U.S. patent application number 14/137158 was filed with the patent office on 2014-04-24 for novel pyridopyrimidine derivatives and use thereof.
This patent application is currently assigned to THE ASAN FOUNDATION. The applicant listed for this patent is The Asan Foundation. Invention is credited to Han Won Cho, Suk Young Cho, Eun Kyung Choi, Albert C. Gyorkos, Jung Jin Hwang, Choung Soo Kim, Gilnam Lee, Chul Soo Lim, Jeongbeob Seo.
Application Number | 20140113915 14/137158 |
Document ID | / |
Family ID | 46828948 |
Filed Date | 2014-04-24 |
United States Patent
Application |
20140113915 |
Kind Code |
A1 |
Lee; Gilnam ; et
al. |
April 24, 2014 |
NOVEL PYRIDOPYRIMIDINE DERIVATIVES AND USE THEREOF
Abstract
The invention provides novel substituted pyridopyrimidines
represented by Formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof, and a
composition comprising these compounds. The compounds provided can
be used as inhibitors of the phosphoinositide 3' OH kinase family
(PI3K) for the treatment of inflammatory diseases, cancer,
cardiovascular diseases, allergy, asthma and autoimmune disorders.
##STR00001##
Inventors: |
Lee; Gilnam; (Seongnam-si,
KR) ; Lim; Chul Soo; (Seoul, KR) ; Cho; Han
Won; (Seoul, KR) ; Seo; Jeongbeob;
(Seongnam-si, KR) ; Gyorkos; Albert C.;
(Westminster, CO) ; Cho; Suk Young; (Seongnam-si,
KR) ; Choi; Eun Kyung; (Seoul, KR) ; Kim;
Choung Soo; (Sungnam, KR) ; Hwang; Jung Jin;
(Seoul, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Asan Foundation |
Seoul |
|
KR |
|
|
Assignee: |
THE ASAN FOUNDATION
Seoul
KR
|
Family ID: |
46828948 |
Appl. No.: |
14/137158 |
Filed: |
December 20, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13423950 |
Mar 19, 2012 |
8664230 |
|
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14137158 |
|
|
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|
61453850 |
Mar 17, 2011 |
|
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Current U.S.
Class: |
514/255.05 ;
514/264.1; 514/264.11 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 37/08 20180101; A61K 31/519 20130101; A61P 37/06 20180101;
A61P 43/00 20180101; A61P 29/00 20180101; A61P 11/06 20180101; C07D
471/04 20130101; A61P 9/00 20180101 |
Class at
Publication: |
514/255.05 ;
514/264.1; 514/264.11 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Claims
1.-3. (canceled)
4. A method for inhibiting PI3K enzyme, the method comprising
contacting PI3K enzyme with an effective amount of a compound of
formula I, ##STR00096## Wherein X is C or O or N or S; Y is CH or
N; R.sub.1 is selected from the group consisting of: acyl, amino,
substituted amino, C1-C6alkyl, substituted C1-C6alkyl,
C3-C7cycloalkyl, substituted C3-C7cycloalkyl,
C3-C7heterocycloalkyl, substituted C3-C7 heterocycloalkyl,
alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, nitro; R.sub.2 is selected from
the group consisting of: hydrogen, halogen, acyl, amino,
substituted amino, C1-C6alkyl, substituted C1-C6alkyl,
C3-C7cycloalkyl, substituted C3-7 Ccycloalkyl,
C3-7Cheterocycloalkyl, substituted C3-C7heterocycloalkyl,
alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, nitro, alkoxy,
C3-C7cycloalkyloxy, substituted C3-C7cycloalkyloxy,
C3-C7heterocycloalkyloxy, substituted C3-7Cheterocycloalkyloxy,
acyloxy, aryloxy; R.sub.3=NR.sub.4'SO.sub.2R.sub.4,
SO.sub.2NR.sub.4'R.sub.4, NR.sub.4'COR.sub.4, CONR.sub.4'R.sub.4,
NR.sub.4'CONHR.sub.4; R.sub.4 is selected from the group consisting
of: alkyl, substituted alkyl, amino, halo, C3-C7cycloalkyl,
substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted
C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl and
substituted heteroaryl; R.sub.4' is H or C1-C6 alkyl; R.sub.5 is
selected from the group consisting of: hydrogen, halogen,
C1-C6alkyl; R.sub.6 is selected from the group consisting of:
hydrogen, halogen, acyl, alkoxy, amino, substituted amino,
arylamino, C1-C6alkyl, substituted C1-C6 alkyl, C3-C7cycloalkyl,
substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted
C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl, and
substituted heteroaryl; n is 0 or 1; m is 0 or 1; or a
pharmaceutically acceptable salt, ester, or tautomer thereof.
5. A method for the treatment or prophylaxis of a PI3K mediated
disorder or disease, the method comprising administering to a
patient in need thereof an effective amount of a compound of
formula I, ##STR00097## Wherein X is C or O or N or S; Y is CH or
N; R.sub.1 is selected from the group consisting of: acyl, amino,
substituted amino, C1-C6alkyl, substituted C1-C6alkyl,
C3-C7cycloalkyl, substituted C3-C7cycloalkyl,
C3-C7heterocycloalkyl, substituted C3-C7 heterocycloalkyl,
alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, nitro; R.sub.2 is selected from
the group consisting of: hydrogen, halogen, acyl, amino,
substituted amino, C1-C6alkyl, substituted C1-C6alkyl,
C3-C7cycloalkyl, substituted C3-7 Ccycloalkyl,
C3-7Cheterocycloalkyl, substituted C3-C7heterocycloalkyl,
alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, nitro, alkoxy,
C3-C7cycloalkyloxy, substituted C3-C7cycloalkyloxy,
C3-C7heterocycloalkyloxy, substituted C3-7Cheterocycloalkyloxy,
acyloxy, aryloxy; R.sub.3=NR.sub.4'SO.sub.2R.sub.4,
SO.sub.2NR.sub.4'R.sub.4, NR.sub.4'COR.sub.4, CONR.sub.4'R.sub.4,
NR.sub.4'CONHR.sub.4; R.sub.4 is selected from the group consisting
of: alkyl, substituted alkyl, amino, halo, C3-C7cycloalkyl,
substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted
C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl and
substituted heteroaryl; R.sub.4' is H or C1-C6 alkyl; R.sub.5 is
selected from the group consisting of: hydrogen, halogen,
C1-C6alkyl; R.sub.6 is selected from the group consisting of:
hydrogen, halogen, acyl, alkoxy, amino, substituted amino,
arylamino, C1-C6alkyl, substituted C1-C6 alkyl, C3-C7cycloalkyl,
substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted
C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl, and
substituted heteroaryl; n is 0 or 1; m is 0 or 1; or a
pharmaceutically acceptable salt, ester, or tautomer.
6. A method for the treatment or prophylaxis of proliferative
disorders, the method comprising administering to a patient in need
thereof an effective amount of a compound of formula I,
##STR00098## Wherein X is C or O or N or S; Y is CH or N; R.sub.1
is selected from the group consisting of: acyl, amino, substituted
amino, C1-C6alkyl, substituted C1-C6alkyl, C3-C7cycloalkyl,
substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted
C3-C7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted
arylalkyl, arylcycloalkyl, substituted arylcycloalkyl,
heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro; R.sub.2
is selected from the group consisting of: hydrogen, halogen, acyl,
amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl,
C3-C7cycloalkyl, substituted C3-7 Ccycloalkyl,
C3-7Cheterocycloalkyl, substituted C3-C7heterocycloalkyl,
alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, nitro, alkoxy,
C3-C7cycloalkyloxy, substituted C3-C7cycloalkyloxy,
C3-C7heterocycloalkyloxy, substituted C3-7Cheterocycloalkyloxy,
acyloxy, aryloxy; R.sub.3=NR.sub.4'SO.sub.2R.sub.4,
SO.sub.2NR.sub.4'R.sub.4, NR.sub.4'COR.sub.4, CONR.sub.4'R.sub.4,
NR.sub.4'CONHR.sub.4; R.sub.4 is selected from the group consisting
of: alkyl, substituted alkyl, amino, halo, C3-C7cycloalkyl,
substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted
C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl and
substituted heteroaryl; R.sub.4' is H or C1-C6 alkyl; R.sub.5 is
selected from the group consisting of: hydrogen, halogen,
C1-C6alkyl; R.sub.6 is selected from the group consisting of:
hydrogen, halogen, acyl, alkoxy, amino, substituted amino,
arylamino, C1-C6alkyl, substituted C1-C6 alkyl, C3-C7cycloalkyl,
substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted
C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl, and
substituted heteroaryl; n is 0 or 1; m is 0 or 1; or a
pharmaceutically acceptable salt, ester, or tautomer thereof.
7. The method of claim 6, wherein the proliferative disorders are
selected from the group consisting of inflammatory diseases,
cancer, cardiovascular diseases, allergy, asthma and autoimmune
disorders.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/423,950, filed Mar. 19, 2012, allowed, which claims the
benefit of and priority to U.S. Provisional Patent Application No.
61/453,850, filed on Mar. 17, 2011. The contents of each of the
foregoing applications are incorporated herein by reference in
their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to a series of substituted
pyridopyrimidine which are kinase inhibitors, especially inhibitors
of the phosphoinositide 3' OH kinase family (hereinafter PI3
Kinase; PI3K.alpha., PI3K.beta., PI3K.gamma. and/or PI3.delta.) for
treatment of inflammatory diseases, cancer, cardiovascular
diseases, allergy, asthma and autoimmune disorders. This invention
also relates to a pharmaceutical composition comprising the
compound of the invention, use of the compound in the preparation
of a medicament, and method of treatment for hyperproliferative
diseases in mammals, especially humans by administering the
compound thereof.
BACKGROUND OF THE INVENTION
[0003] The phosphoinositide 3-kinases (PI3Ks) are a family of
enzymes involved in cellular function such as cell growth,
proliferation, differentiation, motility, survival and
intracellular trafficking, which in turn are involved in cancer.
And the PI3Ks utilize both lipid and protein kinase activity to
regulate numerous intracellular signal transduction pathway, which
in turn coordinate a range of downstream cellular processes.
[0004] The PI3K family is divided into three classes (I, II, and
III). The classifications are based on primary structure,
regulation, and in vitro lipid substrate specificity. Class I PI3Ks
have received the most attention from the scientific community and
are further broken down into two subclasses, 1A and 1B, which are
responsible for the production of Phosphatidylinositol 3-phosphate
(PI(3)P), Phosphatidylinositol (3,4)-bisphosphate (PI(3,4)P.sub.2),
and Phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P.sub.3)
(Vanhaesebroeck et al., Trends Biochem. Sci., 1997, 22(7),
267-272.; Leslie et al., Chem. Rev., 2001, 101(8), 2365-2380) (FIG.
1).
##STR00002##
[0005] The class IA isoforms, PI3K.alpha., PI3K.beta., and
PI3K.delta., are primarily activated by protein tyrosine
kinase-coupled receptors, whereas the sole class IB member,
PI3K.gamma. is activated by G-protein coupled receptors (GPCRs),
such as chemokine receptors (Leevers S J et al., Current Opinion in
Cell Biology 1999, 11(2) 219-225). Class IA PI3K is composed of a
heterodimer between a p110 catalytic subunit and a p85 regulatory
subunit (Carpenter C L et al., J. Biol. Chem. 1990, 265(32),
19704-19711). There are five variants of the p85 regulatory
subunit, designated p85.alpha., p55.alpha., p50.alpha., p85.beta.,
or p55.gamma.. There are also three variants of the p110 catalytic
subunit designated p110.alpha., .beta., or .delta. catalytic
subunit. The first three regulatory subunits are all splice
variants of the same gene (Pik3r1), the other two being expressed
by other genes (Pik3r2 and Pik3r3, p85.beta., and p55.gamma.,
respectively). The most highly expressed regulatory subunit is
p85.alpha.; all three catalytic subunits are expressed by separate
genes (Pik3ca, Pik3cb, and Pik3cd for p110.alpha., p110.beta., and
p110.delta., respectively). The first two p110 isoforms (.alpha.
and .beta.) are expressed in all cells, but p110.delta. is
expressed primarily in leukocytes, and it has been suggested that
it evolved in parallel with the adaptive immune system. The
regulatory p101 and unique catalytic p110.gamma. subunits comprise
the type IB PI3K and are encoded by a single gene each. Each
isoforms have unfolded the close connections between PI3K.alpha.
with oncogenesis, PI3K.beta. with thrombosis, PI3K.delta. with
immune function and PI3K.gamma. with inflammation by
pathophysiologic studies. Class II PI3Ks include PI3K C2a, C2p and
C2y subtypes, which are characterized by containing C2 domains at
the C terminus. The substrate for class III PI3Ks is PI only.
[0006] Wortmannin and LY294002 are well known and studied as a
first generation PI3K inhibitor. Wortmannin was first isolated from
Penicillium wortmanni in 1957 (Brian, P. W. et al., Bri. Mycol.
Soc., 1957, 40, 365-368), but the structure was recognized in 1974
(Wiesinger, D. et al., Cell Mol. Life. Sci., 1974, 30, 135-136). It
was reported for the anti-inflammatory activity (Wiesinger, D. et
al, Experintia, 1974, 30, 135-136) and identified as a PI3K
inhibitor (Powis, G. et al., Cancer Res., 1994, 54, 2419-2423).
LY294002 is the first synthetic PI3K inhibitor with a quercetin
modified chemical structure. LY294002 wa first described as a
competitive PI3K inhibitor in 1994 (Vlahos, C. J. et al., J. Biol.
Chem., 1994, 269, 5241-5248).
[0007] Compounds suitable as PI3K inhibitors are also disclosed in
WO 07/044,729; WO 08/152,390; WO 08/070,740; WO 09/039,140; WO
09/052,145; WO 09/143,317; WO 10/002,954; WO 10/037,765; WO
10/091,996; WO 10/100,144; WO 10/135,014; WO 10/144,513; WO
10/102,958; WO 10/133,318 and WO 10/007,099.
SUMMARY OF THE INVENTION
[0008] This invention provides for novel heterocyclic a compound of
formula I or a pharmaceutically acceptable salt, solvate,
polymorph, ester, tautomer or prodrug thereof:
##STR00003##
wherein
X is C or O or N or S;
Y is C or N;
[0009] R.sub.1 is selected from the group consisting of: acyl,
amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl,
C3-C7cycloalkyl, substituted C3-C7cycloalkyl,
C3-C7heterocycloalkyl, substituted C3-C7 heterocycloalkyl,
alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, nitro; R.sub.2 is selected from
the group consisting of: hydrogen, halogen, acyl, amino,
substituted amino, C1-C6alkyl, substituted C1-C6alkyl,
C3-C7cycloalkyl, substituted C3-7Ccycloalkyl,
C3-7Cheterocycloalkyl, substituted C3-C7heterocycloalkyl,
alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, arylalkyl, substituted arylalkyl,
arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,
substituted heteroarylalkyl, cyano, nitro, alkoxy,
C3-C7cycloalkyloxy, substituted C3-C7cycloalkyloxy,
C3-C7heterocycloalkyloxy, substituted C3-7Cheterocycloalkyloxy,
acyloxy, aryloxy; R.sub.3=NR.sub.4'SO.sub.2R.sub.4,
SO.sub.2NR.sub.4'R.sub.4, NR.sub.4'COR.sub.4, CONR.sub.4'R.sub.4,
NR.sub.4'CONHR.sub.4; R.sub.4 is selected from the group consisting
of: alkyl, substituted alkyl, amino, halo, C3-C7cycloalkyl,
substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted
C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl and
substituted heteroaryl; R.sub.4' is H or C1-C6 alkyl; R.sub.5 is
selected from the group consisting of: hydrogen, halogen,
C1-C6alkyl; R.sub.6 is selected from the group consisting of:
hydrogen, halogen, acyl, alkoxy, amino, substituted amino,
arylamino, C1-C6alkyl, substituted C1-C6 alkyl, C3-C7cycloalkyl,
substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted
C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl, and
substituted heteroaryl; n is 0 or 1; m is 0 or 1; and/or a
pharmaceutically acceptable salt thereof.
[0010] In other embodiments, the present invention provides
compounds represented by the following Formulae:
##STR00004## ##STR00005##
or a pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof.
[0011] Compounds of present invention are inhibitors of PI3K and,
consequently, are useful for treating cancers and other
hyperproliferative diseases.
[0012] Compounds of present invention are inhibitors of PI3K and,
consequently, are also related to a method of treating one or more
disease states selected from: autoimmune disorders, inflammatory
diseases, allergy, asthma, cardiovascular diseases, kidney
diseases, pancreatitis, multiorgan failure and thrombosis.
[0013] In other aspects, the present invention is directed to a
pharmaceutical composition comprising an effective amount of a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof. In some
embodiments, the pharmaceutical composition further comprises a
pharmaceutically acceptable carrier, adjuvants and/or excipients.
In some embodiments, such a composition may contain at least one of
preservatives, agents for delaying absorption, fillers, binders,
adsorbents, buffers, disintegrating agents, solubilizing agents,
and other carriers, adjuvants and/or excipients as inert
ingredients. The composition may be formulated with a method
well-known in the art.
[0014] In some aspects, the present invention is directed to a
method of treating a disease in an individual suffering from said
disease comprising administering to said individual a
therapeutically effective amount of a composition comprising a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof.
[0015] In other aspects, the present invention is directed to a
method of treating a disorder in a mammal, comprising administering
to said mammal a therapeutically effective amount of a compound of
formula I or a pharmaceutically acceptable salt, solvate,
polymorph, ester, tautomer or prodrug thereof.
[0016] In other aspects, the present invention is directed to a
method of treating a disorder in a human, comprising administering
to said human a therapeutically effective amount of a compound of
formula I or a pharmaceutically acceptable salt, solvate,
polymorph, ester, tautomer or prodrug thereof.
[0017] In other aspects, the present invention is directed to a
method of treating an inflammatory disease, condition, or disorder
in a mammal, including a human, comprising administering to said
mammal a therapeutically effective amount of a compound of formula
I or a pharmaceutically acceptable salt, ester, prodrug, solvate,
such as hydrate, polymorph or tautomer thereof.
[0018] In other aspects, the present invention is directed to a
method of treating a disorder or condition which is modulated by
the PI3K cascade in a mammal, including a human, comprising
administering to said mammal an amount of the compound of formula I
or a pharmaceutically acceptable salt, ester, prodrug, solvate,
such as hydrate, polymorph or tautomer thereof, effective to
modulate said cascade. The appropriate dosage for a particular
patient can be determined, according to known methods, by those
skilled in the art.
[0019] In other aspects, the present invention is directed to use
of compound of formula I or a pharmaceutically acceptable salt,
ester, prodrug, solvate, such as hydrate, polymorph or tautomer
thereof in the preparation of a pharmaceutical composition. The
pharmaceutical composition can be used for treating a disorder or
condition which is modulated by the PI3K cascade in a mammal,
including a human. The pharmaceutical composition is useful for
treating cancer, inflammatory disease and other hyperproliferative
diseases.
[0020] In other aspects, the present invention is directed to a
pharmaceutical composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof. In some embodiments, the
pharmaceutical composition is in a form suitable for oral
administration. In further or additional embodiments, the
pharmaceutical composition is in the form of a tablet, capsule,
pill, powder, sustained release formulation, solution and
suspension. In some embodiments, the pharmaceutical composition is
in a form suitable for parenteral injection, such as a sterile
solution, suspension or emulsion; for topical administration as an
ointment or cream or for rectal administration as a suppository. In
further or additional embodiments, the pharmaceutical composition
is in unit dosage forms suitable for single administration of
precise dosages. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg body weight/day. In further or additional
embodiments the amount of compound of formula I is about 0.001 to
about 7 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.002 to about 6 g/day. In further
or additional embodiments the amount of compound of formula I is
about 0.005 to about 5 g/day. In further or additional embodiments
the amount of compound of formula I is about 0.01 to about 5 g/day.
In further or additional embodiments the amount of compound of
formula I is about 0.02 to about 5 g/day. In further or additional
embodiments the amount of compound of formula I is about 0.05 to
about 2.5 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.1 to about 1 g/day. In further or
additional embodiments, dosage levels below the lower limit of the
aforesaid range may be more than adequate. In further or additional
embodiments, dosage levels above the upper limit of the aforesaid
range may be required. In further or additional embodiments the
compound of formula I is administered in a single dose, once daily.
In further or additional embodiments the compound of formula I is
administered in multiple doses, more than once per day. In further
or additional embodiments the compound of formula I is administered
twice daily. In further or additional embodiments the compound of
formula I is administered three times per day. In further or
additional embodiments the compound of formula I is administered
four times per day. In further or additional embodiments the
compound of formula I is administered more than four times per day.
In some embodiments, the pharmaceutical composition is for
administration to a mammal. In further or additional embodiments,
the mammal is human. In further or additional embodiments, the
pharmaceutical composition further comprises a pharmaceutical
carrier, excipient and/or adjuvant. In further or additional
embodiments, the pharmaceutical composition further comprises at
least one therapeutic agent In further or additional embodiments,
the therapeutic agent is selected from the group consisting of
cytotoxic agents, anti-angiogenesis agents and anti-neoplastic
agents. In further or additional embodiments, the anti-neoplastic
agent is selected from the group consisting of alkylating agents,
anti-metabolites, epidophyllotoxins; antineopiastic enzymes,
topoisomerase inhibitors, procarbazines, mitoxantrones, platinum
coordination complexes, biological response modifiers and growth
inhibitors, hormonal/anti-hormonal therapeutic agents, and
haematopoietic growth factors. In further or additional
embodiments, the therapeutic agent is taxol, bortezomib or both. In
further or additional embodiments, the pharmaceutical composition
is administered in combination with an additional therapy. In
further or additional embodiments, the additional therapy is
radiation therapy, chemotherapy or a combination of both. In
further or additional embodiments, the pharmaceutical composition
comprises a pharmaceutically acceptable salt of a compound of
formula I.
[0021] In other aspects, the present invention is directed to a
method for inhibiting a PI3K enzyme. The method comprises
contacting said PI3K enzyme with an amount of a composition
comprising a compound of formula I or a pharmaceutically acceptable
salt, solvate, polymorph, ester, tautomer or prodrug thereof,
sufficient to inhibit said enzyme, wherein said enzyme is
inhibited. In some embodiments, the present invention is directed
to a method for selectively inhibiting a PI3K enzyme.
[0022] In other aspects, the present invention is directed to use
of a compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof in the
preparation of a pharmaceutical composition for inhibiting a PI3K
enzyme.
[0023] In further or additional embodiments the enzyme is at least
about 1% inhibited. In further or additional embodiments the enzyme
is at least about 2% inhibited. In further or additional
embodiments the enzyme is at least about 3% inhibited. In further
or additional embodiments the enzyme is at least about 4%
inhibited. In further or additional embodiments the enzyme is at
least about 5% inhibited. In further or additional embodiments the
enzyme is at least about 10% inhibited. In further or additional
embodiments the enzyme is at least about 20% inhibited. In further
or additional embodiments the enzyme is at least about 25%
inhibited. In further or additional embodiments the enzyme is at
least about 30% inhibited. In further or additional embodiments the
enzyme is at least about 40% inhibited. In further or additional
embodiments the enzyme is at least about 50% inhibited. In further
or additional embodiments the enzyme is at least about 60%
inhibited. In further or additional embodiments the enzyme is at
least about 70% inhibited. In further or additional embodiments the
enzyme is at least about 75% inhibited. In further or additional
embodiments the enzyme is at least about 80% inhibited. In further
or additional embodiments the enzyme is at least about 90%
inhibited. In further or additional embodiments the enzyme is
essentially completely inhibited.
[0024] In other aspects, the present invention is directed to a
method of treatment of a PI3K mediated disorder in an individual
suffering from said disorder comprising administering to said
individual an effective amount of a composition comprising a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof.
[0025] In other aspects, the present invention is directed to use
of a compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof in the
preparation of a pharmaceutical composition for treating a PI3K
mediated disorder.
[0026] In some embodiments, the composition comprising a compound
of formula I is administered orally, intraduodenally, parenterally
(including intravenous, subcutaneous, intramuscular, intravascular
or by infusion), topically or rectally. In some embodiments, the
pharmaceutical composition is in a form suitable for oral
administration. In further or additional embodiments, the
pharmaceutical composition is in the form of a tablet, capsule,
pill, powder, sustained release formulations, solution and
suspension for oral administration, for parenteral injection as a
sterile solution, suspension or emulsion, for topical
administration as an ointment or cream, or for rectal
administration as a suppository. In further or additional
embodiments, the pharmaceutical composition is in unit dosage forms
suitable for single administration of precise dosages. In further
or additional embodiments, the pharmaceutical composition further
comprises a pharmaceutical carrier, excipient and/or adjuvant. In
further or additional embodiments the amount of compound of formula
I is in the range of about 0.001 to about 1000 mg/kg body
weight/day. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.5 to about 50
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is about 0.001 to about 7 g/day. In
further or additional embodiments the amount of compound of formula
I is about 0.01 to about 7 g/day. In further or additional
embodiments the amount of compound of formula I is about 0.02 to
about 5 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.05 to about 2.5 g/day. In further
or additional embodiments the amount of compound of formula I is
about 0.1 to about 1 g/day. In further or additional embodiments,
dosage levels below the lower limit of the aforesaid range may be
more than adequate. In further or additional embodiments, dosage
levels above the upper limit of the aforesaid range may be
required. In further or additional embodiments the compound of
formula I is administered in a single dose, once daily. In further
or additional embodiments the compound of formula I is administered
in multiple doses, more than once per day. In further or additional
embodiments the compound of formula I is administered twice daily.
In further or additional embodiments the compound of formula I is
administered three times per day. In further or additional
embodiments the compound of formula I is administered four times
per day. In further or additional embodiments the compound of
formula I is administered more than four times per day. In some
embodiments, the individual suffering from the PI3K mediated
disorder is a mammal. In further or additional embodiments, the
individual is a human. In some embodiments, the composition
comprising a compound of formula I is administered in combination
with an additional therapy. In further or additional embodiments,
the additional therapy is radiation therapy, chemotherapy or a
combination of both. In further or additional embodiments, the
composition comprising a compound of formula I is administered in
combination with at least one therapeutic agent. In further or
additional embodiments, the therapeutic agent is selected from the
group of cytotoxic agents, anti-angiogenesis agents and
anti-neoplastic agents. In further or additional embodiments, the
anti-neoplastic agent is selected from the group of consisting of
alkylating agents, anti-metabolites, epidophyllotoxins;
antineoplastic enzymes, topoisomerase inhibitors, procarbazines,
mitoxantrones, platinum coordination complexes, biological response
modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic
agents, and haematopoietic growth factors. In further or additional
embodiments, the therapeutic agent is selected from taxol,
bortezomib or both. In some embodiments, the PI3K mediated disorder
is selected from the group consisting of inflammatory diseases,
infections, autoimmune disorders, stroke, ischemia, cardiac
disorder, neurological disorders, fibrogenic disorders,
proliferative disorders, hyperproliferative disorders, non-cancer
hyper-proliferative disorders, tumors, leukemias, neoplasms,
cancers, carcinomas, metabolic diseases, malignant disease,
vascular restenosis, psoriasis, atherosclerosis, rheumatoid
arthritis, osteoarthritis, heart failure, chronic pain, neuropathic
pain, dry eye, closed angle glaucoma and wide angle glaucoma. In
further or additional embodiments, the PI3K mediated disorder is an
inflammatory disease. In further or additional embodiments, the
PI3K mediated disorder is a hyperproliferative disease. In further
or additional embodiments, the PI3K mediated disorder is selected
from the group consisting of tumors, leukemias, neoplasms, cancers,
carcinomas and malignant disease. In further or additional
embodiments, the cancer is brain cancer, breast cancer, lung
cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal
cancer, colorectal cancer or leukemia. In further or additional
embodiments, the fibrogenetic disorder is scleroderma,
polymyositis, systemic lupus, rheumatoid arthritis, liver
cirrhosis, keloid formation, interstitial nephritis or pulmonary
fibrosis. In further or additional embodiments, an effective amount
of a composition comprising a pharmaceutically acceptable salt of a
compound of formula I is administered.
[0027] In other aspects, the present invention is directed to a
method for degrading, inhibiting the growth of or killing a cancer
cell comprising contacting said cell with an amount of a
composition effective to degrade, inhibit the growth of or to kill
said cell, the composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof.
[0028] In other aspects, the present invention is directed to use
of a compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof in the
preparation of a pharmaceutical composition for degrading and/or
inhibiting the growth of or killing a cancer cell.
[0029] In some embodiments, the cancer cells comprise brain,
breast, lung, ovarian, pancreatic, prostate, renal, or colorectal
cancer cells. In further or additional embodiments, the composition
is administered with at least one therapeutic agent. In further or
additional embodiments, the therapeutic agent is taxol, bortezomib
or both. In further or additional embodiments, the therapeutic
agent is selected from the group consisting of cytotoxic agents,
anti-angiogenesis agents and anti-neoplastic agents. In further or
additional embodiments, the anti-neoplastic agents selected from
the group of consisting of alkylating agents, anti-metabolites,
epidophyllotoxins; antineoplastic enzymes, topoisomerase
inhibitors, procarbazines, mitoxantrones, platinum coordination
complexes, biological response modifiers and growth inhibitors,
hormonal/anti-hormonal therapeutic agents, and haematopoietic
growth factors. In some embodiments, the cancer cells are degraded.
In further or additional embodiments, 1% of the cancer cells are
degraded. In further or additional embodiments, 2% of the cancer
cells are degraded. In further or additional embodiments, 3% of the
cancer cells are degraded. In further or additional embodiments, 4%
of the cancer cells are degraded. In further or additional
embodiments, 5% of the cancer cells are degraded. In further or
additional embodiments, 10% of the cancer cells are degraded. In
further or additional embodiments, 20% of the cancer cells are
degraded. In further or additional embodiments, 25% of the cancer
cells are degraded. In further or additional embodiments, 30% of
the cancer cells are degraded. In further or additional
embodiments, 40% of the cancer cells are degraded. In further or
additional embodiments, 50% of the cancer cells are degraded. In
further or additional embodiments, 60% of the cancer cells are
degraded. In further or additional embodiments, 70% of the cancer
cells are degraded. In further or additional embodiments, 75% of
the cancer cells are degraded. In further or additional
embodiments, 80% of the cancer cells are degraded. In further or
additional embodiments, 90% of the cancer cells are degraded. In
further or additional embodiments, 100% of the cancer cells are
degraded. In further or additional embodiments, essentially all of
the cancer cells are degraded. In some embodiments, the cancer
cells are killed. In further or additional embodiments, 1% of the
cancer cells are killed. In further or additional embodiments, 2%
of the cancer cells are killed. In further or additional
embodiments, 3% of the cancer cells are killed. In further or
additional embodiments, 4% of the cancer cells are killed. In
further or additional embodiments, 5% of the cancer cells are
killed. In further or additional embodiments, 10% of the cancer
cells are killed. In further or additional embodiments, 20% of the
cancer cells are killed. In further or additional embodiments, 25%
of the cancer cells are killed. In further or additional
embodiments, 30% of the cancer cells are killed. In further or
additional embodiments, 40% of the cancer cells are killed. In
further or additional embodiments, 50% of the cancer cells are
killed. In further or additional embodiments, 60% of the cancer
cells are killed. In further or additional embodiments, 70% of the
cancer cells are killed. In further or additional embodiments, 75%
of the cancer cells are killed. In further or additional
embodiments, 80% of the cancer cells are killed. In further or
additional embodiments, 90% of the cancer cells are killed. In
further or additional embodiments, 100% of the cancer cells are
killed. In further or additional embodiments, essentially all of
the cancer cells are killed. In further or additional embodiments,
the growth of the cancer cells is inhibited. In further or
additional embodiments, the growth of the cancer cells is about 1%
inhibited. In further or additional embodiments, the growth of the
cancer cells is about 2% inhibited. In further or additional
embodiments, the growth of the cancer cells is about 3% inhibited.
In further or additional embodiments, the growth of the cancer
cells is about 4% inhibited. In further or additional embodiments,
the growth of the cancer cells is about 5% inhibited. In further or
additional embodiments, the growth of the cancer cells is about 10%
inhibited. In further or additional embodiments, the growth of the
cancer cells is about 20% inhibited. In further or additional
embodiments, the growth of the cancer cells is about 25% inhibited.
In further or additional embodiments, the growth of the cancer
cells is about 30% inhibited. In further or additional embodiments,
the growth of the cancer cells is about 40% inhibited. In further
or additional embodiments, the growth of the cancer cells is about
50% inhibited. In further or additional embodiments, the growth of
the cancer cells is about 60% inhibited. In further or additional
embodiments, the growth of the cancer cells is about 70% inhibited.
In further or additional embodiments, the growth of the cancer
cells is about 75% inhibited. In further or additional embodiments,
the growth of the cancer cells is about 80% inhibited. In further
or additional embodiments, the growth of the cancer cells is about
90% inhibited. In further or additional embodiments, the growth of
the cancer cells is about 100% inhibited. In further or additional
embodiments, a composition comprising a pharmaceutically acceptable
salt of a compound of formula I is used.
[0030] In other aspects, the present invention is directed to a
method for the treatment or prophylaxis of a proliferative disease
in an individual comprising administering to said individual an
effective amount of a composition comprising a compound of formula
I or a pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or pro-drug thereof.
[0031] In other aspects, the present invention is directed to use
of a compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof in the
preparation of a pharmaceutical composition for the treatment or
prophylaxis of a proliferative disease.
[0032] In some embodiments, the proliferative disease is cancer,
psoriasis, restenosis, autoimmune disease, or atherosclerosis. In
further or additional embodiments, the proliferative disease is a
hyperproliferative disease. In further or additional embodiments,
the proliferative disease is selected from the group consisting of
tumors, leukemias, neoplasms, cancers, carcinomas and malignant
disease. In further or additional embodiments, the cancer is brain
cancer, breast cancer, lung cancer, ovarian cancer, pancreatic
cancer, prostate cancer, renal cancer, colorectal cancer or
leukemia. In further or additional embodiments, the fibrogenetic
disorder is scleroderma, polymyositis, systemic lupus, rheumatoid
arthritis, liver cirrhosis, keloid formation, interstitial
nephritis or pulmonary fibrosis. In further or additional
embodiments, the cancer is brain cancer, breast cancer, lung
cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal
cancer, colorectal cancer or leukemia. In further or additional
embodiments, the cancer is brain cancer or adrenocortical
carcinoma. In further or additional embodiments, the cancer is
breast cancer. In further or additional embodiments, the cancer is
ovarian cancer. In further or additional embodiments, the cancer is
pancreatic cancer. In further or additional embodiments, the cancer
is prostate cancer. In further or additional embodiments, the
cancer is renal cancer. In further or additional embodiments, the
cancer is colorectal cancer. In further or additional embodiments,
the cancer is myeloid leukemia. In further or additional
embodiments, the cancer is glioblastoma. In further or additional
embodiments, the cancer is follicular lymphoma. In further or
additional embodiments, the cancer is pre-B acute leukemia. In
further or additional embodiments, the cancer is chronic
lymphocytic B-leukemia. In further or additional embodiments, the
cancer is mesothelioma. In further or additional embodiments, the
cancer is small cell line cancer. In some embodiments, the
composition comprising a compound of formula I is administered in
combination with an additional therapy. In further or additional
embodiments, the additional therapy is radiation therapy,
chemotherapy or a combination of both. In further or additional
embodiments, the composition comprising a compound of formula I is
administered in combination with at least one therapeutic agent. In
further or additional embodiments, the therapeutic agent is
selected from the group of cytotoxic agents, anti-angiogenesis
agents and anti-neoplastic agents. In further or additional
embodiments, the anti-neoplastic agent is selected from the group
of consisting of alkylating agents, anti-metabolites,
epidophyllotoxins; antineoplastic enzymes, topoisomerase
inhibitors, procarbazines, mitoxantrones, platinum coordination
complexes, biological response modifiers and growth inhibitors,
hormonal/anti-hormonal therapeutic agents, and haematopoietic
growth factors. In further or additional embodiments, the
therapeutic agent is selected from taxol, bortezomib or both. In
some embodiments, the composition is administered orally,
intraduodenally, parenterally (including intravenous, subcutaneous,
intramuscular, intravascular or by infusion), topically or
rectally. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg body weight/day. In further or additional
embodiments the amount of compound of formula I is about 0.001 to
about 7 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.01 to about 7 g/day. In further or
additional embodiments the amount of compound of formula I is about
0.02 to about 5 g/day. In further or additional embodiments the
amount of compound of formula I is about 0.05 to about 2.5 g/day.
In further or additional embodiments the amount of compound of
formula I is about 0.1 to about 1 g/day. In further or additional
embodiments, dosage levels below the lower limit of the aforesaid
range may be more than adequate. In further or additional
embodiments, dosage levels above the upper limit of the aforesaid
range may be required. In further or additional embodiments the
compound of formula I is administered in a single dose, once daily.
In further or additional embodiments the compound of formula I is
administered in multiple doses, more than once per day. In further
or additional embodiments the compound of formula I is administered
twice daily. In further or additional embodiments the compound of
formula I is administered three times per day. In further or
additional embodiments the compound of formula I is administered
four times per day. In further or additional embodiments the
compound of formula I is administered more than four times per day.
In some embodiments, the individual suffering from the
proliferative disease is a mammal. In further or additional
embodiments, the individual is a human. In further or additional
embodiments, an effective amount of a composition comprising a
pharmaceutically acceptable salt of a compound of formula I is
administered.
[0033] In other aspects, the present invention is directed to a
method for the treatment or prophylaxis of an inflammatory disease
in an individual comprising administering to said individual an
effective amount of a composition comprising a compound of formula
I or a pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof.
[0034] In other aspects, the present invention is directed to use
of a compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof in the
preparation of a pharmaceutical composition for the treatment or
prophylaxis of an inflammatory disease.
[0035] In further or additional embodiments, the inflammatory
disease is selected from chronic inflammatory diseases, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,
juvenile arthritis, acute rheumatic arthritis, enteropathic
arthritis, neuropathic arthritis, psoriatic arthritis, pyogenic
arthritis, atherosclerosis, systemic lupus erythematosus,
inflammatory bowel disease, irritable bowel syndrome, ulcerative
colitis, reflux esophagitis, Crohn's disease, gastritis, asthma,
allergies, respiratory distress syndrome, pancreatitis, chronic
obstructive pulmonary disease, pulmonary fibrosis, psoriasis,
eczema or scleroderma. In some embodiments, the composition
comprising a compound of formula I is administered in combination
with an additional therapy. In further or additional embodiments,
the composition comprising a compound of formula I is administered
in combination with at least one therapeutic agent. In some
embodiments, the composition is administered orally,
intraduodenally, parenterally (including intravenous, subcutaneous,
intramuscular, intravascular or by infusion), topically or
rectally. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg body weight/day. In further or additional
embodiments the amount of compound of formula I is about 0.001 to
about 7 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.01 to about 7 g/day. In further or
additional embodiments the amount of compound of formula I is about
0.02 to about 5 g/day. In further or additional embodiments the
amount of compound of formula I is about 0.05 to about 2.5 g/day.
In further or additional embodiments the amount of compound of
formula I is about 0.1 to about 1 g/day. In further or additional
embodiments, dosage levels below the lower limit of the aforesaid
range may be more than adequate. In further or additional
embodiments, dosage levels above the upper limit of the aforesaid
range may be required. In further or additional embodiments the
compound of formula I is administered in a single dose, once daily.
In further or additional embodiments the compound of formula I is
administered in multiple doses, more than once per day. In further
or additional embodiments the compound of formula I is administered
twice daily. In further or additional embodiments the compound of
formula I is administered three times per day. In further or
additional embodiments the compound of formula I is administered
four times per day. In further or additional embodiments the
compound of formula I is administered more than four times per day.
In some embodiments, the individual suffering from the inflammatory
disease is a mammal. In further or additional embodiments, the
individual is a human. In further or additional embodiments, an
effective amount of a composition comprising a pharmaceutically
acceptable salt of a compound of formula I is administered.
[0036] In other aspects, the present invention is directed to a
method for the treatment or prophylaxis of cancer in an individual
comprising administering to said individual an effective amount of
a composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, polymorph, ester,
tautomer or prodrug thereof.
[0037] In other aspects, the present invention is directed to use
of a compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof in the
preparation of a pharmaceutical composition for the treatment or
prophylaxis of a cancer.
[0038] In further or additional embodiments, the cancer is brain
cancer, breast cancer, lung cancer, ovarian cancer, pancreatic
cancer, prostate cancer, renal cancer, colorectal cancer or
leukemia. In further or additional embodiments, the fibrogenetic
disorder is scleroderma, polymyositis, systemic lupus, rheumatoid
arthritis, liver cirrhosis, keloid formation, interstitial
nephritis or pulmonary fibrosis. In further or additional
embodiments, the cancer is brain cancer, breast cancer, lung
cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal
cancer, colorectal cancer or leukemia. In further or additional
embodiments, the cancer is brain cancer or adrenocortical
carcinoma. In further or additional embodiments, the cancer is
breast cancer. In further or additional embodiments, the cancer is
ovarian cancer. In further or additional embodiments, the cancer is
pancreatic cancer. In further or additional embodiments, the cancer
is prostate cancer. In further or additional embodiments, the
cancer is renal cancer. In further or additional embodiments, the
cancer is colorectal cancer. In further or additional embodiments,
the cancer is myeloid leukemia. In further or additional
embodiments, the cancer is glioblastoma. In further or additional
embodiments, the cancer is follicular lymphoma. In further or
additional embodiments, the cancer is pre-B acute leukemia. In
further or additional embodiments, the cancer is chronic
lymphocytic B-leukemia. In further or additional embodiments, the
cancer is mesothelioma. In further or additional embodiments, the
cancer is small cell line cancer. In some embodiments, the
composition comprising a compound of formula I is administered in
combination with an additional therapy. In further or additional
embodiments, the additional therapy is radiation therapy,
chemotherapy or a combination of both. In further or additional
embodiments, the composition comprising a compound of formula I is
administered in combination with at least one therapeutic agent. In
further or additional embodiments, the therapeutic agent is
selected from the group of cytotoxic agents, anti-angiogenesis
agents and anti-neoplastic agents. In further or additional
embodiments, the anti-neoplastic agent is selected from the group
of consisting of alkylating agents, anti-metabolites,
epidophyllotoxins; antineoplastic enzymes, topoisomerase
inhibitors, procarbazines, mitoxantrones, platinum coordination
complexes, biological response modifiers and growth inhibitors,
hormonal/anti-hormonal therapeutic agents, and haematopoietic
growth factors. In further or additional embodiments, the
therapeutic agent is selected from taxol, bortezomib or both. In
some embodiments, the composition is administered orally,
intraduodenally, parenterally (including intravenous, subcutaneous,
intramuscular, intravascular or by infusion), topically or
rectally. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg body weight/day. In further or additional
embodiments the amount of compound of formula I is about 0.001 to
about 7 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.01 to about 7 g/day. In further or
additional embodiments the amount of compound of formula I is about
0.02 to about 5 g/day. In further or additional embodiments the
amount of compound of formula I is about 0.05 to about 2.5 g/day.
In further or additional embodiments the amount of compound of
formula I is about 0.1 to about 1 g/day. In further or additional
embodiments, dosage levels below the lower limit of the aforesaid
range may be more than adequate. In further or additional
embodiments, dosage levels above the upper limit of the aforesaid
range may be required. In further or additional embodiments the
compound of formula I is administered in a single dose, once daily.
In further or additional embodiments the compound of formula I is
administered in multiple doses, more than once per day. In further
or additional embodiments the compound of formula I is administered
twice daily. In further or additional embodiments the compound of
formula I is administered three times per day. In further or
additional embodiments the compound of formula I is administered
four times per day. In further or additional embodiments the
compound of formula I is administered more than four times per day.
In some embodiments, the individual suffering from cancer is a
mammal. In further or additional embodiments, the individual is a
human. In further or additional embodiments, an effective amount of
a composition comprising a pharmaceutically acceptable salt of a
compound of formula I is administered.
[0039] In other aspects, the present invention is directed to a
method of reducing the size of a tumor, inhibiting tumor size
increase, reducing tumor proliferation or preventing tumor
proliferation in an individual, comprising administering to said
individual an effective amount of a composition comprising a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof.
[0040] In other aspects, the present invention is directed to use
of a compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof in the
preparation of a pharmaceutical composition for reducing the size
of a tumor, inhibiting tumor size increase, reducing tumor
proliferation or preventing tumor proliferation.
[0041] In some embodiments, the size of a tumor is reduced. In
further or additional embodiments, the size of a tumor is reduced
by at least 1%. In further or additional embodiments, the size of a
tumor is reduced by at least 2%. In further or additional
embodiments, the size of a tumor is reduced by at least 3%. In
further or additional embodiments, the size of a tumor is reduced
by at least 4%. In further or additional embodiments, the size of a
tumor is reduced by at least 5%. In further or additional
embodiments, the size of a tumor is reduced by at least 10%. In
further or additional embodiments, the size of a tumor is reduced
by at least 20%. In further or additional embodiments, the size of
a tumor is reduced by at least 25%. In further or additional
embodiments, the size of a tumor is reduced by at least 30%. In
further or additional embodiments, the size of a tumor is reduced
by at least 40%. In further or additional embodiments, the size of
a tumor is reduced by at least 50%. In further or additional
embodiments, the size of a tumor is reduced by at least 60%. In
further or additional embodiments, the size of a tumor is reduced
by at least 70%. In further or additional embodiments, the size of
a tumor is reduced by at least 75%. In further or additional
embodiments, the size of a tumor is reduced by at least 80%. In
further or additional embodiments, the size of a tumor is reduced
by at least 85%. In further or additional embodiments, the size of
a tumor is reduced by at least 90%. In further or additional
embodiments, the size of a tumor is reduced by at least 95%. In
further or additional embodiments, the tumor is eradicated. In some
embodiments, the size of a tumor does not increase. In some
embodiments, tumor proliferation is reduced. In some embodiments,
tumor proliferation is reduced by at least 1%. In some embodiments,
tumor proliferation is reduced by at least 2%. In some embodiments,
tumor proliferation is reduced by at least 3%. In some embodiments,
tumor proliferation is reduced by at least 4%. In some embodiments,
tumor proliferation is reduced by at least 5%. In some embodiments,
tumor proliferation is reduced by at least 10%. In some
embodiments, tumor proliferation is reduced by at least 20%. In
some embodiments, tumor proliferation is reduced by at least 25%.
In some embodiments, tumor proliferation is reduced by at least
30%. In some embodiments, tumor proliferation is reduced by at
least 40%. In some embodiments, tumor proliferation is reduced by
at least 50%. In some embodiments, tumor proliferation is reduced
by at least 60%. In some embodiments, tumor proliferation is
reduced by at least 70%. In some embodiments, tumor proliferation
is reduced by at least 75%. In some embodiments, tumor
proliferation is reduced by at least 80%. In some embodiments,
tumor proliferation is reduced by at least 90%. In some
embodiments, tumor proliferation is reduced by at least 95%. In
some embodiments, tumor proliferation is prevented. In some
embodiments, the composition comprising a compound of formula I is
administered in combination with an additional therapy. In further
or additional embodiments, the additional therapy is radiation
therapy, chemotherapy or a combination of both. In further or
additional embodiments, the composition comprising a compound of
formula I is administered in combination with at least one
therapeutic agent. In further or additional embodiments, the
therapeutic agent is selected from the group of cytotoxic agents,
anti-angiogenesis agents and anti-neoplastic agents. In further or
additional embodiments, the anti-neoplastic agent is selected from
the group of consisting of alkylating agents, anti-metabolites,
epidophyllotoxins; antineoplastic enzymes, topoisomerase
inhibitors, procarbazines, mitoxantrones, platinum coordination
complexes, biological response modifiers and growth inhibitors,
hormonal/anti-hormonal therapeutic agents, and haematopoietic
growth factors. In further or additional embodiments, the
therapeutic agent is selected from taxol, bortezomib or both. In
some embodiments, the composition is administered orally,
intraduodenally, parenterally (including intravenous, subcutaneous,
intramuscular, intravascular or by infusion), topically or
rectally. In further or additional embodiments the amount of
compound of formula I is in the range of about 0.001 to about 1000
mg/kg body weight/day. In further or additional embodiments the
amount of compound of formula I is in the range of about 0.5 to
about 50 mg/kg body weight/day. In further or additional
embodiments the amount of compound of formula I is about 0.001 to
about 7 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.01 to about 7 g/day. In further or
additional embodiments the amount of compound of formula I is about
0.02 to about 5 g/day. In further or additional embodiments the
amount of compound of formula I is about 0.05 to about 2.5 g/day.
In further or additional embodiments the amount of compound of
formula I is about 0.1 to about 1 g/day. In further or additional
embodiments, dosage levels below the lower limit of the aforesaid
range may be more than adequate. In further or additional
embodiments, dosage levels above the upper limit of the aforesaid
range may be required. In further or additional embodiments the
compound of formula I is administered in a single dose, once daily.
In further or additional embodiments the compound of formula I is
administered in multiple doses, more than once per day. In further
or additional embodiments the compound of formula I is administered
twice daily. In further or additional embodiments the compound of
formula I is administered three times per day. In further or
additional embodiments the compound of formula I is administered
four times per day. In further or additional embodiments the
compound of formula I is administered more than four times per day.
In some embodiments, the individual suffering from cancer is a
mammal. In further or additional embodiments, the individual is a
human. In further or additional embodiments, an effective amount of
a composition comprising a pharmaceutically acceptable salt of a
compound of formula I is administered.
[0042] In other aspects, the present invention is directed to a
method for achieving an effect in a patient comprising the
administration of an effective amount of a composition comprising a
compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof, to a
patient, wherein the effect is selected from the group consisting
of inhibition of various cancers, immunological diseases, and
inflammatory diseases. In some embodiments, the effect is
inhibition of various cancers. In further or additional
embodiments, the effect is inhibition of immunological diseases. In
further or additional embodiments, the effect is inhibition
inflammatory diseases.
[0043] In other aspects, the present invention is directed to use
of a compound of formula I or a pharmaceutically acceptable salt,
solvate, polymorph, ester, tautomer or prodrug thereof in the
preparation of a pharmaceutical composition for the inhibiting
various cancers, immunological diseases, and/or inflammatory
diseases.
[0044] In some embodiments, the composition comprising a compound
of formula I is administered in combination with an additional
therapy. In further or additional embodiments, the additional
therapy is radiation therapy, chemotherapy or a combination of
both. In further or additional embodiments, the composition
comprising a compound of formula I is administered in combination
with at least one therapeutic agent. In some embodiments, the
composition is administered orally, intraduodenally, parenterally
(including intravenous, subcutaneous, intramuscular, intravascular
or by infusion), topically or rectally. In further or additional
embodiments the amount of compound of formula I is in the range of
about 0.001 to about 1000 mg/kg body weight/day. In further or
additional embodiments the amount of compound of formula I is in
the range of about 0.5 to about 50 mg/kg body weight/day. In
further or additional embodiments the amount of compound of formula
I is about 0.001 to about 7 g/day. In further or additional
embodiments the amount of compound of formula I is about 0.01 to
about 7 g/day. In further or additional embodiments the amount of
compound of formula I is about 0.02 to about 5 g/day. In further or
additional embodiments the amount of compound of formula I is about
0.05 to about 2.5 g/day. In further or additional embodiments the
amount of compound of formula I is about 0.1 to about 1 g/day. In
further or additional embodiments, dosage levels below the lower
limit of the aforesaid range may be more than adequate. In further
or additional embodiments, dosage levels above the upper limit of
the aforesaid range may be required. In further or additional
embodiments the compound of formula I is administered in a single
dose, once daily. In further or additional embodiments the compound
of formula I is administered in multiple doses, more than once per
day. In further or additional embodiments the compound of formula I
is administered twice daily. In further or additional embodiments
the compound of formula I is administered three times per day. In
further or additional embodiments the compound of formula I is
administered four times per day. In further or additional
embodiments the compound of formula I is administered more than
four times per day. In some embodiments, the individual suffering
from cancer is a mammal. In further or additional embodiments, the
individual is a human. In further or additional embodiments, an
effective amount of a composition comprising a pharmaceutically
acceptable salt of a compound of formula I is administered.
[0045] In other aspects, the present invention is directed to a
process for preparing a compound of formula I or a pharmaceutically
acceptable salt, solvate, polymorph, ester, tautomer or prodrug
thereof.
DETAILED DESCRIPTION
[0046] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized.
[0047] While preferred embodiments of the present invention have
been shown and described herein such embodiments are provided by
way of example only. It should be understood that various
alternatives to the embodiments of the invention described herein
may be employed in practicing the invention. Those ordinary skilled
in the art will appreciate that numerous variations, changes, and
substitutions are possible without departing from the invention. It
is intended that the following claims define the scope of aspects
of the invention and that methods and structures within the scope
of these claims and their equivalents be covered thereby.
[0048] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
the application including, without limitation, patents, patent
applications, articles, books, manuals, and treatises are hereby
expressly incorporated by reference in their entirety for any
purpose.
Certain Chemical Terminology
[0049] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which the claimed subject matter belongs.
All patents, patent applications, published materials referred to
throughout the entire disclosure herein, unless noted otherwise,
are incorporated by reference in their entirety. In the event that
there is a plurality of definitions for terms herein, those in this
section prevail. Where reference is made to a URL or other such
identifier or address, it is understood that such identifiers can
change and particular information on the internet can come and go,
but equivalent information can be found by searching the internet
or other appropriate reference source. Reference thereto evidences
the availability and public dissemination of such information.
[0050] It is to be understood that the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of any subject matter
claimed. In this application, the use of the singular includes the
plural unless specifically stated otherwise. It must be noted that,
as used in the specification and the appended claims, the singular
forms "a", "an" and "the" include plural referents unless the
context clearly dictates otherwise. It should also be noted that
use of "or" means "and/or" unless stated otherwise. Furthermore,
use of the term "including" as well as other forms, such as
"include", "includes", and "included" is not limiting. Likewise,
use of the term "comprising" as well as other forms, such as
"comprise", "comprises", and "comprised" is not limiting.
Definition of standard chemistry terms may be found in reference
works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY
4.sup.TH ED." Vols. A (2000) and B (2001), Plenum Press, New York.
Unless otherwise indicated, conventional methods of mass
spectroscopy, NMR, HPLC, IR and UV/Vis spectroscopy and
pharmacology, within the skill of the art are employed. Unless
specific definitions are provided, the nomenclature employed in
connection with, and the laboratory procedures and techniques of,
analytical chemistry, synthetic organic chemistry, and medicinal
and pharmaceutical chemistry described herein are those known in
the art. Standard techniques can be used for chemical syntheses,
chemical analyses, pharmaceutical preparation, formulation, and
delivery, and treatment of patients. Reactions and purification
techniques can be performed e.g., using kits of manufacturer's
specifications or as commonly accomplished in the art or as
described herein. The foregoing techniques and procedures can be
generally performed of conventional methods well known in the art
and as described in various general and more specific references
that are cited and discussed throughout the present specification.
Throughout the specification, groups and substituents thereof can
be chosen by one skilled in the field to provide stable moieties
and compounds.
[0051] Where substituent groups are specified by their conventional
chemical formulas, written from left to right, they equally
encompass the chemically identical substituents that would result
from writing the structure from right to left. As a non-limiting
example, CH.sub.2O is equivalent to OCH.sub.2.
[0052] Unless otherwise noted, the use of general chemical terms,
such as though not limited to "alkyl," "amine," "aryl," are
equivalent to their optionally substituted forms. For example,
"alkyl," as used herein, includes optionally substituted alkyl.
[0053] The terms "moiety", "chemical moiety", "group" and "chemical
group", as used herein refer to a specific segment or functional
group of a molecule. Chemical moieties are often recognized
chemical entities embedded in or appended to a molecule.
[0054] The term "bond" or "single bond" refers to a chemical bond
between two atoms, or two moieties when the atoms joined by the
bond are considered to be part of larger substructure.
[0055] The term "catalytic group" refers to a chemical functional
group that assists catalysis by acting to lower the activation
barrier to reaction.
[0056] The term "optional" or "optionally" means that the
subsequently described event or circumstance may or may not occur,
and that the description includes instances where said event or
circumstance occurs and instances in which it does not. For
example, "optionally substituted alkyl" means either "alkyl" or
"substituted alkyl" as defined below. Further, an optionally
substituted group may be un-substituted (e.g., CH.sub.2CH.sub.3),
fully substituted (e.g., CF.sub.2CF.sub.3), mono-substituted (e.g.,
CH.sub.2CH.sub.2F) or substituted at a level anywhere in-between
fully substituted and mono-substituted (e.g., CH.sub.2CHF.sub.2,
CF.sub.2CH.sub.3, CFHCHF.sub.2, etc). It will be understood by
those skilled in the art with respect to any group containing one
or more substituents that such groups are not intended to introduce
any substitution or substitution patterns (e.g., substituted alkyl
includes optionally substituted cycloalkyl groups, which in turn
are defined as including optionally substituted alkyl groups,
potentially ad infinitum) that are sterically impractical and/or
synthetically non-feasible. Thus, any substituents described should
generally be understood as having a maximum molecular weight of
about 1,000 daltons, and more typically, up to about 500 daltons
(except in those instances where macromolecular substituents are
clearly intended, e.g., polypeptides, polysaccharides, polyethylene
glycols, DNA, RNA and the like).
[0057] As used herein, C.sub.1-Cn, includes C.sub.1-C.sub.2,
C.sub.1-C.sub.3 . . . C.sub.1-Cn. By way of example only, a group
designated as "C.sub.1-C.sub.4" indicates that there are one to
four carbon atoms in the moiety, i.e. groups containing 1 carbon
atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as
the ranges C.sub.1-C.sub.2 and C.sub.1-C.sub.3. Thus, by way of
example only, "C.sub.1-C.sub.4 alkyl" indicates that there are one
to four carbon atoms in the alkyl group, i.e., the alkyl group is
selected from among methyl, ethyl, propyl, iso-propyl, n-butyl,
isobutyl, sec-butyl, and t-butyl. Whenever it appears herein, a
numerical range such as "1 to 10" refers to each integer in the
given range; e.g., "1 to 10 carbon atoms" means that the group may
have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms,
5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9
carbon atoms, or 10 carbon atoms.
[0058] The term "hydrocarbon" as used herein, alone or in
combination, refers to a compound or chemical group containing only
carbon and hydrogen atoms.
[0059] The terms "heteroatom" or "hetero" as used herein, alone or
in combination, refer to an atom other than carbon and hydrogen.
Heteroatoms are independently selected from among oxygen, nitrogen,
sulfur, phosphorous, silicon, selenium and tin but are not limited
to these atoms. In embodiments in which two or more heteroatoms are
present, the two or more heteroatoms can be the same as each
another, or some or all of the two or more heteroatoms can each be
different from the others.
[0060] The term "alkyl" as used herein, alone or in combination,
refers to an optionally substituted straight-chain, or optionally
substituted branched-chain saturated hydrocarbon monoradical having
from one to about ten carbon atoms, more preferably one to six
carbon atoms. Examples include, but are not limited to methyl,
ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,
2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,
2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,
4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,
4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,
2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,
isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups,
such as heptyl, octyl and the like. Whenever it appears herein, a
numerical range such as "C.sub.1-C.sub.6 alkyl" or
"C.sub.1.sub.--.sub.6 alkyl", means that the alkyl group may
consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon
atoms, 5 carbon atoms or 6 carbon atoms, although the present
definition also covers the occurrence of the term "alkyl" where no
numerical range is designated.
[0061] The term "aliphatic" as used herein, alone or in
combination, refers to an optionally substituted, straight-chain or
branched-chain, non-cyclic, saturated, partially unsaturated, or
fully unsaturated nonaromatic hydrocarbon. Thus, the term
collectively includes alkyl, alkenyl and alkynyl groups.
[0062] The term "carbon chain" as used herein, alone or in
combination, refers to any alkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl or heteroalkynyl group, which is linear, cyclic, or
any combination thereof. If the chain is part of a linker and that
linker comprises one or more rings as part of the core backbone,
for purposes of calculating chain length, the "chain" only includes
those carbon atoms that compose the bottom or top of a given ring
and not both, and where the top and bottom of the ring(s) are not
equivalent in length, the shorter distance shall be used in
determining the chain length. If the chain contains heteroatoms as
part of the backbone, those atoms are not calculated as part of the
carbon chain length.
[0063] The terms "cycle", "cyclic", "ring" and "membered ring" as
used herein, alone or in combination, refer to any covalently
closed structure, including alicyclic, heterocyclic, aromatic,
heteroaromatic and polycyclic fused or non-fused ring systems as
described herein. Rings can be optionally substituted. Rings can
form part of a fused ring system. The term "membered" is meant to
denote the number of skeletal atoms that constitute the ring. Thus,
by way of example only, cyclohexane, pyridine, pyran and pyrimidine
are six-membered rings and cyclopentane, pyrrole, tetrahydrofuran
and thiophene are five-membered rings.
[0064] The term "cycloalkyl" as used herein, alone or in
combination, refers to an optionally substituted, saturated,
hydrocarbon monoradical ring, containing from three to about
fifteen ring carbon atoms or from three to about ten ring carbon
atoms, though may include additional, non-ring carbon atoms as
substituents (e.g. methylcyclopropyl).
[0065] A non-limiting example of "cycloalkyl" includes azinyl,
azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and
quinolizinyl and the like. The terms also include all ring forms of
the carbohydrates, including but not limited to the
monosaccharides, the disaccharides and the oligosaccharides.
[0066] The term "aromatic" as used herein, refers to a planar,
cyclic or polycyclic, ring moiety having a delocalized at-electron
system containing 4n+2 n electrons, where n is an integer. Aromatic
rings can be formed by five, six, seven, eight, nine, or more than
nine atoms. Aromatics can be optionally substituted and can be
monocyclic or fused-ring polycyclic. The term aromatic encompasses
both all carbon containing rings (e.g., phenyl) and those rings
containing one or more heteroatoms (e.g., pyridine).
[0067] The term "aryl" as used herein, alone or in combination,
refers to an optionally substituted aromatic hydrocarbon radical of
six to about twenty ring carbon atoms, and includes fused and
non-fused aryl rings. A fused aryl ring radical contains from two
to four fused rings where the ring of attachment is an aryl ring,
and the other individual rings may be alicyclic, heterocyclic,
aromatic, heteroaromatic or any combination thereof. Further, the
term aryl includes fused and non-fused rings containing from six to
about twelve ring carbon atoms, as well as those containing from
six to about ten ring carbon atoms. A non-limiting example of a
single ring aryl group includes phenyl; a fused ring aryl group
includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and a
non-fused bi-aryl group includes biphenyl.
[0068] The term "heteroaryl" as used herein, alone or in
combination, refers to optionally substituted aromatic
mono-radicals containing from about five to about twenty skeletal
ring atoms, where one or more of the ring atoms is a heteroatom
independently selected from among oxygen, nitrogen, sulfur,
phosphorous, silicon, selenium and tin but not limited to these
atoms and with the proviso that the ring of said group does not
contain two adjacent O or S atoms. In embodiments in which two or
more heteroatoms are present in the ring, the two or more
heteroatoms can be the same as each another, or some or all of the
two or more heteroatoms can each be different from the others. The
term heteroaryl includes optionally substituted fused and non-fused
heteroaryl radicals having at least one heteroatom. The term
heteroaryl also includes fused and non-fused heteroaryls having
from five to about twelve skeletal ring atoms, as well as those
having from five to about ten skeletal ring atoms. Bonding to a
heteroaryl group can be via a carbon atom or a heteroatom. Thus, as
a non-limiting example, an imidiazole group may be attached to a
parent molecule via any of its carbon atoms (imidazol-2-yl,
imidazol-4-yl or imidazol-5-yl), or its nitrogen atoms
(imidazol-1-yl or imidazol-3-yl) Likewise, a heteroaryl group may
be further substituted via any or all of its carbon atoms, and/or
any or all of its heteroatoms. A fused heteroaryl radical may
contain from two to four fused rings where the ring of attachment
is a heteroaromatic ring and the other individual rings may be
alicyclic, heterocyclic, aromatic, heteroaromatic or any
combination thereof. A non-limiting example of a single ring
heteroaryl group includes pyridyl; fused ring heteroaryl groups
include benzimidazolyl, quinolinyl, acridinyl; and a non-fused
bi-heteroaryl group includes bipyridinyl. Further examples of
heteroaryls include, without limitation, furanyl, thienyl,
oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl,
benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl,
benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl,
isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl,
indazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl,
pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl,
quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl,
triazinyl, thiadiazolyl and the like, and their oxides, such as for
example pyridyl-N-oxide and the like.
[0069] The term "heterocycle" as used herein, alone or in
combination, refers collectively to heteroalicyclyl and heteroaryl
groups. Herein, whenever the number of carbon atoms in a
heterocycle is indicated (e.g., C.sub.1-C.sub.6 heterocycle), at
least one non-carbon atom (the heteroatom) must be present in the
ring. Designations such as "C.sub.1-C.sub.6 heterocycle" refer only
to the number of carbon atoms in the ring and do not refer to the
total number of atoms in the ring. Designations such as "4-6
membered heterocycle" refer to the total number of atoms that are
contained in the ring (i.e., a four, five, or six membered ring, in
which at least one atom is a carbon atom, at least one atom is a
heteroatom and the remaining two to four atoms are either carbon
atoms or heteroatoms). For heterocycles having two or more
heteroatoms, those two or more heteroatoms can be the same or
different from one another. Heterocycles can be optionally
substituted. Non-aromatic heterocyclic groups include groups having
only three atoms in the ring, while aromatic heterocyclic groups
must have at least five atoms in the ring. Bonding (i.e. attachment
to a parent molecule or further substitution) to a heterocycle can
be via a heteroatom or a carbon atom.
[0070] The terms "halogen", "halo" or "halide" as used herein,
alone or in combination refer to fluoro, chloro, bromo and
iodo.
[0071] The term "alkoxy" as used herein, alone or in combination,
refers to an alkyl ether radical, O-alkyl, including the groups
O-aliphatic and O-carbocycle, wherein the alkyl, aliphatic and
carbocycle groups may be optionally substituted, and wherein the
terms alkyl, aliphatic and carbocycle are as defined herein.
Non-limiting examples of alkoxy radicals include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tertbutoxy
and the like.
[0072] The term "sulfonyl" as used herein, alone or in combination,
refers to the diradical --S(--O).sub.2.
[0073] The terms "sulfonamide", "sulfonamido" and "sulfonamidyl" as
used herein, alone or in combination, refer to the diradical groups
--S(--O).sub.2--NH-- and --NH--S(.dbd.O).sub.2
[0074] The terms "sulfamide", "sulfamido" and "sulfamidyl" as used
herein, alone or in combination, refer to the diradical group
NHS(--O).sub.2NH.
Certain Pharmaceutical Terminology
[0075] The term "PI3K inhibitor" as used herein refers to a
compound that exhibits an IC.sub.50, with respect to PI3K activity,
of no more than about 100 .mu.M or not more than about 50 .mu.M, as
measured in the PI3 kinase assay described generally herein.
"IC.sub.50" is that concentration of inhibitor which reduces the
activity of an enzyme (e.g., PI3K) to half-maximal level. Compounds
described herein have been discovered to exhibit inhibition against
PI3K. Compounds of the present invention preferably exhibit an
IC.sub.50 with respect to PI3K of no more than about 10 .mu.M, more
preferably, no more than about 5 .mu.M, even more preferably not
more than about 1 .mu.M, and most preferably, not more than about
200 nM, as measured in the PI3 kinase assay described herein.
[0076] The term "subject", "patient" or "individual" as used herein
in reference to individuals suffering from a disorder, a disorder,
a condition, and the like, encompasses mammals and non-mammals.
Examples of mammals include, but are not limited to, any member of
the Mammalian class: humans, non-human primates such as
chimpanzees, and other apes and monkey species; farm animals such
as cattle, horses, sheep, goats, swine; domestic animals such as
rabbits, dogs, and cats; laboratory animals including rodents, such
as rats, mice and guinea pigs, and the like. Examples of
non-mammals include, but are not limited to, birds, fish and the
like. In one embodiment of the methods and compositions provided
herein, the mammal is a human.
[0077] The terms "treat," "treating" or "treatment," and other
grammatical equivalents as used herein, include alleviating,
abating or ameliorating a disease or condition symptoms, preventing
additional symptoms, ameliorating or preventing the underlying
metabolic causes of symptoms, inhibiting the disease or condition,
e.g., arresting the development of the disease or condition,
relieving the disease or condition, causing regression of the
disease or condition, relieving a condition caused by the disease
or condition, or stopping the symptoms of the disease or condition,
and are intended to include prophylaxis. The terms further include
achieving a therapeutic benefit and/or a prophylactic benefit. By
therapeutic benefit is meant eradication or amelioration of the
underlying disorder being treated. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the patient, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions may be
administered to a patient at risk of developing a particular
disease, or to a patient reporting one or more of the physiological
symptoms of a disease, even though a diagnosis of this disease may
not have been made.
[0078] The terms "effective amount", "therapeutically effective
amount" or "pharmaceutically effective amount" as used herein,
refer to a sufficient amount of at least one agent or compound
being administered which will relieve to some extent one or more of
the symptoms of the disease or condition being treated. The result
can be reduction and/or alleviation of the signs, symptoms, or
causes of a disease, or any other desired alteration of a
biological system. For example, an "effective amount" for
therapeutic uses is the amount of the composition comprising a
compound as disclosed herein required to provide a clinically
significant decrease in a disease. An appropriate "effective"
amount in any individual case may be determined using techniques,
such as a dose escalation study.
[0079] The terms "administer," "administering", "administration,"
and the like, as used herein, refer to the methods that may be used
to enable delivery of compounds or compositions to the desired site
of biological action. These methods include, but are not limited to
oral routes, intraduodenal routes, parenteral injection (including
intravenous, subcutaneous, intraperitoneal, intramuscular,
intravascular or infusion), topical and rectal administration.
Those of skill in the art are familiar with administration
techniques that can be employed with the compounds and methods
described herein, e.g., as discussed in Goodman and Gilman, The
Pharmacological Basis of Therapeutics, current ed.; Pergamon; and
Remington's, Pharmaceutical Sciences (current edition), Mack
Publishing Co., Easton, Pa. In preferred embodiments, the compounds
and compositions described herein are administered orally.
[0080] The term "acceptable" as used herein, with respect to a
formulation, composition or ingredient, means having no persistent
detrimental effect on the general health of the subject being
treated.
[0081] The term "pharmaceutically acceptable" as used herein,
refers to a material, such as a carrier or diluent, which does not
abrogate the biological activity or properties of the compounds
described herein, and is relatively nontoxic, i.e., the material
may be administered to an individual without causing undesirable
biological effects or interacting in a deleterious manner with any
of the components of the composition in which it is contained.
[0082] The term "pharmaceutical composition," as used herein,
refers to a biologically active compound, optionally mixed with at
least one pharmaceutically acceptable chemical component, such as,
though not limited to carriers, stabilizers, diluents, dispersing
agents, suspending agents, thickening agents, and/or
excipients.
[0083] The term "carrier" as used herein, refers to relatively
nontoxic chemical compounds or agents that facilitate the
incorporation of a compound into cells or tissues.
[0084] The term "agonist," as used herein, refers to a molecule
such as a compound, a drug, an enzyme activator or a hormone
modulator which enhances the activity of another molecule or the
activity of a receptor site.
[0085] The term "antagonist," as used herein, refers to a molecule
such as a compound, a drug, an enzyme inhibitor, or a hormone
modulator, which diminishes, or prevents the action of another
molecule or the activity of a receptor site.
[0086] The term "modulate," as used herein, means to interact with
a target either directly or indirectly so as to alter the activity
of the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0087] The term "modulator," as used herein, refers to a molecule
that interacts with a target either directly or indirectly. The
interactions include, but are not limited to, the interactions of
an agonist and an antagonist.
[0088] The term "pharmaceutically acceptable salt" as used herein,
refers to salts that retain the biological effectiveness of the
free acids and bases of the specified compound and that are not
biologically or otherwise undesirable. Compounds described herein
may possess acidic or basic groups and therefore may react with any
of a number of inorganic or organic bases, and inorganic and
organic acids, to form a pharmaceutically acceptable salt. These
salts can be prepared in situ during the final isolation and
purification of the compounds of the invention, or by separately
reacting a purified compound in its free base form with a suitable
organic or inorganic acid, and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those salts
prepared by reaction of the compounds described herein with a
mineral or organic acid or an inorganic base, such salts including,
acetate, acrylate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, bisulfite, bromide, butyrate,
butyn-1,4-dioate, camphorate, camphorsulfonate, caprylate,
chlorobenzoate, chloride, citrate, cyclopentanepropionate,
decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate,
dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptanoate, glycerophosphate, glycolate, hemisulfate,
heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,
y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,
malonate, methanesulfonate, mandelate, metaphosphate,
methoxybenzoate, methylbenzoate, monohydrogenphosphate,
1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,
palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,
picrate, pivalate, propionate, pyrosulfate, pyrophosphate,
propiolate, phthalate, phenylacetate, phenylbutyrate,
propanesulfonate, salicylate, succinate, sulfate, sulfite,
suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate
undeconate and xylenesulfonate. Other acids, such as oxalic, while
not in themselves pharmaceutically acceptable, may be employed in
the preparation of salts useful as intermediates in obtaining the
compounds of the invention and their pharmaceutically acceptable
acid addition salts (See examples at Berge et al., J. Pharm. Sci.
1977, 66, 1-19.). Further, those compounds described herein which
may comprise a free acid group may react with a suitable base, such
as the hydroxide, carbonate or bicarbonate of a pharmaceutically
acceptable metal cation, with ammonia, or with a pharmaceutically
acceptable organic primary, secondary or tertiary amine.
Representative alkali or alkaline earth salts include the lithium,
sodium, potassium, calcium, magnesium, and aluminum salts and the
like. Illustrative examples of bases include sodium hydroxide,
potassium hydroxide, choline hydroxide, sodium carbonate, IV'
(C.sub.1.sub.--.sub.4 alkyl).sub.4, and the like. Representative
organic amines useful for the formation of base addition salts
include ethylamine, diethylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine and the like. It should be understood
that the compounds described herein also include the quaternization
of any basic nitrogen-containing groups they may contain. Water or
oil-soluble or dispersible products may be obtained by such
quaternization. See, for example, Berge et al., supra.
[0089] The term "solvate" as used herein refers to a combination of
a compound of this invention with a solvent molecule formed by
solvation. In some situations, the solvate refers to a hydrate,
i.e., the solvent molecule is a water molecule, the combination of
a compound of this invention and water forms a hydrate.
[0090] The term "polymorph" or "polymorphism" as used herein refers
to a compound of this invention present in different crystal
lattice forms.
[0091] The term "ester" as used herein refers to a derivative of a
compound of this invention derived from an oxoacid group and a
hydroxyl group, either one of which can be present at the compound
of this invention.
[0092] The term "tautomer" as used herein refers to an isomer
readily interconverted from a compound of this invention by e.g.,
migration of a hydrogen atom or proton.
[0093] The term "pharmaceutically acceptable derivative or prodrug"
as used herein, refers to any pharmaceutically acceptable salt,
ester, salt of an ester or other derivative of a compound of this
invention, which, upon administration to a recipient, is capable of
providing, either directly or indirectly, a compound of this
invention or a pharmaceutically active metabolite or residue
thereof. Particularly favored derivatives or prodrugs are those
that increase the bioavailability of the compounds of this
invention when such compounds are administered to a patient (e.g.,
by allowing orally administered compound to be more readily
absorbed into blood) or which enhance delivery of the parent
compound to a biological compartment (e.g., the brain or lymphatic
system).
[0094] Pharmaceutically acceptable prodrugs of the compounds
described herein include, but are not limited to, esters,
carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl
derivatives, quaternary derivatives of tertiary amines, N-Mannich
bases, Schiff bases, amino acid conjugates, phosphate esters, metal
salts and sulfonate esters. Various forms of prodrugs are well
known in the art. See for example Design of Prodrugs, Bundgaard, A.
Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al.,
Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and
Application of Prodrugs" in A Textbook of Drug Design and
Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter
5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review,
1992, 8, 1-38, each of which is incorporated herein by reference.
The prodrugs described herein include, but are not limited to, the
following groups and combinations of these groups; amine derived
prodrugs: Hydroxy prodrugs include, but are not limited to
acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters,
aryl esters and disulfide containing esters.
[0095] The terms "enhance" or "enhancing," as used herein, means to
increase or prolong either in potency or duration of a desired
effect. Thus, in regard to enhancing the effect of therapeutic
agents, the term "enhancing" refers to the ability to increase or
prolong, either in potency or duration, the effect of other
therapeutic agents on a system.
[0096] An "enhancing-effective amount," as used herein, refers to
an amount adequate to enhance the effect of another therapeutic
agent in a desired system.
[0097] The terms "pharmaceutical combination", "administering an
additional therapy", "administering an additional therapeutic
agent" and the like, as used herein, refer to a pharmaceutical
therapy resulting from mixing or combining more than one active
ingredient and includes both fixed and non-fixed combinations of
the active ingredients. The term "fixed combination" means that at
least one of the compounds described herein, and at least one
co-agent, are both administered to a patient simultaneously in the
form of a single entity or dosage. The term "non-fixed combination"
means that at least one of the compounds described herein, and at
least one co-agent, are administered to a patient as separate
entities either simultaneously, concurrently or sequentially with
variable intervening time limits, wherein such administration
provides effective levels of the two or more compounds in the body
of the patient. These also apply to cocktail therapies, e.g. the
administration of three or more active ingredients.
[0098] The terms "co-administration", "administered in combination
with" and their grammatical equivalents or the like, as used
herein, are meant to encompass administration of the selected
therapeutic agents to a single patient, and are intended to include
treatment regimens in which the agents are administered by the same
or different route of administration or at the same or different
times. In some embodiments the compounds described herein will be
co-administered with other agents. These terms encompass
administration of two or more agents to an animal so that both
agents and/or their metabolites are present in the animal at the
same time. They include simultaneous administration in separate
compositions, administration at different times in separate
compositions, and/or administration in a composition in which both
agents are present. Thus, in some embodiments, the compounds of the
invention and the other agent (s) are administered in a single
composition.
[0099] The term "metabolite," as used herein, refers to a
derivative of a compound which is formed when the compound is
metabolized.
[0100] The term "active metabolite," as used herein, refers to a
biologically active derivative of a compound that is formed when
the compound is metabolized.
[0101] The term "metabolized," as used herein, refers to the sum of
the processes (including, but not limited to, hydrolysis reactions
and reactions catalyzed by enzymes) by which a particular substance
is changed by an organism. Thus, enzymes may produce specific
structural alterations to a compound. For example, cytochrome P450
catalyzes a variety of oxidative and reductive reactions while
uridine diphosphate glucuronyltransferases catalyze the transfer of
an activated glucuronic-acid molecule to aromatic alcohols,
aliphatic alcohols, carboxylic acids, amines and free sulphydryl
groups. Further information on metabolism may be obtained from The
Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill
(1996).
Synthetic Procedures and Examples
The Preparation of Compounds of Formula I is Outlined Below
##STR00006##
[0103] Scheme 1 above illustrates the preparation of
pyridopyrimidine intermediates (8).
[0104] Cyanopyridine derivative (2) can be prepared via cyanation
of dichloropyridine (1). Cyanopyridine (2) was treated with
ammonium hydroxide and sodium hydrosulfite to give aminopyridine
(3). The pyridopyrimidone (4) was obtained by cyclization using
triethoxymethane. Subsequent chlorination of pyrimidone (4) gave
dichloropyridopyrimidine (5). The pyridopyrimidine (5) was
substituted by a compound (6) to provide compound (7), which was
coupled with synthesized Suzuki reagent to give the desired
pyridopyrimidines (8).
##STR00007##
[0105] Scheme 2 illustrates the preparation of arylsulfonamide
derivatives (12). Aminopyridine or pyrimidine (11) was reacted with
arylsulfonylchloride (10) to provide sulfonamide (11). The
sulfonamide (11) was reacted with pinacol borane to give the
desired borate (12) utilized in the Suzuki reaction described in
Scheme 1.
Intermediate 1
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
##STR00008##
[0106] Step A: 6-chloro-3-nitropicolinonitrile
##STR00009##
[0108] To a solution of 2,6-dichloro-3-nitropyridine (6.00 g, 31.1
mmol) in NMP (23.0 mL) was added copper(I) cyanide (3.06 g, 34.2
mmol) at room temperature. After stirred for 40 min at 180.degree.
C., the reaction mixture was cooled to room temperature, and then
poured into ice water. After stirring for 10 min, the mixture was
extracted with EtOAc, washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by column chromatography on SiO.sub.2 (Hex:EtOAc=10:1)
to give 6-chloro-3-nitropicolinonitrile (2.54 g, 44%) as a yellow
solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 7.79 (1H,
d, J=8.4 Hz), 8.58 (1H, d, J=8.4 Hz).
Step B: 3-amino-6-chloropicolinamide
##STR00010##
[0110] To a suspension of 6-chloro-3-nitropicolinonitrile (2.54 g,
13.8 mmol) in water (27.0 mL) was added NH.sub.4OH (5.61 mL, 36.0
mmol) at room temperature. After stirring for 20 min at room
temperature, Na.sub.2S.sub.2O.sub.4 (13.7 g, 79.0 mmol) was added
to the mixture. After stirring for 3 hours at room temperature, the
reaction mixture was filtered, and washed with water. The
filtercake was dried under vacuum to give
3-amino-6-chloropicolinamide (1.67 g, 70%) as a yellow solid.
.sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 5.36 (1H, brs),
6.00 (2H, brs), 7.00 (1H, d, J=8.8 Hz), 7.18 (1H, d, J=8.8 Hz),
7.63 (1H, brs).
Step C: 6-chloropyrido[3,2-d]pyrimidin-4(1H)-one
##STR00011##
[0112] A suspension of 3-amino-6-chloropicolinamide (1.67 g, 9.74
mmol) in triethyl orthoformate (73.0 mL) was refluxed for 3 hours.
The reaction mixture was cooled to room temperature, and then
filtered. The filtercake was dried under vacuum to give
6-chloropyrido[3,2-d]pyrimidin-4(1H)-one (1.45 g, 82%) as a brown
solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 7.66 (1H,
d, J=8.4 Hz), 8.00 (1H, s), 8.03 (1H, d, J=1.2 Hz), 12.57 (1H,
brs).
Step D: 4,6-dichloropyrido[3,2-d]pyrimidine
##STR00012##
[0114] To a solution of 6-chloropyrido[3,2-d]pyrimidin-4(1H)-one
(150 mg, 0.83 mmol) in POCl.sub.3 (2.0 mL) was added DIPEA (0.22
mL, 1.24 mmol) at room temperature. After stirring for 1 hour at
110.degree. C., the reaction mixture was cooled to room
temperature. The reaction mixture was concentrated in vacuo, and
then diluted with water and extracted with dichlormethane. The
combined organic layers were washed brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by column chromatography on SiO.sub.2 (Hex:EtOAc=10:1)
to give 4,6-dichloropyrido[3,2-d]pyrimidine (120 mg, 73%) as a
yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 7.87
(1H, d, J=8.8 Hz), 8.35 (1H, d, J=8.8 Hz), 9.14 (1H, s).
Step E:
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
##STR00013##
[0116] To a solution of tetrahydro-2H-pyran-4-ol (0.042 mL, 0.440
mmol) in DMF (1.60 mL) was added NaH (21.0 mg, 55% dispersion in
mineral oil, 0.480 mmol) at 0.degree. C. After stirring for 30 min
at room temperature, 4,6-dichloropyrido[3,2-d]pyrimidine (80.0 mg,
0.400 mmol) was added to the mixture at 0.degree. C. After stirring
for 2 hours at room temperature, the reaction mixture was quenched
with saturated aq. NH.sub.4Cl, and then extracted with EtOAc. The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=3:1) to give
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
(60.0 mg, 57%) as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian
400 MHz) .delta. 2.02-2.11 (2H, m), 2.18-2.23 (2H, m), 3.62-3.68
(2H, m), 4.08-4.13 (2H, m), 5.59-5.63 (1H, m), 7.74 (1H, d, J=8.8
Hz), 8.19 (2H, d, J=8.8 Hz), 8.81 (1H, s).
Intermediate 2
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulf-
onamide
##STR00014##
[0117] Step A: N-(5-bromopyridin-3-yl)benzenesulfonamide
##STR00015##
[0119] To a solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol)
in pyridine (3.00 mL) was added benzenesulfonyl chloride (0.75 mL,
5.78 mmol) dropwise at 0.degree. C. The mixture was stirred for 40
min at room temperature. The resulting solid was filtered, washed
with water, and dried under vacuum to give
N-(5-bromopyridin-3-yl)benzenesulfonamide (1.39 g, 77%) as a brown
solid. .sup.1H-NMR (DMSO-d.sub.6, Varian 400 MHz) .delta. 7.58-7.68
(4H, m), 7.79-7.81 (2H, m), 8.27 (1H, d, J=2.4 Hz), 8.37 (1H, d,
J=2.0 Hz), 10.91 (1H, brs).
Step B:
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ben-
zene-sulfonamide
##STR00016##
[0121] A mixture of N-(5-bromopyridin-3-yl)benzenesulfonamide (1.00
g, 3.19 mmol), bis(pinacolato)diboron (0.89 g, 3.51 mmol),
PdCl.sub.2(dppf).sub.2CH.sub.2Cl.sub.2 (0.13 g, 0.16 mmol) and
potassium acetate (0.94 g, 9.58 mmol) in 1,4-dioxane (7.51 mL) was
stirred at 100.degree. C. for 3 hours in a sealed tube. The
reaction mixture was cooled to room temperature, filtered through a
Celite pad and washed with EtOAc. The filtrate was concentrated in
vacuo. The residue was triturated with dichloromethane and the
resulting solid was filtered. The filtercake was dried under vacuum
to give
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesul-
fonamide (1.50 g, quent) as a brown solid. .sup.1H-NMR (CDCl.sub.3,
Varian 400 MHz) .delta. 1.34 (12H, s), 7.46 (2H, t, J=7.6 Hz), 7.57
(1H, t, J=7.6 Hz), 7.76 (2H, d, J=7.2 Hz), 7.84 (1H, d, J=1.2 Hz),
8.35 (1H, d, J=2.4 Hz), 8.71 (1H, d, J=1.2 Hz); NH peak was not
detected.
Intermediate 3
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2-
,4-difluorobenzenesulfonamide
##STR00017##
[0122] Step A: 5-bromo-2-chloro-3-nitropyridine
##STR00018##
[0124] To a solution of 5-bromo-3-nitropyridin-2(1H)-one (4.62 g,
21.10 mmol) in POCl.sub.3 (46.2 ml) was added DMF (4.62 ml, 59.7
mmol) at room temperature. The mixture was refluxed for 2 hours,
and then cooled to room temperature and concentrated in vacuo. The
residue was treated with saturated aq. NaHCO.sub.3 and extracted
with EtOAc. The combined organic layers were washed with brine,
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by column chromatography on
SiO.sub.2 (Hex:EtOAc=3:1) to give 5-bromo-2-chloro-3-nitropyridine
(4.24 g, 85%) as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian
400 MHz) .delta. 8.37 (1H, d, J=2.4 Hz), 8.70 (1H, d, J=2.0
Hz).
Step B: 5-bromo-2-chloropyridin-3-amine
##STR00019##
[0126] To a solution of 5-bromo-2-chloro-3-nitropyridine (4.24 g,
17.86 mmol) in EtOH (89 ml) was added Tin(II) chloride (16.9 g,
89.0 mmol) at room temperature. The mixture was refluxed for 1
hour, and then cooled to room temperature, filtered through a
Celite pad and washed with EtOAc. The filtrate was concentrated in
vacuo. The residue was treated with saturated aq. NaHCO.sub.3, and
extracted with EtOAc. The combined organic layers were washed
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=3:1) to give
5-bromo-2-chloropyridin-3-amine (2.7 g, 73%) as a white solid.
.sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 5.89 (2H, brs),
7.30 (1H, d, J=2.0 Hz), 7.66 (1H, d, J=2.4 Hz).
Step C:
N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide
##STR00020##
[0128] To a solution of 5-bromo-2-chloropyridin-3-amine (0.900 g,
4.34 mmol) in DCM (8.68 ml) was added pyridine (0.541 ml, 6.69
mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (0.851 ml, 6.33
mmol) at 0.degree. C. After stirring overnight at room temperature,
the reaction mixture was diluted with DCM and treated with
saturated aq. NaHCO.sub.3. The resulting solid was collected by
filtration and washed with water to give
N-(5-bromo-2-chloropyridin-3-yl)-N-(2,4-difluorophenylsulfonyl)-2,4--
difluorobenzenesulfonamide (0.65 g, 27%) as a white solid. The
filtrate was extracted with DCM (2.times.50 mL), the combined
organic layers were washed brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by column chromatography on SiO.sub.2 (Hex:EtOAc=5:1)
to give
N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide
(0.20 g, 12%) as a white solid. .sup.1H-NMR (CDCl.sub.3, Varian 400
MHz) .delta. 7.26 (1H, t, J=8.4 Hz), 7.59 (1H, t, J=10.0 Hz), 7.81
(1H, dd, J=16.0, 7.6 Hz), 8.04 (1H, d, J=2.4 Hz), 8.46 (1H, d,
J=2.4 Hz), 11.1 (1H, brs).
Step D:
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
-3-yl)-2,4-difluorobenzenesulfonamide
##STR00021##
[0130] A mixture of
N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide
(1.12 g, 2.92 mmol), potassium acetate (1.14 g, 11.6 mmol), BISPIN
(0.890 g, 3.50 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct
(0.119 g, 0.146 mmol) in dioxane (6.87 ml) was refluxed for 3
hours. After cooling to room temperature, the reaction mixture was
filtered through a Celite pad and washed with CH.sub.2Cl.sub.2. The
filtrate was diluted with water and extracted with CH.sub.2Cl.sub.2
(2.times.100 mL). The combined organic layers were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=5:1) to give
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)--
2,4-difluorobenzenesulfonamide (0.835 g, 66%) as a brown oil.
.sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 1.30 (12H, s),
6.88-6.95 (2H, m), 7.79-7.85 (1H, m), 8.20 (1H, d, J=1.6 Hz), 8.40
(1H, d, J=1.6 Hz), 7.63 (1H, brs); NH peak was not observed.
Intermediate 4
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluo-
ro benzenesulfonamide
##STR00022##
[0131] Step A:
N-(5-bromopyridin-3-yl)-2,4-difluorobenzenesulfonamide
##STR00023##
[0133] To a solution of 5-bromo-2-chloropyridin-3-amine (0.500 g,
2.89 mmol) in pyridine (1.45 ml) was dropwise added
2,4-difluorobenzene-1-sulfonyl chloride (0.614 ml, 2.89 mmol) at
0.degree. C. The mixture was stirred for 40 min at room temperature
and acidified with 1 N HCl. The residue was extracted with EtOAc
and the combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give N-(5-bromopyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.70
g, 70% yield) as a white solid. .sup.1H-NMR (CDCl.sub.3, Varian 400
MHz) .delta. 6.92-7.04 (2H, m), 7.76-7.84 (1H, m), 7.86-7.95 (1H,
m), 8.27 (1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.4 Hz); NH peak was not
observed.
Step B:
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,-
4-difluorobenzene sulfonamide
##STR00024##
[0135] A mixture of
N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide
(0.70 g, 2.01 mmol), Potassium acetate (0.590 g, 6.01 mmol), BISPIN
(0.611 g, 2.41 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct
(0.164 g, 0.200 mmol) in dioxane (7.51 ml) was refluxed for 3
hours. After cooling to room temperature, the reaction mixture was
filtered through a Celite pad and washed with CH.sub.2Cl.sub.2. The
filtrate was diluted with water and extracted with CH.sub.2Cl.sub.2
(2.times.100 mL). The combined organic layers were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=5:1) to give
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-diflu-
oro benzenesulfonamide (0.110 g, 14%) as a brown oil. .sup.1H-NMR
(CDCl.sub.3, Varian 400 MHz) .delta. 1.33 (12H, s), 6.86-6.95 (2H,
m), 7.82-7.98 (2H, m), 8.46 (1H, d, J=2.8 Hz), 8.70 (1H, d, J=1.2
Hz); NH peak was not observed.
Intermediate 5
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)be-
nzenesulfonamide
##STR00025##
[0136] Step A:
N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide
##STR00026##
[0138] To a solution of 5-bromo-2-chloropyridin-3-amine (1.00 g,
4.82 mmol) in pyridine (2.41 ml) was dropwise added benzenesulfonyl
chloride (0.851 g, 4.82 mmol) at 0.degree. C. The mixture was
stirred for 40 min at room temperature and acidified with 1 N HCl.
The residue was extracted with EtOAc and the combined organic
layers were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give
N-(5-bromo-2-chloropyridin-3-yl)-N-(phenylsulfonyl)benzenesulfonamid-
e (0.606 g, 26% yield) as a white solid. .sup.1H-NMR (CDCl.sub.3,
Varian 400 MHz) .delta. 7.02 (1H, s), 7.47-7.56 (2H, m), 7.59-7.66
(1H, m), 7.78-7.86 (2H, m), 8.16 (2H, dd, J=2.4, 7.2 Hz).
Step B:
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
-3-yl)benzene sulfon amide
##STR00027##
[0140] A mixture of
N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide (0.100 g, 0.288
mmol), Potassium acetate (0.085 g, 0.863 mmol), BISPIN (0.080 g,
0.316 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.023 g,
0.029 mmol) in dioxane (0.8 ml) was subjected to microwave
irradiation for 1 hour at 110.degree. C. After cooling to room
temperature, the reaction mixture was filtered through a Celite pad
and washed with CH.sub.2Cl.sub.2. The filtrate was diluted with
water and extracted with CH.sub.2Cl.sub.2 (2.times.100 mL). The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
get
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)b-
enzenesulfonamide (quant.) as a brown solid, which was used for the
next step without further purification.
Intermediate 6
6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine
##STR00028##
[0142] To a solution of 1-methylpiperidin-4-ol (0.095 g, 0.825
mmol) in DMF (2.500 ml) was added NaH (0.041 g, 55% dispersion in
mineral oil, 0.945 mmol) at 0.degree. C. After stirring for 30 min
at room temperature, the reaction mixture was cooled to 0.degree.
C., followed by the addition of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.15 g, 0.750 mmol). After stirring for 2
hours at room temperature, the reaction mixture was diluted with
water, and extracted with EtOAc. The organic layers were dried over
MgSO.sub.4, filtered and concentrated in vacuo. The residue was
purified by column chromatography on SiO.sub.2 (Hex:EtOAc=5:1) to
give 6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine
(0.09 g, 43%) as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian
400 MHz) .delta. 2.03-2.12 (2H, m), 2.17-2.21 (2H, m), 2.22-2.32
(2H, m), 2.34 (3H, s), 2.84-2.89 (2H, m), 5.38-5.45 (1H, m), 7.73
(1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.81 (1H, s).
Intermediate 7
tert-butyl
4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxyl-
ate
##STR00029##
[0144] To a solution of tert-butyl
4-hydroxypiperidine-1-carboxylate (0.201 g, 1.000 mmol) in DMF
(5.00 ml) was added NaH (0.052 g, 55% dispersion in mineral oil,
1.20 mmol) at 0.degree. C. After stirring for 30 min at room
temperature, the reaction mixture was cooled to 0.degree. C. and
4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.2
g, 1.000 mmol) was added to the mixture. After stirring for 3 hours
at room temperature, the reaction mixture was diluted with water,
and extracted with EtOAc. The organic layers were dried over
MgSO.sub.4, filtered and concentrated in vacuo. The residue was
purified by column chromatography on SiO.sub.2 (Hex:EtOAc=5:1) to
give tert-butyl
4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate
(0.236 g, 65%) as a white solid. .sup.1H-NMR (CDCl.sub.3, Varian
400 MHz) .delta. 1.49 (9H, s), 1.91-1.99 (2H, m), 2.10-2.13 (2H,
m), 3.21-3.27 (2H, m), 3.83-3.97 (2H, m), 5.55-5.62 (1H, m), 7.74
(1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.41 (1H, s).
Intermediate 8
6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine
##STR00030##
[0146] To a solution of pyridin-3-ol (0.048 g, 0.500 mmol) in DMF
(1.67 ml) was added NaH (0.027 g, 55% dispersion in mineral oil,
0.630 mmol) at 0.degree. C. After stirring for 30 min at room
temperature, the reaction mixture was cooled to 0.degree. C. and
4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1
g, 0.500 mmol) was added to the mixture. After stirring for 2 hours
at room temperature, the reaction mixture was diluted with water,
and extracted with EtOAc. The organic layers were dried over
MgSO.sub.4, filtered and concentrated in vacuo. The residue was
purified by column chromatography on SiO.sub.2 (Hex:EtOAc=5:1) to
give 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g,
70%) as a white solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz)
.delta. 7.46 (1H, dd, J=8.0 and 4.8 Hz), 7.66-7.69 (1H, m), 7.86
(1H, d, J=8.8 Hz), 8.31 (1H, d, J=8.8 Hz), 8.61 (1H, d, J=4.4 Hz),
8.65 (1H, d, J=2.8 Hz), 8.80 (1H, s).
Intermediate 9
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2-(N,N-bis(boc-amino))pyrazin-
e
##STR00031##
[0147] Step A: 6-chloro-2-(N,N-bis(boc-amino)pyrazine
##STR00032##
[0149] To a solution of 6-chloropyrazin-2-amine (0.3 g, 2.31 mmol)
in THF (11.5 ml) was added (Boc).sub.2O (1.34 ml, 5.79 mmol) and
DMAP (0.141 g, 1.16 mmol) at room temperature. After stirring for 2
hours at room temperature, the reaction mixture was concentrated in
vacuo. The residue was purified by column chromatography on
SiO.sub.2 (Hex:EtOAc=4:1) to give
6-chloro-2-(N,N-bis(boc-amino)pyrazine (0.747 g, 98%) as a white
solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 1.47 (18H,
s), 8.48 (1H, d, J=0.8 Hz), 8.53 (1H, d, J=0.8 Hz).
Step B:
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2-(N,N-Bis(Boc-amino)-
)-pyrazine
##STR00033##
[0151] A mixture of 6-chloro-2-(N,N-bis(boc-amino)pyrazine (0.10 g,
0.303 mmol), bis(pinacolato) diboron (0.085 g, 0.334 mmol),
potassium acetate (0.089 g, 0.910 mmol) and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.012 g, 0.015 mmol) in
dioxane (1.52 ml) was subjected to microwave irradiation for 1 hour
at 110.degree. C., and cooled to room temperature. The reaction
mixture was filtered through a Celite pad and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo to give
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2-(N,N-Bis(Boc-amino))pyrazi-
ne (0.128 g, quant) as a brown oil, which was used for the next
step without further purification. .sup.1H-NMR (CDCl.sub.3, Varian
400 MHz) .delta. 1.39 (12H, s), 1.42 (12H, s), 8.52 (1H, s), 8.86
(1H, s).
Intermediate 10
6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-2-(N,N-Bis(-
Boc-amino))-pyrazine
##STR00034##
[0153] A mixture of
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2-(N,N-bis(boc-amino))pyrazi-
ne (0.872 g, 2.070 mmol) (Intermediate 9),
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
(0.5 g, 1.882 mmol) (Intermediate 1),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.154 g, 0.188 mmol) and
1N aq. sodium bicarbonate (3.76 ml, 3.76 mmol) in dioxane (9.41 ml)
was refluxed for 1 hour. The reaction mixture was cooled to room
temperature, and the reaction mixture was filtered through a pad of
Celite and washed with CH.sub.2Cl.sub.2. The filtrate was diluted
with water and extracted with CH.sub.2Cl.sub.2 (2.times.100 mL).
The combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give
6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-2-(N,N-bis-
(boc-amino))pyrazine (0.845 g, 86%) as a yellow solid. .sup.1H-NMR
(CDCl.sub.3, Varian 400 MHz) .delta. 1.27 (18H, s), 2.05-2.13 (2H,
m), 2.17-2.19 (2H, m), 3.71-3.77 (2H, m), 4.12-4.17 (2H, m),
5.67-5.71 (1H, m), 8.39 (1H, d, J=8.8 Hz), 8.69 (1H, s), 8.78 (1H,
d, J=8.8 Hz), 8.85 (1H, s), 9.77 (1H, s).
Intermediate 11
4-bromo-2-chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
-3-yl)benzene sulfonamide
##STR00035##
[0154] Step A:
4-bromo-N-(5-bromopyridin-3-yl)-2-chlorobenzenesulfonamide
##STR00036##
[0156] To a solution of 5-bromopyridin-3-amine (0.300 g, 1.73 mmol)
in pyridine (8.67 ml) was slowly added
4-bromo-2-chlorobenzene-1-sulfonyl chloride (0.600 g, 2.08 mmol) at
0.degree. C. The reaction mixture was stirred for 2 hours at room
temperature. The reaction mixture was quenched with 1 N aq. HCl,
and then extracted with DCM (2.times.50 mL). The combined organic
layers were washed brine, dried over anhydrous MgSO.sub.4, filtered
and concentrated in vacuo. The resulting residue was recrystallized
from EtOAc-hexanes to give
4-bromo-N-(5-bromopyridin-3-yl)-2-chlorobenzenesulfonamide (0.530
g, 72%) as a red solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz)
.delta. 7.53-7.55 (1H, m), 7.71 (1H, d, J=1.6 Hz), 7.78 (1H, t,
J=2.2 Hz), 7.89 (1H, d, J=8.4 Hz), 8.26 (1H, d, J=2.0 Hz). 8.44
(1H, d, J=2.4 Hz).
Step B:
4-bromo-2-chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)pyridin-3-yl)benzenesulfonamide
##STR00037##
[0158] A mixture of
4-bromo-N-(5-bromopyridin-3-yl)-2-chlorobenzenesulfonamide (0.330
g, 0.774 mmol), bis(pinacolato)diboron (0.216 g, 0.851 mmol),
potassium acetate (0.228 g, 2.32 mmol) and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.0320 g, 0.039 mmol) in dioxane
(3.87 ml) was refluxed for 4 hours, and cooled to room temperature.
The reaction mixture was filtered through a Celite pad and washed
with DCM. The combined organic layers were washed brine, dried over
anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=10:1) to give
4-bromo-2-chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl)benzenesulfonamide (0.145 g, 40%) as a yellow solid.
.sup.1H-NMR (CDCl.sub.3, Varian 400 MHz): .delta. 1.34 (12H, s),
7.35 (1H, s), 7.76-7.78 (2H, m), 7.92 (1H, s), 8.00 (1H, d, J=8.0
Hz), 8.24 (1H, d, J=2.4 Hz), 8.40 (1H, d, J=2.0 Hz).
Intermediate 12
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-am-
ine
##STR00038##
[0159] Step A: 5-bromo-3-(N,N-bis(boc-amino)pyridine
##STR00039##
[0161] To a solution of 5-bromopyridin-3-amine (2.00 g, 11.6 mmol)
in THF (57.8 ml) were added (Boc).sub.2O (6.44 ml, 27.7 mmol) and
DMAP (0.706 g, 5.78 mmol) at room temperature. After stirred for 2
hours at room temperature, the reaction mixture was concentrated in
vacuo. The residue was purified by column chromatography on
SiO.sub.2 (Hex:EtOAc=30:1) to give
5-bromo-3-(N,N-bis(boc-amino)pyridine (3.00 g, 70%) as a yellow
solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 1.44 (18H,
s), 7.68 (1H, t, J=2.2 Hz), 8.36 (1H, d, J=2.4 Hz), 8.60 (1H, d,
J=2.0 Hz)
Step B:
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(N,N-bis(boc-ami-
no)pyridine
##STR00040##
[0163] A mixture of 5-bromo-3-(N,N-bis(boc-amino)pyridine (0.100 g,
0.268 mmol), BISPIN (0.075 g, 0.295 mmol), potassium acetate (0.079
g, 0.804 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (10.9 mg,
0.013 mmol) in dioxane (1.340 ml) was subjected to microwave
irradiation for 1 hour at 110.degree. C., and cooled to room
temperature. The reaction mixture was filtered through a Celite pad
and washed with DCM. The filtrate was concentrated in vacuo to give
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(N,N-bis(boc-amino)pyri-
dine (0.113 g, quant) as a yellow solid, which was used for the
next step without further purification. .sup.1H-NMR (CDCl.sub.3,
Varian 400 MHz) .delta. 1.27 (9H, s), 1.36 (9H, s), 1.43 (12H, s),
7.85-7.86 (1H, m), 8.47 (1H, d, J=2.8 Hz), 8.84 (1H, d, J=1.6
Hz).
Step C:
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-3-(-
N,N-bis(boc-amino)pyridine
##STR00041##
[0165] A mixture of
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(N,N-bis(boc-amino)pyri-
dine (0.1 g, 0.238 mmol), BISPIN (0.070 g, 0.262 mmol), 1N aq.
sodium bicarbonate (0.476 ml, 0.476 mmol) and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.019 g, 0.024 mmol) in dioxane
(1.20 ml) was subjected to microwave irradiation for 1 hour at
110.degree. C., and cooled to room temperature. The reaction
mixture was filtered through a Celite pad and washed with DCM. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-3-(N,N-bis-
(boc-amino)pyridine (0.09 g, 89%) as a brown solid. .sup.1H-NMR
(CDCl.sub.3, Varian 400 MHz) .delta. 1.55 (9H, s), 2.03-2.11 (2H,
m), 2.22-2.26 (2H, m), 3.64-3.79 (2H, m), 4.10-4.16 (2H, m),
5.64-5.69 (1H, m), 7.16 (1H, s), 8.27 (1H, d, J=8.8 Hz), 8.34 (1H,
d, J=8.8 Hz), 8.65 (1H, s), 8.80-8.72 (2H, m), 9.09 (1H, s).
Step D:
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyri-
din-3-amine
##STR00042##
[0167] To a solution of
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-3-(N,N-bis-
(boc-amino)pyridine (0.500 g, 0.955 mmol) in DCM (4.77 ml) was
slowly added TFA (2.207 ml, 28.6 mmol) at 0.degree. C. After
stirred for 4 hours at room temperature, the reaction mixture was
quenched with 1N aq. NaOH, extracted with DCM. The organic layers
was dried over MgSO.sub.4, filtered and concentrated in vacuo to
give
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-a-
mine (0.309 g, quant) as a yellow solid, which was used for the
next step without further purification. .sup.1H-NMR (CDCl.sub.3,
Varian 400 MHz) .delta. 2.04-2.12 (2H, m), 2.23-2.28 (2H, m),
3.67-3.74 (2H, m), 3.91 (2H, s), 4.10-4.15 (2H, m), 5.63-5.70 (1H,
m), 7.85-7.86 (1H, s), 8.21-8.24 (2H, m), 8.32 (1H, d, J=8.8 Hz),
8.73 (1H, d, J=2.0 Hz), 8.81 (1H, s).
Intermediate 13
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide
##STR00043##
[0168] Step A: N-(5-bromopyridin-3-yl)benzamide
##STR00044##
[0170] To a solution of 5-bromopyridin-3-amine (0.3 g, 1.734 mmol)
in THF (8.67 ml) was added TEA (0.363 ml, 2.60 mmol), and then
benzoyl chloride (0.292 g, 2.081 mmol) was added to the mixture at
0.degree. C. After stirred for 2 hours at room temperature, the
reaction mixture was quenched with saturated aq. NaHCO.sub.3 (50
mL) and extracted with EtOAc (2.times.50 mL). The combined organic
layers were washed with water and brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by column chromatography on SiO.sub.2 (Hex:EtOAc=10:1)
to give N-(5-bromopyridin-3-yl)benzamide (0.435 g, 91%) as a yellow
solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 7.48 (2H,
t, J=7.6 Hz), 7.58 (1H, t, J=7.4 Hz), 7.85-7.88 (2H, m), 8.38 (1H,
brs), 8.40 (1H, d, J=1.6 Hz), 8.56-8.58 (2H, m).
Step B:
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ben-
zamide
##STR00045##
[0172] A mixture of N-(5-bromopyridin-3-yl)benzamide (0.435 g, 1.57
mmol), BISPIN (0.438 g, 1.73 mmol), potassium acetate (0.462 g,
4.71 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.064 g, 0.078
mmol) in dioxane (7.85 ml) was refluxed for 2 hours, and cooled to
room temperature. The reaction mixture was filtered through a
Celite pad and washed with DCM. The combined organic layers were
washed brine, dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=1:1) to give
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide
(0.247 g, 49%) as a yellow oil. .sup.1H-NMR (CDCl.sub.3, Varian 400
MHz) .delta. 1.36 (12H, s), 7.38-7.58 (4H, m), 7.90 (2H, d, J=7.2
Hz), 8.45 (1H, s), 8.72 (1H, s), 8.95 (1H, s).
Intermediate 14
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2-
,4-difluoro benzamide
##STR00046##
[0173] Step A: 2,4-difluorobenzoyl chloride
##STR00047##
[0175] To a solution of 2,4-difluorobenzoic acid (0.100 g, 0.633
mmol) in DCM (3.16 ml) were added oxalyl chloride (0.066 ml, 0.759
mmol) and DMF (0.490 .mu.l, 6.33 .mu.mol) at 0.degree. C. The
reaction mixture was stirred for overnight at room temperature. The
reaction mixture was concentrated in vacuo, which was used for the
next step without further purification. .sup.1H-NMR (CDCl.sub.3,
Varian 400 MHz) .delta. 6.92-9.98 (1H, m), 7.01-7.06 (1H, m),
8.16-8.22 (1H, m).
Step B: N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzamide
##STR00048##
[0177] To a solution of 2,4-difluorobenzoyl chloride (0.33 g, 1.591
mmol) in CHCl.sub.3 (15.9 ml) were slowly added TEA (0.443 ml, 3.18
mmol) and 5-bromo-2-chloropyridin-3-amine (0.337 g, 1.91 mmol) at
0.degree. C. The reaction mixture was stirred for 5 hours at room
temperature. The reaction mixture was quenched with saturated aq.
NaHCO.sub.3, and extracted with DCM (2.times.50 mL). The combined
organic layers were washed brine, dried over anhydrous MgSO.sub.4,
filtered and concentrated in vacuo. The residue was purified by
column chromatography on SiO.sub.2 (Hex:EtOAc=30:1) to give
N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzamide (0.185 g,
34%) as a white solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz)
.delta. 6.93-7.26 (2H, m), 8.21-8.27 (2H, m), 9.08-9.12 (1H, m),
9.16-9.16 (1H, m).
Step C:
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
-3-yl)-2,4-difluorobenzamide
##STR00049##
[0179] A mixture of
N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzamide (0.127 g,
0.365 mmol), BISPIN (0.102 g, 0.402 mmol), potassium acetate (0.108
g, 1.10 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.015 g, 0.018
mmol) in dioxane (1.83 ml) was refluxed for 2 hours, and cooled to
room temperature. The reaction mixture was filtered through a
Celite pad and washed with DCM. The combined organic layers were
washed brine, dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (only EtOAc) to give
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl)-2,4-difluorobenzamide (0.127 g, 88%) as a white solid.
.sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 1.36 (12H, s),
6.96-7.02 (1H, m), 7.07-7.12 (1H, m), 8.22-8.28 (1H, m), 8.48 (1H,
s), 9.03-9.07 (1H, m), 9.17 (1H, s).
Intermediate 15
6-chloro-4-(cyclohexylthio)pyrido[3,2-d]pyrimidine
##STR00050##
[0181] To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.1 g, 0.500 mmol) in ACN (2.500 ml) were
added cyclohexanethiol (0.058 g, 0.500 mmol) and K.sub.2CO.sub.3
(0.069 g, 0.500 mmol) at room temperature. After stirring overnight
at room temperature, the reaction mixture was diluted with water
and extracted with EtOAc (2.times.50 mL). The combined organic
layers were washed with 1N aq. NaOH and then washed with 1N aq.
HCl. The organic layers were dried over anhydrous MgSO.sub.4,
filtered and concentrated in vacuo. The residue was purified by
column chromatography on SiO.sub.2 (Hex:EtOAc=5:1) to give
6-chloro-4-(cyclo hexylthio)pyrido[3,2-d]pyrimidine (0.129 g, 92%)
as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
1.36-1.42 (1H, m), 1.48-1.69 (5H, m), 1.80-1.86 (2H, m), 2.14-2.20
(2H, m), 4.10-4.16 (1H, m), 7.73 (1H, d, J=8.8 Hz), 8.19 (1H, d,
J=8.8 Hz), 8.98 (1H, s).
Intermediate 16
6-chloro-4-(cyclopentyloxy)pyrido[3,2-d]pyrimidine
##STR00051##
[0183] To a solution of cyclopentanol (0.050 ml, 0.550 mmol) in DMF
(2.500 ml) was added NaH (0.026 g, 55% dispersion in mineral oil,
0.600 mmol) at 0.degree. C. The reaction mixture was stirred for 30
min. at room temperature, 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.1 g, 0.500 mmol) was added to the
mixture at 0.degree. C. After being stirred for 2 hours at room
temperature, the reaction mixture was diluted with water, and
extracted with EtOAc. The organic layers were dried over MgSO.sub.4
filtered and concentrated in vacuo. The residue was purified by
column chromatography on SiO.sub.2 (Hex:EtOAc=5:1) to give
6-chloro-4-(cyclopentyloxy)pyrido[3,2-d]pyrimidine (0.04 g, 32%) as
a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz): .delta.
1.63-1.74 (2H, m), 1.86-1.96 (2H, m), 1.99-2.07 (2H, m), 2.12-2.20
(2H, m), 5.72-5.77 (1H, m), 7.72 (1H, d, J=8.8 Hz), 8.18 (1H, d,
J=8.8 Hz), 8.83 (1H, s).
Intermediate 17
6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine
##STR00052##
[0185] A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.05 g, 0.250 mmol),
tetrahydro-2H-pyran-4-amine (0.029 ml, 0.275 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (2.041 mg, 2.500 .mu.mol)
and sodium tert-butoxide (0.048 g, 0.500 mmol) in dioxane (1.250
ml) was refluxed for 3 hours. After cooling to room temperature,
the reaction mixture was filtered through a Celite pad and washed
with CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=2:1) to give
6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine
(0.027 g, 41%) as a yellow solid.
[0186] .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 1.68-1.78
(2H, m), 2.03-2.13 (2H, m), 3.58-3.67 (2H, m), 4.05-4.09 (2H, m),
4.36-4.46 (1H, m), 6.90 (1H, brs), 7.63 (1H, d, J=8.8 Hz), 8.05
(1H, d, J=8.8 Hz), 8.62 (1H, s).
Intermediate 18
6-chloro-N-cyclopentylpyrido[3,2-d]pyrimidin-4-amine
##STR00053##
[0188] A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclopentanamine
(0.054 ml, 0.550 mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct
(4.08 mg, 5.00 .mu.mol) and sodium tert-butoxide (0.096 g, 1.00
mmol) in dioxane (2.50 ml) was refluxed for 3 hours. After cooling
to room temperature, the reaction mixture was filtered through a
Celite pad and washed with CH.sub.2Cl.sub.2. The filtrate was
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=1:1) to give
6-chloro-N-cyclopentylpyrido[3,2-d]pyrimidin-4-amine (0.043 g, 35%)
as a yellow oil. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz)): .delta.
1.60-1.83 (6H, m), 2.15-2.21 (2H, m), 4.55-4.60 (1H, m), 6.96 (1H,
d, J=6.4 Hz), 7.59-7.62 (1H, m), 8.02-8.04 (1H, m), 8.63 (1H,
s).
Intermediate 19
6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine
##STR00054##
[0190] A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclobutanamine
(0.047 ml, 0.550 mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct
(4.08 mg, 5.00 .mu.mol) and sodium tert-butoxide (0.096 g, 1.00
mmol) in dioxane (2.50 ml) was refluxed for 4 hours. After cooling
to room temperature, the reaction mixture was filtered through a
Celite pad and washed with CH.sub.2Cl.sub.2. The filtrate was
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=1:1) to give
6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine (0.098 g, 84%)
as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
1.79-1.89 (2H, m), 2.06-2.17 (2H, m), 2.48-2.56 (2H, m), 4.71-4.82
(1H, m), 7.11 (1H, brs), 7.61 (1H, d, J=8.8 Hz), 8.03 (1H, d, J=8.8
Hz), 8.61 (1H, s).
Intermediate 20
6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine
##STR00055##
[0192] A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclopropanamine
(0.038 ml, 0.550 mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct
(4.08 mg, 5.00 .mu.mol) and sodium tert-butoxide (0.096 g, 1.00
mmol) in dioxane (2.50 ml) was refluxed for 4 hours. After cooling
to room temperature, the reaction mixture was filtered through a
Celite pad and washed with CH.sub.2Cl.sub.2. The filtrate was
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=1:1) to give
6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine (0.060 g, 54%)
as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
0.76-0.79 (2H, m), 0.99-1.03 (2H, m), 3.02-3.06 (1H, m), 7.12 (1H,
brs), 7.61-7.63 (1H, m), 8.04-8.07 (1H, m), 8.73 (1H, s).
Intermediate 21
N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine
##STR00056##
[0194] A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.100 g, 0.500 mmol),
3,5-dimethylisoxazol-4-amine (0.140 g, 1.250 mmol) and sodium
acetate (0.123 g, 1.50 mmol) in 5 ml of solvent (THF:H.sub.2O=1:1)
was refluxed for 1 hour. The reaction mixture was diluted with
EtOAc. The organics were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crued was purified
by column chromatography on SiO.sub.2 (Hex:EtOAc=1:1) to get
N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine
(0.082 g, 59%) as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian
400 MHz) .delta. 2.24 (3H, s), 2.40 (3H, s), 7.74 (1H, d, J=8.8
Hz), 7.93 (1H, brs), 8.16 ((1H, d, J=8.8 Hz), 8.69 (1H, s).
Intermediate 22
6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine
##STR00057##
[0196] A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.100 g, 0.500 mmol),
6-methoxypyridin-3-amine (0.155 g, 1.250 mmol) and sodium acetate
(0.123 g, 1.50 mmol) in 5 ml of solvent (THF:H.sub.2O=1:1) was
refluxed for 1 hour. The reaction mixture was diluted with EtOAc.
The organics were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The crued was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=1:1) to get
6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine
(0.085 g, 59%) as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian
400 MHz) .delta. 3.97 (3H, s), 6.85 (1H, d, J=8.8 Hz), 7.71 (1H, d,
J=8.8 Hz), 8.14 (1H, d, J=8.8 Hz), 8.20 (1H, dd, J=2.8, 8.8 Hz),
8.55 (1H, d, J=2.8 Hz), 8.67 (1H, br s), 8.73 (1H, s).
Intermediate 23
6-chloro-N-(4-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine
##STR00058##
[0198] A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.200 g, 1.00 mmol),
4-(trifluoromethoxy)aniline (0.177 g, 1.00 mmol) and sodium acetate
(0.246 g, 3.00 mmol) in 5 ml of solvent (THF:H.sub.2O=1:1) was
refluxed for 1 hour. The reaction mixture was diluted with EtOAc.
The organics were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The crued was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=1:1) to get
6-chloro-N-(4-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine
(0.32 g, 94%) as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian
400 MHz) .delta. 7.30 (1H, d, J=8.4 Hz), 7.72 (1H, d, J=8.8 Hz),
7.98 (1H, d, J=9.2 Hz), 8.15 (1H, dd, J=8.8 Hz), 8.80 (1H, s), 8.90
(1H, br s).
Intermediate 24
tert-butyl
4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carbox-
ylate
##STR00059##
[0200] A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine
(Intermediate 1, step D) (0.100 g, 0.500 mmol), tert-butyl
4-aminopiperidine-1-carboxylate (0.110 g, 0.550 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (4.08 mg, 5.00 .mu.mol) and
sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was
refluxed for 4 hours After cooling to room temperature, the
reaction mixture was filtered through a Celite pad and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give tert-butyl
4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate
(0.089 g, 49%) as a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian
400 MHz) .delta. 1.49 (9H, s), 1.52-1.75 (2H, m), 2.05-2.16 (2H,
m), 2.92-3.10 (2H, m), 4.08-4.25 (2H, m), 4.35-4.42 (1H, m), 6.87
(1H, d, J=8.4 Hz), 7.63 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.8 Hz),
8.62 (1H, s).
Example 1
N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-
-yl)benzenesulfonamide
##STR00060##
[0202] To a solution of
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
(Intermediate 1) (60.0 mg, 0.226 mmol) in 1,4-dioxane (1.20 mL) was
added
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesul-
fonamide (Intermediate 2) (122 mg, 0.339 mmol),
PdCl.sub.2(dppf).sub.2CH.sub.2Cl.sub.2 (18.0 mg, 0.0230 mmol), and
1N aq. NaHCO.sub.3 (0.452 mL, 0.452 mmol) at room temperature. The
reaction mixture was subjected to microwave irradiation for 30 min
at 120.degree. C., and cooled to room temperature. The reaction
mixture was filtered through a Celite pad and washed with EtOAc.
The filtrate was diluted with water and extracted with EtOAc. The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=3:1) to give
N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin--
3-yl)benzenesulfonamide (20.0 mg, 19%) as a yellow solid.
.sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 2.02-2.11 (2H, m),
2.23-2.27 (2H, m), 3.68-3.74 (2H, m), 4.10-4.15 (2H, m), 5.64-5.69
(1H, m), 7.07 (1H, brs), 7.47-7.51 (2H, m), 7.56-7.60 (1H, m),
7.85-7.88 (2H, m), 8.21 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz),
8.38 (1H, s), 8.43 (1H, t, J=2.2 Hz), 8.83 (1H, s), 9.16 (1H, s);
m/z=464.2 [M+1].sup.+.
Example 2
N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-
pyridin-3-yl)-2,4-difluorobenzenesulfonamide
##STR00061##
[0204] A mixture of
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)--
2,4-difluorobenzenesulfonamide (0.02 g, 0.075 mmol) (Intermediate
3), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
(Intermediate 1) (0.032 g, 0.075 mmol), sodium bicarbonate (0.151
ml, 0.151 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (6.15
mg, 7.53 .mu.mol) in dioxane (0.376 ml) was refluxed for 3 hours.
The reaction mixture was cooled to room temperature, filtered
through a Celite pad and washed with CH.sub.2Cl.sub.2. The filtrate
was concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=2:1) to give
N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl-
)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.02 g, 50%) as a
yellow solid.
[0205] .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 2.06-2.12
(2H, m), 2.23-2.30 (2H, m), 3.66-3.76 (2H, m), 4.02-4.17 (2H, m),
5.66-5.72 (1H, m), 6.73-7.01 (2H, m), 7.53 (1H, brs), 7.92-7.98
(1H, m), 8.20 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8 Hz), 8.80 (1H,
d, J=2.4 Hz), 8.84 (1H, s), 8.92 (1H, d, J=2.4 Hz). m/z=534.3
[M+1].sup.+.
Example 3
N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-
-yl)-2,4-difluorobenzenesulfonamide
##STR00062##
[0207] A mixture of
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-diflu-
oro benzenesulfonamide (0.110 g, 0.278 mmol) (Intermediate 4),
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
(Intermediate 1) (0.081 g, 0.305 mmol), 1 N aq. sodium bicarbonate
(0.555 ml, 0.555 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct
(23.0 mg, 2.80 .mu.mol) in dioxane (2.78 ml) was subjected to
microwave irradiation for 1 hour at 110.degree. C. The reaction
mixture was cooled to room temperature, filtered through a Celite
pad and washed with CH.sub.2Cl.sub.2. The filtrate was concentrated
in vacuo. The residue was purified by column chromatography on
SiO.sub.2 (Hex:EtOAc=2:1) to give
N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin--
3-yl)-2,4-difluorobenzenesulfonamide (0.15 g, 18%) as a yellow
solid. .sup.1H-NMR (DMSO-d.sub.6, Varian 400 MHz) .delta. 1.78-1.98
(2H, m), 2.12-2.26 (2H, m), 3.55-3.72 (2H, m), 3.90-4.05 (2H, m),
5.58-5.72 (1H, m), 7.20-7.42 (1H, m), 7.48-7.62 (2H, m), 7.90-8.05
(1H, m), 8.36-8.52 (2H, m), 8.58 (1H, d, J=8.2 Hz), 8.86 (1H, s),
9.13 (1H, s), 11.29 (1H, br s). m/z=500.1 [M+1].sup.+.
Example 4
N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-
pyridin-3-yl)benzenesulfonamide
##STR00063##
[0209] A mixture of
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)b-
enzene sulfonamide (0.114 g, 0.290 mmol) (Intermediate 5),
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
(Intermediate 1) (0.070 g, 0.263 mmol), 1 N aq. sodium bicarbonate
(0.527 ml, 0.527 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct
(22.0 mg, 2.60 .mu.mol) in dioxane (1.5 ml) was subjected to
microwave irradiation for 1 hour at 110.degree. C. The reaction
mixture was cooled to room temperature, filtered through a Celite
pad and washed with CH.sub.2Cl.sub.2. The filtrate was concentrated
in vacuo. The residue was purified by column chromatography on
SiO.sub.2 (Hex:EtOAc=2:1) to give
N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl-
)pyridin-3-yl)benzenesulfonamide (0.030 g, 23%) as a yellow solid.
.sup.1H-NMR (DMSO-d.sub.6, Varian 400 MHz) .delta. 1.75-1.98 (2H,
m), 2.12-2.26 (2H, m), 3.55-3.72 (2H, m), 3.90-4.05 (2H, m),
5.58-5.72 (1H, m), 7.50-7.70 (3H, m), 7.85 (1H, d, J=7.6 Hz), 8.45
(1H, d, J=8.4 Hz), 8.58-8.72 (2H, m), 8.87 (1H, s), 9.04 (1H, br
s), 10.55 (1H, s). m/z=498.09 [M+1].sup.+.
Example 5
N-(2-chloro-5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)py-
ridin-3-yl)-2,4-difluorobenzenesulfonamide
##STR00064##
[0211] A mixture of
6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine
(Intermediate 6) (0.03 g, 0.108 mmol),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)--
2,4-difluorobenzenesulfonamide (Intermediate 3) (0.046 g, 0.108
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (8.79 mg, 10.76
.mu.mol) and sodium bicarbonate (0.215 ml, 0.215 mmol) in dioxane
(0.538 ml) was refluxed for 3 hours. After cooling to room
temperature, the reaction mixture was filtered through a Celite pad
and washed with CH.sub.2Cl.sub.2. The filtrate was concentrated in
vacuo. The residue was purified by prep TLC (EtOAc:MeOH=10:1) to
give
N-(2-chloro-5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)p-
yridin-3-yl)-2,4-difluorobenzene-sulfonamide (0.02 g, 34%) as a
yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
2.10-2.22 (2H, m), 2.37 (2H, s), 2.62 (3H, s), 2.88-2.95 (2H, m),
3.13-3.17 (2H, m), 5.64 (1H, brs), 6.86-6.94 (2H, m), 7.86-7.92
(1H, m), 8.21 (1H, d, J=9.2 Hz), 8.34 (1H, d, J=8.8 Hz), 8.79 (1H,
d, J=2.0 Hz), 8.82 (1H, s), 8.91 (1H, brs). m/z=547.4
[M+1].sup.+.
Example 6
N-(5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-y-
l)benzene-sulfonamide
##STR00065##
[0213] A mixture of
6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine
(Intermediate 6) (0.074 g, 0.265 mmol),
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzene
sulfonamide (Intermediate 2) (0.143 g, 0.398 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (43.4 mg, 53.0 .mu.mol) and
1N aq. sodium bicarbonate (0.531 ml, 0.531 mmol) in dioxane (1.06
ml) was refluxed for 3 hours. After cooling to room temperature,
the reaction mixture was filtered through a Celite pad and washed
with CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by prep TLC (EtOAc only) to give
N-(5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3--
yl)benzenesulfonamide (0.018 g, 14%) as a yellow solid. .sup.1H-NMR
(DMSO-d.sub.6, Varian 400 MHz) .delta. 1.88-1.99 (2H, m), 2.12-2.21
(2H, m), 2.26 (3H, s), 2.28-2.36 (2H, m), 2.77-2.85 (2H, m), 5.43
(1H, s), 6.54 (1H, brs), 7.47-7.60 (4H, m), 7.83-7.89 (2H, m),
8.31-8.39 (2H, m), 8.49 (1H, d, J=8.8 Hz), 8.84 (1H, s), 8.91 (1H,
s). m/z=477.2 [M+1].sup.+.
Example 7
tert-butyl
4-(6-(5-(phenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin--
4-yloxy)-piperidine-1-carboxylate
##STR00066##
[0215] A mixture of tert-butyl
4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate
(0.3 g, 0.822 mmol),
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzene-su-
lfonamide (Intermediate 2) (0.355 g, 0.987 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.067 g, 0.082 mmol) and
1N aq. sodium bicarbonate (1.64 ml, 1.64 mmol) in dioxane (4.11 ml)
was subjected to microwave irradiation for 30 min at 120.degree.
C., and cooled to room temperature. The reaction mixture was
filtered through a Celite pad and washed with EtOAc. The filtrate
was diluted water and extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by column chromatography on SiO.sub.2 (Hex:EtOAc=1:1)
to give tert-butyl
4-(6-(5-(phenylsulfonamido)-pyridine-3-yl)pyrido[3,2-d]pyrimidin-4-yloxy)-
piperidine-1-carboxylate (0.15 g, 32%) as a yellow solid.
.sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 1.49 (9H, s),
1.95-2.05 (2H, m), 2.14-2.18 (2H, m), 3.36-3.43 (2H, m), 3.89-3.95
(2H, m), 5.63-5.37 (1H, m), 7.46-7.52 (2H, m), 7.56-7.60 (1H, m),
7.85 (1H, d, J=7.2 Hz), 8.21 (1H, d, J=8.8 Hz), 8.34 (1H, s), 8.37
(1H, d, J=2.4 Hz), 8.41 (1H, d, J=2.0 Hz), 8.83 (1H, s), 9.14 (1H,
d, J=1.6 Hz).
Example 8
N-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzen-
esulfonamide
##STR00067##
[0217] To a solution of tert-butyl
4-(6-(5-(phenylsulfonamido)-pyridine-3-yl)pyrido[3,2-d]pyrimidin-4-yloxy)-
piperidine-1-carboxylate (0.15 g, 0.267 mmol) in DCM (1.333 ml) was
added TFA (0.205 ml, 2.67 mmol) at room temperature. After stirring
for 30 min at room temperature, the reaction mixture was evaporated
in vacuo, to give
N-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-
benzenesulfonamide (0.123 g, 100%) as a yellow oil, which was used
in the next step without further purification. .sup.1H-NMR
(CDCl.sub.3, Varian 400 MHz) .delta. 1.87-1.92 (2H, m), 2.15-2.22
(2H, m), 2.79-2.85 (2H, m), 3.20-3.24 (2H, m), 5.58-5.62 (1H, m),
7.39-7.42 (3H, m), 7.92-7.94 (2H, m), 8.18-8.20 (2H, m), 8.28 (1H,
s), 8.59 (1H, d, J=1.6 Hz), 8.74 (1H, s).
Example 9
N-(5-(4-(1-acetylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-y-
l)benzene-sulfonamide
##STR00068##
[0219] To a solution of
N-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benze-
ne-sulfonamide (0.082 g, 0.177 mmol) in DCM (0.886 ml) was added
TEA (0.062 ml, 0.443 mmol) at room temperature. After stirring for
2 hours at room temperature, AcCl (0.019 ml, 0.266 mmol) was added
to the mixture at 0.degree. C. After stirring overnight at room
temperature, the reaction mixture was diluted with water and
extracted with CH.sub.2Cl.sub.2. The combined organic layers were
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The residue was purified by prep TLC
(DCM:MeOH=20:1) to give
N-(5-(4-(1-acetylpiperidin-4-yloxy)-pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-
-yl)benzenesulfonamide (0.007 g, 7%) as a white solid. .sup.1H-NMR
(CDCl.sub.3, Varian 400 MHz) .delta. 2.05-2.18 (2H, m), 2.19 (3H,
s), 3.53-3.59 (2H, m), 3.65-3.76 (2H, m), 3.89-3.40 (2H, m),
5.74-8.79 (1H, m), 7.44-7.48 (2H, m), 7.53-7.57 (1H, m), 7.86-7.89
(2H, m), 8.23 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.46 (1H,
d, J=2.8 Hz), 8.53 (1H, d, J=2.4 Hz), 8.84 (1H, s), 9.12 (1H, d,
J=1.6 Hz). m/z=505.1 [M+1].sup.+.
Example 10
N-(5-(4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenes-
ulfonamide
##STR00069##
[0221] A mixture of
6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g, 0.348
mmol) (Intermediate 8),
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesul-
fonamide (0.150 g, 0.418 mmol) (Intermediate 2),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.057 g, 0.070 mmol) and
1N aq. sodium bicarbonate (0.70 ml, 0.70 mmol) in dioxane (1.74 ml)
was subjected to microwave irradiation for 30 min at 120.degree.
C., and cooled to room temperature. The reaction mixture was
filtered through a Celite pad and washed with EtOAc. The filtrate
was diluted water and extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by column chromatography on SiO.sub.2 (EtOAc only) to
give
N-(5-(4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-
sulfonamide (0.20 g, 13%) as a yellow solid. .sup.1H-NMR
(DMSO-d.sub.6, Varian 400 MHz) .delta. 7.45-7.49 (2H, m), 7.51-7.56
(1H, m), 7.61 (1H, dd, J=8.4 and 4.8 Hz), 7.84-7.87 (2H, m),
7.92-7.95 (1H, m), 8.38 (1H, d, J=2.8 Hz), 8.45 (1H, s), 8.49-8.51
(2H, m), 8.53 (1H, dd, J=4.8 and 1.2 Hz), 8.66 (1H, d, J=2.4 Hz),
8.73 (1H, s), 9.06 (1H, d, J=2.0 Hz). m/z=457 [M+1].sup.+.
Example 11
N-(6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-
-yl)benzene sulfonamide
##STR00070##
[0223] To a solution of
6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-2-(N,N-bis-
(boc-amino))pyrazine (Intermediate 10) (0.845 g, 1.61 mmol) in DCM
(8.05 ml) was slowly added TFA (2.48 ml, 32.2 mmol) at 0.degree. C.
After stirring for 4 hours at room temperature, the reaction
mixture was quenched with 1N NaOH, and extracted with DCM. The
organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo to give
6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-a-
mine (0.27 g, 52%) as a yellow solid. To a solution of
6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-a-
mine (0.1 g, 0.308 mmol) in pyridine (1.542 ml) was slowly added
benzenesulfonyl chloride (0.050 ml, 0.385 mmol) at 0.degree. C.
After stirring for 6 hours at room temperature, the reaction
mixture was diluted with DCM and quenched with 1N aq. HCl. The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was washed with EtOAc and the resulting solid was collected
by filtration to give
N-(6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin--
2-yl)benzenesulfonamide (0.02 g, 14%) as a yellow solid.
.sup.1H-NMR (DMSO-d.sub.6, Varian 400 MHz) .delta. 1.82-1.90 (2H,
m), 2.14-2.17 (2H, m), 3.57-3.62 (2H, m), 3.92-4.06 (2H, m),
5.59-5.63 (1H, m), 7.63-7.65 (3H, m), 8.10 (2H, dd, J=2.0, 7.6 Hz),
8.43 (1H, s), 8.49 (1H, d, J=8.8 Hz), 8.55 (1H, d, J=8.8 Hz), 8.89
(1H, s), 9.21 (1H, s), 11.96 (1H, s). m/z=465.0 [M+1].sup.+.
Example 12
4-bromo-2-chloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimid-
in-6-yl) pyridin-3-yl)benzenesulfonamide
##STR00071##
[0225] A mixture of
4-bromo-2-chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl)benzenesulfonamide (Intermediate 10) (0.0740 g, 0.279 mmol),
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
(Intermediate 1) (0.145 g, 0.306 mmol), 1N aq. sodium bicarbonate
(0.557 ml, 0.557 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
(0.0230 g, 0.0280 mmol) in dioxane (1.40 ml) was subjected to
microwave irradiation for 1 hour at 110.degree. C., and cooled to
room temperature. The reaction mixture was filtered through a
Celite pad and washed with DCM. The combined organic layers were
washed brine, dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (Hex:EtOAc=1:1) to give
4-bromo-2-chloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimi-
din-6-yl)pyridin-3-yl)benzenesulfonamide (0.032 g, 20%) as a yellow
solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 2.04-2.12
(2H, m), 2.23-2.27 (2H, m), 3.68-3.74 (2H, m), 4.10-4.15 (2H, m),
5.63-5.69 (1H, m), 7.83 (1H, t, J=2.2 Hz), 7.92 (1H, brs),
8.13-8.16 (1H, m), 8.22 (1H, d, J=8.0 Hz), 8.34-8.42 (4H, m), 8.84
(1H, s). m/z=577.9 [M+1].sup.+.
Example 13
2-bromo-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimid-
in-6-yl) pyridine 3-yl)benzenesulfonamide
##STR00072##
[0227] To a solution of
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-a-
mine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773
ml) was slowly added 2-bromo-4-fluorobenzene-1-sulfonyl chloride
(0.0510 g, 0.186 mmol) at 0.degree. C. After stirred for 1 hour at
room temperature, the reaction mixture was diluted with DCM and
quenched with 1N. aq HCl. The combined organic layers were washed
brine, dried over anhydrous MgSO.sub.4, filtered and concentrated
in vacuo. The residue was recrystallized from EtOAc-Hexane to give
2-bromo-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimi-
din-6-yl)pyridin-3-yl)benzene-sulfonamide (0.0400 g, 46%) as a
purple solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
2.02-2.11 (2H, m), 2.24-2.28 (2H, m), 3.69-3.75 (2H, m), 4.11-4.16
(2H, m), 5.65-5.71 (1H, m), 7.08-7.13 (1H, m), 7.46-7.49 (1H, m),
8.14-8.18 (1H, m), 8.22 (1H, d, J=8.8 Hz), 8.38 (1H, d, J=8.8 Hz),
8.55 (1H, s), 8.62 (1H, s), 8.84 (1H, s), 9.16 (1H, s). m/z=562.0
[M+1].sup.+.
Example 14
4-bromo-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimid-
in-6-yl) pyridin-3-yl)benzenesulfonamide
##STR00073##
[0229] To a solution of
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-a-
mine (Intermediate 12) (0.050 g, 0.155 mmol) in pyridine (0.773 ml)
was slowly added 4-bromo-2-fluorobenzene-1-sulfonyl chloride (0.051
g, 0.186 mmol) at 0.degree. C. After stirred for 1 hour at room
temperature, the reaction mixture was diluted with DCM and quenched
with 1 N. aq HCl. The combined organic layers were washed brine,
dried over anhydrous MgSO.sub.4, filtered and concentrated in
vacuo. The residue was recrystallized from EtOAc-Hexane to give
4-bromo-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimi-
din-6-yl)pyridin-3-yl)benzene-sulfonamide (0.028 g, 32%) as a
purple solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
2.03-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.10-4.16
(2H, m), 5.66-5.71 (1H, m), 7.38-7.41 (2H, m), 7.79-7.83 (1H, m),
8.25 (1H, d, J=8.8 Hz), 8.40 (1H, d, J=8.8 Hz), 8.72 (1H, s), 8.85
(1H, s), 9.20 (1H, m). m/z=562.1 [M+1].sup.+.
Example 15
4-chloro-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimi-
din-6-yl) pyridin-3-yl)benzenesulfonamide
##STR00074##
[0231] To a solution of
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-a-
mine (Intermediate 12) (0.050 g, 0.155 mmol) in pyridine (0.773 ml)
was slowly added 4-chloro-2-fluorobenzene-1-sulfonyl chloride
(0.043 g, 0.186 mmol) at 0.degree. C. After stirred for 1 hour at
room temperature, the reaction mixture was diluted with DCM and
quenched with 1N. aq HCl. The combined organic layers were washed
brine, dried over anhydrous MgSO.sub.4, filtered and concentrated
in vacuo. The residue was recrystallized from EtOAc-Hexane to give
4-chloro-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrim-
idin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.034 g, 43%) as a
purple solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
2.03-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16
(2H, m), 5.65-5.71 (1H, m), 7.24 (1H, d, J=8.4 Hz), 7.86-7.90 (1H,
m), 8.24 (1H, d, J=8.8 Hz), 8.39 (1H, d, J=8.8 Hz), 8.66 (1H, d,
J=7.6 Hz), 8.85 (1H, s), 9.19 (1H, s). m/z=516.1 [M+1].sup.+.
Example 16
2-chloro-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimi-
din-6-yl) pyridin-3-yl)benzenesulfonamide
##STR00075##
[0233] To a solution of
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-a-
mine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773
ml) was slowly added 2-chloro-4-fluorobenzene-1-sulfonyl chloride
(0.0430 g, 0.186 mmol) at 0.degree. C. After stirred for 1 hour at
room temperature, the reaction mixture was diluted with DCM and
quenched with 1N. aq HCl. The combined organic layers were washed
brine, dried over anhydrous MgSO.sub.4, filtered and concentrated
in vacuo. The residue was recrystallized from EtOAc-Hexane to give
2-chloro-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrim-
idin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.0500 g, 63%) as a
purple solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
2.02-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16
(2H, m), 5.65-5.70 (1H, m), 7.04-7.09 (1H, m), 7.26-7.28 (2H, m),
8.11-8.15 (1H, m), 8.22 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8 Hz),
8.54 (1H, s), 8.60 (1H, s), 9.16 (1H, s). m/z=516.1
[M+1].sup.+.
Example 17
2,4-dibromo-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6--
yl)pyridin-3-yl)benzenesulfonamide
##STR00076##
[0235] To a solution of
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-a-
mine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773
ml) was slowly added 2,4-dibromobenzene-1-sulfonyl chloride (0.0620
g, 0.186 mmol) at 0.degree. C. After stirred for 1 hour at room
temperature, the reaction mixture was diluted with DCM and quenched
with 1N. aq HCl. The combined organic layers were washed brine,
dried over anhydrous MgSO.sub.4, filtered and concentrated in
vacuo. The residue was recrystallized from EtOAc-Hexane to give
2,4-dibromo-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-
-yl)pyridin-3-yl)benzenesulfonamide (0.0550 g, 57%) as a purple
solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 2.03-2.11
(2H, m), 2.24-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H, m),
5.65-5.71 (1H, m), 7.53 (1H, dd, J=2.0, 8.4 Hz), 7.90 (1H, d, J=1.6
Hz), 7.97 (1H, d, J=8.4 Hz), 8.21 (1H, d, J=8.8 Hz), 8.37 (1H, d,
J=8.8 Hz), 8.52 (1H, s), 8.59 (1H, d, J=2.8 Hz), 8.84 (1H, s), 9.16
(1H, d, J=2.0 Hz). m/z=622.0 [M+1].sup.+.
Example 18
2,4-dichloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-
-yl)pyridin-3-yl)benzenesulfonamide
##STR00077##
[0237] To a solution of
5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-a-
mine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773
ml) was slowly added 2,4-dichlorobenzene-1-sulfonyl chloride
(0.0460 g, 0.186 mmol) at 0.degree. C. After stirred for 1 hour at
room temperature, the reaction mixture was diluted with DCM and
quenched with 1N. aq HCl. The combined organic layers were washed
brine, dried over anhydrous MgSO.sub.4, filtered and concentrated
in vacuo. The residue was recrystallized from EtOAc-Hexane to give
2,4-dichloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin--
6-yl)pyridin-3-yl)benzenesulfonamide (0.0340, 41%) as a purple
solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 2.02-2.11
(2H, m), 2.24-2.29 (2H, m), 3.70-3.75 (2H, m), 4.10-4.16 (2H, m),
5.65-5.71 (1H, m), 7.33 (1H, dd, J=1.8, 8.6 Hz), 7.54 (1H, d, J=2.0
Hz), 8.05 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=9.2 Hz), 8.36 (1H, d,
J=8.8 Hz), 8.48-8.55 (2H, m), 8.84 (1H, s), 9.15 (1H, d, J=1.6 Hz).
m/z=532.0 [M+1].sup.+.
Example 19
N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-
-yl)benzamide
##STR00078##
[0239] A mixture of
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide
(Intermediate 13) (0.07 g, 0.216 mmol),
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
(Intermediate 1) (0.063 g, 0.238 mmol), 1N aq. sodium bicarbonate
(0.432 ml, 0.432 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.018
g, 0.022 mmol) in dioxane (1.08 ml) was subjected to microwave
irradiation for 1 hour at 110.degree. C., and cooled to room
temperature. The reaction mixture was filtered through a Celite pad
and washed with DCM. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2 (only
EtOAc) to give
N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin--
3-yl)benzamide (0.058 g, 63%) as a pink solid. .sup.1H-NMR
(CDCl.sub.3, Varian 400 MHz) .delta. 2.04-2.11 (2H, m), 2.23-2.27
(2H, m), 3.67-3.73 (2H, m), 4.10-4.15 (2H, m), 5.63-5.70 (1H, m),
7.53-7.56 (2H, m), 7.60-7.63 (1H, m), 7.94 (2H, d, J=7.2 Hz), 8.12
(1H, brs), 8.29 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.83
(1H, s), 8.91 (1H, d, J=2.8 Hz), 9.01 (1H, t, J=2.2 Hz), 9.20 (1H,
d, J=2.0 Hz). m/z=428.2 [M+1].sup.+.
Example 20
N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-
pyridin-3-yl)-2,4-difluorobenzamide
##STR00079##
[0241] A mixture of
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)--
2,4-difluorobenzamide (Intermediate 14) (0.100 g, 0.253 mmol),
6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine
(Intermediate 1) (0.074 g, 0.279 mmol), 1N aq. sodium bicarbonate
(0.043 g, 0.507 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.021
g, 0.025 mmol) in dioxane (1.26 ml) was subjected to microwave
irradiation for 1 hour at 110.degree. C., and cooled to room
temperature. The reaction mixture was filtered through a Celite pad
and washed with DCM. The combined organic layers were washed brine,
dried over anhydrous MgSO.sub.4, filtered and concentrated in
vacuo. The residue was purified by column chromatography on
SiO.sub.2 (Hex:EtOAc=1:1) to give
N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl-
)pyridin-3-yl)-2,4-difluorobenzamide (0.020 g, 16%) as a yellow
solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 2.05-2.13
(2H, m), 2.23-2.27 (2H, m), 3.70-3.76 (2H, m), 4.11-4.18 (2H, m),
5.65-5.71 (1H, m), 7.00-7.05 (1H, m), 7.10-7.15 (1H, m), 8.25-8.38
(3H, m), 8.84 (1H, s), 8.03 (1H, d, J=2.4 Hz), 9.19-9.24 (1H, m),
9.71 (1H, d, J=2.4 Hz). m/z=498.0 [M+1].sup.+.
Example 21
N-(5-(4-(cyclohexylthio)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesu-
lfonamide
##STR00080##
[0243] A mixture of
6-chloro-4-(cyclohexylthio)pyrido[3,2-d]pyrimidine (Intermediate
15) (0.12 g, 0.429 mmol),
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesul-
fonamide (Intermediate 2) (0.12 g, 0.429 mmol), 1 N aq. sodium
bicarbonate (0.858 ml, 0.858 mmol) and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.035 g, 0.043 mmol) in dioxane
(2.14 ml) was subjected to microwave irradiation for 1 hour at
110.degree. C., and cooled to room temperature. The reaction
mixture was filtered through a Celite pad and washed with DCM. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give
N-(5-(4-(cyclohexylthio)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenes-
ulfon-amide (0.09 g, 89%) as a brown solid. .sup.1H-NMR
(CDCl.sub.3, Varian 400 MHz) .delta. 1.26-1.28 (1H, m), 1.34-1.43
(1H, m), 1.52-1.85 (4H, m), 1.85-1.87 (2H, m), 2.19-2.23 (2H, m),
4.12-4.19 (1H, m), 7.48-7.58 (3H, m), 7.92 (2H, d, J=8.8 Hz), 8.21
(1H, d, J=8.8 Hz), 8.32 (1H, d, J=9.2 Hz), 8.41-8.43 (2H, m), 8.99
(1H, s), 9.13 (1H, s). m/z=478.1 [M+1].sup.+.
Example 22
N-(2-chloro-5-(4-(cyclopentyloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-
-2,4-difluoro benzenesulfonamide
##STR00081##
[0245] A mixture of
6-chloro-4-(cyclopentyloxy)pyrido[3,2-d]pyrimidine (Intermediate
16) (0.04 g, 0.160 mmol),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)--
2,4-difluorobenzenesulfonamide (Intermediate 2) (0.083 g, 0.192
mmol), 1 N aq. sodium bicarbonate (0.320 ml, 0.320 mmol) and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.31 mg, 1.60 .mu.mol) in
dioxane (0.8 ml) was subjected to microwave irradiation for 1 hour
at 110.degree. C., and cooled to room temperature. The reaction
mixture was filtered through a Celite pad and washed with DCM. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give
N-(2-chloro-5-(4-(cyclopentyloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl-
)-2,4-difluorobenzene sulfonamide (0.04 g, 48%) as a white solid.
.sup.1H-NMR (CDCl.sub.3, Varian 400 MHz): .delta. 1.70-1.80 (2H,
m), 1.92-2.01 (2H, m), 2.04-2.11 (2H, m), 2.13-2.22 (2H, m),
5.79-5.83 (1H, m), 6.92-7.00 (2H, m), 7.46 (1H, s), 7.93-7.99 (1H,
m), 8.17 (1H, d, J=8.8 Hz), 8.35 (1H, d, J=8.8 Hz), 8.79 (1H, s),
8.86 (1H, s), 8.90 (1H, s). m/z=517.9 [M+1].sup.+.
Example 23
N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-ylamino)pyrido[3,2-d]pyrimidin-6-y-
l)-pyridin-3-yl)-2,4-difluorobenzenesulfonamide
##STR00082##
[0247] A mixture of
6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine
(0.026 g, 0.098 mmol) (Intermediate 17),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3)
(0.051 g, 0.118 mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct
(0.802 mg, 0.982 .mu.mol) and sodium bicarbonate (0.196 ml, 0.196
mmol) in dioxane (0.491 ml) was refluxed for 3 hours. After cooling
to room temperature, the reaction mixture was filtered through
Celite and washed with CH.sub.2Cl.sub.2. The filtrate was
concentrated in vacuo. The residue was purified by column
chromatography on SiO.sub.2 (only EtOAc) to give
N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-ylamino)pyrido[3,2-d]pyrimidin-6--
yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.015 g, 29%) as a
white solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
1.68-1.83 (2H, m), 2.13-2.20 (2H, m), 3.58-3.65 (2H, m), 4.05-4.12
(2H, m), 4.41-4.50 (1H, m), 6.94-7.02 (2H, m), 7.18 (1H, d, J=8.0
Hz), 7.84-7.90 (1H, m), 8.09 (1H, d, J=8.8 Hz), 8.24 (1H, d, J=8.4
Hz), 8.65 (1H, s), 8.74 (1H, d, J=2.0 Hz), 8.84 (1H, d, J=2.4 Hz).
NH peak was not observed. m/z=533.4 [M+1].sup.+.
Example 24
N-(2-chloro-5-(4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-y-
l)-2,4-difluoro benzenesulfonamide
##STR00083##
[0249] A mixture of
6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine
(Intermediate 18) (0.043 g, 0.173 mmol),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-
-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.089 g, 0.207
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (1.41 mg, 1.73
.mu.mol) and 1 N aq. sodium bicarbonate (0.346 ml, 0.346 mmol) in
dioxane (0.864 ml) subjected to microwave irradiation for 1 hour at
110.degree. C. After cooling to room temperature, the reaction
mixture was filtered through Celite and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(cyclo pentyl
amino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfon-
amide (0.046 g, 52%) as a white solid. .sup.1H-NMR (CDCl.sub.3,
Varian 400 MHz) .delta. 1.65-1.89 (6H, m), 2.18-2.25 (2H, m),
4.61-4.66 (1H, m), 6.93-7.01 (2H, m), 7.22 (1H, d, J=7.6 Hz),
7.85-7.90 (1H, m), 8.07 (1H, d, J=8.8 Hz), 8.21 (1H, d, J=8.8 Hz),
8.66 (1H, s), 8.74 (1H, d, J=2.0 Hz), 8.82 (1H, d, J=2.0 Hz).
m/z=517.2 [M+1].sup.+.
Example 25
N-(2-chloro-5-(4-(cyclobutylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl-
)-2,4-difluoro benzenesulfonamide
##STR00084##
[0251] A mixture of
6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine (Intermediate
19) (0.050 g, 0.213 mmol),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-
-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.110 g, 0.256
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 Adduct (1.74 mg, 2.13
.mu.mol) and 1 N aq. sodium bicarbonate (0.426 ml, 0.426 mmol) in
dioxane (1.00 ml) subjected to microwave irradiation for 1 hour at
110.degree. C. After cooling to room temperature, the reaction
mixture was filtered through Celite and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give
N-(2-chloro-5-(4-(cyclobutylamino)pyrido[3,2-d]pyrimidin-6-yl)
pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.087 g, 81%) as a
yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
1.84-1.95 (2H, m), 2.10-2.20 (2H, m), 2.54-2.62 (2H, m), 4.77-4.87
(1H, m), 6.94-7.02 (2H, m), 7.34 (1H, d, J=8.0 Hz), 7.86-7.92 (1H,
m), 8.07 (1H, d, J=8.8 Hz), 8.21 (1H, d, J=8.8 Hz), 8.65 (1H, s),
8.73 (1H, d, J=2.4 Hz), 8.84 (1H, d, J=2.4 Hz). m/z=503.2
[M+1].sup.+.
Example 26
N-(2-chloro-5-(4-(cyclopropylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-y-
l)-2,4-difluoro benzenesulfonamide
##STR00085##
[0253] A mixture of
6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine (Intermediate
20) (0.060 g, 0.272 mmol),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-
-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.141 g, 0.326
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 Adduct (2.221 mg, 2.72
.mu.mol) and 1 N aq. sodium bicarbonate (0.544 ml, 0.544 mmol) in
dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at
110.degree. C. After cooling to room temperature, the reaction
mixture was filtered through Celite and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give
N-(2-chloro-5-(4-(cyclopropylamino)pyrido[3,2-d]pyrimidin-6-yl)
pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.070 g, 53%) as a
yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
0.78-0.82 (2H, m), 1.04-1.09 (2H, m), 3.08-3.13 (1H, m), 6.95-7.02
(2H, m), 7.30 (1H, brs), 7.85-7.91 (1H, m), 8.08 (1H, d, J=8.8 Hz),
8.24 (1H, d, J=8.8 Hz), 8.67 (1H, d, J=2.0 Hz), 8.76 (1H, s), 8.81
(1H, d, J=2.0 Hz). m/z=489.2 [M+1].sup.+.
Example 27
N-(2-chloro-5-(4-(3,5-dimethylisoxazol-4-ylamino)pyrido[3,2-d]pyrimidin-6--
yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide
##STR00086##
[0255] A mixture of
N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine
(Intermediate 21) (0.040 g, 0.145 mmol),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-
-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.069 g, 0.160
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.012 g, 0.015
.mu.mol) and 1 N aq. sodium bicarbonate (0.290 ml, 0.290 mmol) in
dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at
110.degree. C. After cooling to room temperature, the reaction
mixture was filtered through Celite and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give
N-(2-chloro-5-(4-(3,5-dimethylisoxazol-4-ylamino)pyrido[3,2-d]pyrimidin-6-
-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.021 g, 27%) as
a yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta.
2.30 (3H, s), 2.45 (3H, s), 6.89-7.05 (2H, m), 7.27 (1H, s),
7.79-7.92 (1H, m), 8.20 (1H, d, J=8.8 Hz), 8.26 (1H, s), 8.36 (1H,
d, J=8.8 Hz), 8.73 (1H, s), 8.76 (1H, s), 8.89 (1H, s). m/z=544.1
[M+1].sup.+.
Example 28
N-(2-chloro-5-(4-(6-methoxypyridin-3-ylamino)pyrido[3,2-d]pyrimidin-6-yl)p-
yridin-3-yl)-2,4-difluorobenzenesulfonamide
##STR00087##
[0257] A mixture of
6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine
(Intermediate 22) (0.040 g, 0.139 mmol),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-
-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.066 g, 0.153
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.011 g, 0.014
mmol) and 1 N aq. sodium bicarbonate (0.278 ml, 0.278 mmol) in
dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at
110.degree. C. After cooling to room temperature, the reaction
mixture was filtered through Celite and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give
N-(2-chloro-5-(4-(6-methoxypyridin-3-ylamino)pyrido[3,2-d]pyrimidin-6-yl)-
pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.024 g, 31%) as a
yellow solid.
[0258] .sup.1H-NMR (DMSO-d.sub.6, Varian 400 MHz) .delta. 3.89 (3H,
s), 6.94 (3H, s), 6.89-7.05 (1H, d, J=8.4 Hz), 7.17-7.28 (1H, m),
7.50-7.65 (1H, m), 7.74-7.86 (1H, m), 8.17 (1H, dd, J=2.4, 8.8 Hz),
8.33 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.57 (1H, d, J=8.8
Hz), 8.62 (2H, s), 8.82 (1H, s), 9.48 (1H, s), 10.33 (1H, s), 10.98
(1H, br s). m/z=556.2 [M+1].sup.+.
Example 29
N-(2-chloro-5-(4-(4-(trifluoromethoxy)phenylamino)pyrido[3,2-d]pyrimidin-6-
-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide
##STR00088##
[0260] A mixture of
6-chloro-N-(4-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine
(Intermediate 23) (0.050 g, 0.147 mmol),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-
-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.070 g, 0.161
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (5.99 mg, 7.34
.mu.mol) and 1 N aq. sodium bicarbonate (0.294 ml, 0.294 mmol) in
dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at
110.degree. C. After cooling to room temperature, the reaction
mixture was filtered through Celite and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by column chromatography on SiO.sub.2
(Hex:EtOAc=1:1) to give
N-(2-chloro-5-(4-(4-(trifluoromethoxy)phenylamino)pyrido[3,2-d]pyrimidin--
6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.049 g, 55%) as
a yellow solid.
[0261] .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 6.88-7.05
(2H, m), 7.34 (2H, d, J=8.8 Hz), 7.85-7.95 (1H, m), 8.05-8.10 (2H,
m), 8.19 (1H, d, J=8.8 Hz), 8.34 (1H, d, J=8.4 Hz), 8.84 (1H, s),
8.85-8.90 (2H, m), 9.26 (1H, br s). 1NH was not detected. m/z=609.1
[M+1].sup.+.
Example 30
tert-butyl
4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)py-
rido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate
##STR00089##
[0263] A mixture of tert-butyl
4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate
(Intermediate 24) (0.050 g, 0.137 mmol),
N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)pyridine-3-yl)-2-
,4-difluorobenzenesulfonamide (Intermediate 3) (0.065 g, 0.151
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (5.61 mg, 6.87
.mu.mol) and 1 N aq. sodium bicarbonate (0.275 ml, 0.275 mmol) in
dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at
110.degree. C. After cooling to room temperature, the reaction
mixture was filtered through Celite and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo. The
residue was purified by prep TLC (Hex:EtOAc=1:2) to give tert-butyl
4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)pyrido[3,2-d-
]pyrimidin-4-ylamino)piperidine-1-carboxylate (3.90 mg, 4.5%) as a
yellow solid. .sup.1H-NMR (CDCl.sub.3, Varian 400 MHz) .delta. 1.48
(9H, s), 1.55-1.72 (2H, m), 2.05-2.22 (2H, m), 2.92-3.12 (2H, m),
4.02-4.25 (2H, m), 4.30-4.48 (1H, m), 6.90-7.04 (2H, m), 7.14 (1H,
J=8.0 Hz), 7.80-7.92 (1H, m), 8.07 (1H, d, J=8.8 Hz), 8.22 (1H, d,
J=8.8 Hz), 8.69 (1H, s), 8.70 (1H, br s), 8.79 (1H, br s).
m/z=632.2 [M+1].sup.+.
Biological Activity
Materials and Preparation of Reagents
[0264] The PI3 Kinase Activity/Inhibitor Assay Kit was purchased
from Millipore. The dimethylsulfoxide was purchased from
Sigma-Aldrich.
Assay Principle
[0265] The PI3 Kinase Activity/Inhibitor Assay is a competitive
assay used for the fast and sensitive quantitation of activity of
the four class I PI3 kinases (p110 .alpha., .beta., .gamma.,
.delta.). The PI3 Kinase Activity/Inhibitor Assay works on the
principle that PI3 Kinase phosphorylates PI(3,4)P2 (PIP2),
converting it to PI(3,4,5)P3 (PIP3). The PH domain of the protein
GRP-1 binds PIP3 with high affinity and specificity. The kit
includes this recombinant protein that is used as the capture
protein. This protein binds to the glutathione plate and captures
either the PIP3 generated as part of the kinase reaction or the
biotinylated-PIP3 tracer included in the kit. The captured
biotinylated-PIP3 is detected using streptavidin-HRP conjugate and
a colorimetric read out (OD 450). The lower the signal, the higher
the PI3 Kinase activity.
Assay Protocol
[0266] PI3-Kinase included in the Kit was diluted at the ratio of
1:10 with distilled water and stored on ice. The compound was
prepared by diluting the stock compound to 100.times. of the final
concentration and then diluted again at the ratio of 1:50 to make
2.times. of the final concentration with distilled water.
[0267] The prepared PI3-Kinase (5 .mu.L/well) and the compound (5
.mu.L/well) were added to Glutathione-Coated Plate and
pre-incubated at room temperature for 10 minutes. After adding 5
.mu.L of 5.times. Kinase reaction buffer per well, PIP2 was diluted
at the ratio of 1:20 with distilled water and 54, were added into
each well. Distilled water was added up to 25 .mu.L, and the
reaction mixture was incubated at room temperature for an hour.
Biotinylated-PIP3 was diluted at the ratio of 1:18 with 1.times.TBS
solution and 25 .mu.L of the mixture were put in each well
excluding the buffer control well. GRP1-GST was diluted at the
ratio of 1:1000 with 1.times.TBS solution and 50 .mu.L of it was
added to every well. The mixture was incubated at room temperature
for an hour.
[0268] After removing the solution contained in the wells, the
wells were washed 4 times with 200 .mu.L of 1.times.TBST. SA-HRP
was diluted at the ratio of 1:2000 with 1.times.TBST, then 50 .mu.L
of it was added into every well and incubated at room temperature
for an hour. Again after removing the solution, they were washed 5
times by adding 200 .mu.L of 1.times.TBST to each well. 100 .mu.L
of TMB solution was added to every well. The plate was developed in
the dark for 5-20 minutes. As blue color appeared, the reaction was
stopped by adding 100 .mu.L of stop solution to every well, and the
plate was read at 450 nm with ELISA Reader (TECAN).
Data Analysis
[0269] For the calculation of relative percentage to
biotinylated-PIP3, we take the direct absorbance at 450 nm (A450)
and set the positive Biotinylated-PIP3 wells as 100 percentage. All
the other signals are divided by the Biotinylated-PIP3 average, and
multiplied by 100 to show the relative percentage to the positive
signal.
Relative % to B-PIP3=(A450 of samples include buffer, kinase &
inhibitors/A450 of Biotinylated-PIP3 average).times.100
[0270] IC.sub.50 values were calculated from the values read at 450
nm by using Graphpad Prism 5 software.
Biological Data for Select Compounds
[0271] Select compounds prepared as described above were assayed
according to the biological procedures described herein. The
results are given in the table below:
TABLE-US-00001 IC.sub.50(uM) Structure PI3K.alpha. PI3K.gamma.
PI3K.delta. ##STR00090## <10 <1 <10 ##STR00091## <10
<1 <10 ##STR00092## <1 <1 <1 ##STR00093## <1
<10 <1 ##STR00094## <10 <10 <10 ##STR00095## <10
<10 <10
* * * * *