
mixture of diastereoisomers 28a: Ret= Ethyl: diastereoisomer 1
28b: Ret= Ethyl: diastereoisomer 2
P
.
IV
tO
Ø
--I
tO
0
tO
Zi
IV
0
I:1
I
I¨'
I¨'
I
0
La
.0
n
t = .. )
o
u ,
-1
o
o
o
u ,
- = . 1

1
Scheme 4 ) POCI3
THF
0 2) L-Leucine methyl
ester 0 0
NH2
e
HN-1( hydrochloride
HN-1( n.)
'
_____________ N DElmaiFdic acid
..õ...---....õ =
1¨,
____________________________________ ( ( )6 __ \ Et3N I
= 4 __ ( ( )6 \_ un
HOcC)pN¨µ __ 1 e N THF Olr n
N 1¨,
4
0 HOC)Np
N¨µ NH;
\
P-0C4¨µ ( \6
cA
1¨,OH
H14 .6.
ZAOH ig0H
HO ..-/
HO ..........(111. --z
0 HO
14
0 \ 15
P
.
,,
,
'a-D,
.
,)
0
ig
,
,
,
,
0
L.
,-o
n
,-i
w
u,
7:-:--,
,.z
u,
-4

Scheme 5
0
NHdMTr
NHdMTr w
o
vi
(---N
(r- N
Pyridine Et3NH 1) PiyCI Tr0,>c s 9 oe
HO N ---.0 0 +
o
,.>.(I -NONIN --µ0
w
N
Tr0 s P 0 H
0 H 2) CCI4
i
HO benzylamine
0 HO
CH2Cl2
lb 2a
4c
NH2 NH2
P
0 ('N 0
N .
,)
F3CCO2H HO.r S 0 - P Ammonia
solution
N ---0 7N in methanol HO-
P-0 .
,
,
CH2Cl2 I ---'0 I
-NONIN
,
, _2,.. 0 NH
LOH ___________ 0,- NH
4,0H
'
NO
z
,
i.
0 1-16 0 HO
,
,
,
,
.
5c
16
od
n
,-i
,-,
=
-
-a' A
=
=
,.,
u,
-4

Scheme 6
0
NH2 NH2
6"
.
(Nx--(N
0 z/N____r/N
\
on
oe
PivCI
Tr >Y0-114-0 N N---:"&F
HO) N N-----:"(F
c:
Pyridine
H n.)
.6.
0 _)õ. 0 0
-
Ho \r0
110
.-.
HO
\.0
/
0 p -A Et3NH-F
0
R H 0-
17
* 2b
0
2b: R= TrOCH2C(CH3)2C(0)S(CH2)2-
NH2 P
NH2
.
,,
,,,,,r,N
,,,,,
0014 (/NIZTN
0 .
0
i,
, Benzylannine Tr ->rSO-A-0 Ni/N N---:-."(F CH2Cl2
HO.r SO-P-0 N.----(NCF .
i\.-) CH2Cl2 1 TFA
NH 0 _______________________ "
.
-30. 0 NH L. o -310.
0
l'''
Ha \r.0
Ha
\.0
/
r
r
e:
0 0
0 0
18 *
19
*
NH2
NH2
Nx(
1\1_____,(
od
0 \
/ N NH3 0
\
/ N
, N--L4
n
1-3
Pd black HOr So-A-o 0 yN 1\1-;"(F
7N in methanol HO-P-0 `-' y N¨ \F
E
Et0H ______________________________________________________________ xii
--]iii..
0 NH L...OH NH
/...OH o
HO
HO u,
7a5
101 0
=
=
,c,
u,
-4
21

CA 02947939 2016-11-03
WO 2015/181624 PCT/1B2015/000957
Scheme 7
Cbz 1/ POC13 Cbz
HN" THE HN"
e(
2/ B1 or B2 2N H
N Et3N, CH3CN
e(N
3/ B2 or B3 or B5 N4 BC13, 1.0M in DCM
...[(N4N o
HO--\\,,V4 ,2---.0-yi.
DCM
R2.Ø_\(0
______________________ x _______________________ x
Lo a DMAP o La
: or .
R3 Cbz o Cbz L. 0 H
1/ POC13
HO
22a R3=CBz THE
22b R3=H 2/ B3 or B4 23a-e 24a-e
Et3N, CH3CN
o
(DMAP)
N ii A
24a R2=
....Ø..... 0 ' in
02N N NH
I
1.1
o
N ii A
.....41,.......,0-1¨µ
131: benzylamine 24b R2= 02N s
B2: (3-methyl-2-nitro-imidazol-4-yOmethanol ra
B3: (2-nitrothiazol-5-ypmethanol
B4: (5-nitro-2-furyl)methanol
e(S
B5: (5-nitro-2-thienyl)methanol
N=(
NO2
o
N ii A
24c R2=
....Ø.......,
02N s a
N=(
NO2
a
N ii A
24d R2= .....CLO'n
02N S NH
Om
a
24e R2=
....n.........õ0---7- k
02N 0 0
((:)
¨
NO2

CA 02947939 2016-11-03
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Scheme 8:
1/113uMgC1, 1.0M in THF
THF
NHDMTr N H 2
(4N R2 o . NO2
Cl
e(N
H 0*\ *". O N¨(
N/0 ________________________ OXII¨(
2/ TFA, CH2C12 0
_________ [...OH OH
z
HO HO
lb 25 R2= 02N
)Thi 0
0-,pI
NH
I.
Scheme 9:
1/ pock
,MMTR Proton Sponge /MMTR
HN THE HN
1-4
2/ B6
NH2
N Et3N, CH3CN r(N
0 N4
3/B5 R2._ 0.....\/),,¨( TEA
r(N
0 DMAP 0 DCM L R2-0-0,i0N
_____________________________ o >.
__________________________________________ 0\
MMTR- MMTR MMTR- MMTR z __ LOH
HO
22c
23f 24
9 a
O______,
B6: Benzyl (25)-2-aminopropanoate 24f: R2= 02N s
H N
CD....._..c
0
I.
Scheme 10:
1/113uMgC1, 1.0M in THF
N H 2 THF N H 2
NO2 Nx,IN
N N
1 N N R2 0
D1 R2..,0 I
H OA
04i\I NF0 N"---LF
_______________________________ 0
OCBz 2/H2, Pd Black A '10H
. EON
HO HO
29: R2= 0 -----<
N-p f
r 0
rµO

CA 02947939 2016-11-03
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General procedure A
Step 1: To a stirred solution of compound 22a or 22b (9.97mmol) in THF
(10mL/mmol) at -10 C was added phosphorus oxychloride (11.96mmol). The
reaction mixture
was stirred from -10 C to room temperature overnight and then, a solution of
reagent B1
(9.97mmol) and triethylamine (49.85mmol) in acetonitrile (2.4mL/mmol) was
added at 0 C.
The reaction mixture was stirred for 1 hour at 0 C. Then, reagent B2 (29.9
lmmol) and DMAP
(29.91mmol) were added at 0 C and the reaction mixture was stirred from 0 C to
room
temperature for 2 hours. The reaction mixture was then diluted with ethyl
acetate, washed with
HC1 1N solution, water and brine. The organic layer was filtered and
concentrated under
reduced pressure. The crude residue was purified by flash chromatography on
silica gel
(DCM/methanol: 0 to 5%) to afford the expected compound.
Step 2: To a stirred suspension of compound 23a-c (2.40mmol) in DCM
(50mL/mmol) at -80 C under nitrogen was added a solution of boron trichloride,
1.0M in DCM
(12.02mmol). The reaction mixture was stirred from -80 C to -40 C for 4 hours.
Then Me0H
(2mL) was added at -80 C and the reaction mixture was concentrated under
reduced pressure at
C. The crude residue was purified by RP18 chromatography (H20/CH3CN) to afford
the
expected compound as solid. In some cases, the mixture of diastereoisomers was
purified by
chiral HPLC to afford the expected diastereoisomer.
20 General procedure B
Step 1: To a stirred solution of compound 22a (1.86mmol) in THF (10mL/mmol)
at -10 C under nitrogen was added phosphorus oxychloride (2.23mmol). The
reaction mixture
was stirred from -10 C to room temperature overnight and then, cooled down to
0 C. Then, a
solution of reagent B3 (3.72mmol) and triethylamine (9.31mmol) in acetonitrile
(2.4mL/mmol)
25 was added at 0 C. The reaction mixture was stirred at room temperature
overnight. The reaction
mixture was then diluted with ethyl acetate and washed with a saturated NH4C1
solution. The
organic layer was filtered and concentrated under reduced pressure. The crude
residue was
purified by flash chromatography on silica gel (DCM/methanol: 0 to 3%) to
afford the expected
compound.

CA 02947939 2016-11-03
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Step 2: according to step 2 of general procedure A.
General procedure C
Step 1: To a solution of compound lb (2.20mmol) in THF (10mL/mmol) at 0 C
was added a solution of tert-butylmagnesium chloride, 1M in THF (4.60mmol).
The reaction
mixture was stirred for 1 hour at room temperature, then cooled to 0 C. To
this reaction mixture
was added a solution of the appropriate reagent Cl (2.40mmol) in THF
(10mL/mmol). The
reaction mixture was stirred for 1 hour at 0 C and at room temperature
overnight. The reaction
mixture was diluted with ethyl acetate and washed with a saturated NH4C1
solution, water and
brine. The organic layer was dried, filtered and concentrated under reduced
pressure. The crude
residue was purified by flash chromatography on silica gel (DCM/methanol) to
afford the
expected intermediate as a mixture of diastereoisomers;
Step 2: To a solution of the previous intermediate (0.52mmol) in DCM
(30mL/mmol) was added trifluoroacetic acid (10.27mmol). The reaction mixture
was stirred at
room temperature for 3 hours and purified by flash chromatography on silica
gel
(DCM/methanol: 0 to 20%) followed by RP18 chromatography ((H20/CH3CN) to
afford the
expected compound as mixture of diastereoisomers. This mixture was purified by
MS-
preparative HPLC or by chiral HPLC to afford the 2 expected diastereoisomers
as pure solid
compounds.
General procedure D
Step 1: To a stirred solution of 4-nitrophenol (29.36mmol) and phosphorus
oxychloride (14.68mmol) in diethyl ether (10mL/mmol) at -80 C under nitrogen
was added
triethylamine (29.36mmol). The reaction mixture was stirred at room
temperature overnight.
Then, DCM (10mL/mmol) and the appropriate L-alanine ester hydrochloride
(14.68mmol) were
added at 0 C under nitrogen. To the reaction mixture was added dropwise at 0 C
triethylamine
(29.36mmol). The reaction mixture was stirred at room temperature overnight,
and then,
filtrated. The filtrate was concentrated under reduced pressure. The crude
residue was purified
by flash chromatography on silica gel (PE/Et20: 0 to 50%) to afford the
expected intermediate
9.

CA 02947939 2016-11-03
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Step 2: To a solution of compound la (1.55mmol) in THF (7mL/mmol) was
added at room temperature under nitrogen a solution of 1,8-
diazabicyclo[5.4.0]undec-7-ene
(3.71mmol) in acetonitrile (12mL/mmol), followed by a solution of the
appropriate compound 9
(1.86mmol) in DCM (12mL/mmol). The reaction mixture was stirred at room
temperature
overnight, and then, quenched on tampon phosphate pH=7. The reaction mixture
was extracted
with DCM and the organic layer was dried, filtered and concentrated under
reduced pressure.
The crude residue was purified by flash chromatography on silica gel
(DCM/methanol: 0 to
10%) to afford the expected compound as a mixture of diastereoisomers. This
mixture was
purified by MS-Preparative HPLC to afford the pure diastereoisomer.
Compounds 10 and 11
(2 diastereomers)
Ethyl
(2S)-2-[[(4aR,6R,75,7aR)-6-(6-amino-2-chloro-purin-9-y1)-7-fluoro-2-oxo-
4a,6,7,7a-
tetrahydro-4H-furo[3,2-d1[1,3,2]dioxaphosphinin-2-yl]amino]propanoate
N 2
Nci
\ I
0 /
N 0
0
0
Compounds 10 and 11 were synthesized from compound la according to scheme 3
and to the
general procedure D.
Compound 21
R2R,3S,4S,5R)-5-(6-amino-2-fluoro-purin-9-y1)-3,4-dihydroxy-tetrahydrofuran-2-
yl]methoxy-
N-benzyl-phosphonamidic acid

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N H2
0 \N
H
N H H
z
H 0
Compound 21 was synthesized according to scheme 6 and to the following general
procedure:
To a solution of 2'0CBz fludarabine (3.38mmol) and 2-(2,2-dimethy1-3-
trityloxypropanoy1)-
sulfanylethoxyphosphinic acid (5.08mmol) in pyridine (12mL/mmol) at 0 C was
slowly added
pivaloyl chloride (6.77mmol). The reaction mixture was stirred for 1 hour at 0
C and for 2 hours
at room temperature. The reaction was monitored by LC/MS. The reaction mixture
was
quenched with a 1M solution of NH4C1 and extracted with ethyl acetate. The
organic layer was
dried, filtered and concentrated under reduced pressure to afford the expected
intermediate 17.
To a solution of compound 17 (1.1mmol) in carbon tetrachloride (20mL/mmol) and
DCM
(15mL/mmol) were added benzylamine (5.5mmol) and triethylamine (6.6mmol) at
room
temperature. The reaction mixture was stirred overnight, and then,
concentrated under reduced
pressure and purified by flash chromatography on silica (DCM/methanol) to
afford the expected
intermediate 18.
To a solution of compound 18 (0.49mmol) in DCM (30mL/mmol) was added
trifluoroacetic acid
(7.4mmol) under nitrogen. The reaction mixture was stirred at room temperature
overnight and
purified by flash chromatography on silica (DCM/methanol: 0 to 20%) followed
by MS-
preparative HPLC to afford the mixture of diastereoisomers 19.
To a solution of compound 19 in Et0H (5mL/mmol) was added Palladium Black
under nitrogen.
After several flush N2/vaccum and vaccum/H2, the reaction mixture was stirred
under H2
Atmosphere for 6hours at room temperature. The reaction mixture was filtered
on Celite and
concentrated under reduced pressure to afford the expected intermediate 20.
The compound 20 (0.35mmol) was dissolved in a 7N ammonia solution in methanol
(50mL/mmol) and the reaction mixture was stirred at room temperature for 4
hours. The reaction
mixture was concentrated under reduced pressure and purified by RP-18
chromatography
(H20+TEAB/CH3CN) to afford the expected compound as solid.

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Compound 24a
12 Diastereomers)
4-amino-1 -[(2R,3 S,4S,5R)-5-[[(benzylamino)-[(3 -methy1-2-nitro-imidazol-4-
yl)methoxy]phosphoryl]oxymethy1]-3,4-dihydroxy-tetrahydrofuran-2-yllpyrimidin-
2-one
iNH2
0 e 1\1
N
\ o
02N- "-N
N H 0 H
O
Compound 24a was synthesized from compound 22a with reagent B1 and B2
according to
scheme 7 and general procedure A.
Compound 24a: (Diastereoisomer 1): 11-1 NMR (DMSO-d6, 400MHz) 6 (ppm) 7.54 (d,
J=7.51Hz, 1H), 7.32-7.27 (m, 4H), 7.26-7.21 (m, 1H), 7.20 (s, 1H), 7.11 (brs,
1H), 7.01 (brs,
1H), 6.09 (d, J=3.69Hz, 1H), 5.80 (dt, J=12.73Hz and 7.20Hz, 1H), 5.64 (d,
J=7.51Hz, 1H),
5.59-5.53 (m, 2H), 5.05 (dd, J=13.26Hz and 7.79Hz, 1H), 5.00 (dd, J=13.26Hz
and 7.34Hz,
1H), 4.14-3.88 (m, 7H), 3.86 (s, 3H); 3113 NMR (DMSO-d6, 162MHz) 6 (ppm) 10.27
(s, 1P);
MS (ESI) m/z = 550.1 (Miff).
Compound 24a: (Diastereoisomer 2): 11-1 NMR (DMSO-d6, 400MHz) 6 (ppm) 7.59 (d,
J=7.43Hz, 1H), 7.323-7.29 (m, 4H), 7.26-7.20 (m, 1H), 7.19 (s, 1H), 7.11 (brs,
1H), 7.01 (brs,
1H), 6.10 (d, J=3.74Hz, 1H), 5.80 (dt, J=12.55Hz and 7.14Hz, 1H), 5.63 (d,
J=7.43Hz, 1H),
5.58-5.56 (m, 2H), 5.05 (dd, J=13.24Hz and 7.83Hz, 1H), 4.99 (dd, J=13.24Hz
and 7.31Hz,
1H), 4.16-4.09 (m, 1H), 4.06-3.91 (m, 5H), 3.90-3.88 (m, 1H), 3.85 (s, 3H);
3113 NMR (DMS0-
d6, 162MHz) 6 (ppm) 10.19 (s, 1P); MS (ESI) m/z = 552.1 (MH+).
Compound 24b

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[(2R,3S,4S,5R)-5-(4-amino-2-oxo-pyrimidin-1-y1)-3,4-dihydroxy-tetrahydrofuran-
2-yl]methyl
bis[(2-nitrothiazol-5-yl)methyl] phosphate
N11-12
0 e \ N
N
N
0¨\,r ON/ ________________________ \
0
02N s 0 L 0 H
H 0
S
N=
NO2
Compound 24b was synthesized from compound 22a with reagent B3 according to
scheme 7
and general procedure B.
Compound 24b: 11-1 NMR (DMSO-d6, 400MHz) 6 (ppm) 8.07 (s, 1H); 8.05 (s, 1H);
7.56 (d,
J=7.46Hz, 1H), 7.11 (brs, 1H), 7.01 (brs, 1H), 6.11 (d, J=3.48Hz, 1H), 5.64-
5.58 (m, 3H), 5.47-
5.40 (m, 4H), 4.32-4.21 (m, 2H), 4.00-3.91 (m, 2H), 3.90-3.84 (m, 1H); 3113
NMR (DMSO-d6,
162MHz) 6 (ppm) -1.37 (s, 1P); MS (ESI) m/z = 608.0 (MH+).
Compound 24c
(Mixture of diastereomers 64/36)
R2R,3S,45,5R)-5-(4-amino-2-oxo-pyrimidin-1-y1)-3,4-dihydroxy-tetrahydrofuran-2-
yl]methyl
(3-methy1-2-nitro-imidazol-4-y1)methyl (2-nitrothiazol-5-yl)methyl phosphate
N11-12
0 e __ \ N
4"T"---
02N 0
s 0 L 0 H
HO
N=(
NO2

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Compound 24c was synthesized from compound 22a with reagents B2 and B3
according to
scheme 7 and general procedure A.
Compound 24c: 11-1 NMR (DMSO-d6, 400MHz) 6 (ppm) 8.06 (s, 0.64H), 8.04 (s,
0.36H), 7.57
(d, J=7.49Hz, 0.64H), 7.56 (d, J=7.49Hz, 0.36H), 7.31-7.25 (m, 1H), 7.11 (brs,
1H), 7.02 (brs,
1H), 6.10 (d, J=3.48Hz, 1H), 5.65-5.57 (m, 3H), 5.44-5.37 (m, 2H), 5.28-5.21
(m, 2H), 4.28-
4.18 (m, 2H), 3.98-3.83 (m, 6H); 3113 NMR (DMSO-d6, 162MHz) 6 (ppm) -1.43 (s,
1P); MS
(ESI) m/z = 605.2 (MH+).
Compound 24d
(2 diastereomers)
4-amino-1-[(2R,3S,45,5R)-5-[[(benzylamino)-[(5-nitro-2-
thienyl)methoxylphosphoryl]oxymethy1]-3,4-dihydroxy-tetrahydrofuran-2-
yllpyrimidin-2-one
/N H2
0 \ N
02N s'0
N H
H 0
Compound 24d was synthesized from compound 22b with reagents B1 and B5
according to
scheme 7 and general procedure A.
Compound 24d: (Diastereoisomer 1): 11-1 NMR (DMSO-d6, 400M1-1z) 6 (ppm) 8.02
(d,
J=4.21Hz, 1H), 7.54 (d, J=7.49Hz, 1H), 7.35-7.26 (m, 4H), 7.26-7.20 (m, 1H),
7.19 (d,
J=4.21Hz, 1H), 7.10 (brs, 1H), 7.00 (brs, 1H), 6.09 (d, J=3.69Hz, 1H), 5.85
(dt, J=12.62Hz and
7.13Hz, 1H), 5.62 (d, J=7.50Hz, 1H), 5.58-5.53 (m, 2H), 5.17 (dd, J=13.81Hz
and 8.51Hz, 1H),
5.11 (dd, J=13.81Hz and 8.51Hz, 1H), 4.15-3.87 (m, 7H); 3113 NMR (DMSO-d6,
162MHz) 6
(ppm) 10.37 (s, 1P); MS (ESI) m/z = 554.2 (MH+).
Compound 24d: (Diastereoisomer 2): 11-1 NMR (DMSO-d6, 400M1-1z) 6 (ppm) 8.01
(d,
J=4.20Hz, 1H), 7.59 (d, J=7.49Hz, 1H), 7.33-7.28 (m, 4H), 7.25-7.21 (m, 1H),
7.18 (d,
J=4.18Hz, 1H), 7.09 (brs, 1H), 7.00 (brs, 1H), 6.10 (d, J=3.66Hz, 1H), 5.89-
5.82 (m, 1H), 5.61

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(d, J=7.51Hz, 1H), 5.57-5.55 (m, 2H), 5.17 (dd, J=13.90Hz and 8.62Hz, 1H),
5.11 (dd,
J=13.90Hz and 8.43Hz, 1H), 4.17-4.11 (m, 1H), 4.07-3.92 m, 5H), 3.89-3.88 (m,
1H); 31P NMR
(DMSO-d6, 162MHz) 6 (ppm) 10.28 (s, 1P); MS (ESI) m/z = 554.2 (MH+).
Compound 24e
[(2R,3 S,4 S,5R)-5 -(4 -amino -2 -oxo-pyrimi din-1 -y1)-3 ,4-dihydroxy-
tetrahydrofuran-2 -yl] methyl
bis[(5-nitro-2-furyl)methyl] phosphate
iN H2
0 e 1\1
0
0
0 H
(H 0
0
NO2
Compound 24e was synthesized from compound 22a with reagent B4 according to
scheme 7
and general procedure B.
Compound 24e: 11-1 NMR (DMSO-d6, 400MHz) 6 (ppm) 7.65 (d, J=3.77Hz, 1H), 7.64
(d,
J=3.77Hz, 1H), 7.54 (d, J=7.48Hz, 1H), 7.11 (brs, 1H), 7.02 (brs, 1H), 6.97
(d, J=3.77Hz, 1H),
6.94 (d, J=3.77Hz, 1H), 6.09 (d, J=3.48Hz, 1H), 5.63 (d, J=7.48Hz, 1H), 5.60
(d, J=3.92Hz,
1H), 5.58 (d, J=4.82Hz, 1H), 5.21-5.14 (m, 4H), 4.27-4.21 (m, 2H), 3.98-3.90
(m, 2H), 3.89-
3.84 (m, 1H); 3113 NMR (DMSO-d6, 162MHz) 6 (ppm) -1.27 (s, 1P); MS (ESI) m/z =
574.2
Compound 24f
(2 diastereomers)
Benzyl (2 S)-2-[ [ [(2R,3 S,4 S,5R)-5 -(4-amino -2 -oxo-pyrimi din-1 -y1)-
3,4-dihydroxy-
tetrahydrofuran-2-yl] methoxy-[(5 -nitro -2-thi enyl)methoxy] pho sphoryl]
amino] propanoate

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1\11-12
0 e \ N
02N 0-r- Pr ON140
HN LOH
HO
0
Compound 24f was synthesized from compound 22c with reagents B6 and B5
according to
scheme 9 and general procedure A step 1. In this case, the addition of
phosphorus oxychloride
was followed by the addition of Proton sponge. Step 2 was done according to
step 2 of general
procedure C.
Compound 24f: (Diastereoisomer 1): 11-1 NMR (DMSO-d6, 400MHz) 6 (ppm) 8.03 (d,
J=4.21Hz, 1H), 7.53 (d, J=7.41Hz, 1H), 7.38-7.28 (m, 5H), 7.21 (d, J=4.21Hz,
1H), 7.11 (brs,
1H), 7.02 (brs, 1H), 6.08 (d, J=3.69Hz, 1H), 5.90 (dd, J=9.96Hz and 12.07Hz,
1H), 5.64 (d,
J=7.41Hz, 1H), 5.58-5.54 (m, 2H), 5.20-5.15 (m, 2H), 5.15-5.07 (m, 2H), 4.13-
4.03 (m, 2H),
3.99-3.80 (m, 4H), 1.31 (d, J=7.17Hz, 3H); 3113 NMR (DMSO-d6, 162MHz) 6 (ppm)
8.57 (s,
1P); MS (ESI) m/z = 626.2 (MIT').
Compound 24f: (Diastereoisomer 2): 11-1 NMR (DMSO-d6, 400MHz) 6 (ppm) 8.02 (d,
J=4.21Hz, 1H), 7.57 (d, J=7.41Hz, 1H), 7.38-7.28 (m, 5H), 7.19 (d, J=4.21Hz,
1H), 7.10 (brs,
1H), 7.01 (brs, 1H), 6.10 (d, J=3.69Hz, 1H), 5.95 (dd, J=10.15Hz and 12.64Hz,
1H), 5.61 (d,
J=7.41Hz, 1H), 5.59-5.55 (m, 2H), 5.20-5.06 (m, 4H), 4.19-4.03 (m, 2H), 3.99-
3.91 (m, 2H),
3.90-3.78 (m, 2H), 1.31 (d, J=7.17Hz, 3H); 3113 NMR (DMSO-d6, 162MHz) 6 (ppm)
8.16 (s,
1P); MS (ESI) m/z = 626.2 (MIT').
Compound 25
(2 diastereomers)
4-amino-1 -[(2R,3 S,45,5R)-5-[[(benzylamino)-[(5-nitro-2-
furyl)methoxy] pho sphoryl] oxymethyl] -3 ,4 -d ihydroxy-tetrahy drofuran-2-
yl] pyrimidin-2 -one

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iN H2
0 e 1\1
O¨Nz NtO
0
02N 0
11 0 H
H
4101
Compound 25 was synthesized with reagent Cl according to scheme 8 and general
procedure
C.
Compound 25: (Diastereoisomer 1): 11-1 NMR (DMSO-d6, 400MHz) 6 (ppm) 7.66 (d,
J=3.74Hz, 1H), 7.54 (d, J=7.40Hz, 1H), 7.33-7.28 (m, 4H), 7.25-7.21 (m, 1H),
7.11 (brs, 1H),
7.03 (brs, 1H), 6.88 (d, J=3. 74Hz, 1H), 6.09 (d, J=3 .69Hz, 1H), 5.81(dt,
J=12.52Hz and
7.15Hz, 1H), 5.63 (d, J=7.40Hz, 1H), 5.58-5.56 (m, 2H), 5.04-4.94 (m, 2H),
4.10-4.05 (m, 2H),
4.02-3.88 (m, 5H); 3113 NMR (DMSO-d6, 162MHz) 6 (ppm) 10.49 (s, 1P); MS (ESI)
m/z = 538
(MH+).
Compound 25: (Diastereoisomer 2): 11-1 NMR (DMSO-d6, 400MHz) 6 (ppm) 7.65 (d,
J=3.78Hz, 1H), 7.58 (d, J=7.43Hz, 1H), 7.33-7.28 (m, 4H), 7.25-7.21 (m, 1H),
7.10 (brs, 1H),
7.02 (brs, 1H), 6.87 (d, J=3.78Hz, 1H), 6.09 (d, J=3.65Hz, 1H), 5.82(dt,
J=12.45Hz and
7.17Hz, 1H), 5.63 (d, J=7.43Hz, 1H), 5.58-5.56 (m, 2H), 5.04-4.93 (m, 2H),
4.15-4.09 (m, 1H),
4.06-3.91 (m, 5H), 3.89-3.87 (m, 1H); 3113 NMR (DMSO-d6, 162MHz) 6 (ppm) 10.39
(s, 1P);
MS (ESI) m/z = 538 (MIT).
Compound 26:
(2 diastereomers)
Benzyl (25)-2-[[(4aR,6R,75,7aR)-6-(6-amino-2-chloro-purin-9-y1)-7-fluoro-
2-oxo-4a,6,7,7a-
tetrahydro-4H-furo[3,2-d1[1,3,2]dioxaphosphinin-2-yl]amino]propanoate

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N H2
N CI
P
0
411
Compound 26 was synthesized from compound la according to scheme 3 and to the
following
procedure D.
Compound 26a (Diastereoisomer 1): 1E1 NMR (DMSO-d6, 400MHz) 6 (ppm) 8.35 (d,
J=1.43Hz,
1H), 7.97 (brs, 2H), 7.41-7.29 (m, 5H), 6.60 (dd, J=5.14Hz and 6.61Hz, 1H),
6.14 (dd,
J=10.15Hz and 13.40Hz, 1H), 5.80 (td, J=55.34Hz and 7.34Hz, 1H), 5.39-5.26 (m,
1H), 5.18 (d,
J=12.62Hz, 1H), 5.14 (d, J=12.62Hz, 1H), 4.63-4.52 (m, 1H), 4.52-4.42 (m, 1H),
4.28-4.18 (m,
1H), 4.00-3.87 (m, 1H), 1.37 (d, J=7.15Hz, 3H); 31PNMR (DMSO-d6, 162MHz) 6
(ppm) 2.75 (s,
IP); 19F NMR (DMSO-d6, 376MHz) 6 (ppm) -199.64 (s, IF); MS (ESI) m/z = 527.0
(MH+).
Compound 26a (Diastereoisomer 2): 1E1 NMR (DMSO-d6, 400MHz) 6 (ppm) 8.55 (d,
J=1.41Hz,
1H), 7.95 (brs, 2H), 7.40-7.34 (m, 5H), 6.60-6.57 (m, 1H), 6.30 (dd, J=13.69Hz
and 9.94Hz, 1H),
5.75 (td, J=55.52Hz and 7.13Hz, 1H), 5.48-5.39 (m, 1H), 5.19-5.12 (m, 2H),
4.56-4.51 (m, 1H),
4.42-4.34 (m, 1H), 4.08-4.02 (m, 1H), 3.96-3.86 (m, 1H), 1.37 (d, J=7.10Hz,
3H); 3113 NMR
(DMSO-d6, 162MHz) 6 (ppm) 4.82 (s, IP); 19F NMR (DMSO-d6, 376MHz) 6 (ppm) -
199.46 (s,
IF); MS (ESI) m/z = 527.0 (MH+).
Compound 28a and 28b
(2 diastereomers)
Ethyl (25)-2-[[(4aR,6R,7S,7aS)-6-(6-amino-2-fluoro-purin-9-y1)-7-hydroxy-
2-oxo-4a,6,7,7a-
tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]amino]propanoate

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N H2
0 /0¨\coN N F
0 H
0-4-0
Compound 28 was synthesized from 2'0CBz-fludarabine according to scheme 3bis
and to the
procedure D. In this case, additional step of deprotection using H2, Pd/C 5%
in ethanol was used
to afford the 2 expected diastereoisomers.
Compound 28a (Diastereoisomer 1): 31P NMR (DMSO-d6, 162M1-1z) 6 (ppm) 3.01 (s,
1P); MS
(ESI) m/z = 447 (MH+).
Compound 28b (Diastereoisomer 2): 31P NMR (DMSO-d6, 162MHz) 6 (ppm) 4.97 (s,
1P); MS
(ESI) m/z = 447 (MIT').
Compound 29
(Mixture of diastereomers)
Methyl (25)-2- [ [ [(2R,3 S ,4S, 5R)-5 -(6-amino-2-flu oro-purin-9-y1)-3 ,4-
dihydroxy-tetrahydrofuran-
2-yl] methoxy-(2-methoxy-2-oxo -ethoxy)phosphoryl] amino]-4 -m ethyl-p
entanoate
0 N H2
rN
H 9p- 0\c NF
0 H 0
0 \
Compound 29 was synthesized according to scheme 10 and to the following
procedure.
To a solution of 2'0CBz-fludarabine (1.19mmol) in THF (10mL/mmol) at 0 C was
added a
solution of tert-butylmagnesium chloride, 1M in THF (3.70mmol). The reaction
mixture was
stirred at room temperature for lhour, and then cooled down to 0 C. The
appropriate reagent D1
(1.31mmol) in THF (10mL/mmol) was added, and the reaction mixture was stirred
at 0 C for
lhour and for 3days at room temperature. The reaction mixture was diluted with
ethyl acetate
and washed with a saturated solution of NH4C1, water and brine. The combined
organic layers

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were dried, filtered and concentrated under reduced pressure. The crude
residue was purified by
flash chromatography on silica (DCM/ethanol or DCM/methanol) to afford the
expected
intermediate;
To a solution of this intermediate (0.07mmol) in Et0H (5mL/mmol) was added
Palladium Black
(0.28mmol) under nitrogen. After several flush N2/vaccum and vaccum/H2, the
reaction mixture
was stirred under H2 Atmosphere for 1h at room temperature. The reaction
mixture was filtered
on Celite and concentrated under reduced pressure. The crude residue was
triturated in a
DCM/pentane mixture, and then purified by flash chromatography on silica gel
(DCM/methanol:
0 to 5%) to afford the expected compound as solid as mixture of
diastereoisomers.
Compound 29: 11-1NMR (DMSO-d6, 400MHz) 6 (ppm) 8.13 (s, 0.4H), 8.11 (s, 0.6H),
7.83 (brs,
2H), 6.18-6.16 (m, 1H), 5.78-5.65 (m, 2H), 4.52-4.44 (m, 2H), 4.26-4.09 (m,
4H), 3.99-3.93 (m,
1H), 3.76-3.69 (m, 1H), 3.68 (s, 1.8H), 3.66 (s, 1.2H), 3.62 (s, 1.2H), 3.60
(s, 1.8H), 1.73-1.65
(m, 1H), 1.52-1.22(m, 2H), 0.88-0.82(m, 6H); 31P NMR (DMSO-d6, 162MHz) 6 (ppm)
8.68(s,
0.6P), 8.51 (s, 0.4P); 19F NMR (DMSO-d6, 376MHz) 6 (ppm) -52.38 (m, 1F); MS
(ESI) m/z =
565 (MH+).
Characterization data of the compounds provided herein are described in Table
1:
Structure
LC/MS NMR
N H2
11-1 NMR (400 MHz,
DMSO-d6) 6 (ppm)
N
HO 98.24 (s, 1H), 7.88
A, NiN N"01 (brs, 2H),
7.32-7.30
H F
(m, 2H), 7.26-7.22
H
(m, 2H), 7.16-7.13
(m, 1H), 6.30 (dd,
J=5.0 Hz and 12.14
MS (ESI) m/z = 473 Hz, 1H), 5.26 (td,
(MR). J=4.67 Hz and 53.0
Hz, 1H), 4.48 (td,
J=4.94 Hz and 19.75
Hz, 1H), 3.95-3.87
(m, 5H), 2.87 (brs,
4H), 1.10 (t, J=6.95
Hz,
6H).
31P NMR (162 MHz,
DM5O-d6) 6 (ppm)

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6.59 (1P, s).
19F NMR (376 MHz,
DMSO-d6) 6 (ppm) -
198.12 (s, 1F).
114 NMR (400 MHz,
NH2 DMSO-d6) 6 (ppm)
v
</NI 8.19 (d, J=2.10 Hz,
Q 9
1H), 7.89 (brs, 2H),
OH 0.\c -Nt N - CI 7.32-7.25 (m, 4H),
H N L. F 7.23-7.17 (m, 1H),
HO 6.35 (dd, J=4.37 Hz
and 15.3 Hz, 1H),
6.13 (d, J=5.1 Hz,
1H), 5.68-5.62 (m,
MS (ESI) m/z = 1H), 5.24 (td, J=4.0
diastereomer 1 633.2 (MIH). Hz and 52.34 Hz,
1H), 4.93-4.90 (m,
1H), 4.51-4.43 (m,
1H), 4.19-4.01 (m,
3H), 3.97-3.82 (m,
4H), 3.42 (d, J=5.4
Hz, 2H), 3.03-3.0 (m,
2H), 1.09 (s, 6H).
31P NMR (162 MHz,
DMSO-d6) 6 (ppm)
9.93 (1P, s).
111 NMR (400 MHz,
NH2 DMSO-d6) 6 (ppm)
v 0 8.21 (d, J=2.19 Hz,
,o N
1H), 7.89 (brs, 2H),
n N
OH P- e\c -Nt N
CI 7.31-7.28 (m, 4H),
HIV L.F 7.24-7.19 (m, 1H),
HO 6.36 (dd, J=4.4 Hz
and 15.41 Hz, 1H),
6.12 (d, J=5.1 Hz,
MS (ESI) m/z = 1H), 5.70-5.64 (m,
633.2 (MH). 1H), 5.23 (td, J=3.93
diastereomer 2 Hz and 52.23 Hz,
1H), 4.92-4.89 (m,
1H), 4.50-4.42 (m,
1H), 4.14-4.11 (m,
2H), 4.05-4.01 (m,
1H), 3.98-3.80 (m,
4H), 3.41 (d, J=5.42
Hz, 2H), 3.02-2.99
(m, 2H), 1.08 (s, 6H).

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31P NMR (162 MHz,
DMSO-d6) 6 (ppm)
9.84 (s, 1P).
N H2 11-1 NMR (400 MHz,
v 0
( DMSO-d6) 6 (ppm)
.9 N 7.56 (d, J=7.41 Hz,
OH
0 1H), 7.34-7.28 (m,
H N \ LOH 4H), 7.25-7.20 (m,
HO 1H), 7.08 (brs, 1H),
6.99 (brs, 1H), 6.08
(d, J=3.76 Hz, 1H),
MS (ESI) m/z = 5.66-5.59 (m, 2H),
diastereomer 1 573.2 (MH+). 5.54-5.52 (m, 2H),
4.92 (t, J=5.53 Hz,
1H), 4.09-3.80 (m,
9H), 3.45-3.40 (m,
2H), 3.02 (t, J=6.61
Hz, 2H), 1.10 (s, 6H).
31P NMR (162 MHz,
DMSO-d6) 6 (ppm)
9.89 (s, 1P).
,N 2 11-1 NMR (400 MHz,
Me0D) 6 (ppm) 7.78
(d, J=7.58 Hz,
0
H 0 0.55H), 7.73 (d,
N-P-0 z OH J=7.58 Hz, 0.45H),
HO
7.34-7.28 (m, 4H),
7.26-7.21 (m, 1H),
7.15 (s, 0.45H), 7.14
\=N
-0-N (s, 0.55H), 6.23 (d,
0 J=3.67 Hz, 0.55H),
MS (ESI) m/z = 6.21 (d, J=3.67 Hz,
Mixture of diastereomers 552.2 (MH+). 0.45H), 5.79
(d,
J=7.56 Hz, 0.45H),
5.78 (d, J=7.49 Hz,
0.55H), 5.15-5.03 (m,
2H), 4.35-4.00 (m,
7H), 3.93 (s, 1.35H),
3.92 (s,
1.65H).
31P NMR (162 MHz,
Me0D) 6 (ppm)
10.24 (s, 0.45P),
10.06 (s, 0.55P).

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11-1 NMR (400 MHz,
Me0D) 6 (ppm) 8.53
(brs, 0.65H), 7.83-
-0
0 N N J=3.74 Hz, 0.57H),
Y 6.22 (d, J=3.74 Hz,
o N-P-0 0
HO -
OH 0.43H), 5.89 (d,
H HO
J=7.49 Hz, 0.57H),
Oo 5.88 (d, J=7.40 Hz,
0.43H), 4.62-4.55 (m,
2H), 4.41 - 4.21 (m,
2H), 4.20-4.18 (m,
MS (ESI) m/z = 523
1H), 4.11-4.06 (m,
1H), 4.04-4.03 (m,
1H), 3.95-3.86 (m,
1H), 3.77 (s, 1.29H),
3.76 (s, 1.71H), 3.71
(s, 3H), 1.84-1.74 (m,
1H), 1.57-1.53 (m,
2H), 0.95-0.92 (m,
6H).
31P NMR (162 MHz,
DMSO-d6) 6 (ppm)
8.98 (s, 0.43P), 8.59
(s, 0.57P).
11-1 NMR (400 MHz,
DMSO-d6) 6 (ppm)
7.53 (d, J= 7.43Hz,
NH2 1H), 7.13 (brs, 1H),
0 N N 7.02 (brs, 1H), 6.08
O Y N-P_ (d, J= 3.67Hz, 1H),
0 0
H ' OH 5.68-5.64 (m, 2H),
Ho
5.55-5.54 (m, 2H),
(:)XOo 4.50 (d, J= 9.71Hz,
MS (ESI) m/z = 2H), 4.15 (q, J=
551.0 (MH+).
7.14Hz, 2H), 4.12-
4.04 (m, 4H), 3.97-
diastereomer 1 3.95 (m, 1H), 3.93-
3.89 (m, 1H), 3.87-
3.85 (m, 1H), 3.76-
3.68 (m, 1H), 1.75-
1.68 (m, 1H), 1.53-
1.39 (m, 2H), 1.20
(dt, J= 10.96Hz and
7.14Hz, 6H), 0.87 (t,
J= 6.89Hz, 6H);

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31P NMR (162 MHz,
DMSO-d6) 6 (ppm)
8.82 (s, 1P).
11-1 NMR (400 MHz,
DMSO-d6) 6 (ppm)
( N H2
7.57 (d, J 7.44Hz,
1H), 7.13 (brs, 1H),
0 N4_0 0
H A 1/4-, HO OH 7.02 (brs, 1H), 6.10
r
(d, J= 3.70Hz, 1H),
5.67 (dd, J 13.07Hz
and 10.23Hz, 1H),
diastereomer 2 5.65 (d, J 7.44Hz,
1H), 5.57 (d,
J=
6.01Hz, 1H), 5.56 (d,
J= 6.85Hz, 1H),
MS (ESI) m/z =
4.50-4.39 (m, 2H),
551.0 (MH+).
4.19-4.04 (m, 6H),
3.97-3.91 (m, 2H),
3.87-3.85 (m, 1H),
3.72-3.64 (m, 1H),
1.76-1.66 (m, 1H),
1.53-1.38 (m, 2H),
1.22-1.16 (m, 6H),
0.87 (t, J= 5.98Hz,
6H).
31P NMR (162 MHz,
DM5O-d6) 6 (ppm)
8.52 (s, 1P).

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/ 11-1
NMR (400 MHz,
o 3
CDC13) 6 (ppm)
N
N9 0 NNI)....t NH2
0 1-11.F:-
8.075 (d, J=2.4 Hz,
µF N( N
H 0 1H),
6.47 (dd, J=4
CI
o¨(
o Hz and 17.2 Hz, 1H),
5.77 (brs, 2H), 5.18
diastereomer 1
(td, J=3.4 Hz and
51.6 Hz, 1H), 4.75-
4.25 (m, 5H), 4.18-
4.12 (m, 1H), 3.98-
3.90 (m, 1H), 3.81 (s,
3H), 3.74 (s, 3H),
MS (ESI) m/z =
583.04 (MH+). 3.37
(t, J=10.6 Hz,
1H), 1.79-1.70 (m,
1H), 1.65-1.48 (m,
2H), 1.32-1.26 (m,
1H), 0.95-0.93 (m,
6H).
31P NMR (162 MHz,
DM5O-d6) 6 (ppm)
8.54 (s, 1P).
19F NMR (376 MHz,
DM5O-d6) 6 (ppm)
-197.48 (s, 1F).
11-1 NMR (400 MHz,
/
CDC13) 6 (ppm)
0
8.044 (d, J=3.2 Hz,
N
N, p N N H2 1H),
6.46 (dd, J=3.6
0 H c)/ MS
(ESI) m/z = Hz and 18.4 Hz, 1H),
N
0 HO F
583.04 (MH+). 5.84
(brs, 2H), 5.14
CI (td, J=2.8 Hz and
51.6 Hz, 1H), 4.67-
4.52 (m, 3H), 4.42-
4.27 (m, 2H), 4.20-

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diastereomer 2 4.15 (m, 1H), 4-3.92
(m, 1H), 3.81 (s, 3H),
3.74 (s, 3H), 3.52 (t,
J=10.4 Hz, 1H),
1.80-1.72 (m, 1H),
1.63-1.46 (m, 2H),
1.32-1.26 (m, 1H),
0.95-0.93 (m, 6H).
31P NMR (162 MHz,
DMSO-d6) 6 (PPm)
8.68 (s, 1P).
19F NMR (376 MHz,
DMSO-d6) 6 (PPm)
-197.62 (s, 1F).
11-1 NMR (400 MHz,
N H2
DMSO-d6) 6 (PPm)
8.34 (d, J=1.38 Hz,
\ 1H), 7.94 (brs, 2H),
6.58 (dd, J=5.07 Hz
,.,
and 6.61 Hz, 1H),
p F
6.02 (dd, J=10.13 Hz
H
a and 13.30 Hz, 1H), 0
5.78 (td, J=7.0 Hz N
and 55.3 Hz, 1H),
5.35-5.26 (m, 1H),
4.62-4.55 (m, 1H),
MS (EST) m/z =
4.52-4.45 (m, 1H),
+
diastereomer 2 487.1 (MNa). 4.25-4.18 (m, 1H),
4.15-4.07 (m, 2H),
3.88-3.78 (m, 1H),
1.33 (d, J=7.14 Hz,
3H), 1.18 (t, J=7.1
Hz, 3H).
31P NMR (162 MHz,
DM5O-d6) 6 (PPm)
2.68 (s, 1P).
19F NMR (376 MHz,
DMSO-d6) d (ppm) -
199.81 (s, 1F).

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N H 2 11-1
NMR (400 MHz,
DMSO-d6) 6 (ppm)
NeN
N 8.56
(d, J=1.57 Hz,
ON)_N N CI 1H),
7.95 (brs, 2H),
0-1 6.60
(dd, J=5.56 Hz
P F
zand 6.59 Hz, 1H),
H 6 6.22
(dd, J=9.92 Hz
0 and
13.60 Hz, 1H),
0 5.75
(td, J=7.16 Hz
and, 55.49 Hz, 1H),
5.49-5.39 (m, 1H),
diastereomer 1 MS
(ESI) m/z = 4.59-4.44 (m, 2H),
487.1 (MNa+). 4.13-
4.03 (m, 1H),
4.12 (d, J=7.02 Hz,
2H), 3.87-3.77 (m,
1H), 1.30 (d, J=7.14
Hz, 3H), 1.21 (t,
J=7.06 Hz, 3H).
31P NMR (162 MHz,
DMSO-d6) 6 (ppm)
4.89 (s, 1P).
19F NMR (376 MHz,
DMSO-d6) 6 (ppm) -
199.49 (s, 1F).
11-1 NMR (400 MHz,
DM5O-d6) 6 (ppm)
H 0
10.79 (brs, 1H), 8.11-
8.08 (m, 1H), r4 7.23-
N
7.20 (m, 1H), 6.11-
N 0
0
OH
7_1 0 H 6.08
(m, 1H), 5.64-
0 \ 5.59
(m, 2H), 5.38-
5.32 (m, 2H), 4.77-
4.69 (m, 2H), 4.11-
4.03 (m, 2H), 4-3.86
MS (ESI) m/z = (m, 3H), 3.75-3.68
842.4 (MIH). (m, 2H), 3.61-3.56
(m, 6H), 2.40-2.34
(m, 2H), 1.96-1.89
(m, 4H), 1.75-1.64
(m, 2H), 1.57-1.35
(m, 6H), 1.32-1.19
(m, 20H), 0.89-0.81
cm,
15H).
1P NMR (162 MHz,
DM5O-d6) 6 (ppm)
13.05 (s, 1P).

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N H2 11-1 NMR (400 MHz,
(
N DMSO-d6) 6 (ppm)
7.61 (d, J=7.41 Hz,
0
Ho, ,....0\(0 0
NIN¨( 1H), 7.34-7.31 (m,
HN1 0 H 2H), 7.27-7.23 (m,
HO
2H), 7.18-7.13 (m,
110 2H), 6.93 (brs, 1H),
6.01 (d, J=4.27 Hz,
1H), 5.96 (d, J=2.82
MS (ESI) m/z = Hz, 1H), 5.87 (d,
413.2 (MH+). J=5.72 Hz, 1H), 5.63
(d, J=7.38 Hz, 1H),
4.09-4.06 (m, 1H),
3.91-3.86 (m, 3H),
3.82-3.73 (m, 3H),
3.53-3.36 (m, 1H),
3.13-3.09 (m, 1H).
31P NMR (162 MHz,
DMSO-d6) 6 (ppm)
6.44 (s, 1P).
N H2 11-1 NMR (400 MHz,
DM5O-d6) 6 (ppm)
0
n N 8.23 (s, 1H), 7.78
H 0¨ P¨ 0\( F (brs, 2H), 7.31-7.28
NH LAOH (m, 2H), 7.23-7.17
HO (m, 2H), 7.14-7.09
(m, 1H), 6.41 (brs,
1H), 6.14 (brs, 1H),
6.08 (d, J=5.20 Hz,
MS (ESI) m/z = 455 1H), 4.30-4.25 (m,
1H), 4.14-4.11 (m,
1H), 4.01-3.93 (m,
1H), 3.91-3.83 (m,
4H).
31P NMR (162 MHz,
DMSO) 6 (ppm) 5.38
cs, 1P).
9F NMR (376 MHz,
DMSO-d6) d (ppm) -
52.47 (s, 1F).

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NH2 11-1 NMR (400 MHz,
N,......)N DMSO-d6) 6 (ppm)
HO8.21 (d, J= 2.22Hz,
0
ii (:),---N*C1
1H), 7.88 (brs, 2H),
>.(Scl-P(1)-.0,1"-c 6.37 (dd, J= 15.70Hz
0 f HO F and
4.45Hz, 1H),
6.14 (d, J= 5.14Hz,
S 1H), 5.32-5.17
(m,
"----7L0 MS
(ESI) m/z = 1H), 4.91-4.88 (m,
2H), 4.50-4.42 (m,
OH 704.1 (MH+).
1H), 4.29-4.25 (m,
2H), 4.08-3.97 (m,
5H), 3.41 (t, J=
5.04Hz, 4H), 3.07 (q,
J= 6.48Hz, 4H), 1.09
(d, J= 6.24Hz, 12H).
31P NMR (162 MHz,
DM5O-d6) 6 (ppm) -
1.76(s, 1P).
[00391]
Using similar procedures, the following additional compounds were also
prepared.
NH2 NH2
N-..........):-.N N-
...)=:=-..N
NH2 NNF NNF -N F
-IR ,N )1\1 0/.......(__
,,- p_W I. OH
Lr's µ-' H 0....,p_o,' ii:_i
OH
0 N 0,1D-O¨NzON C NH NH
/ \
NH4 \ LoOH -......<1"=( _____//hH( 11' OH
0 0
) )
Diastereomer 1 Diastereomer 2
N NH2 NH2
o
Q
rµN
)¨C
0 I ;5)0Aco N Nc F HO,>rS,041_0(0eN--(N F
HO N
NN NH
--P
OF-...1....\., r I 0 z OH
.-'-- ,
HO OH 1**-
a HO
0 0 q...... F

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_O 0
0 Ny______.(NH2 0 N .._NH2
r \
N,.__,----= N N,y----- N HO
NHN .-- (
04;--dos- OH 1 0-1-0µµ 10H 1 1:" -
\4 F \.(-) F II 0
0 L....c.. /=N
I
-,
Diastereomer 1 Diastereomer 2 Hd OH N N-
Iv
F
I
o
r0 N NH2
0 -----A/ Q----N
.õ
0
----0)Li 0
NH: ----- H N-
HN-4 o/......qo N,y,..f\-...õ(
' 1 1, , . 0
i'l y0
-----rNci H OH N,__ N 0 HO
0\o e 1
F 0 \ 0
/
0
/ NH2 NH2
O Ni
NH2
N.........)z:N N....,..----Lc. N
(
õx
.,_ ,L I
v i µ N
\(ONfN
H N N------ i.....,0 N N F 4.......00 N
' el"- F
F
----<
.__OH : \--- I. ---L
¨p.... s' OH ¨p.._ s' :. OH
0
HO 0-- s 0 H 0" 5 0 H
NH NH
0 \
0 0
--j\---0 j\---0
(mixture of diastereoisomers)
Diastereomer 1 Diastereomer 2
NH2 NH2 e
NN N-....,./LN N-_,..../L. N
I I
N N F 0 N N Fm.-",.. ."...----.
0 '' N NH2
...µp 0 R s'' :COH _p_ === - OH OH
0-- 5-' 0-- "0 R
NH NH NH
0 0
Diastereomer 1 Diastereomer 2 Diastereomer 1

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0
N.......) N 0
I N-..,./LN
cr.s(01OH --N NH2 I o-
/......(01--N NH2 0
HO,>/rS /N
0-11LONC)t NH
0 ,
,..p 1
-s.._ H n0 -0
NH ' .=- OH
NP--- \' P '
- " s H Ha
NH
0
0
0
Diastereomer 2
0---
e_zr_
o N
II N
HO-P-Oy N'...--k NH2
I
NH _ OH
HO
Using similar procedures, the following additional compounds were also
prepared:
)
0 NH2
Nc0
N
i
\ N
0 N
-----<
H\ 0 p---
0 0
N------(
F
// 0 HO
0
\-------

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N H2
N
ON/
(3/4"..
0=P
0
N H
0
(diasteromer 1)
N H2
O
N
ON/
H
o
N H
0
(diasteromer 2)
Pharmaceutical Compositions and Methods of Administration
Derivatives of a variety of therapeutic agents can be formulated into
pharmaceutical
compositions using methods available in the art and those disclosed herein.
Therapeutic agents
that can be derivatized to phosphate derivatives include any anti-cancer agent
that includes, or
has been derivatized to include a reactive group for attachment of the
phosphate moiety,

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PCT/1B2015/000957
including but not limited to nucleosides and nucleoside analogues including
acyclic nucleosides.
Any of the compounds disclosed herein can be provided in the appropriate
pharmaceutical
composition and be administered by a suitable route of administration.
The methods provided herein encompass administering pharmaceutical
compositions containing
at least one compound as described herein, including a compound of general
Formulas I, Ha,
Hb, or IIc, if appropriate in the salt form, either used alone or in the form
of a combination with
one or more compatible and pharmaceutically acceptable carriers, such as
excipients, diluents or
adjuvants, or with another anti-cancer agent.
In certain embodiments, the second agent can be formulated or packaged with
the compound
provided herein. Of course, the second agent will only be formulated with the
compound
provided herein when, according to the judgment of those of skill in the art,
such co-formulation
should not interfere with the activity of either agent or the method of
administration. In certain
embodiments, the compound provided herein and the second agent are formulated
separately.
They can be packaged together, or packaged separately, for the convenience of
the practitioner
of skill in the art.
In clinical practice the active agents provided herein may be administered by
any conventional
route, in particular orally, parenterally, rectally or by inhalation (e.g. in
the form of aerosols). In
certain embodiments, the compound provided herein is administered orally.
Use may be made, as solid compositions for oral administration, of tablets,
pills, hard gelatin
capsules, powders or granules. In these compositions, the active product is
mixed with one or
more inert diluents or adjuvants, such as sucrose, lactose, or starch.
These compositions can comprise substances other than diluents, for example a
lubricant, such
as magnesium stearate, or a coating intended for controlled release.
Use may be made, as liquid compositions for oral administration, of solutions
which are
pharmaceutically acceptable, suspensions, emulsions, syrups, and elixirs
containing inert
diluents, such as water or liquid paraffin. These compositions can also
comprise substances
other than diluents, for example wetting, sweetening or flavoring products.
The compositions for parenteral administration can be emulsions or sterile
solutions. Use may
be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol,
vegetable oils, in

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particular olive oil, or injectable organic esters, for example ethyl oleate.
These compositions
can also contain adjuvants, in particular wetting, isotonizing, emulsifying,
dispersing, and
stabilizing agents. Sterilization can be carried out in several ways, for
example using a
bacteriological filter, by radiation or by heating. They can also be prepared
in the form of
sterile solid compositions which can be dissolved at the time of use in
sterile water or any other
injectable sterile medium.
The compositions for rectal administration are suppositories or rectal
capsules which contain, in
addition to the active principle, excipients such as cocoa butter, semi-
synthetic glycerides or
polyethylene glycols.
The compositions can also be aerosols. For use in the form of liquid aerosols,
the compositions
can be stable sterile solutions or solid compositions dissolved at the time of
use in apyrogenic
sterile water, in saline or any other pharmaceutically acceptable vehicle. For
use in the form of
dry aerosols intended to be directly inhaled, the active principle is finely
divided and combined
with a water-soluble solid diluent or vehicle, for example dextran, mannitol,
or lactose.
In one embodiment, a composition provided herein is a pharmaceutical
composition or a single
unit dosage form. Pharmaceutical compositions and single unit dosage forms
provided herein
comprise a prophylactically or therapeutically effective amount of one or more
prophylactic or
therapeutic agents (e.g., a compound provided herein, or other prophylactic or
therapeutic
agent), and a typically one or more pharmaceutically acceptable carriers or
excipients. In a
specific embodiment and in this context, the term "pharmaceutically
acceptable" means
approved by a regulatory agency of the Federal or a state government or listed
in the U.S.
Pharmacopeia or other generally recognized pharmacopeia for use in animals,
and more
particularly in humans. The term "carrier" includes a diluent, adjuvant (e.g.,
Freund's adjuvant
(complete and incomplete)), excipient, or vehicle with which the therapeutic
is administered.
Such pharmaceutical carriers can be sterile liquids, such as water and oils,
including those of
petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean
oil, mineral oil,
sesame oil and the like. Water can be used as a carrier when the
pharmaceutical composition is
administered intravenously. Saline solutions and aqueous dextrose and glycerol
solutions can
also be employed as liquid carriers, particularly for injectable solutions.
Examples of suitable

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pharmaceutical carriers are described in "Remington 's Pharmaceutical
Sciences" by E.W.
Martin.
Typical pharmaceutical compositions and dosage forms comprise one or more
excipients.
Suitable excipients are well-known to those skilled in the art of pharmacy,
and non-limiting
examples of suitable excipients include starch, glucose, lactose, sucrose,
gelatin, malt, rice,
flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium
chloride, dried skim
milk, glycerol, propylene, glycol, water, ethanol, and the like. Whether a
particular excipient is
suitable for incorporation into a pharmaceutical composition or dosage form
depends on a
variety of factors well known in the art including, but not limited to, the
way in which the
dosage form will be administered to a subject and the specific active
ingredients in the dosage
form. The composition or single unit dosage form, if desired, can also contain
minor amounts
of wetting or emulsifying agents, or pH buffering agents.
Lactose free compositions provided herein can comprise excipients that are
well known in the
art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF
(XVI). In general,
lactose free compositions comprise an active ingredient, a binder/filler, and
a lubricant in
pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary
lactose free
dosage forms comprise an active ingredient, microcrystalline cellulose, pre
gelatinized starch,
and magnesium stearate.
Further encompassed herein are anhydrous pharmaceutical compositions and
dosage forms
comprising active ingredients, since water can facilitate the degradation of
some compounds.
For example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a
means of simulating long term storage in order to determine characteristics
such as shelf life or
the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug
Stability: Principles
& Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water
and heat
accelerate the decomposition of some compounds. Thus, the effect of water on a
formulation
can be of great significance since moisture and/or humidity are commonly
encountered during
manufacture, handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms provided herein can be
prepared
using anhydrous or low moisture containing ingredients and low moisture or low
humidity
conditions. Pharmaceutical compositions and dosage forms that comprise lactose
and at least

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one active ingredient that comprises a primary or secondary amine can be
anhydrous if
substantial contact with moisture and/or humidity during manufacturing,
packaging, and/or
storage is expected.
An anhydrous pharmaceutical composition should be prepared and stored such
that its
anhydrous nature is maintained. Accordingly, anhydrous compositions can be
packaged using
materials known to prevent exposure to water such that they can be included in
suitable
formulary kits. Examples of suitable packaging include, but are not limited
to, hermetically
sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
Further provided are pharmaceutical compositions and dosage forms that
comprise one or more
compounds that reduce the rate by which an active ingredient will decompose.
Such
compounds, which are referred to herein as "stabilizers," include, but are not
limited to,
antioxidants such as ascorbic acid, pH buffers, or salt buffers.
The pharmaceutical compositions and single unit dosage forms can take the form
of solutions,
suspensions, emulsion, tablets, pills, capsules, powders, sustained-release
formulations, and the
like. Oral formulation can include standard carriers such as pharmaceutical
grades of mannitol,
lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium
carbonate, etc.
Such compositions and dosage forms will contain a prophylactically or
therapeutically effective
amount of a prophylactic or therapeutic agent, in certain embodiments, in
purified form,
together with a suitable amount of carrier so as to provide the form for
proper administration to
the subject. The formulation should suit the mode of administration. In a
certain embodiment,
the pharmaceutical compositions or single unit dosage forms are sterile and in
suitable form for
administration to a subject, for example, an animal subject, such as a
mammalian subject, for
example, a human subject.
A pharmaceutical composition is formulated to be compatible with its intended
route of
administration. Examples of routes of administration include, but are not
limited to, parenteral,
e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous,
oral, buccal,
sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intra-
tumoral, intra-
synovial, and rectal administration. In a specific embodiment, the composition
is formulated in
accordance with routine procedures as a pharmaceutical composition adapted for
intravenous,
subcutaneous, intramuscular, oral, intranasal, or topical administration to
human beings. In an

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embodiment, a pharmaceutical composition is formulated in accordance with
routine procedures
for subcutaneous administration to human beings. Typically, compositions for
intravenous
administration are solutions in sterile isotonic aqueous buffer.
Where necessary, the
composition may also include a solubilizing agent and a local anesthetic such
as lignocamne to
ease pain at the site of the injection.
Examples of dosage forms include, but are not limited to: tablets; caplets;
capsules, such as soft
elastic gelatin capsules; cachets; troches; lozenges; dispersions;
suppositories; ointments;
cataplasms (poultices); pastes; powders; dressings; creams; plasters;
solutions; patches; aerosols
(e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral
or mucosal
administration to a subject, including suspensions (e.g., aqueous or non
aqueous liquid
suspensions, oil in water emulsions, or a water in oil liquid emulsions),
solutions, and elixirs;
liquid dosage forms suitable for parenteral administration to a subject; and
sterile solids (e.g.,
crystalline or amorphous solids) that can be reconstituted to provide liquid
dosage forms
suitable for parenteral administration to a subject.
The composition, shape, and type of dosage forms provided herein will
typically vary
depending on their use. For example, a dosage form used in the initial
treatment of viral
infection may contain larger amounts of one or more of the active ingredients
it comprises than
a dosage form used in the maintenance treatment of the same infection.
Similarly, a parenteral
dosage form may contain smaller amounts of one or more of the active
ingredients it comprises
than an oral dosage form used to treat the same disease or disorder. These and
other ways in
which specific dosage forms encompassed herein will vary from one another will
be readily
apparent to those skilled in the art. See, e.g., Remington 's Pharmaceutical
Sciences, 20th ed.,
Mack Publishing, Easton PA (2000).
Generally, the ingredients of compositions are supplied either separately or
mixed together in
unit dosage form, for example, as a dry lyophilized powder or water free
concentrate in a
hermetically sealed container such as an ampoule or sachette indicating the
quantity of active
agent. Where the composition is to be administered by infusion, it can be
dispensed with an
infusion bottle containing sterile pharmaceutical grade water or saline. Where
the composition
is administered by injection, an ampoule of sterile water for injection or
saline can be provided
so that the ingredients may be mixed prior to administration.

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Typical dosage forms comprise a compound provided herein, or a
pharmaceutically acceptable
salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to
about 1000 mg per
day, given as a single once-a-day dose in the morning or as divided doses
throughout the day
taken with food. Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4,
0.5, 1.0, 2.0, 2.5, 5.0,
10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500, or 1000 mg of the active
compound.
Oral Dosage Forms
Pharmaceutical compositions that are suitable for oral administration can be
presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g., chewable
tablets), caplets, capsules,
and liquids (e.g., flavored syrups). Such dosage forms contain predetermined
amounts of active
ingredients, and may be prepared by methods of pharmacy well known to those
skilled in the art.
See generally, Remington 's Pharmaceutical Sciences, 20th ed., Mack
Publishing, Easton PA
(2000).
In certain embodiments, the oral dosage forms are solid and prepared under
anhydrous
conditions with anhydrous ingredients, as described in detail in the sections
above. However, the
scope of the compositions provided herein extends beyond anhydrous, solid oral
dosage forms.
As such, further forms are described herein.
Typical oral dosage forms are prepared by combining the active ingredient(s)
in an intimate
admixture with at least one excipient according to conventional pharmaceutical
compounding
techniques. Excipients can take a wide variety of forms depending on the form
of preparation
desired for administration. For example, excipients suitable for use in oral
liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils, alcohols,
flavoring agents,
preservatives, and coloring agents. Examples of excipients suitable for use in
solid oral dosage
forms (e.g., powders, tablets, capsules, and caplets) include, but are not
limited to, starches,
sugars, micro crystalline cellulose, diluents, granulating agents, lubricants,
binders, and
disintegrating agents.
Because of their ease of administration, tablets and capsules represent the
most advantageous
oral dosage unit forms, in which case solid excipients are employed. If
desired, tablets can be
coated by standard aqueous or nonaqueous techniques. Such dosage forms can be
prepared by
any of the methods of pharmacy. In general, pharmaceutical compositions and
dosage forms are
prepared by uniformly and intimately admixing the active ingredients with
liquid carriers, finely

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divided solid carriers, or both, and then shaping the product into the desired
presentation if
necessary.
For example, a tablet can be prepared by compression or molding. Compressed
tablets can be
prepared by compressing in a suitable machine the active ingredients in a free
flowing form such
as powder or granules, optionally mixed with an excipient. Molded tablets can
be made by
molding in a suitable machine a mixture of the powdered compound moistened
with an inert
liquid diluent.
Examples of excipients that can be used in oral dosage forms include, but are
not limited to,
binders, fillers, disintegrants, and lubricants. Binders suitable for use in
pharmaceutical
compositions and dosage forms include, but are not limited to, corn starch,
potato starch, or other
starches, gelatin, natural and synthetic gums such as acacia, sodium alginate,
alginic acid, other
alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g.,
ethyl cellulose,
cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl
cellulose), polyvinyl
pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl
cellulose, (e.g., Nos.
2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof
Examples of fillers suitable for use in the pharmaceutical compositions and
dosage forms
disclosed herein include, but are not limited to, talc, calcium carbonate
(e.g., granules or
powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid,
sorbitol, starch, pre gelatinized starch, and mixtures thereof
The binder or filler in
pharmaceutical compositions is typically present in from about 50 to about 99
weight percent of
the pharmaceutical composition or dosage form.
Suitable forms of microcrystalline cellulose include, but are not limited to,
the materials sold as
AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and
mixtures
thereof A specific binder is a mixture of microcrystalline cellulose and
sodium carboxymethyl
cellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture excipients
or additives
include AVICEL PH 103Tm and Starch 1500 LM.
Disintegrants are used in the compositions to provide tablets that
disintegrate when exposed to an
aqueous environment. Tablets that contain too much disintegrant may
disintegrate in storage,
while those that contain too little may not disintegrate at a desired rate or
under the desired

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conditions. Thus, a sufficient amount of disintegrant that is neither too much
nor too little to
detrimentally alter the release of the active ingredients should be used to
form solid oral dosage
forms. The amount of disintegrant used varies based upon the type of
formulation, and is readily
discernible to those of ordinary skill in the art. Typical pharmaceutical
compositions comprise
from about 0.5 to about 15 weight percent of disintegrant, specifically from
about 1 to about 5
weight percent of disintegrant.
Disintegrants that can be used in pharmaceutical compositions and dosage forms
include, but are
not limited to, agar agar, alginic acid, calcium carbonate, microcrystalline
cellulose,
croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch
glycolate, potato or
tapioca starch, pre gelatinized starch, other starches, clays, other algins,
other celluloses, gums,
and mixtures thereof.
Lubricants that can be used in pharmaceutical compositions and dosage forms
include, but are
not limited to, calcium stearate, magnesium stearate, mineral oil, light
mineral oil, glycerin,
sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium
lauryl sulfate, talc,
hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil,
corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar,
and mixtures thereof
Additional lubricants include, for example, a syloid silica gel (AEROSIL 200,
manufactured by
W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica
(marketed by
Degussa Co. of Plano, TX), CAB 0 SIL (a pyrogenic silicon dioxide product sold
by Cabot Co.
of Boston, MA), and mixtures thereof If used at all, lubricants are typically
used in an amount
of less than about 1 weight percent of the pharmaceutical compositions or
dosage forms into
which they are incorporated.
Delayed Release Dosage Forms
Active ingredients such as the compounds provided herein can be administered
by controlled
release means or by delivery devices that are well known to those of ordinary
skill in the art.
Examples include, but are not limited to, those described in U.S. Patent Nos.:
3,845,770;
3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;
5,120,548;
5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;
5,922,356;
5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350;
6,248,363;
6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and
6,699,500; each of which

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is incorporated herein by reference in its entirety. Such dosage forms can be
used to provide
slow or controlled release of one or more active ingredients using, for
example,
hydropropylmethyl cellulose, other polymer matrices, gels, permeable
membranes, osmotic
systems, multilayer coatings, microparticles, liposomes, microspheres, or a
combination thereof
to provide the desired release profile in varying proportions. Suitable
controlled release
formulations known to those of ordinary skill in the art, including those
described herein, can be
readily selected for use with the active ingredients provided herein. Thus
encompasseed herein
are single unit dosage forms suitable for oral administration such as, but not
limited to, tablets,
capsules, gelcaps, and caplets that are adapted for controlled release.
All controlled release pharmaceutical products have a common goal of improving
drug therapy
over that achieved by their non controlled counterparts. Ideally, the use of
an optimally designed
controlled release preparation in medical treatment is characterized by a
minimum of drug
substance being employed to cure or control the condition in a minimum amount
of time.
Advantages of controlled release formulations include extended activity of the
drug, reduced
dosage frequency, and increased subject compliance. In addition, controlled
release formulations
can be used to affect the time of onset of action or other characteristics,
such as blood levels of
the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
Most controlled release formulations are designed to initially release an
amount of drug (active
ingredient) that promptly produces the desired therapeutic effect, and
gradually and continually
release of other amounts of drug to maintain this level of therapeutic or
prophylactic effect over
an extended period of time. In order to maintain this constant level of drug
in the body, the drug
must be released from the dosage form at a rate that will replace the amount
of drug being
metabolized and excreted from the body. Controlled release of an active
ingredient can be
stimulated by various conditions including, but not limited to, pH,
temperature, enzymes, water,
or other physiological conditions or compounds.
In certain embodiments, the drug may be administered using intravenous
infusion, an
implantable osmotic pump, a transdermal patch, liposomes, or other modes of
administration. In
one embodiment, a pump may be used (see, Sefton, CRC CriL Ref Blamed. Eng.
/4:201 (1987);
Buchwald et aL, Surgery 88:507 (1980); Saudek et aL, N. Engl. J. Med. 32/:574
(1989)). In
another embodiment, polymeric materials can be used. In yet another
embodiment, a controlled

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release system can be placed in a subject at an appropriate site determined by
a practitioner of
skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g.,
Goodson, Medical
Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other
controlled release
systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).
The active
ingredient can be dispersed in a solid inner matrix, e.g.,
polymethylmethacrylate,
polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,
plasticized nylon,
plasticized polyethyleneterephthalate, natural rubber, polyisoprene,
polyisobutylene,
polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone
rubbers,
polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers
such as hydrogels
of esters of acrylic and methacrylic acid, collagen, cross-linked
polyvinylalcohol and cross-
linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer
polymeric
membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers,
ethylene/ethyl
acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers,
polydimethyl siloxanes,
neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride
copolymers with
vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer
polyethylene terephthalate,
butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,
ethylene/vinyl
acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that
is insoluble in
body fluids. The active ingredient then diffuses through the outer polymeric
membrane in a
release rate controlling step. The percentage of active ingredient in such
parenteral compositions
is highly dependent on the specific nature thereof, as well as the needs of
the subject.
Parenteral Dosage Forms
In one embodiment, provided are parenteral dosage forms. Parenteral dosage
forms can be
administered to subjects by various routes including, but not limited to,
subcutaneous,
intravenous (including bolus injection), intramuscular, and intraarterial.
Because their
administration typically bypasses subjects' natural defenses against
contaminants, parenteral
dosage forms are typically sterile or capable of being sterilized prior to
administration to a
subject. Examples of parenteral dosage forms include, but are not limited to,
solutions ready for
injection, dry products ready to be dissolved or suspended in a
pharmaceutically acceptable
vehicle for injection, suspensions ready for injection, and emulsions.

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Suitable vehicles that can be used to provide parenteral dosage forms are well
known to those
skilled in the art. In certain embodiments, examples of a suitable vehicle
include, but are not
limited to: Water for Injection USP; aqueous vehicles such as, but not limited
to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride
Injection, and Lactated Ringer's Injection; water miscible vehicles such as,
but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non aqueous
vehicles such as,
but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl
oleate, isopropyl
myristate, and benzyl benzoate.
Compounds that increase the solubility of one or more of the active
ingredients disclosed herein
can also be incorporated into the parenteral dosage forms.
Transdermal, Topical & Mucosal Dosage Forms
Also provided are transdermal, topical, and mucosal dosage forms. Transdermal,
topical, and
mucosal dosage forms include, but are not limited to, ophthalmic solutions,
sprays, aerosols,
creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other
forms known to one
of skill in the art. See, e.g., Remington 's Pharmaceutical Sciences, 16th,
18th and 20th eds.,
Mack Publishing, Easton PA (1980, 1990 & 2000); and Introduction to
Pharmaceutical Dosage
Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for
treating mucosal
tissues within the oral cavity can be formulated as mouthwashes or as oral
gels. Further,
transdermal dosage forms include "reservoir type" or "matrix type" patches,
which can be
applied to the skin and worn for a specific period of time to permit the
penetration of a desired
amount of active ingredients.
Suitable excipients (e.g., carriers and diluents) and other materials that can
be used to provide
transdermal, topical, and mucosal dosage forms encompassed herein are well
known to those
skilled in the pharmaceutical arts, and depend on the particular tissue to
which a given
pharmaceutical composition or dosage form will be applied. With that fact in
mind, typical
excipients include, but are not limited to, water, acetone, ethanol, ethylene
glycol, propylene
glycol, butane -1,3- diol, isopropyl myristate, isopropyl palmitate, mineral
oil, and mixtures
thereof to form lotions, tinctures, creams, emulsions, gels or ointments,
which are non toxic and
pharmaceutically acceptable. Moisturizers or humectants can also be added to
pharmaceutical
compositions and dosage forms if desired. Examples of such additional
ingredients are well

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known in the art. See, e.g., Remington 's Pharmaceutical Sciences, 16th, 18th
and 20th eds., Mack
Publishing, Easton PA (1980, 1990 & 2000).
Depending on the specific tissue to be treated, additional components may be
used prior to, in
conjunction with, or subsequent to treatment with active ingredients provided.
For example,
penetration enhancers can be used to assist in delivering the active
ingredients to the tissue.
Suitable penetration enhancers include, but are not limited to: acetone;
various alcohols such as
ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl
sulfoxide; dimethyl
acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as
polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various water soluble or
insoluble sugar
esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
The pH of a pharmaceutical composition or dosage form, or of the tissue to
which the
pharmaceutical composition or dosage form is applied, may also be adjusted to
improve delivery
of one or more active ingredients. Similarly, the polarity of a solvent
carrier, its ionic strength,
or tonicity can be adjusted to improve delivery. Compounds such as stearates
can also be added
to pharmaceutical compositions or dosage forms to advantageously alter the
hydrophilicity or
lipophilicity of one or more active ingredients so as to improve delivery. In
this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying agent or
surfactant, and as a
delivery enhancing or penetration enhancing agent. Different salts, hydrates
or solvates of the
active ingredients can be used to further adjust the properties of the
resulting composition.
Method of Use
In one embodiment, provided herein is a method for treating a proliferative
disease in a subject,
which comprises administering to the subject a therapeutically effective
amount of a compound
provided herein, e.g., a compound of Formulas I, Ha, IIb, or IIc, including an
enantiomer, a
mixture of enantiomers, a diastereomer, a mixture of two or more
diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof; or a
pharmaceutically
acceptable salt, solvate, or a hydrate thereof.
In certain embodiments, the therapeutically effective amount is ranging from
about 0.1 to about
100 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about
40 mg/kg/day,
from about 0.1 to about 30 mg/kg/day, from about 0.1 to about 25 mg/kg/day,
from about 0.1 to
about 20 mg/kg/day, from about 0.1 to about 15 mg/kg/day, from about 0.1 to
about 10

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mg/kg/day, or from about 0.1 to about 5 mg/kg/day. In one embodiment, the
therapeutically
effective amount is ranging from about 0.1 to about 100 mg/kg/day. In another
embodiment, the
therapeutically effective amount is ranging from about 0.1 to about 50
mg/kg/day. In yet another
embodiment, the therapeutically effective amount is ranging from about 0.1 to
about 40
mg/kg/day. In yet another embodiment, the therapeutically effective amount is
ranging from
about 0.1 to about 30 mg/kg/day. In yet another embodiment, the
therapeutically effective
amount is ranging from about 0.1 to about 25 mg/kg/day. In yet another
embodiment, the
therapeutically effective amount is ranging from about 0.1 to about 20
mg/kg/day. In yet another
embodiment, the therapeutically effective amount is ranging from about 0.1 to
about 15
mg/kg/day. In yet another embodiment, the therapeutically effective amount is
ranging from
about 0.1 to about 10 mg/kg/day. In still another embodiment, the
therapeutically effective
amount is ranging from about 0.1 to about 5 mg/kg/day.
It is understood that the administered dose can also be expressed in units
other than mg/kg/day.
For example, doses for parenteral administration can be expressed as
mg/m2/day. One of
ordinary skill in the art would readily know how to convert doses from
mg/kg/day to mg/m2/day
to given either the height or weight of a subject or both (see,
www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1 mg/m2/day
for a 65 kg
human is approximately equal to 38 mg/kg/day.
In certain embodiments, the subject is a mammal. In certain embodiments, the
subject is a
human.
In one embodiment is a compound or a pharmaceutically acceptable salt, or
solvate thereof, or
stereoisomeric, tautomeric, or polymorphic form thereof for use in therapy.
In certain embodiments, the proliferative disease is a carcinoma, including,
but not limited to,
Kit-mediated carcinomas, adenocarcinoma, squamous cell carcinoma,
adenosquamous
carcinoma, teratocarcinoma, head and neck cancer, brain cancer, intracranial
carcinoma,
glioblastoma (including PDGFR-mediated glioblastoma), glioblastoma multiforme
(including
PDGFR-mediated glioblastoma multiforme), neuroblastoma, cancer of the larynx,
multiple
endocrine neoplasias 2A and 2B (MENS 2A and MENS 2B) (including RET-mediated
MENS),
thyroid cancer (including sporadic and familial medullary thyroid carcinoma),
papillary thyroid
carcinoma, parathyroid carcinoma (including any RET-mediated thyroid
carcinoma), follicular

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thyroid cancer, anaplastic thyroid cancer, bronchial carcinoid, oat cell
carcinoma, lung cancer,
small-cell lung cancer (including FLT3 and/or Kit-mediated small cell lung
cancer), non-small-
cell lung cancer, stomach/gastric cancer, gastrointestinal cancer,
gastrointestinal stromal tumors
(GIST) (including Kit-mediated GIST and PDGFR a¨mediated GIST), colon cancer,
colorectal
cancer, pancreatic cancer, islet cell carcinoma, hepatic/liver cancer,
metastases to the liver,
bladder cancer, renal cell cancer (including PDGFR-mediated renal cell
cancer), cancers of the
genitourinary tract, ovarian cancer (including Kit-mediated and/or PDGFR-
mediated ovarian
cancer), endometrial cancer (including CSF-1R-mediated endometrial cancer),
cervical cancer,
breast cancer (including FLT3-mediated and/or PDGFR-mediated breast cancer),
prostate cancer
(including Kit-mediated prostate cancer), germ cell tumors (including Kit-
mediated germ cell
tumors), seminomas (including Kit-mediated seminomas), dysgerminomas
(including Kit-
mediated dysgerminomas), melanoma (including PDGFR-mediated melanoma),
metastases to
the bone (including CSF-1R-mediated bone metastases), metastatic tumors
(including VEGFR-
mediated tumors), stromal tumors, neuroendocrine tumors, tumor angiogenesis
(including
VEGFR-mediated tumor angiogenesis), and mixed mesodermal tumors.
In certain embodiments, the proliferative disease is sarcomas, including, but
not limited to,
PDGFR-mediated sarcomas, osteosarcoma, osteogenic sarcoma, bone cancer, glioma
(including
PDGFR-mediated and/or CSF-1R-mediated glioma), astrocytoma, vascular tumors
(including
VEGFR-mediated vascular tumors), Kaposi's sarcoma, carcinosarcoma,
hemangiosarcomas
(including VEGFR3-mediated hemangiosarcomas), and lymphangiosarcoma (including
VEGFR3-mediated lymphangiosarcoma).
In certain embodiments, the proliferative disease is a hematologic malignancy.
In certain
embodiments, the proliferative disease is a relapsed hematologic malignancy.
In certain
embodiments, the proliferative disease is a refractory hematologic malignancy.
In certain
embodiments, the proliferative disease is a drug-resistant hematologic
malignancy. In certain
embodiments, the proliferative disease is a multidrug-resistant hematologic
malignancy. In
certain embodiments, the proliferative disease is a Bcr-Abl kinase inhibitor-
resistant hematologic
malignancy. In certain embodiments, the proliferative disease is an
imatinib-resistant
hematologic malignancy. In certain embodiments, the proliferative disease is a
dasatinib-
resistant hematologic malignancy. In certain embodiments, the proliferative
disease is a
nilatinib-resistant hematologic malignancy. In certain embodiments, the
proliferative disease is a

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bosutinib-resistant hematologic malignancy. In certain embodiments, the
proliferative disease is
a cytarabine-resistant hematologic malignancy.
In certain embodiments, the hematologic malignancy is myeloma, leukemia,
myeloproliferative
diseases, acute myeloid leukemia (AML) (including FLT3 mediated and/or KIT-
mediated and/or
CSF1R-mediated acute myeloid leukemia), chronic myeloid leukemias (CIVIL)
(including FLT3-
mediated and/or PDGFR-mediated chronic myeloid leukemia), myelodysplastic
leukemias
(including FLT3-mediated myelodysplastic leukemia), myelodysplastic syndrome
(including
FLT3 mediated and/or Kit-mediated myelodysplastic syndrome), idiopathic
hypereosinophilic
syndrome (I-IES) (including PDGFR-mediated HES), chronic eosinophilic leukemia
(CEL)
(including PDGFR-mediated CEL), chronic myelomonocytic leukemia (CM_ML), mast
cell
leukemia (including Kit-mediated mast cell leukemia), or systemic mastocytosis
(including Kit-
mediated systemic mastocytosis).
In certain embodiments, the hematologic malignancy is lymphoma,
lymphoproliferative diseases,
acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemias, T-
cell acute
lymphoblastic leukemias, chronic lymphocytic leukemia (CLL), natural killer
(NK) cell
leukemia, B-cell lymphoma, T-cell lymphoma, or natural killer (NK) cell
lymphoma.
In an embodiment, the hematologic malignancy is myelodysplastic syndrome
(MDS).
In certain embodiments, the hematologic malignancy is Langerhans cell
histiocytosis (including
CSF-1R-mediated and/or FLT3-mediated Langerhans cell histiocytosis), mast cell
tumors, or
mastocytosis.
In certain embodiments, the hematologic malignancy is leukemia. In certain
embodiments, the
hematologic malignancy is relapsed leukemia. In certain embodiments, the
hematologic
malignancy is refractory leukemia. In certain embodiments, the hematologic
malignancy is
drug-resistant leukemia. In certain embodiments, the hematologic malignancy is
multidrug-
resistant leukemia. In certain embodiments, the hematologic malignancy is a
Bcr-Abl kinase
inhibitor-resistant leukemia. In certain embodiments, the hematologic
malignancy is imatinib-
resistant leukemia. In certain embodiments, the hematologic malignancy is
dasatinib-resistant
leukemia. In certain embodiments, the hematologic malignancy is nilatinib-
resistant leukemia.
In certain embodiments, the hematologic malignancy is bosutinib-resistant
leukemia. In certain
embodiments, the hematologic malignancy is cytarabine-resistant leukemia.

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In certain embodiments, the leukemia is acute leukemia. In certain
embodiments, the leukemia
is relapsed acute leukemia. In certain embodiments, the leukemia is refractory
acute leukemia.
In certain embodiments, the leukemia is drug-resistant acute leukemia. In
certain embodiments,
the leukemia is multidrug-resistant acute leukemia. In certain embodiments,
the leukemia is a
Bcr-Abl kinase inhibitor-resistant acute leukemia. In certain embodiments, the
leukemia is
imatinib-resistant acute leukemia. In certain embodiments, the leukemia is
dasatinib-resistant
acute leukemia. In certain embodiments, the leukemia is nilatinib-resistant
acute leukemia. In
certain embodiments, the leukemia is bosutinib-resistant acute leukemia.
In certain
embodiments, the leukemia is cytarabine-resistant acute leukemia. In certain
embodiments, the
leukemia is a hereditary leukemia. In certain embodiments, the hereditary
leukemia is severe
congenital neutropenia (SCN). In certain embodiments, the hereditary leukemia
is familial
platelet disorder with acute myelogenous leukemia (FDP/AML). In certain
embodiments, the
leukemia is caused by LEF1. In certain embodiments, the leukemia is mediated
by LEF1. In
certain embodiments, the leukemia is caused by GSK3.
In certain embodiments, the leukemia is ALL. In certain embodiments, the
leukemia is relapsed
ALL. In certain embodiments, the leukemia is refractory ALL. In certain
embodiments, the
leukemia is drug-resistant ALL. In certain embodiments, the leukemia is
multidrug-resistant
ALL. In certain embodiments, the leukemia is a Bcr-Abl kinase inhibitor-
resistant ALL. In
certain embodiments, the leukemia is imatinib-resistant ALL. In certain
embodiments, the
leukemia is dasatinib-resistant ALL. In certain embodiments, the leukemia is
nilatinib-resistant
ALL. In certain embodiments, the leukemia is bosutinib-resistant ALL. In
certain embodiments,
the leukemia is cytarabine-resistant ALL.
In one embodiment, ALL is leukemia that originates in the blast cells of the
bone marrow (B-
cells), thymus (T-cells), or lymph nodes. ALL is categorized according to the
French-American-
British (FAB) Morphological Classification Scheme as Li - mature-appearing
lymphoblasts (T-
cells or pre-B-cells), L2 - immature and pleomorphic (variously shaped)
lymphoblasts (T-cells or
pre-B-cells), and L3 - lymphoblasts (B-cells; Burkitt's cells). In another
embodiment, ALL
originates in the blast cells of the bone marrow (B-cells). In yet another
embodiment, ALL
originates in the thymus (T-cells). In yet another embodiment, ALL originates
in the lymph
nodes. In yet another embodiment, ALL is Li type characterized by mature-
appearing
lymphoblasts (T-cells or pre-B-cells). In yet another embodiment, ALL is L2
type characterized

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by immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-
cells). In still
another embodiment, ALL is L3 type characterized by lymphoblasts (B-cells;
Burkitt's cells).
In certain embodiments, the leukemia is AML. In certain embodiments, the
leukemia is relapsed
AML. In certain embodiments, the leukemia is refractory AML. In certain
embodiments, the
leukemia is drug-resistant AML. In certain embodiments, the leukemia is
multidrug-resistant
AML. In certain embodiments, the leukemia is a Bcr-Abl kinase inhibitor-
resistant AML. In
certain embodiments, the leukemia is imatinib-resistant AML. In certain
embodiments, the
leukemia is dasatinib-resistant AML. In certain embodiments, the leukemia is
nilatinib-resistant
AML. In certain embodiments, the leukemia is bosutinib-resistant AML. In
certain
embodiments, the leukemia is cytarabine-resistant AML. In certain embodiments,
AML has a
RAS mutation. In certain embodiments, the RAS mutation is NRAS, KRAS, or BRAS.
In
certain embodiments, the RAS mutation is NRAS. In certain embodiments, the RAS
mutation is
KRAS. In certain embodiments, the RAS mutation is BRAS.
In certain embodiments, AML is undifferentiated AML (MO), myeloblastic
leukemia (M1),
myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]),
myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic
leukemia
(M5), erythroleukemia (M6), or megakaryoblastic leukemia (M7). In one
embodiment, AML is
undifferentiated AML (MO). In another embodiment, AML is myeloblastic leukemia
(M1). In
yet another embodiment, AML is myeloblastic leukemia (M2). In yet another
embodiment,
AML is promyelocytic leukemia (M3 or M3 variant [M3V]). In yet another
embodiment, AML
is myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]). In yet
another
embodiment, AML is monocytic leukemia (M5). In yet another embodiment, AML is
erythroleukemia (M6). In still another embodiment, AML is megakaryoblastic
leukemia (M7).
In certain embodiments, the leukemia is chronic leukemia. In certain
embodiments, the leukemia
is relapsed chronic leukemia. In certain embodiments, the leukemia is
refractory chronic
leukemia. In certain embodiments, the leukemia is drug-resistant chronic
leukemia. In certain
embodiments, the leukemia is multidrug-resistant chronic leukemia. In certain
embodiments, the
leukemia is a Bcr-Abl kinase inhibitor-resistant chronic leukemia. In certain
embodiments, the
leukemia is imatinib-resistant chronic leukemia. In certain embodiments, the
leukemia is
dasatinib-resistant chronic leukemia. In certain embodiments, the leukemia is
nilatinib-resistant

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chronic leukemia. In certain embodiments, the leukemia is bosutinib-resistant
chronic leukemia.
In certain embodiments, the leukemia is cytarabine-resistant chronic leukemia.
In certain embodiments, the leukemia is CLL. In certain embodiments, the
leukemia is relapsed
CLL. In certain embodiments, the leukemia is refractory CLL. In certain
embodiments, the
leukemia is drug-resistant CLL. In certain embodiments, the leukemia is
multidrug-resistant
CLL. In certain embodiments, the leukemia is a Bcr-Abl kinase inhibitor-
resistant CLL. In
certain embodiments, the leukemia is imatinib-resistant CLL. In certain
embodiments, the
leukemia is dasatinib-resistant CLL. In certain embodiments, the leukemia is
nilatinib-resistant
CLL. In certain embodiments, the leukemia is bosutinib-resistant CLL. In
certain embodiments,
the leukemia is cytarabine-resistant CLL.
In certain embodiments, the leukemia is CIVIL. In certain embodiments, the
leukemia is relapsed
CIVIL. In certain embodiments, the leukemia is refractory CIVIL. In certain
embodiments, the
leukemia is drug-resistant CIVIL. In certain embodiments, the leukemia is
multidrug-resistant
CIVIL. In certain embodiments, the leukemia is a Bcr-Abl kinase inhibitor-
resistant CIVIL. In
certain embodiments, the leukemia is imatinib-resistant CIVIL. In certain
embodiments, the
leukemia is dasatinib-resistant CIVIL. In certain embodiments, the leukemia is
nilatinib-resistant
CIVIL. In certain embodiments, the leukemia is bosutinib-resistant CIVIL.
In certain
embodiments, the leukemia is cytarabine-resistant CIVIL. In certain
embodiments, the leukemia
is juvenile CIVIL. In certain embodiments, the leukemia is juvenile CIVIL with
one or more NF-1
mutations.
In certain embodiments, the leukemia is T-cell leukemia. In one embodiment,
the T-cell
leukemia is peripheral T-cell leukemia, T-cell lymphoblastic leukemia,
cutaneous T-cell
leukemia, and adult T-cell leukemia. In another embodiment, the T-cell
leukemia is peripheral
T-cell leukemia. In yet another embodiment, the T-cell leukemia is T-cell
lymphoblastic
leukemia. In yet another embodiment, the T-cell leukemia is cutaneous T-cell
leukemia. In still
another embodiment, the T-cell leukemia is adult T-cell leukemia.
In certain embodiments, the leukemia is Philadelphia positive. In one
embodiment, the
Philadelphia positive leukemia is Philadelphia positive AML, including, but
not limited to,
undifferentiated AML (MO), myeloblastic leukemia (M1), myeloblastic leukemia
(IV12),
promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4
or M4

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variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia
(M6), or
megakaryoblastic leukemia (M7). In another embodiment, the Philadelphia
positive leukemia is
Philadelphia positive ALL.
In certain embodiments, the proliferative disease is cancer, including, but
not limited to, head
and neck cancer (originating lip, oral cavity, oropharynx, hypopharynx,
larynx, nasopharynx,
nasal cavity, paranasal sinuses, or salivary glands), lung cancer (including
small cell lung cancer
and non-small cell lung cancer), gastrointestinal tract cancers (including
esophageal cancer),
gastric cancer, colorectal cancer, anal cancer, pancreatic cancer, liver
cancer, gallbladder cancer,
extrahepatic bile duct cancer, cancer of the ampulla of vater, breast cancer,
gynecologic cancers
(including cancer of uterine cervix), cancer of the uterine body, vaginal
cancer, vulvar cancer,
ovarian cancer, gestational trophoblastic cancer neoplasia, testicular cancer,
urinary tract cancers
(including renal cancer), urinary blader cancer, prostate cancer, penile
cancer, urethral cancer,
neurologic tumors, endocrine neoplasms (including carcinoid and islet cell
tumors),
pheochromocytoma, adrenal cortical carcinoma, parathyroid carcinoma, and
metastases to
endocrine glands.
Further examples of cancers are basal cell carcinoma, squamous cell carcinoma,
chondrosarcoma
(a cancer arising in cartilage cells), mesenchymal-chondrosarcoma, soft tissue
sarcomas
(including malignant tumors that may arise in any of the mesodermal tissues
(muscles, tendons,
vessels that carry blood or lymph, joints and fat)), soft tissue sarcomas
(include alveolar soft-part
sarcoma), angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant
fibrous
histiocytoma, hemangiopericytoma, mesenchymoma, schwannoma, peripheral
neuroectodermal
tumours, rhabdomyosarcoma, synovial sarcoma, gestational trophoblastic tumor
(malignancy in
which the tissues formed in the uterus following conception become cancerous),
Hodgkin's
lymphoma, and laryngeal cancer.
In certain embodiments, the proliferative disease is a nonmalignant
proliferation disease,
including, but not limited to, atherosclerosis (including PDGFR-mediated
atherosclerosis),
restenosis following vascular angioplasty (including PDGFR-mediated
restenosis), and
fibroproliferative disorders (including obliterative bronchiolitis and
idiopathic myelofibrosis).
In certain embodiments, the proliferative disease is an inflammatory disease
or disorder related
to immune dysfunction, immunodeficiency, or immunomodulation, including, but
not limited to,

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autoimmune diseases, tissue transplant rejection, graft-versus-host disease,
wound healing,
kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis,
allergic rhinitis,
inflammatory bowel diseases (including Crohn's disease and ulcerative colitis
(UC)), systemic
lupus erythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis,
osteoporosis, asthma,
and chronic obstructive pulmonary disease (COPD).
In certain embodiments, the proliferative disease is an infectious disease.
In certain
embodiments, the infectious disease is fungal infection. In certain
embodiments, the infectious
disease is a superficial mycose (e.g., Tinea versicolor). In certain
embodiments, the infectious
disease is a cutaneous mycose (e.g., epidermis). In certain embodiments, the
infectious disease
is a subcutaneous mycose. In certain embodiments, the infectious disease is a
systemic mycose.
In certain embodiments, the proliferative disease is leukemia, adult T-cell
leukemia,
promyelocytic leukemia, pre-B cell leukemia, lymphoma, Mantle cell lymphoma,
breast cancer,
pancreatic cancer, prostate cancer, head and neck cancer, ovarian cancer,
melanoma, giloma,
liver cancer, renal cancer, colorectal cancer, rhabdomyosarcoma, tongue
cancer, stomach cancer,
multiple myeloma, bladder cancer, thyroid cancer, epidermoid carcinoma, lung
cancer, NSC lung
cancer, or large cell lung cancer.
In certain embodiments, the proliferative disease is adult T-cell leukemia,
promyelocytic
leukemia, pre-B cell leukemia, lymphoma, mantle cell lymphoma, pancreatic
cancer, prostate
cancer, head and neck cancer, ovarian cancer, melanoma, giloma, liver cancer,
renal cancer,
colorectal cancer, rhabdomyosarcoma, tongue cancer, stomach cancer, multiple
myeloma,
bladder cancer, thyroid cancer, epidermoid carcinoma, NSC lung cancer, or
large cell lung
cancer.
In certain embodiments, the proliferative disease is leukemia, adult T-cell
leukemia,
promyelocytic leukemia, pre-B cell leukemia, lymphoma, mantle cell lymphoma,
breast cancer,
head and neck cancer, ovarian cancer, colorectal cancer, tongue cancer,
multiple myeloma, or
large cell lung cancer.
In an embodiment, the cancers which can be treated by the compounds described
herein
include, but are not limited to, Acute Lymphoblastic Leukemia; Acute Myeloid
Leukemia;
Adrenocortical Carcinoma; AIDS-Related Lymphoma; AIDS-Related Malignancies;
Anal
Cancer; Astrocytoma; Bile Duct Cancer; Bladder Cancer; Bone Cancer,

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Osteosarcoma/NIalignant Fibrous Histiocytoma; Brain Stem Glioma; Brain Tumor,
Cerebellar
Astrocytoma; Brain Tumor, Cerebral Astrocytoma/NIalignant Glioma; Brain Tumor,
Ependymoma; Brain Tumor, Medulloblastoma; Brain Tumor, Supratentorial
Primitive
Neuroectodermal Tumors; Brain Tumor, Visual Pathway and Hypothalamic Glioma;
Breast
Cancer; Bronchial Adenomas/Carcinoids; Carcinoid Tumor; Carcinoid Tumor,
Gastrointestinal;
Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Central Nervous System
Lymphoma,
Primary; Cerebral Astrocytoma/NIalignant Glioma; Cervical Cancer; Chronic
Lymphocytic
Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders;
Clear Cell
Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer; Cutaneous T-Cell
Lymphoma;
Endometrial Cancer; Ependymoma; Epithelial Cancer, Ovarian; Esophageal Cancer;
Esophageal
Cancer; Ewing's Family of Tumors; Extracranial Germ Cell Tumor; Extrahepatic
Bile Duct
Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma;
Gallbladder Cancer;
Gastric (Stomach) Cancer; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor,
Extracranial,
Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian;
Gestational
Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual
Pathway and
Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular
(Liver) Cancer;
Hodgkin's Lymphoma; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway
Glioma;
Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's
Sarcoma; Kidney
Cancer; Laryngeal Cancer; Leukemia, Acute Lymphoblastic; Leukemia, Acute
Myeloid;
Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy
Cell; Lip
and Oral Cavity Cancer; Liver Cancer; Lung Cancer, Non-Small Cell; Lung
Cancer, Small Cell;
Lymphoblastic Leukemia; Lymphoma, AIDS- Related; Lymphoma, Central Nervous
System
(Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's; Lymphoma,
Hodgkin's
During Pregnancy; Lymphoma, Non-Hodgkin's; Lymphoma, Primary Central Nervous
System;
Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma;
Malignant
Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel
Cell
Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with
Occult Primary;
Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell
Neoplasm;
Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic;
Myeloid
Leukemia; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal
Cavity and
Paranasal Sinus Cancer; Nasopharyngeal Cancer; Neuroblastoma; Non-Hodgkin's
Lymphoma;

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Non-Small Cell Lung Cancer; Oral Cancer; Oral Cavity and Lip Cancer;
Oropharyngeal Cancer;
steosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Epithelial Cancer;
Ovarian Germ
Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer;
Paranasal Sinus and
Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma;
Pineal and
Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Plasma Cell
Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast
Cancer;
Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma;
Primary
Central Nervous System Lymphoma; Primary Liver Cancer; Prostate Cancer; Rectal
Cancer;
Renal Cell (Kidney) Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer;
Retinoblastoma;
Rhabdomyosarcoma; Salivary Gland Cancer; Sarcoma, Ewing's Family of Tumors;
Sarcoma,
Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone;
Sarcoma, Soft
Tissue; Sezary Syndrome; Skin Cancer; Skin Cancer (Melanoma); Skin Carcinoma,
Merkel Cell;
Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; Squamous
Neck Cancer
with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Supratentorial
Primitive
Neuroectodermal Tumors; T- Cell Lymphoma, Cutaneous; Testicular Cancer;
Thymoma,
Malignant; Thyroid Cancer; Transitional Cell Cancer of the Renal Pelvis and
Ureter;
Trophoblastic Tumor, Gestational; Ureter and Renal Pelvis, Transitional Cell
Cancer; Urethral
Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic
Glioma; Vulvar
Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor.
In one embodiment, a cancer potentially associated with mutant IDH enzyme
activity is brain cancer, such as an astrocytic tumor (e.g., pilocytic
astrocytoma, subependymal
giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma,
anaplastic
astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary
glioblastoma,
primary adult glioblastoma, and primary pediatric glioblastoma);
oligodendroglial tumor (e.g.,
oligodendroglioma, and anaplastic oligodendroglioma); oligoastrocytic tumor
(e. g. ,
oligoastrocytoma, and anaplastic oligoastrocytoma); ependymoma (e.g.,
myxopapillary
ependymoma, and anaplastic ependymoma); medulloblastoma; primitive
neuroectodermal
tumor, schwannoma, meningioma, meatypical meningioma, anaplastic meningioma;
and
pituitary adenoma. In another embodiment, the brain cancer is glioma,
glioblastoma multiforme,
paraganglioma, or suprantentorial primordial neuroectodermal tumors (sPNET).

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In another embodiment, a cancer potentially associated with mutant IDH enzyme
activity is leukemia, such as acute myeloid leukemia (AML), myelodysplastic
syndrome (MDS),
chronic myelogenous leukemia (CIVIL), myeloproliferative neoplasm (MPN), post-
MPN AML,
post-MDS AML, del(5q)-associated high risk MDS or AML, blast-phase chronic
myelogenous
leukemia, angioimmunoblastic lymphoma and acute lymphoblastic leukemia.
In one embodiment, a cancer potentially associated with mutant IDH enzyme
activity is skin cancer, including melanoma. In another embodiment, a cancer
potentially
associated with mutant IDH enzyme activity is prostate cancer, breast cancer,
thyroid cancer,
colon cancer, or lung cancer. In another embodiment, a cancer potentially
associated with
mutant IDH enzyme activity is sarcoma, including central chondro sarcoma,
central and
periosteal chondroma, and fibrosarcoma. In another embodiment, a cancer
potentially associated
with mutant IDH enzyme activity is cholangiocarcinoma.
Also provided are compounds described herein for use in the treatments
described herein.
Also provided are uses of compounds described herein for the manufacture of
medicaments for the treatments described herein.
In certain embodiments, the subject to be treated with one of the methods
provided herein has
not been treated with anticancer therapy for the proliferative disease to be
treated prior to the
administration of a compound provided herein, e.g., a compound of Formulas I,
II, or Ha,
including an enantiomer, a mixture of enantiomers, a diastereomer, a mixture
of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or
a pharmaceutically acceptable salt, solvate, or hydrate thereof
In certain embodiments, the subject to be treated with one of the methods
provided herein has
been treated with anticancer therapy for the proliferative disease to be
treated prior to the
administration of a compound provided herein, e.g., a compound of Formulas I,
Ha, Hb, or IIc,
including an enantiomer, a mixture of enantiomers, a diastereomer, a mixture
of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or
a pharmaceutically acceptable salt, solvate, or hydrate thereof
In certain embodiments, the subject to be treated with one of the methods
provided herein has
developed drug resistance to the anticancer therapy.

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The methods provided herein encompass treating a subject regardless of
patient's age, although
some diseases or disorders are more common in certain age groups. Further
provided herein is a
method for treating a subject who has undergone surgery in an attempt to treat
the disease or
condition at issue, as well as the one who have not. Because the subjects with
cancer have
heterogeneous clinical manifestations and varying clinical outcomes, the
treatment given to a
particular subject may vary, depending on his/her prognosis. The skilled
clinician will be able to
readily determine without undue experimentation, specific secondary agents,
types of surgery,
and types of non-drug based standard therapy that can be effectively used to
treat an individual
subject with cancer.
Depending on the disease to be treated and the subject's condition, a compound
provided herein,
e.g., a compound of Formulas I, Ha, IIb, or Hc, including an enantiomer, a
mixture of
enantiomers, a diastereomer, a mixture of two or more diastereomers, a
tautomer, a mixture of
two or more tautomers, or an isotopic variant thereof; or a pharmaceutically
acceptable salt,
solvate, or hydrate thereof, may be administered by oral, parenteral (e.g.,
intramuscular,
intraperitoneal, intravenous, CIV, intracistemal injection or infusion,
subcutaneous injection, or
implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g.,
transdermal or local)
routes of administration. A compound provided herein, e.g., an enantiomer, a
mixture of
enantiomers, a diastereomer, a mixture of two or more diastereomers, a
tautomer, a mixture of
two or more tautomers, or an isotopic variant thereof; or a pharmaceutically
acceptable salt,
solvate, or hydrate thereof, may be formulated, alone or together, in suitable
dosage unit with
pharmaceutically acceptable excipients, carriers, adjuvants and vehicles,
appropriate for each
route of administration.
In one embodiment, a compound provided herein, e.g., a compound of Formulas I,
Ha, IIb, or
Hc, including an enantiomer, a mixture of enantiomers, a diastereomer, a
mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or
a pharmaceutically acceptable salt, solvate, or hydrate thereof, is
administered orally. In another
embodiment, a compound provided herein, e.g., a compound of Formulas I, Ha,
IIb, or IIc,
including an enantiomer, a mixture of enantiomers, a diastereomer, a mixture
of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or
a pharmaceutically acceptable salt, solvate, or hydrate thereof, is
administered parenterally. In
yet another embodiment, a compound provided herein, e.g., a compound of
Formulas I, Ha, IIb,

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or IIc, including an enantiomer, a mixture of enantiomers, a diastereomer, a
mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers, or an
isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
is administered
intravenously. In yet another embodiment, a compound provided herein, e.g., a
compound of a
diastereomer, including an enantiomer, a mixture of enantiomers, a
diastereomer, a mixture of
two or more diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate
thereof, is administered
intramuscularly. In yet another embodiment, a compound provided herein, e.g.,
a compound of
Formulas I, Ha, Hb, or IIc, including an enantiomer, a mixture of enantiomers,
a diastereomer, a
mixture of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an
isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or
hydrate thereof, is
administered subcutaneously. In still another embodiment, a compound provided
herein, e.g., a
compound of Formulas I, Ha, Hb, or Hc, including an enantiomer, a mixture of
enantiomers, a
diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of
two or more
tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, or
hydrate thereof, is administered topically.
A compound provided herein, e.g., a compound of Formulas I, Ha, Hb, or Hc,
including an
enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more
diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or a
pharmaceutically acceptable salt, solvate, or hydrate thereof, can be
delivered as a single dose
such as, e.g., a single bolus injection, or oral tablets or pills; or over
time such as, e.g.,
continuous infusion over time or divided bolus doses over time. The compound
provided herein
can be administered repetitively if necessary, for example, until the patient
experiences stable
disease or regression, or until the patient experiences disease progression or
unacceptable
toxicity. For example, stable disease for solid tumors generally means that
the perpendicular
diameter of measurable lesions has not increased by 25% or more from the last
measurement.
Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of
the National
Cancer Institute 92(3): 205-216 (2000). Stable disease or lack thereof is
determined by methods
known in the art such as evaluation of patient symptoms, physical examination,
visualization of
the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other
commonly
accepted evaluation modalities.

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A compound provided herein, e.g., a compound of Formulas I, Ha, Hb, or Hc,
including an
enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more
diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or a
pharmaceutically acceptable salt, solvate, or hydrate thereof, can be
administered once daily
(QD), or divided into multiple daily doses such as twice daily (BID), and
three times daily (TID).
In addition, the administration can be continuous, i.e., every day, or
intermittently. The term
"intermittent" or "intermittently" as used herein is intended to mean stopping
and starting at
either regular or irregular intervals. For example, intermittent
administration of a compound
provided herein, e.g., a compound of Formulas I, Ha, Hb, or IIc, including an
enantiomer, a
mixture of enantiomers, a diastereomer, a mixture of two or more
diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof; or a
pharmaceutically
acceptable salt, solvate, or hydrate thereof, is administration for one to six
days per week,
administration in cycles (e.g., daily administration for two to eight
consecutive weeks, then a rest
period with no administration for up to one week), or administration on
alternate days.
In certain embodiments, a compound provided herein, e.g., a compound of
Formulas I, Ha, Hb,
or IIc, including an enantiomer, a mixture of enantiomers, a diastereomer, a
mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers, or an
isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
is cyclically
administered to a patient. Cycling therapy involves the administration of an
active agent for a
period of time, followed by a rest for a period of time, and repeating this
sequential
administration. Cycling therapy can reduce the development of resistance to
one or more of the
therapies, avoid or reduce the side effects of one of the therapies, and/or
improves the efficacy of
the treatment.
In one embodiment is a combination comprising an effective amount of a
compound as provided
herein, e.g., a compound of Formulas I, Ha, Hb, or Hc, including an
enantiomer, a mixture of
enantiomers, a diastereomer, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, or solvate thereof, or a tautomeric, or polymorphic form
thereof and one, two,
three or more other therapeutic agents, e.g. anti-cancer agents.
A compound provided herein, e.g., a compound of Formulas I, Ha, Hb, or Hc,
including an
enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more
diastereomers, a

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tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or a
pharmaceutically acceptable salt, solvate, or hydrate thereof, can also be
combined or used in
combination with other therapeutic agents useful in the treatment and/or
prevention of a disease
described herein.
As used herein, the term "in combination" includes the use of more than one
therapy (e.g., one or
more prophylactic and/or therapeutic agents). However, the use of the term "in
combination"
does not restrict the order in which therapies (e.g., prophylactic and/or
therapeutic agents) are
administered to a subject with a disease or disorder. A first therapy (e.g., a
prophylactic or
therapeutic agent such as a compound provided herein) can be administered
prior to (e.g., 5
minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6
hours, 12 hours, 24
hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8
weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5
minutes, 15 minutes,
30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours,
48 hours, 72 hours,
96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12
weeks after) the
administration of a second therapy (e.g., a prophylactic or therapeutic agent)
to the subject.
Triple therapy is also contemplated herein.
The route of administration of a compound provided herein, e.g., a compound of
Formulas I, Ha,
Hb, or Hc, including an enantiomer, a mixture of enantiomers, a diastereomer,
or a mixture of
diastereomers thereof; or a pharmaceutically acceptable salt, or solvate
thereof, is independent of
the route of administration of a second therapy. In one embodiment, a compound
provided
herein, e.g., a compound of Formulas I, Ha, Hb, or Hc, including an
enantiomer, a mixture of
enantiomers, a diastereomer, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, or solvate thereof, is administered orally. In another
embodiment, a compound
provided herein, e.g., a compound of Formulas I, Ha, IIb, or IIc, including an
enantiomer, a
mixture of enantiomers, a diastereomer, or a mixture of diastereomers thereof;
or a
pharmaceutically acceptable salt, or solvate thereof, is administered
intravenously. Thus, in
accordance with these embodiments, a compound provided herein, e.g., a
compound of Formulas
I, Ha, IIb, or IIc, including an enantiomer, a mixture of enantiomers, a
diastereomer, or a mixture
of diastereomers thereof; or a pharmaceutically acceptable salt, or solvate
thereof, is
administered orally or intravenously, and the second therapy can be
administered orally,
parenterally, intraperitoneally, intravenously, intraarterially,
transdermally, sublingually,

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intramuscularly, rectally, transbuccally, intranasally, liposomally, via
inhalation, vaginally,
intraoccularly, via local delivery by catheter or stent, subcutaneously,
intraadiposally,
intraarticularly, intrathecally, or in a slow release dosage form. In one
embodiment, a compound
provided herein, e.g., a compound of Formulas I, Ha, Hb, or IIc, including an
enantiomer, a
mixture of enantiomers, a diastereomer, or a mixture of diastereomers thereof;
or a
pharmaceutically acceptable salt, or solvate thereof, and a second therapy are
administered by
the same mode of administration, orally or by IV. In another embodiment, a
compound provided
herein, e.g., a compound of Formulas I, Ha, Hb, or Hc, including an
enantiomer, a mixture of
enantiomers, a diastereomer, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, or solvate thereof, is administered by one mode of
administration, e.g., by IV,
whereas the second agent (an anticancer agent) is administered by another mode
of
administration, e.g., orally.
In certain embodiments, each method provided herein may independently, further
comprise the
step of administering a second therapeutic agent. In one embodiment, the
second therapeutic
agent is an anticancer agent. In another embodiment, the anticancer agent is
an antimetabolite,
including, but not limited to, 5-fluoro uracil, methotrexate, cytarabine (also
known as cytosine
arabinoside or Ara-C), and EIDAC (high dose cytarabine) and fludarabine. In
yet another
embodiment, the anticancer agent is an antimicrotubule agent, including, but
not limited to, vinca
alkaloids (e.g., vincristine and vinblastine) taxanes (e.g., paclitaxel and
docetaxel), and
epothilones and their derivatives (e.g., ixabepilone). In yet another
embodiment, the anticancer
agent is an alkylating agent, including, but not limited to, cyclophosphamide,
melphalan,
carmustine, and nitrosoureas (e.g., bischloroethylnitrosurea and hydroxyurea).
In yet another
embodiment, the anticancer agent is a platinum agent, including, but not
limited to, cisplatin,
carboplatin, oxaliplatin, satraplatin (JM-216), and CI-973. In yet another
embodiment, the
anticancer agent is an anthracycline, including, but not limited to,
doxrubicin and daunorubicin.
In yet another embodiment, the anticancer agent is an antitumor antibiotic,
including, but not
limited to, mitomycin, idarubicin, adriamycin, and daunomycin (also known as
daunorubicin).
In yet another embodiment, the anticancer agent is a topoisomerase inhibitor,
e.g., etoposide and
camptothecins. In yet another embodiment, the anticancer agent is selected
from the group
consisting of adriamycin, busulfan, cytarabine, cyclophosphamide,
dexamethasone, fludarabine,

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fluorouracil, hydroxyurea, interferons, oblimersen, platinum derivatives,
taxol, topotecan, and
vincristine.
In another embodiment, the anticancer agent is a Bcr-Abl kinase inhibitor. In
one embodiment,
the Bcr-Abl kinase inhibitor is imatinib, BMS354825 (dasatinib), AMN107
(nilotinib),
AP23464, AZD0530, CGP76030, 0N012380, INN-0406 (NS-187), SKI-606 (bosutinib),
VX-
680, or pyrrolo[2,3-d]pyrimidines including PD166326, PD173955 and PD180970.
In another
embodiment, the Bcr-Abl kinase inhibitor is imatinib. In yet another
embodiment, the Bcr-Abl
kinase inhibitor is dasatinib. In yet another embodiment, the Bcr-Abl kinase
inhibitor is
nilotinib. In yet another embodiment, the Bcr-Abl kinase inhibitor is AP23464.
In yet another
embodiment, the Bcr-Abl kinase inhibitor is AZD0530. In yet another
embodiment, the Bcr-Abl
kinase inhibitor is CGP76030. In yet another embodiment, the Bcr-Abl kinase
inhibitor is SKI-
606. In yet another embodiment, the Bcr-Abl kinase inhibitor is 0N012380. In
yet another
embodiment, the Bcr-Abl kinase inhibitor is INN-0406 (NS-187). In yet another
embodiment,
the Bcr-Abl kinase inhibitor is a pyrrolo[2,3-d]pyrimidine. In another
embodiment, the Bcr-Abl
kinase inhibitor is VX-680. In another embodiment, the Bcr-Abl kinase
inhibitor is PD166326.
In yet another embodiment, the Bcr-Abl kinase inhibitor is PD173955. In still
another
embodiment, the Bcr-Abl kinase inhibitor is PD180970.
In still another embodiment, the anticancer agent is a FLT3 kinase inhibitor.
In one embodiment,
the FLT3 kinase inhibitor is PKC 412, MLN 578, CEP-701, CT 53518, CT-53608, CT-
52923,
D-64406, D-65476, AGL-2033, AG1295, AG1296, KN-1022, PKC-412, SU5416, SU5614,
SU11248, L-00021649, or CHIR-258. In another embodiment, the FLT3 kinase
inhibitor is PKC
412. In yet another embodiment, the FLT3 kinase inhibitor is MLN 578. In yet
another
embodiment, the FLT3 kinase inhibitor is CEP-701. In yet another embodiment,
the FLT3
kinase inhibitor is CT 53518. In yet another embodiment, the FLT3 kinase
inhibitor is CT-
53608. In yet another embodiment, the FLT3 kinase inhibitor is CT-52923. In
yet another
embodiment, the FLT3 kinase inhibitor is D-64406. In yet another embodiment,
the FLT3
kinase inhibitor is D-65476. In yet another embodiment, the FLT3 kinase
inhibitor is
AGL-2033. In yet another embodiment, the FLT3 kinase inhibitor is AG1295. In
yet another
embodiment, the FLT3 kinase inhibitor is AG1296. In yet another embodiment,
the FLT3 kinase
inhibitor is KN-1022. In yet another embodiment, the FLT3 kinase inhibitor is
KN-1022. In yet
another embodiment, the FLT3 kinase inhibitor is SU5416. In yet another
embodiment, the

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FLT3 kinase inhibitor is SU5614. In yet another embodiment, the FLT3 kinase
inhibitor is
SU11248. In yet another embodiment, the FLT3 kinase inhibitor is L-00021649.
In still another
embodiment, the FLT3 kinase inhibitor is CHIR-258.
Other therapies or anticancer agents that may be used in combination with a
compound provided
herein, e.g., a compound of Formulas I, Ha, Hb, or Hc, including an
enantiomer, a mixture of
enantiomers, a diastereomer, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, or solvate thereof, include surgery, radiotherapy (e.g.,
gamma-radiation, neutron
beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy,
and systemic
radioactive isotopes), endocrine therapy, biologic response modifiers (e.g.,
interferons,
interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy,
agents to
attenuate any adverse effects (e.g., antiemetics), and other approved
chemotherapeutic drugs,
including, but not limited to, alkylating drugs (mechlorethamine,
chlorambucil,
cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine
(also known as
cytosine arabinoside or Ara-C), HDAC (high dose cytarabine), and
methotrexate), purine
antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil,
cytarbine, and
gemcitabine), spindle poisons (vinblastine, vincristine, vinorelbine, and
paclitaxel),
podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics
(daunorubicin, doxorubicin,
bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), inorganic
ions (cisplatin
and carboplatin), enzymes (asparaginase), and hormones (tamoxifen, leuprolide,
flutamide, and
megestrol), imatinib, adriamycin, dexamethasone, and cyclophosphamide. For a
more
comprehensive discussion of updated cancer therapies see,
http://www.nci.nih.gov/, a list of the
FDA approved oncology drugs at http://www.fda.gov, and The Merck Manual,
Seventeenth Ed.
1999, the entire contents of which are hereby incorporated by reference.
In one embodiment, the other anticancer agent is selected from the group
consisting of
vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase
II inhibitors,
smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-
metabolites, retinoids,
immunomodulatory agents including but not limited to anti-cancer vaccines,
CTLA-4, LAG-3,
PD-1 antagonists and BET bromodomain inhibitors.
Examples of vascular endothelial growth factor (VEGF) receptor inhibitors
include, but are not limited to, bevacizumab (sold under the trademark AVASTIN
by
Genentech/Roche), axitinib, (N-methyl-2-[[3-R[pound])-2-pyridin-2-yletheny1]-1
H-indazol-6-

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yl]sulfanyl]benzamide, also known as AG013736, and described in PCT
Publication No. WO 01
/002369), Brivanib Alaninate
((S)-((R)-1 -(4 -(4-F luoro-2-methy1-1H-indo1-5 -yl oxy)-5 -
methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-y1)2-aminopropanoate, also
known as BMS-
582664), motesanib (N-(2,3 -dihydro-3 ,3 -dimethyl-1
H-indoi-6-y!)-2-[(4-
pyridinyimethyDamino]-3-pyfidinecarboxamide. and described in PCT Publication
No. WO
02/068470), pasireotide (also known as SO 230, and described in PCT
Publication No. WO
02/010192), and sorafenib (sold under the tradename NEXAVAR).
Examples of topoisomerase II inhibitors, include but are not limited to,
etoposide
(also known as VP-16 and Etoposide phosphate, sold under the tradenames
TOPOSAR,
VEPESID and ETOPOPHOS), and teniposide (also known as VM-26, sold under the
tradename
VUMON).
Examples of alkylating agents, include but are not limited to, 5-azacytidine
(sold
under the trade name VIDAZA), decitabine (sold under the trade name of
DECOGEN),
temozolomide (sold under the trade names TEMODAR and TEMODAL by Schering-
Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the
tradename
COSMEGEN), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine
mustard,
sold under the tradename ALKERAN), altretamine (also known as
hexamethylmelamine
(EIMM), sold under the tradename HEXALEN), carmustine (sold under the
tradename BCNU),
bendamustine (sold under the tradename TREANDA), busulfan (sold under the
tradenames
Busulfex(R) and Myleran(R)), carboplatin (sold under the tradename
Paraplatin(R)), lomustine
(also known as CCNU, sold under the tradename CeeNU(R)), cisplatin (also known
as CDDP,
sold under the tradenames Platinol(R) and Platinol(R)-AQ), chlorambucil (sold
under the
tradename Leukeran(R)), cyclophosphamide (sold under the tradenames Cytoxan(R)
and
Neosar(R)), dacarbazine (also known as DTIC, DIC and imidazole carboxamide,
sold under the
tradename DTIC-Dome(R)), altretamine (also known as hexamethylmelamine (EIMM)
sold
under the tradename Hexalen(R)), ifosfamide (sold under the tradename
Ifex(R)), procarbazine
(sold under the tradename Matulane(R)), mechlorethamine (also known as
nitrogen mustard,
mustine and mechloroethamine hydrochloride, sold under the tradename
Mustargen(R)),
streptozocin (sold under the tradename Zanosar(R)), thiotepa (also known as
thiophosphoamide,
TESPA and TSPA, and sold under the tradename Thioplex(R).

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Examples of anti-tumor antibiotics include, but are not limited to,
doxorubicin
(sold under the tradenames Adriamycin(R) and Rubex(R)), bleomycin (sold under
the tradename
lenoxane(R)), daunorubicin (also known as dauorubicin hydrochloride,
daunomycin, and
rubidomycin hydrochloride, sold under the tradename Cerubidine(R)),
daunorubicin liposomal
(daunorubicin citrate liposome, sold under the tradename DaunoXome(R)),
mitoxantrone (also
known as DHAD, sold under the tradename Novantrone(R)), epirubicin (sold under
the
tradename Ellence(TM)), idarubicin (sold under the tradenames Idamycin(R),
Idamycin PFS(R)),
and mitomycin C (sold under the tradename Mutamycin(R)).
Examples of anti-metabolites include, but are not limited to, claribine (2-
chlorodeoxyadenosine, sold under the tradename leustatin(R)), 5-fluorouracil
(sold under the
tradename Adrucil(R)), 6-thioguanine (sold under the tradename Purinethol(R)),
pemetrexed
(sold under the tradename Alimta(R)), cytarabine (also known as
arabinosylcytosine (Ara-C),
sold under the tradename Cytosar-U(R)), cytarabine liposomal (also known as
Liposomal Ara-C,
sold under the tradename DepoCyt(TM)), decitabine (sold under the tradename
Dacogen(R)),
hydroxyurea (sold under the tradenames Hydrea(R), Droxia(TM) and Mylocel(TM)),
fludarabine
(sold under the tradename Fludara(R)), floxuridine (sold under the tradename
FUDR(R)),
cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the
tradename
Leustatin(TM)), methotrexate (also known as amethopterin, methotrexate sodium
(MTX), sold
under the tradenames Rheumatrex(R) and Trexall(TM)), and pentostatin (sold
under the
tradename Nipent(R)).
Examples of retinoids include, but are not limited to, alitretinoin (sold
under the
tradename Panretin(R)), tretinoin (all-trans retinoic acid, also known as
ATRA, sold under the
tradename Vesanoid(R)), Isotretinoin (13-c/s-retinoic acid, sold under the
tradenames
Accutane(R), Amnesteem(R), Claravis(R), Clarus(R), Decutan(R), Isotane(R),
Izotech(R),
Oratane(R), Isotret(R), and Sotret(R)), and bexarotene (sold under the
tradename Targretin(R)).
"PD-1 antagonist" means any chemical compound or biological molecule that
blocks binding of PD-Li expressed on a cancer cell to PD-1 expressed on an
immune cell (T
cell, B cell or NKT cell) and preferably also blocks binding of PD-L2
expressed on a cancer cell
to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and
its ligands
include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4,
CD274
and B7-H for PD-Li; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any
of the

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treatment method, medicaments and uses of the present invention in which a
human individual is
being treated, the PD-1 antagonist blocks binding of human PD-Li to human PD-
1, and
preferably blocks binding of both human PD-Li and PD-L2 to human PD-1. Human
PD-1
amino acid sequences can be found in NCBI Locus No.: NP 005009. Human PD-Li
and PD-L2
amino acid sequences can be found in NCBI Locus No.: NP 054862 and NP 079515,
respectively.
PD-1 antagonists useful in any of the treatment method, medicaments and uses
of
the present invention include a monoclonal antibody (mAb), or antigen binding
fragment thereof,
which specifically binds to PD-1 or PD-L1, and preferably specifically binds
to human PD-1 or
human PD-Li. The mAb may be a human antibody, a humanized antibody or a
chimeric
antibody, and may include a human constant region. In some embodiments the
human constant
region is selected from the group consisting of IgGl, IgG2, IgG3 and IgG4
constant regions, and
in preferred embodiments, the human constant region is an IgG1 or IgG4
constant region. In
some embodiments, the antigen binding fragment is selected from the group
consisting of Fab,
Fab'-SH, F(ab')2, scFv and Fv fragments.
Examples of mAbs that bind to human PD-1, and useful in the treatment method,
medicaments and uses of the present invention, are described in US7488802,
US7521051,
US8008449, US8354509, US8168757, W02004/004771, W02004/072286, W02004/056875,
and US2011/0271358.
Examples of mAbs that bind to human PD-L1, and useful in the treatment
method, medicaments and uses of the present invention, are described in
W02013/019906,
W02010/077634 Al and US8383796. Specific anti-human PD-Li mAbs useful as the
PD-1
antagonist in the treatment method, medicaments and uses of the present
invention include
MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and an antibody which comprises
the
heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21,
respectively,
of W02013/019906.
Other PD-1 antagonists useful in any of the treatment method, medicaments and
uses of the present invention include an immunoadhesin that specifically binds
to PD-1 or PD-
L1, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a
fusion protein
containing the extracellular or PD-1 binding portion of PD-Li or PD-L2 fused
to a constant
region such as an Fc region of an immunoglobulin molecule. Examples of
immunoadhesion

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molecules that specifically bind to PD-1 are described in W02010/027827 and
W02011/066342. Specific fusion proteins useful as the PD-1 antagonist in the
treatment
method, medicaments and uses of the present invention include AMP-224 (also
known as B7-
DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.
Examples of other cytotoxic agents include, but are not limited to, arsenic
trioxide
(sold under the tradename Trisenox(R)), asparaginase (also known as L-
asparaginase, and
Erwinia L-asparaginase, sold under the tradenames Elspar(R) and Kidrolase(R)).
In an embodiment, the other anticancer agent is a BET bromodomain inhibitor.
Examples of BET bromodomain inhibitor include the compounds described in U.S.
Patent No.
5712274, W01994006802, U.S. Patent No. 8476260 and W02009/084693.
The compounds provided herein can also be provided as an article of
manufacture
using packaging materials well known to those of skill in the art. See, e.g.,
U.S. Pat. Nos.
5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging
materials include,
but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags,
vials, containers,
syringes, and any packaging material suitable for a selected formulation and
intended mode of
administration and treatment.
Kits
In certain embodiments, provided herein also are kits which, when used by the
medical
practitioner, can simplify the administration of appropriate amounts of active
ingredients to a
subject. In certain embodiments, the kit provided herein includes a container
and a dosage form
of a compound or composition provided herein, including a single enantiomer, a
mixture of
enantiomers, a diastereomer, or a mixture of diastereomers thereof; or a
pharmaceutically
acceptable salt, or solvate thereof
In certain embodiments, the kit includes a container comprising a dosage form
of the compound
provided herein, including a single enantiomer, a mixture of enantiomers, a
diastereomer, or a
mixture of diastereomers thereof; or a pharmaceutically acceptable salt, or
solvate thereof, in a
container comprising one or more other therapeutic agent(s) described herein.
Kits provided herein can further include devices that are used to administer
the active
ingredients. Examples of such devices include, but are not limited to,
syringes, needle-less

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injectors drip bags, patches, and inhalers. The kits provided herein can also
include condoms for
administration of the active ingredients.
Kits provided herein can further include pharmaceutically acceptable vehicles
that can be used to
administer one or more active ingredients. For example, if an active
ingredient is provided in a
solid form that must be reconstituted for parenteral administration, the kit
can comprise a sealed
container of a suitable vehicle in which the active ingredient can be
dissolved to form a
particulate-free sterile solution that is suitable for parenteral
administration. Examples of
pharmaceutically acceptable vehicles include, but are not limited to: aqueous
vehicles, including,
but not limited to, Water for Injection USP, Sodium Chloride Injection,
Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated
Ringer's Injection;
water-miscible vehicles, including, but not limited to, ethyl alcohol,
polyethylene glycol, and
polypropylene glycol; and non-aqueous vehicles, including, but not limited to,
corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.
In certain embodiments, provided herein is a method of inhibiting the growth
of a cell,
comprising the step of contacting the cell with a compound provided herein,
e.g., a compound of
Formulas I, Ha, Ilb, or IIc, including an enantiomer, a mixture of
enantiomers, a diastereomer, a
mixture of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an
isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or
hydrate thereof.
In certain embodiment, the effective amount of the compound provided herein
ranges from about
1 pM to about 1 mM, from about 10 pM to about 10 p,M, from about 100 pM to
about 2 p,M, or
from about 1 nM to about 1 p.M.
In certain embodiments, the cell is a mammalian cell. In certain embodiments,
the mammal cell
is a human cell. In certain embodiment, the cell is a tumor cell. In certain
embodiment, the cell
is a mammalian tumor cell. In certain embodiment, the cell is a human tumor
cell. In certain
embodiment, the cell is a cancerous cell. In certain embodiment, the cell is a
mammalian
cancerous cell. In certain embodiment, the cell is a human cancerous cell. In
certain
embodiment, the cancerous cell is a metastatic cancerous cell. In certain
embodiment, the
cancerous cell is a metastatic microbial cell. In certain embodiment, the
cancerous cell is a
metastatic bacterial cell. In certain embodiment, the cancerous cell is a
metastatic fungal cell.

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In certain embodiment, the cell is a hematologic malignancy cell. In certain
embodiment, the
cell is a leukemia cell. In certain embodiments, the cell is a relapsed
leukemia cell. In certain
embodiments, the cell is a refractory leukemia cell. In certain embodiments,
the cell is a drug-
resistant leukemia cell. In certain embodiments, the cell is a multidrug-
resistant leukemia cell.
In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant
leukemia cell. In certain
embodiments, the cell is an imatinib-resistant leukemia cell. In certain
embodiments, the cell is a
dasatinib-resistant leukemia cell. In certain embodiments, the cell is a
nilatinib-resistant
leukemia cell. In certain embodiments, the cell is a bosutinib-resistant
leukemia cell. In certain
embodiments, the cell is a cytarabine-resistant leukemia cell.
In certain embodiment, the cell is a leukemia stem cell. In certain
embodiments, the cell is a
relapsed leukemia stem cell. In certain embodiments, the cell is a refractory
leukemia stem cell.
In certain embodiments, the cell is a drug-resistant leukemia stem cell. In
certain embodiments,
the cell is a multidrug-resistant leukemia stem cell. In certain embodiments,
the cell is a Bcr-Abl
kinase inhibitor-resistant leukemia stem cell. In certain embodiments, the
cell is an imatinib-
resistant leukemia stem cell. In certain embodiments, the cell is a dasatinib-
resistant leukemia
stem cell. In certain embodiments, the cell is a nilatinib-resistant leukemia
stem cell. In certain
embodiments, the cell is a bosutinib-resistant leukemia stem cell. In certain
embodiments, the
cell is a cytarabine-resistant leukemia stem cell.
In certain embodiment, the cell is an acute leukemia cell. In certain
embodiments, the cell is a
relapsed acute leukemia cell. In certain embodiments, the cell is a refractory
acute leukemia cell.
In certain embodiments, the cell is a drug-resistant acute leukemia cell. In
certain embodiments,
the cell is a multidrug-resistant acute leukemia cell. In certain embodiments,
the cell is a Bcr-
Abl kinase inhibitor-resistant acute leukemia cell. In certain embodiments,
the cell is an
imatinib-resistant acute leukemia cell. In certain embodiments, the cell is a
dasatinib-resistant
acute leukemia cell. In certain embodiments, the cell is a nilatinib-resistant
acute leukemia cell.
In certain embodiments, the cell is a bosutinib-resistant acute leukemia cell.
In certain
embodiments, the cell is a cytarabine-resistant acute leukemia cell.
In certain embodiments, the cell is an ALL cell. In certain embodiments, the
cell is a relapsed
ALL cell. In certain embodiments, the cell is a refractory ALL cell. In
certain embodiments, the
cell is a drug-resistant ALL cell. In certain embodiments, the cell is a
multidrug-resistant ALL

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cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant
ALL cell. In certain
embodiments, the cell is an imatinib-resistant ALL cell. In certain
embodiments, the cell is a
dasatinib-resistant ALL cell. In certain embodiments, the cell is a nilatinib-
resistant ALL cell.
In certain embodiments, the cell is a bosutinib-resistant ALL cell. In certain
embodiments, the
cell is a cytarabine-resistant ALL cell.
In certain embodiments, the cell is an AML cell. In certain embodiments, the
cell is a relapsed
AML cell. In certain embodiments, the cell is a refractory AML cell. In
certain embodiments,
the cell is a drug-resistant AML cell. In certain embodiments, the cell is a
multidrug-resistant
AML cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-
resistant AML cell. In
certain embodiments, the cell is an imatinib-resistant AML cell. In certain
embodiments, the cell
is a dasatinib-resistant AML cell. In certain embodiments, the cell is a
nilatinib-resistant AML
cell. In certain embodiments, the cell is a bosutinib-resistant AML cell. In
certain embodiments,
the cell is a cytarabine-resistant AML cell.
In certain embodiments, the cell is a chronic leukemia cell. In certain
embodiments, the cell is a
relapsed chronic leukemia cell. In certain embodiments, the cell is a
refractory chronic leukemia
cell. In certain embodiments, the cell is a drug-resistant chronic leukemia
cell. In certain
embodiments, the cell is a multidrug-resistant chronic leukemia cell. In
certain embodiments,
the cell is a Bcr-Abl kinase inhibitor-resistant chronic leukemia cell. In
certain embodiments, the
cell is an imatinib-resistant chronic leukemia cell. In certain embodiments,
the cell is a
dasatinib-resistant chronic leukemia cell. In certain embodiments, the cell is
a nilatinib-resistant
chronic leukemia cell. In certain embodiments, the cell is a bosutinib-
resistant chronic leukemia
cell. In certain embodiments, the cell is a cytarabine-resistant chronic
leukemia cell.
In certain embodiments, the cell is a CLL cell. In certain embodiments, the
cell is a relapsed
CLL cell. In certain embodiments, the cell is a refractory CLL cell. In
certain embodiments, the
cell is a drug-resistant CLL cell. In certain embodiments, the cell is a
multidrug-resistant CLL
cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistant
CLL cell. In certain
embodiments, the cell is an imatinib-resistant CLL cell. In certain
embodiments, the cell is a
dasatinib-resistant CLL cell. In certain embodiments, the cell is a nilatinib-
resistant CLL cell. In
certain embodiments, the cell is a bosutinib-resistant CLL cell. In certain
embodiments, the cell
is a cytarabine-resistant CLL cell.

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In certain embodiments, the cell is a CIVIL cell. In certain embodiments, the
cell is a relapsed
CIVIL cell. In certain embodiments, the cell is a refractory CIVIL cell. In
certain embodiments,
the cell is a drug-resistant CIVIL cell. In certain embodiments, the cell is a
multidrug-resistant
CIVIL cell. In certain embodiments, the cell is a Bcr-Abl kinase inhibitor-
resistant CIVIL cell. In
certain embodiments, the cell is an imatinib-resistant CIVIL cell. In certain
embodiments, the cell
is a dasatinib-resistant CIVIL cell. In certain embodiments, the cell is a
nilatinib-resistant CIVIL
cell. In certain embodiments, the cell is a bosutinib-resistant CIVIL cell. In
certain embodiments,
the cell is a cytarabine-resistant CIVIL cell.
In certain embodiments, the cell is Philadelphia positive leukemia cell. In
one embodiment, the
cell is a Philadelphia positive ALL cell. In another embodiment, the cell is a
Philadelphia
positive AML cell. In yet another embodiment, the cell is a Philadelphia
positive CLL cell. In
still another embodiment, the cell is a Philadelphia positive CIVIL cell.
The inhibition of cell growth can be gauged by, e.g., counting the number of
cells contacted
with a compound of interest, comparing the cell proliferation with otherwise
identical cells not
contacted with the compound, or determining the size of the tumor that
encompasses the cells.
The number of cells, as well as the size of the cells, can be readily assessed
using any method
known in the art (e.g., trypan blue exclusion and cell counting, measuring
incorporation of 3H-
thymidine into nascent DNA in a cell).
Assay Methods
Patient samples were obtained from a non-interventional and prospective study.
The study
included samples from adult patients over 18 years of age who were diagnosed
with Acute
Myeloid Leukemia (AML).
In one embodiment, the method of data acquisition was performed as follows: on
day 1 bone
marrow (BM) or peripheral blood (PB) patient sample was received. A small part
was
separated from the rest of the sample for validation, while the majority of
the sample was
diluted with culture media and plated into 96-well plates previously prepared
with the desired
compounds and compound combinations, e.g., a compound or compound combination
described herein. The number of live leukemic cells seeded in each well was
fixed between
8000 and 32000, depending on the percentage of leukemic cells for each sample.
These plates
were incubated for 72 hours and analyzed on day 4. Antibodies were added to
identify

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leukemic cells using a gating strategy based on FSC/SSC and expression or lack
of expression
of different surface markers. The monoclonal antibodies selection was
performed to optimize
the identification of leukemic cell in each sample.
In one embodiment, non-limiting examples of biomarkers such as the biomarkers
CD34, CD45,
CD117, and HLADR known as "backbone markers" for AML (van Dongen, J. J. and A.
Orfao,
EuroFlow: Resetting leukemia and lymphoma immunophenotyping. Basis for
companion
diagnostics and personalized medicine, Leukemia, 2012, 26, 1899-907) were
included in the
combination.
In one embodiment, antibody combinations such as CD117/CD45, CD34/CD45, and
HLADR/CD45 were used. Live leukemic cells were identified by their light
scatter properties
(FSCii/ SSC') in the absence of Annexin-V-FITC staining. FSC/SSC selection was
performed to exclude debris. The average percentage of cell viability upon
receipt of the
sample was 80% and samples were only processed if the viability was greater
than 50%.
In one embodiment, sample validation was performed as follows: BM and PB
samples were
extracted under sterile conditions and received in the laboratory within 24
hours of extraction.
Initial analysis evaluated the number of pathological cells and their
viability. Different volumes
of sample (1 [IL, 3 [IL, 5 [IL and 7 [IL) were aliquoted in duplicate into a
96-well plate. To lyse
red blood cells, 180 [IL of ammonium chloride lysis solution was added to each
well (2g
KHCO3, 16.58g NH4C1, 0.074g Na2EDTA.2H20, H20 to 1L). Following a 10 min
incubation
period at 4 C, plate was centrifuged for 5 min at 1200 rpm and the supernatant
removed. The
lysis step was performed twice. To analyze, 20 [IL of a combination of Annexin
V-FITC
(Immunostep, Salamanca, Spain), binding buffer (BB, 2.4g HEPES, 8.19g NaC1,
0.37g C12Ca,
H20 to 1L), and the following monoclonal antibodies (mAb) were added to each
well: CD117
(clone 104D2)-PE (Becton Dickinson, San Jose, CA, US), CD34 (clone 581)-PerCP
(BioLegend, San Diego, CA, US), HLADR (clone L243)-PB (BioLegend) and CD45
(HI30)-
P0 (Life Technologies, Carlsbad, CA, US) (van Dongen, J.J., et al., EuroFlow
antibody panels
for standardized n-dimensional flow cytometric immunophenotyping of normal,
reactive and
malignant leukocytes, Leukemia, 2012, 26, 1908-75). After 15 min of incubation
at room
temperature in the dark, a wash step was performed using binding buffer
solution. The pellet
was resuspended in 30 [IL BB for analysis in Vivia's ExviTech platform. Cell
count and

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viability upon arrival were computed and the optimal volume of sample to use
per well was
determined.
In one embodiment, the assay was performed according to following method: the
whole sample
was diluted with RPMI 1640, supplemented with 20% (v/v) FBS (Thermo
Scientific, Waltham,
MA, US), 2% HEPES, 1% antibiotic (Zell Shield, Labclinics, Barcelona, Spain)
and 1% L-
glutamine 200mM (Lonza, Hopkinton, MA, US) to a final volume of 60 [IL per
well. The
mixture was dispensed into 96-well plates containing a compound described
herein with a
Multidrop Combi Smart (Thermo Scientific, Waltham, MA, US). Drug plates were
previously
prepared using an Echo 550 Liquid Handler (LabCyte, Sunnyvale, CA, US). Five
or eight
concentrations were used for each compound tested, adjusted to cover the range
of activities
across patients. The compounds tested were also tested against the
corresponding parent as a
control. The plates were incubated for 48 hours or 72 hours at 37 C in
humidified air
containing 5% CO2.
In one embodiment, data analysis was conducted with Summit software (Beckman
Coulter).
Identification of pathological cells was performed using a gating strategy
based on FSC/SSC
and expression or lack of expression of the different mAb markers. Depletion
was measured as
the difference in the number of live cells in a well with the compounds
described herein vs the
control wells without the compounds. Annexin V was then used to exclude dying
cells and
measure only the number of live cells in the drug wells and in the control
wells. Those cells
without Annexin V staining and appropriate FSC/SSC were considered as live
cells (Koopman,
G., et al., Annexin V for flow cytometric detection of phosphatidylserine
expression on B cells
undergoing apoptosis, Blood, 1994, 84, 1415-20). Using the above parameters,
FCS Analyzer
was used to determine the effect of each of the individual compound. Data were
transfered to
ActivityBase (IDBS, Guildford, UK) for final analysis.
The disclosure will be further understood by the following non-limiting
examples.
The ex-vivo effect of the compounds on AML samples when the plates were
incubated for 72
hours is illustrated in Table 2:
Compound EC50 abs. Emax (%)
(1M)

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NH2 A A
11
1\1---NCI
-P¨Oss F
NH
diastereomer 1
0
NH2
N1/LN
0 N N CI
0=F:sds AF
NH
diastereomer 2
NH2 A A
NN
F(N N, CI
HO¨P¨
HN
OH H
101
NH2
0
F N N CI
O H
HN
H
0

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NH2 A B
Nxjzz--... N
1
HOr
N eLCI
9
SO-P-07_,LF/
0 HN
OH H
diastereomer 1
NH2 B B
NN
1
HOAr
N eLCI
9
F/
0 HN
40 OH H
diastereomer 2
NH2 B C
-----c N--_,..--LN
I
0 F 0 N"Nr CI
-\1\1.4.- --1c4://
_.-0 H \
0
OH H
/0
0 diastereomer 1
\
NH2 B B
----( N,...N
I
o 3 0 F N " N a
-\H 1\14¨c)
1
, \
--11 K
0
OH H
0
0 diastereomer 2
\

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NH2 C A
)1\1
0 t
H
HO¨P-0704/0H N 0
HN
OH H
0
NH2 B B
t
0 : OH N 0
:) K
..õ.0 H \
0
( OH H
/0
0
\
diastereomer 1
NH2 C A
-----(
I N
0 0 OHIN _ ,_,
U
=
--Ill
_-.0 H \
0
( OH H
/0
0
\
diastereomer 2

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NH2 B A
0 01-IN
/ 0
-1c_04
H\
0
( OH H
0
diastereomer 1
NH2 B A
N
= 0
0 OH/ IN U
Tc24
H\
0
OH H
0
0
diastereomer 2
NH2 B A
0
=
I I r) 01-IN 0
0
OH H
N NO2
diastereomer 1

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NH2 B A
ell
0
II r)
.
HN-P----lc_IKO
\
0 OH N 0
OH H
----N
N\-..NO2
diastereomer 2
o C C
HN
0, I O t
1N 0
......0 H 1
HN
õ..LircõOH H
0
NH2 C A
1 I 0
HO( Soo N 0
so-ig-o
1
7c24/
0 HN
OH H
lei
NH2 B B
HO
0
II oreLCI
µ-' 0
0 f 1-kfl F
S
----,L0
OH

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The ex-vivo effect of the compounds on AML samples when the plates were
incubated for 48
hours is illustrated in Table 3:
Compound EC50 abs. (p,M) Emax (%)
Chiral
2
=7
0
0
)_0
OH
A
HO
Ch ire I
,
( ,(\
C..--
=="*".(%
Diastereomer 1
NH ,
N
=:)H
- D A
/1
Diastereomer 2

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Chiral
NH 2
,N
0 N
II
B A
HO ¨P¨ON A
I F
NH OH
i
HO.
0
Chiral
/7\.........r
0
N Z N H 2
0/1.....---
\ r N
0 N=y
0 OH C C
0 F
Diastereomer 1
Chiral
q......r
0 N H 2
N Z
0 /....
N
r
OH NI \ D C
0 F
Diastereomer 2
Chiral
HO
HO ..../ %,_(
N .' C C
0 1.....(0 ,....,9,1 ,,(NH 2
1
HO OH N yN
F

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Chiral
0 *".....(i
0
0
,/ /........q.....qt,N H 2
HN D B
......_ ip,.
o I
X6 NEI HOS. OH NyN
0
F
0
/
Chiral
1
'" '= N.--::"(
. ,.
õ,...C)H
-----< ..
:.
0 HO
zi
0 \
Chiral
NH 2
N
..õ--..y F Nk
/
-P A OH
C C
0 rNH a
.... j ---\\O
Diastereomer 1
Chiral
NH 2
.....,
0\(:3 N N
0--- / F
------P OH
C c
..rNH 5
----/0---\\
Diastereomer 2

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EC50values are provided as follows:
A < 1 uM, 1 <B < 10 uM, 10< C <20 uM, D? 20 uM;
Emax values are provided as follows:
A = 0-10%; B = 10-20%; C >20%
In Vitro Inhibition
Materials
Cells were grown in RPMI-1640 supplemented with L-Glutamine and 10% FBS of the
following
cancer cell lines:
CCRF-CEM; CCRF-CEM-cytarabine resistant; HL-60;
Method
18, 96 well plates of each cell line were seeded with the optimized number of
cells per well in a
total volume of 50 [IL per well. The plates were left overnight. Plate wells
were seeded with 100
pL media for media control. The following day, cells were exposed to test
compounds as
described below. At the same time as drug exposure, a CTG assay was conducted
on the 18th
plate for the 0 hr count.
The compounds were added to cells and medium already on the plate to give
desired final
concentrations. 50 [IL media were added to cell control wells, and 50 [IL of
mix added to vehicle
control wells. 10 uM Doxorubicin was added to appropriate wells as control.
Cells exposed to
test compound were incubated at 37 C for 72 hr followed by a CTG assay.
CellTiter-Glo (CTG)
At the end of the 72 hr exposure period, plates were removed for a CellTiter-
Glo (CTG) assay
from a 37 C, 5% CO2 incubator and placed on the bench at room temperature for
30 mins. 100
[IL of CellTiter-Glo reagent was added and mixed for 2 mins, followed by a
further 10 min
incubation at room temperature. Luminescence was recorded using Synergy 4Ø

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All the exemplified compounds were tested in accordance with this method and
were found to
have 1050 values of less than 100[IM at each cell line. The results for
compounds are provided in
Table 4.
Table 4 ¨ In vitro inhibition of CCRF-CEM; CCRF-CEM-cytarabine resistant and
HL-60.
Compound CCRF-CEM CCRF-CEM- HL-60
cytarabine resistant
IC 50 (.IM)
Compound 10 A
Compound 11 A B A
Compound 24b A C A
Compound 24c A C A
Compound 24e A C A
Compound 24f A
(diastereoisomer 1)
Compound 24f A
(diastereoisomer 2)
Compound 25 A
(diastereoisomer 1)
Compound 25 A
(diastereoisomer 2)
Compound 26a A B A
Compound 26b A B A
The IC50 values in Tables 1 are as follows:
A = < 1 [IM
B = > land 10 < [IM

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C = > 10 and < 25 [IM
D = >25 and < 100 [IM
The embodiments described above are intended to be merely exemplary, and those
skilled in the
art will recognize, or will be able to ascertain using no more than routine
experimentation,
numerous equivalents of specific compounds, materials, and procedures. All
such equivalents
are considered to be within the scope of the claimed subject matter and are
encompassed by the
appended claims.
Since modifications will be apparent to those of skill in the art, it is
intended that the claimed
subject matter be limited only by the scope of the appended claims.