Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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THIENO[2,3-D]PYRIMIDINE COMPOUNDS AS INHIBITORS OF ADP-MEDIATED PLATELETS
AGGREGATION
CROSS REFERENCE TO OTHER APPLICATIONS
This application claims priority to U.S. Provisional application number
60/647,340, filed January
26, 2005 and U.S. Provisional application number 60/659,337, filed March 7,
2005.
FIELD OF THE INVENTION
The present invention comprises a novel class of thieno[2,3-djpyrimidine
compounds having the
structure of Formula I (including tautomers and salts of those compounds) and
pharmaceutical
compositions comprising a compound of Formula 1. The present invention also
comprises
methods of treating a subject by administering a therapeutically effective
amount of a compound
of Formula I to the subject. In general, these compounds, in whole or in part,
inhibit ADP-
mediated platelet aggregation. The present invention further comprises methods
for making the,
compounds of Formula I and corresponding intermediates.
BACKGROUND OF THE INVENTION
Thrombosis is a pathological process in which a platelet aggregate and/or a
fibrin clot occludes a
blood vessel. Arterial thrombosis may result in ischemic necrosis of the
tissue supplied by the
artery. Venous thrombosis may cause edema and inflammation in the tissue
drained by the vein.
Compounds that inhibit platelet function can be administered to a patient to
decrease the risk of
occlusive arterial events in patients suffering from or susceptible to
atherosclerotic
cardiovascular, cerebrovascular and peripheral arterial diseases. Commercially
available drugs
that inhibit platelet function typically fall within one of three classes of
drugs that antagonize
different molecular targets: (1) cycloxygenase inhibitors, such as aspirin
(see Awtry, E.H. et al.,
Circulation, 2000, Vol. 101, pg. 1206); (2) glycoprotein Ilb-Illa antagonists,
such as tirofiban (see
Scarborough, R.M. et al., Journal of Medicinal Chemistry, 2000, Vol. 43, pg.
3453); and (3)
P2Y12 receptor antagonists (also known as ADP receptor antagonists), such as
the
thienopyridine compounds ticlopidine and clopidogrel (see Quinn, M.J. et al.,
Circulation, 1999,
Vol.100, pg.1667.
There are several disadvantages associated with use of the P2Y12 receptor
antagonists
ticlopidine and clopidogrel. First, although both compounds selectively
inhibit platelet
aggregation by blocking the P2Y12 receptor, such inhibition is irreversible
and increases the
bleeding risk to the patient. Second, both ticlopidine and clopidogrel each
have a relatively slow
onset of action. Both compounds apparently are prodrugs that first must be
metabolized by the
liver into the corresponding active metabolites. Third, a number of patients
are resistant to
treatment with clopidogrel. Such resistance may result, in whole or in part,
from drug-drug
interactions between clopidogrel and other drugs commonly administered to
atherosclerotic
patients. Fourth, both ticlopidine and clopidogrel have been associated with
side-effects such as
thrombocytopenia in some patients (see Bennett, C.L. et al., New England
Journal of Medicine,
2000, Vol. 342, pg. 1773).
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Other compounds have been reported in the literature as useful for the
treatment of
cardiovascular events such as thrombosis:
US2003/0153566 Al (published August 14, 2003)describes a class of piperazine
compounds as
ADP receptor antagonists.
WIPO Int'I Publ. No. WO99/05144 Al (published February 4, 1999) describes a
class of
triazolo[4,5-d]pyrimidine compounds as P2T antagonists.
WIPO Int'I Publ. No. W099/36425 Al (published July 22, 1999) describes a class
of tricyclic
compounds as ADP receptor antagonists.
WIPO Int'I Publ. No. W001/57037 Al (published August 9, 2001) describes a
class of
compounds including sulfonylureas as ADP receptor antagonists.
US 5,057,517 (granted October 15, 1991) describes a class of heteroaromatic
compounds
including 6-piperazinopurines as antidiabetic agents.
US 4,459,296 (granted July 10, 1984) describes a class of N-(benzimidazolyl,
indolyl, purinyl or
benzotriazolyl)-piperazine compounds as antihypertensive agents.
Humphries et al. describe several purine compounds as selective ADP receptor
antagonists in an
animal thrombosis model. Trends in Pharmacological Sciences, 1995, Vol. 16,
pg. 179. These
compounds are further described in lngall, A.H et al., Journal of Medicinal
Chemistry, 1999, Vol.
42, pg. 213.
Accordingly, a need still exists for new drug therapies for the treatment of
subjects suffering from
or susceptible to a platelet aggregation mediated condition. In particular, a
need still exists for
new P2Y12 antagonists having one or more improved properties (such as safety
profile, efficacy,
or physical properties) relative to currently available P2Y12 antagonists.
SUMMARY OF THE INVENTION
In one embodiment, the invention comprises a class of compounds (including the
pharmaceutically acceptable salts of the compounds) having the structure of
Formula I:
R4 X4 ~
A1 AB
A2 A7
A3 A6
N
A4 A5
R5
s t N
I X
6 6
~
RS OR2
Formula I
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wherein Ai, A2, A3, A4, A5, A6, A', A8, X4, X6, R2, R4, R5, and R6 are as
defined in the detailed
description of the invention.
In another embodiment, the invention comprises a pharmaceutical composition
comprising a
compound having the structure of Formula I.
In another embodiment, the invention comprises methods of treating a condition
in a subject by
administering to a subject a therapeutically effective amount of a compound
having the structure
of Formula I. The conditions that can be treated in accordance with the
present invention
include, but are not limited to, atherosclerotic cardiovascular diseases,
cerebrovascular diseases
and peripheral arterial diseases. Other conditions that can be treated in
accordance with the
present invention include hypertension and angiogenesis.
In another embodiment, the invention comprises methods for inhibiting platelet
aggregation in a
subject by administering to the subject a compound having a structure of
Formula I.
In another embodiment, the invention comprises methods of making compounds
having the
structure of Formula I.
In another embodiment, the invention comprises intermediates useful in the
synthesis of
compounds having the structure of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
This detailed description of embodiments is intended only to acquaint others
skilled in the art with
Applicants' inventions,, its principles, and its practical application so that
others skilled in the art
may adapt and apply the inventions in their numerous forms, as they may be
best suited to the
requirements of a particular use. These inventions, therefore, are not limited
to the embodiments
described in this specification, and may be variously modified.
A. Abbreviations and Definitions
TABLE A - Abbreviations
1-HOAT 1 -hdrox -7-azabenzotriazole
1 -HOBt 1 -h drox benzotriazole hydrate
ADP Adenosine di hos hate (the natural ligand of P2Y12)
AMP Adenosine mono hos ate
ASA Acet Isalic lic acid
ATP Adenosine triphosphate
Boc tert-butox carbon l
BOP-CI bis 2-oxo-3-oxazolidin I hos hinic chloride
br Broad
BSA Bovine serum albumin
Cbz benz lox carbon I
CD30D Deuterated methanol
CDCI3 Deuterated chloroform
CDI 1,1'-carbon Idiimidazole
d Doublet
DBN 1 ,5-diazabic clo 4.3.0 non-5-ene
DBU 1,8-diazabic clo 5.4.0]undec-7-ene
DCC 1 ,3-dic clohex lcarbodiimide
DCM dichloromethane
dd Doublet of doublets
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DEPC dieth f c ano hos honate
DIEA diiso ro leth lamine
DMF N,N-dimethylformamide
DMSO dimethyl sul hoxide
DPBS Dulbecco's Phosphate Buffered Saline
EBSS Earle's Balanced Salt Solution
EDC 1 - 3-dimeth lamino ro I-3-eth Icarbodiimide hydrochloride
EDTA eth lenediaminetetraacetic acid
EGTA eth lene I col-bis -aminoeth I-N,N,N',N'-tetraacetic Acid
ESI Electrospray Ionization for mass s ectrometr
Et3N trieth lamine
EtOAc ethyl acetate
EtOH ethanol
FBS Fetal bovine serum
Fmoc Fluorene meth lox carbon I
HATU 0-(7-azabenzotriazol-1-yl)-N,N, N', N'-tetram ethyl uron ium
hexafluoro hoshate
HBTU 0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluoro hos hate
HCI Hydrochloric acid
HEK Human embryonic kidney
HEPES 4- 2-h drox eth I-1-Pi erazineethane sulfonic acid
HRMS High Resolution Mass Spectroscopy (electrospray ionization
positive scan)
K3PO4 Potassium phosphate
LCMS Liquid Chromato ra h- Mass S ectrosco
LRMS Low Resolution Mass Spectroscopy (electrospray or thermospray
ionization positive scan)
LRMS (ES-) Low Resolution Mass Spectroscopy (electrospray ionization
negative scan)
m Multiplet
m/z Mass spectrum peak
MEM Minimum essential medium
MeOH methanol
MHz Megahertz
MS Mass sp ectrosco
NaH Sodium hydride
NMM N-methylmorpholine
NMP 1 -meth1-2- rrolidinone
NMR Nuclear Magnetic Resonance
PG Protecting group. Exemplary protecting groups include Boc, Cbz,
Fmoc and benzyl
Pg. Page
PPP Platelet poor plasma
PRP Platelet rich plasma
Quartet
Rpm Revolutions per minute
s Singlet
t Triplet
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC Thin layer chromatography
Vol. Volume
8 Chemical shift
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The term "alkyl" refers to a linear or branched-chain saturated hydrocarbyl
substituent (i.e., a
substituent containing only carbon and hydrogen) containing in one embodiment,
from about one
-'to about-twenty-carbon atoms; in another embodiment from about* one-toabout
twelve carbon
atoms; in another embodiment, from about one to about ten carbon atoms; in
another
embodiment, from about one to about six carbon atoms; and in another
embodiment, from about
one to about four carbon atoms. Examples of such substituents include methyl,
ethyl, propyl
(including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-
butyl and tert-butyl),
pentyl, iso-amyl, hexyl and the like.
_The term "alkenyl" refers to a linear or branched-chain hydrocarbyl
substituent containing one or
more double bonds and from about two to about twenty carbon atoms; in another
embodiment,
from about two to about twelve carbon atoms; in another embodiment, from about
two to about
six carbon atoms; and in another embodiment, from about two to about four
carbon atoms.
Examples of alkenyl include ethenyl (also known as vinyl), allyl, propenyl
(including 1 -propenyl
and 2-propenyl) and butenyl (including 1-butenyl, 2-butenyl and 3-butenyl).
The term "alkenyl"
embraces substituents having "cis" and "trans" orientations, or alternatively,
"E" and "Z"
orientations.
The term "alkynyl" refers to linear or branched-chain hydrocarbyl substituents
containing one or
more triple bonds and from about two to about twenty carbon atoms; in another
embodiment,
from about two to about twelve carbon atoms; in another embodiment, from about
two to about
six carbon atoms; and in another embodiment, from about two to about four
carbon atoms.
Examples of alkynyl substituents include ethynyl, propynyl (including 1-
propynyl and 2-propynyl)
and butynyl (including 1-butynyl, 2-butynyl and 3-butynyl).
The term "benzyl" means a methyl radical substituted with phenyl, i.e., the
following structure:
~ \ ..
4__
The term "carbocyclyl" refers to a saturated cyclic (i.e., "cycloalkyl"),
partially saturated cyclic
(i.e., "cycloalkenyl"), or completely unsaturated (i.e., "aryl") hydrocarbyl
substituent containing
from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bound together to
form the ring or
rings of a cyclic substituent). A carbocyclyl may be a single ring, which
typically contains from 3
to 6 ring atoms. Examples of such single-ring carbocyclyls include
cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,
cyclohexadienyl, and
phenyl. A carbocyclyl alternatively may be 2 or 3 rings fused together, such
as naphthalenyl,
tetrahydronaphthalenyl (also known as "tetralinyl"), indenyl, isoindenyl,
indanyl, bicyclodecanyl,
anthracenyl, phenanthrene, benzonaphthenyl (also known as "phenalenyl"),
fluorenyl, and
decalinyl.
The term "cycloalkyl" refers to a saturated carbocyclic substituent having
three to about fourteen
carbon atoms. In another embodiment, a cycloalkyl substituent has three to
about eight carbon
atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
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The term "cycloalkylalkyl" refers to alkyl substituted with cycloalkyl.
Examples of cycloalkylalkyl
include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and
cyclohexylmethyl.
The term "cycloalkenyl" refers to a partially unsaturated carbocyclyl
substituent. Examples of
cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
The term "aryl" refers to a carbocyclic aromatic system containing one, two or
three rings wherein
such rings may be attached together in a pendent manner or may be fused. The
term "aryl"
refers to aromatic substituents such as phenyl, naphthyl, tetrahydronaphthyl,
indanyl and
biphenyl.
The term "arylalkyl" means alkyl substituted with aryl.
In some instances, the number of carbon atoms in a hydrocarbyl substituent
(e.g., alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix "CX
Cy-," wherein x is the
minimum and y is the maximum number of carbon atoms in the substituent. Thus,
for example,
"C1-C6-aIkyP" refers to an alkyl substituent containing from 1 to 6 carbon
atoms. Illustrating
further, C3-C6-cycloalkyl means a saturated carbocyclyl containing from 3 to 6
carbon ring atoms.
The term "hydrogen" means a hydrogen substituent, and may be depicted as -H.
The term "hydroxy" refers to -OH. When used in combination with another
term(s), the prefix
"hydroxy" indicates that the substituent to which the prefix is attached is
substituted with one or
more hydroxy substituents. Compounds bearing a carbon to which one or more
hydroxy
substituents include, for example, alcohols, enols and phenol.
The term "phenol" refers to a hydroxy substituent bonded to a benzene ring.
The term "hydroxyalkyl" refers to an alkyl substituent wherein at least one
hydrogen substituent is
replaced with a hydroxy substituent. Examples of hydroxyalkyl substituents
include
hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
The term "nitro" means -NO2.
N
II)
C
The term "cyano" (also referred to as "nitrileõ)-CN, which also may be
depicted:
.
O
The term "carbonyl" means-C(O)-, which also may be depicted as:
The term "amino" refers to -NH2.
The term "alkylamino" refers to an amino group, wherein at least one alkyl
chain is bonded to the
amino nitrogen in place of a hydrogen atom. Examples of alkylamino
substituents include
monoalkylamino such as methylamino (exemplified by the formula -NH(CH3)),
which may also
1-11, CH3
be depicted: H and dialkylamino such as dimethylamino, (exemplified by the
formula
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CH3
N
-N((CH3)2), which may also be depicted: \CHs ,-
O
~~kNH2
The term "aminocarbonyl" means -C(O)-NH2, which also may be depicted as:.
The term "halogen" refers to fluorine (which may be depicted as -F), chlorine
(which may be
depicted as -CI), bromine (which may be depicted as -Br), or iodine (which may
be depicted as
-I). 'In one embodiment, the halogen is chlorine. In another embodiment, the
halogen is a
fluorine.
The prefix "halo" indicates that the substituent to which the prefix is
attached is substituted with
one or more independently selected halogen substituents. For example,
haloalkyl means an
alkyl substituent wherein at least one hydrogen substituent is replaced with a
halogen
substituent. Where there are more than one hydrogens replaced with halogens,
the halogens
may be the identical or different. Examples of haloalkyls include
chloromethyl, dichloromethyl,
difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl,
fluoromethyl,
difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl,
pentafluoroethyl, difluoropropyl,
dichloropropyl, and heptafluoropropyl. Illustrating further, "haloalkoxy'
means an alkoxy
substituent wherein at least one hydrogen substituent is replaced by a halogen
substituent.
Examples of haloalkoxy substituents include chloromethoxy, 1 -bromoethoxy,
fluoromethoxy,
difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and
2,2,2-trifluoroethoxy. It should be recognized that if a substituent is
substituted by more than
one halogen substituent, those halogen substituents may be identical or
different (unless
otherwise stated).
The prefix "perhalo" indicates that each hydrogen substituent on the
substituent to which the
prefix is attached is replaced with an independently selected halogen
substituent. If all the
halogen substituents are identical, the prefix may identify the halogen
substituent. Thus, for
example, the term "perfluoro" means that every hydrogen substituent on the
substituent to which
the prefix is attached is substituted with a fluorine substituent. To
illustrate, the term
"perfluoroalkyl" means an alkyl substituent wherein a fluorine substituent is
in the place of each
hydrogen substituent. Examples of perfluoroalkyl substituents include
trifluoromethyl (-CF3),
perfluorobutyl, perfluoroisopropyl, perfluorododecyl, and perfluorodecyl. To
illustrate further, the
term "perfluoroalkoxy' means an alkoxy substituent wherein each hydrogen
substituent is
replaced with a fluorine substituent. Examples of perfluoroalkoxy substituents
include
trifluoromethoxy (-O-CF3), perfluorobutoxy, perfluoroisopropoxy,
perfluorododecoxy, and
perfluorodecoxy.
The term "oxo" refers to =0.
The term "oxy' means an ether substituent, and may be depicted as -0-.
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The-term "alkoxy' refers to-an-alkyl-linked to an oxygen (sometimes referred
to as an oxygen
bridge), which may also be represented as -O-R, wherein the R represents the
alkyl group.
Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.
The term "alkylthio" means -S-alkyl. For example, "methylthio" is -S-CH3.
Other examples of
alkylthio include ethylthio, propylthio, butylthio, and hexylthio.
The term "alkylcarbonyl" means -C(O)-alkyl. For example, "ethylcarbonyl" may
be depicted
O
CH3
as: . Examples of other alkylcarbonyl include methylcarbonyl,
propylcarbonyl, butylcarbonyl, pentylcarbonyl, and hexylcarbonyl. -
The term "aminoalkylcarbonyl" means -C(O)-alkyl-NH2. For example,
"aminomethylcarbonyl"
O
NH2
may be depicted as:
The term "alkoxycarbonyl" means -C(O)-O-alkyl. For example, "ethoxycarbonyl"
may be
O
O/\CH3
depicted as: . Examples of other alkoxycarbonyl include
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
pentoxycarbonyl, and
hexyloxycarbonyl. In another embodiment, where the carbon atom of the carbonyl
is attached to
a carbon atom of a second alkyl, the resulting functional group is an ester.
The term "carbocyclylcarbonyl" means -C(O)-carbocyclyi. For example,
"phenylcarbonyl" may be
0
depicted as: Similarly, the term "heterocyclylcarbonyl," alone or in
combination with another term(s), means -C(O)-heterocyclyl.
The term "carbocyclylalkylcarbonyl" means -C(O)-alkyl-carbocyclyl. For
example,
0
"phenylethylcarbonyl" may be depicted as: Similarly, the term
"heterocyclylalkylcarbonyl," alone or in combination with another term(s),
means
-C(O)-alkyl-heterocyclyl.
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The term "carbocyclyloxycarbonyl," means -C(O)-O-carbocyclyl. For example,
o I \
"phenyloxycarbonyl" may be depicted as:
o c
The term "carbocyclylaikoxycarbonyl" means -C(O)-O-alkyl-carbocyclyl. For
example,
O
"phenylethoxycarbonyl" may be depicted as:
The terms "thio" and "thia" mean a divalent sulfur atom and such a substituent
may be depicted
as -S-. For example, a thioether is represented as "alkyl-thio-alkyl" or,
alternatively, alkyl-S-alkyl.
The term "thiol" means a sulfhydryl substituent, and may be depicted as -SH.
The term "thione" refers to =S.
\\~~
The term "sulfonyl" means -S(0)2-, which also may be depicted as: Thus, for
example, "alkyl-sulfonyl-alkyl" means alkyl-S(0)2-alkyl. Examples of
alkylsulfonyl include
methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
\//
NH2
The term "aminosulfonyl" means -S(0)2-NH2, which also may be depicted as.
0
I I
S
The term "sulfinyl" or "sulfoxido" means _S(O)_, which also may be depicted
as:
.
Thus, for example, "aikylsulfinylalkyl" or "alkylsulfoxidoalkyl" means alkyl-
S(O)-alkyl. Exemplary
alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and
hexyisulfinyl.
The term "heterocyclyl" means a saturated (i.e., "heterocycloalkyl"),
partially saturated (i.e.,
"heterocycloalkenyl"), or completely unsaturated (i.e., "heteroaryl") ring
structure containing a
total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom
(i.e., oxygen, nitrogen,
or sulfur), with the remaining ring atoms being independently selected from
the group consisting
of carbon, oxygen, nitrogen, and sulfur.
A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring
atoms, more
typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
Examples of
single-ring heterocyclyls include furanyl, dihydrofurnayl, tetradydrofurnayl,
thiophenyl (also
known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl,
isopyrrolyl, pyrrolinyl,
pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl,
pyrazolyl, pyrazolinyl,
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pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl;
isoxazolyi, thiazolyl, isothiazolyl,
thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl,
oxathiazolyl, oxadiazolyl
(including oxadiazolyl, 1,2,4-oxadiazolyl (also known as "azoximyl"), 1,2,5-
oxadiazolyl (also
known as "furazanyl"), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-
oxatriazolyl or
1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-
dioxazolyl, 1,3,2-dioxazolyl, or
1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including
1,2-pyranyl or
1,4-pyranyl), dihydropyranyl, pyridinyl (also known as "azinyl"), piperidinyl,
diazinyl (including
pyridazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known as "1,3-
diazinyl" or "pyrimidyl"),
or pyrazinyl (also known as "1,4-diazinyl")), piperazinyl, triazinyl
(including s-triazinyl (also known
as "1,3,5-triazinyl"), as-triazinyl (also known 1,2,4-triazinyl), and v-
triazinyl (also known as
"1,2,3-triazinyl")), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-
oxazinyl (also known as
"pentoxazolyl"), 1,2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl (including o-
isoxazinyl or p-isoxazinyl),
oxazolidinyl,'isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or
1,2,6-oxathiazinyl),
oxadiazinyl (including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl), morpholinyl,
azepinyl, oxepinyl,
thiepinyl, and diazepinyl.
A heterocyclyl alternatively may be 2 or 3 rings fused together, wherein at
least one such ring
contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur).
Examples of 2-fused-ring
heterocyclyls include, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-
quinolizinyl, purinyl,
naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-
b]-pyridinyl, or
pyrido[4,3-b]-pyridinyl), and pteridinyl, indolyl, isoindolyl, indoleninyl,
isoindazolyi, benzazinyl,
phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl,
benzothiopyranyl,
benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl,
benzoxadiazolyl,
benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl,
benzothiadiazolyl,
benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and
tetrahydroisoquinolinyl.
Other examples of fused-ring heterocyclyls include benzo-fused heterocyclyls,
such as indolyl,
isoindolyl (also known as "isobenzazolyl" or "pseudoisoindolyl"), indoleninyl
(also known as .
"pseudoindolyl"), isoindazolyl (also known as "benzpyrazolyl"), benzazinyl
(including quinolinyl
(also known as "1-benzazinyl") or isoquinolinyl (also known as "2-
benzazinyl")), phthalazinyl,
quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as
"1,2-benzodiazinyl")
or quinazolinyl (also known as "1,3-benzodiazinyl")), benzopyranyl (including
"chromanyl" or
"isochromanyl"), benzothiopyranyl (also known as "thiochromanyl"),
benzoxazolyl, indoxazinyl
(also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl,
benzoxadiazolyl,
benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also
known as
"benzothiophenyl," "thionaphthenyl," or "benzothiofuranyl"), isobenzothienyl
(also known as
"isobenzothiophenyl," "isothionaphthenyl," or "isobenzothiofuranyl"),
benzothiazolyl,
benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including
1,3,2-benzoxazinyl ,
1,4,2-benzoxazinyl , 2,3,1 -benzoxazinyl , or 3,1,4-benzoxazinyl ),
benzisoxazinyl (including
1,2-benzisoxazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinolinyl ,
carbazolyl, xanthenyl, and
acridinyl.
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The term "heteroaryl" means an aromatic heterocyclyl containing from 5 to 14
ring atoms. A
heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl
substituents include
6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and
pyridazinyl; 5-membered
ring substituents such as triazolyl, imidazyl, furanyl, thiophenyl, pyrazolyl,
oxazolyl, isoxazolyl,
thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-
membered fused ring
substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl,
benzoxazolyl,
purinyl, and anthranilyl; and 6/6-membered fused rings such as quinolinyl,
isoquinolinyl,
cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl.
The term "heterocyclylalkyl" means alkyl substituted with a heterocyclyl.
The term "heterocycloalkyl" means a fully saturated heterocyclyl.
A substituent is "substitutable" if it comprises at least one carbon, sulfur,
oxygen or nitrogen atom
that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen,
halogen, and
cyano do not fall within this definition.
If a substituent is described as being "substituted," a non-hydrogen
substituent is in the place of a
hydrogen substituent on a carbon or nitrogen of the substituent. Thus, for
example, a substituted
alkyl substituent is an alkyl substituent wherein at least one non-hydrogen
substituent is in the
place of a hydrogen substituent on the alkyl substituent. To illustrate,
monofluoroalkyl is alkyl
substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted
with two fluoro
substituents. It should be recognized that if there are more than one
substitutions on a
substituent, each non-hydrogen substituent may be identical or different
(unless otherwise
stated). ,
If a substituent is described as being "optionally substituted," the
substituent may be either (1)
not substituted, or (2) substituted. If a carbon of a substituent is described
as being optionally
substituted with one or more of a list of substituents, one or more of the
hydrogens on the carbon
(to the extent there are any) may separately and/or together be replaced with
an independently
selected optional substituent. If a nitrogen of a substituent is described as
being optionally
substituted with one or more of a list of substituents, one or more of the
hydrogens on the
nitrogen (to the extent there are any) may each be replaced with an
independently selected
optional substituent.
One exemplary substituent may be depicted as -NR'R," wherein R' and R"
together with the
nitrogen atom to which they are attached, may form a heterocyclic ring. The
heterocyclic ring
formed from R' and R" together with the nitrogen atom to which they are
attached may be
partially or fully saturated. In one embodiment, the heterocyclic ring
consists of 3 to 7 atoms. In
another embodiment, the heterocyclic ring is selected from the group
consisting of pyrrolyl,
imidazolyl, pyrazolyl, triazolyl and tetrazolyl.
This specification uses the terms "substituent," "radical," and "group"
interchangeably.
If a group of substituents are collectively described as being optionally
substituted by one or
more of a list of substituents, the group may include: (1) unsubstitutable
substituents, (2)
substitutable substituents that are not substituted by the optional
substituents, and/or (3)
substitutable substituents that are substituted by one or more of the optional
substituents.
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-If a substituent is described as being optionally substituted with up to a
particular number of non-
hydrogen substituents, that substituent may be either (1) not substituted; or
(2) substituted by up
to that particular number of non-hydrogen substituents or by up to the maximum
number of
substitutable positions on the substituent, whichever is less. Thus, for
example, if a substituent is
described as a heteroaryl optionally substituted with up to 3 non-hydrogen
substituents, then any
heteroaryl with less than 3 substitutable positions would be optionally
substituted by up to only as
many non-hydrogen substituents as the heteroaryl has substitutable positions.
To illustrate,
tetrazolyl (which has only one substitutable position) would be optionally
substituted with up to
one non-hydrogen substituent. To illustrate further, if an amino nitrogen is
described as being
optionally substituted with up to 2 non-hydrogen substituents, then the
nitrogen will be optionally
substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a
primary nitrogen,
whereas the amino nitrogen will be optionally substituted with up to only 1
non-hydrogen
substituent if the amino nitrogen is a secondary nitrogen.
A prefix attached to a multi-moiety substituent only applies to the first
moiety. To illustrate, the
term "alkylcycloalkyl" contains two moieties: alkyl and cycloalkyl. Thus, the
Ci-C6- prefix on
Cl-C6-alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl
contains from 1 to 6
carbon atoms; the Cl-C6- prefix does not describe the cycloalkyl moiety. To
illustrate further, the
prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the
alkoxyalkyl substituent
is substituted with one or more halogen substituents. If halogen substitution
may alternatively or
additionally occur on the alkyl moiety, the substituent would instead be
described as
"halogen-substituted alkoxyalkyl" rather than "haloalkoxyalkyl." And finally,
if the halogen
substitution may on/yoccur on the alkyl moiety, the substituent would instead
be described as
"alkoxyhaloalkyl."
When a substituent is comprised of multiple moieties, unless otherwise
indicated, it is the
intention for the final moiety to serve as the point of attachment to the
remainder of the molecule.
For example, in a substituent A-B-C, moiety C is attached to the remainder of
the molecule. In a
substituent A-B-C-D, moiety D is attached to the remainder of the molecule.
Similarly, in a
substituent aminocarbonylmethyl, the methyl moiety is attached to the
remainder of the molecule,
H2N H2C-j
where the substituent may also be be depicted as 0 . In a substituent
trifluoromethylaminocarbonyl, the carbonyl moiety is attached to the remainder
of the molecule,
H C" 0
F N~
where the substituent may also be depicted as F F
If substituents are described as being "independently selected" from a group,
each substituent is
selected independent of the other. Each substituent therefore may be identical
to or different
from the other substituent(s).
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B. Comgounds
The present invention comprises, in part, a novel class of thieno[2,3-
4pyrimidine compounds.
These compounds are useful as inhibitors of platelet mediated aggregation.
The present invention is directed, in part, to a class of compounds and
pharmaceutically
-acceptable salts of the compounds or tautomers are disclosed, wherein the
compounds have the
structure of Formula I:
R4
x4
A1 I A8
A2 A7
A3 A6
N
R5 A4 A5
s ~ N
3
X6 6
R6 S 1~
N OR2
Formula I
wherein:
A', A2, A3, A4, A5, A6, A' and A8 are independently selected from the group
consisting of
hydrogen, alkyl, and haloalkyl;
R2 is selected from the group consisting of -C(O)R2a, -C(S)R2a, -C(O)OR2a
-C(O)NR2aR2b, -C(S)NR2aR2b, -R2o1 and -R2 2 wherein: R2a and R2b are
independently selected
from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, and heterocyclyl;
wherein the R2a and R2b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
selected from the group consisting of halogen, -CN, =0, =S, -SR2d, -NO2, -R2d,
-C(O)R2d,
-C(S)R2d
-C(O)OR2d, -C(S)OR2d, -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR28, -OR2d, -OC(O)R2d,
-OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e,
-NR2dC(S)Rze, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -
S(O)õR2d,
-S(O)2NR2dR2e, and -SC(O)R2d;
R2o1 is Ci-C6-alkyl, wherein the R2c1 Ci-C6-alkyl substituent is substituted
with one or
more substituents independently selected from the group consisting of alkenyl,
alkynyl,
cycloalkyl, aryl, heterocyclyl, -Cl, -Br, -I, -CN, =0, =S, -SR2d, -NO2, -
C(O)R2d, -C(S)R2d
-C(O)OR2d, -C(S)OR2d, -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, _OR2d, -OC(O)R2d,
-OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dRze, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e,
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-NR2dCO R2e, -NR 2dC(O)OR 2e, -NR 2dC(S)OR 2e , -NR 2dS(0)2R 2e, -NR 2dC(O)NR
2e R 2f,_._S(O),,R 2d
,
-S(O)2NR2dR2e, and -SC(O)R2d;
wherein the alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents
of the R2c1 Cj-
C6-alkyl substituent may be optionally substituted with one or more
substituents
independently selected from the group consisting of halogen, -CN, =0, =S, -
NO2, -R2g, -
SR29,
-C(O)R2g, -C(S)R29, -C(O)OR29, -C(S)OR29, -C(O)SR29, -C(O)NR2gR2h, -
C(S)NR29R2h
-C(O)OC(O)R2g, -C(O)SC(O)R2g, -OR29, -OC(O)R29, -OC(S)R29, -OC(O)OR29,
-OC(O)NR29R2n, -OC(S)NR29R2n, -NR2gR2n, -NR2gC(O)R2n, -NR29C(S)R2n, -
NR29C(0)OR2h,
-NR29C(S)OR2h, -NR2gS(O)2R2h, -NR29C(0)NR2hR21, -S(O)PR29, -S(O)2NR29R2h, and -
SC(O)R29;
R 2C2 is selected from the group consisting of C7-C20-alkyl, alkenyl, alkynyl,
cycloalkyl, aryl
and heterocyclyl, wherein the R2 2 C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl,
aryl and
heterocyclyl substituents may be optionally substituted with one or more
substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl,
aryl, heterocyclyl, halogen, -CN, =0, =S, -SR2d, -NO2, -C(O)R2d, -C(S)R2d, -
C(O)OR2d, -
C(S)OR2d,
-C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, _OR2d, -OC(O)R2d, -OC(S)R2d, -
OC(O)OR2d,
-OC(O)NR2dR2e, -OC(S)NR2dR2e, _NR2dR2e, _NR2dC(O)R2e, _NR2dC(S)R2e, -
NR2dC(O)OR2e,
-NR2dC(S)OR2e, -NR2dS(0)2R2e, -NR2dC(O)NR2eR2f, -S(O)nR2d, -S(O)2NR2dR2e, and -
SC(O)R2d;
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl
substituents of the
R 2c2 substituents may be optionally substituted with one or more substituents
independently selected from the group consisting of halogen, -CN, =0, =S, -
NO2, -R2g, -
SR2g, -C(O)R~9,
-C(S)R29, -C(O)OR29, -C(S)OR29, -C(O)SR2g, -C(O)NR29R2h, -C(S)NR29R2h, -
C(O)OC(O)R2g, -
C(O)SC(O)R29, -OR2g, -OC(O)R29, -OC(S)R2g,-OC(O)OR29, -OC(O)NR2gR2h, -
OC(S)NR2gR2h, -
NR2yR2n, -NR29C(O)R2", -NR2gC(S)R2n, -NR29C(O)OR2h, -NR29C(S)OR2h, -
NR29S(0)2R2n,
-NR29C(O)NR2nR2', -S(0)pR2g, -S(O)2NR29R2n, and -SC(O)R29;
n is 1 or 2;
R2d, R2e and R2f are independently selected from the group consisting of
hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
wherein the R2d, R2e and R2f alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
selected from the group consisting of halogen, -CN, =0, =S, -NO2, -R29, -SR29,
-C(O)R29,
-C(S)R29,
-C(O)OR29, -C(S)OR29, -C(O)SR29, =C(O)NR29R2h, -C(S)NR29R2h, -C(O)OC(O)R29,
,
-C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R2g,-OC(O)OR29, -OC(O)NR29R21
-OC(S)NR29R2n, -NR29R2n, -NR29C(O)R2n, -NR29C(S)R2n, -NR29C(O)OR2i', -
NR2gC(S)OR2i',
-NR29S(0)2R2n, -NR29C(0)NR2nR2i, -S(O)PR2g, -S(O)2NR29R2n, and -SC(O)R2g;
p is 1 or 2;
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R29 R2h and R2i are independently selected from the group consisting of
hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
wherein the R29'R2h and R2i alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
5 selected from the group consisting of halogen and R2"';
R2ni is selected from the group consisting of -CN, -NO2, -NH2, =0, =S, -SR2n,
alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C(O)R2n, -C(S)R2", -
C(O)OR2", -C(S)OR2"
-C(O)SR2n, -C(O)NR2"R2o, -C(S)NR2nR2o, -OR2n, -OC(O)R2", -OC(S)R2", -
OC(O)OR2",
10 -OC(O)NR2nR2o, -OC(S)NR2nR2o, -NR2nR2o, -NR2nC(O)R2o, -NR2nC(S)R2o, -
NR2nC(O)OR2o,'
-NR2nC(S)OR2o, -NR2nS(O)2R2 , -NR2"C(O)NR2 R2p, -S(O)qR2", -S(0)2NR2"R2 , and
-SC(O)R2n;
q is 1 or 2;
R2n R2o and R2p are independently selected from the group consisting of
hydrogen, alkyl,
15 alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
wherein the R2rn, R2", R2o and R2p alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
selected from the group consisting of halogen, -CN, -NO2, =O,'=S, -SR2q, -R2q,
-C(O)R2q,
-C(S)R2q
-C(O)OR2q, -C(S)OR2q, -C(O)SR2q, -C(O)NR2qR2r, -C(S)NR2qR2r, -C(O)OC(O)R2q,
-C(O)SC(O)R2q, -OR2q, -OC(O)R2r, -OC(S)R2q-OC(O)OR2q-OC(O)NR2qR21 -
OC(S)NR2qR2,, -NR2qRa', -NR2qC(O)R2r, -NRzqC(S)R2', -NR2qC(O)OR2r, -
NR2qC(S)OR2',
-NR2qS(0)2R2r, -NR2qC(O)NR2rR2s, -S(O),R2q, -S(O)2NR2qR2r, and -SC(O)R2q;
r is 1 or 2;
R2q R2r and R2s are independently selected from the group consisting of
hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
wherein the RZq, R2r and R2s alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -
NO2, amino,
alkyl, haloalkyl, carboxy, alkoxy, alkylamino and alkoxycarbonyl;
X4 is selected from the group consisting of -C(O)-, -C(S)-, -S(O)- and -S(0)2-
;
R4 is selected from the group consisting of -CN, -R4a, -OR4a, -C(O)R4a, -
OC(O)Raa~
NRaaRab, _NRaaC(O)Rab, -NR4aS(O)zR4b, -SR4a, and -SC(O)R4a; wherein:
R4a and R4b are independently selected from the group consisting of hydrogen,
alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
wherein the R4a and R4b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
selected from the group consisting of halogen, haloalkyl, hydroxyalkyl, =0,
=S, -CN, -
NO2, -R4d, -OR4d, -C(O)R4d, -C(O)OR4d, -C(O)NRadRae, -OC(O)R4d, -OC(0)NR4dR4e-
NRadR4e, -NR4dC(O)R4e,
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-NR4dS(O)2R48, -S(O)bR4a, -SC(O)R4d, and -SC(O)NR4aR4e;
b is 0, 1 or 2;
R4d and R4e are independently selected from the group consisting of hydrogen,
alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
wherein the R4d and R4e alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
selected from the group. consisting of halogen, haloalkyl, =0, =S, -CN; -NO2, -
R4f,
C(O)R41, -C(O)OR41
-C(O)NR4fR4g, -OR4f, -OC(O)R4f, -OC(O)NR4fR4g, --NR4fR4g, -NR4C(O)R4g, -
NR4fS(O)2R4g,
-S(O)cR4f, -S(O)2NR4fR4g, -SC(O)R4f, and -SC(O)NR4fR4g; . .
cis0,1 or2;
R4fand R4g are independently selected from the group consisting of hydrogen,
alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
the R4f and R4g alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl
substituents may
be optionally substituted with one or more substituents selected from the
group
consisting of halogen, haloalkyl, - =0, =S, -CN, -NO2, -SR4h, -R4h, -C(O)R4h, -
C(O)OR4h, -
C(O)NR4hR41-OR4h, -OC(O)R4i, -OC(O)NR4hR4i, -NR4hR4i, -NR4hC(O)R4i, -
NR4hS(O)2R41 , :S(O)aR4h,
-S(O)2NR4hR4i, -SC(O)R4h, and -SC(O)NR4hRa';
d is 1 or 2;
R4h and R4i are independently selected from the group consisting of hydrogen,
alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocycljrl;
R5 is selected from the group consisting of hydrogen, halogen, alkyl,
cycloalkyl, aryl,
heterocyclyl, and -OR5a;
R5a is selected from the group consisting of alkyl, cycloalkyl, aryl, and
heterocyclyl;
wherein the R5 and R5a alkyl, cycloalkyl, aryl, and heterocyclyl substituents
may be
optionally substituted with one or more substituents selected from the group
consisting of
halogen, hydroxy, haloalkyl, and hydroxyalkyl;
X6 represents a bond or is -C(O)-; wherein:
when X6 is -C(O)-, R6 is selected from the group consisting of halogen, -CN, -
NO2, -Rsa-OR6a, -OC(O)R6a, -OC(O)NRsaRsb, -NRsaRsb, -NRsaC(O)Rsb, -
NR6aS(O)2R6b, -SR6a, -
SC(O)R6a, and -SC(O)NRsaRsb~
and when X6 represents a bond, R6 is selected from the group consisting of
halogen, -
CN, -NO2, -Rsa, -SRsa, -ORsa, -S(O)RRsa, -S(O)2NR6aR6b, _OC(O)Rsa, -S(O)XORsa,
-
S(O)xOC(O)Rsa-OC(O)NRsaRsb, -NRsaRsb, _NRsaC(O)Rsb, _NR6aS(O)2R6b, -SR6a, -
SC(O)Rsa, and
-SC(O)NRsaRsb;
x is i or 2;
R6a and R6b are independently selected from the group consisting of hydrogen,
alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
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" Wherein the R 6a arid R6b alkyl, alkenyl;-"alkynyl, cycloalkyl, aryl, and
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
selected from the group consisting of halogen, -CN, =0, =S, -NO2, -SR6c, -R6c,
-C(O)R6o,
-C(O)OR6o,
-C(O)NR6cRed, -C(O)SRsc, -OR6o, -OC(0)R6 , -OC(O)NRscRsd, -NRsoR6d, -
NRecC(O)Rsd,
-NRs S(O)2Rsa, -S(O),R6o, -S(0)2NR6cR6d, -SC(O)Rsc , and -SC(O)NRscRsd;
v is 1 or 2; and
R6c and R6d are independently selected from the group consisting of hydrogen,
alkyl,
haloalkyl, hydroxyalkyl, alkoxy, carboxy, alkoxycarbonyl, alkenyl, alkynyl,
cycloalkyl, aryl,
and heterocyclyl.
In one embodiment of the compounds of Formula (I), A', A2, A3, A4, A5, A6, A7
and ASare each
hydrogen. In another embodiment, A', A2, A4, A5, As, A' and Aeare each
hydrogen and A3 is
methyl. In still another embodiment, A2, A3, A4, A5, As, A' and AB are each
hydrogen and A' is
methyl.
In another embodiment of the compounds of Formula (I), R5 is selected from the
group consisting
of hydrogen, halogen, alkyl, and -ORSa, wherein the R5 alkyl substituent may
be optionally
substituted as provided in other embodiments herein, and R5a is defined as
provided in other
embodiments herein. In another embodiment, R5 is selected from the group
consisting of
hydrogen, halogen, and alkyl, wherein the R5 alkyl substituent may be
optionally substituted as
above. In still another embodiment, R5 is selected from the group consisting
of hydrogen,
halogen and methyl,. In still another embodiment, R5 is hydrogen.
In another embodiment of the compounds of Formula (I), R 6 is selected from
the group consisting
of halogen, -Rsa and -ORsa, wherein Rsa is defined as provided in other
embodiments herein. In
one embodiment, R6 is halogen. In another embodiment, R6 is fluorine. In
another embodiment,
R6 is chlorine. In another embodiment, R6 is bromine.
In still another embodiment, X6 represents a bond and R6 is -R6a, wherein R6a
is defined as
provided in other embodiments herein. In still another embodiment, X6 is -C(O)-
and R6 is -
OR6a, wherein R6a is defined as provided in claim 1. In still another
embodiment, R6 is selected
from the group consisting of -R6a and -OR6a, and Rsa is selected from the
group consisting of
hydrogen, alkyl, cycloalkyl, aryl and heterocyclyl, wherein the R 6a alkyl,
cycloalkyl, aryl and
heterocyclyl substituents may be optionally substituted as provided in other
embodiments herein.
In still another embodiment, R6 is selected from the group consisting of -R6a
and -OR6a, and Rsa
is selected from the group consisting of hydrogen, alkyl and aryl, wherein the
Rsa alkyl and aryl
substituents may be optionally substituted as provided in other embodiments
herein. In still
another embodiment, X6 represents a bond, R 6 is -Rsa; and R6a is hydrogen and
alkyl, wherein
the R 6a alkyl substituent may be optionally substituted as provided in other
embodiments herein.
In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is
hydrogen.
In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is
selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl and phenyl. In still
another embodiment, X6
represents a bond, R6 is -R6a; and R6a is selected from the group consisting
of methyl, ethyl,
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18
propyl, butyl, pentyl, and hexyl. In still another embodiment, X6 represents a
bond, R6 is -Rsa;
and R6a is selected from the group consisting of methyl, ethyl, propyl, butyl,
and pentyl. In
another embodiment, X6 represents a bond, R6 is -R6a; and R 6a is
unsubstituted alkyl.
In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is
selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R6a
substituent is
substituted with one or more halogen substituents. In still another
embodiment, X6 represents a
bond, R6 is -R6a; and R6a is selected from the group consisting of methyl,
ethyl, propyl, butyl,
pentyl and hexyl, wherein said R6a substituent is substituted with one or more
fluorine
substituents. In another embodiment, X6 represents a bond, R6 is =R6a; and R6a
is selected from
the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl,
wherein said R6a substituent
is substituted with one or more chlorine substituents. In another embodiment,
X6 represents a
bond, R6 is -R6a; and R 6a is selected from the group consisting of methyl,
ethyl, propyl, butyl,
pentyl and hexyl, wherein said Rsa substituent is substituted with one or more
bromine
substituents.
In another embodiment of the compounds of Formula (I), X4 is -C(O)-.
In another embodiment of the compounds of Formula (I), R4 is selected from the
group consisting
of -R4a, -OR4a, and -NR4aR4b; and R4a and R4b are independently selected from
the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl, wherein the R4a
and R4b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl
substituents may be optionally
substituted as provided in other embodiments herein. In another embodiment, R4
is selected
from the group consisting of -R4a, -OR4a, and -NR4aR4b; R4a is selected from
the group consisting
of hydrogen, alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the R4a alkyl,
cycloalkyl, aryl, and
heterocyclyl substituents may be optionally substituted as provided in other
embodiments herein;
and R4b is selected from the group consisting of hydrogen and alkyl, wherein
the R4b alkyl
substituent may be optionally substituted as provided in other embodiments
herein.
In another embodiment of the compounds of Formula (I), R4 is -R4a; ahd R4a is
selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl, wherein the R4a alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be
optionally substituted as
provided in other embodiments herein. In another embodiment, R4 is -R4a; and
R4a is selected
from the group consisting of phenyl, oxadiazolyl, thiazolyl, pyridinyl,
cyclopropyl, methyl, ethyl
and fluorenyl; wherein the R4a substituents may be optionally substituted as
provided in other
embodiments herein. In still another embodiment, R4 is -OR4a; and R4a is
selected from the
group consisting of methyl and ethyl, wherein the R4a substituents may be
optionally substituted
as provided in other embodiments herein. In still another embodiment, R4 is -
NRaaRab; and R4a
is selected from the group consisting of methyl and R4b is hydrogen, wherein
the R4a methyl may
be optionally substituted as provided in other embodiments herein.
In still another embodiment, R4 is -R4a; and R4a is selected from the group
consisting of methyl,
ethyl, propyl, butyl, pentyl and hexyl, wherein said R4a substituent is
substituted with one or more
halogen substituents. In still another embodiment, R4 is -R4a; and R4a is
selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R4a
substituent is
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19
substituted with one or more fluorine substituents. In another embodiment, R4
is -R4a; and R4a is
selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and
hexyl, wherein said
R4a substituent is substituted with one or more chlorine substituents. In
another embodiment, R4
is -R4a; and R4a is selected from the group consisting of methyl, ethyl,
propyl, butyl, pentyl and
hexyl, wherein said R4a substituent is substituted with one or more bromine
substituents.
In another embodiment of the compounds of Formula (I), A', A2, A3, A4, A5, A6,
A7 and AB are
each hydrogen; R2 is selected from the group consisting of -R2o1 and -R2 2; X4
is -C(O)-; R4 is
selected from the group consisting of -R4a, -OR4a, and -NR4aR4b; R4a and R4b
are independently
selected from the group consisting of hydrogen; alkyl, cycloalkyl, aryl, and
heterocyclyl, wherein
the R4a and R4b alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be
optionally substituted
as provided in other embodiments herein; R5 is selected from the group
consisting of hydrogen,
halogen, alkyl, and -ORSa, wherein the R5 alkyl substituent may be optionally
substituted as
provided in other embodiments herein, and R5a is defined as provided in other
embodiments
herein; and R6 is selected from the group consisting of -R6a and -OR6a,
wherein R6a is defined as
provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), A', A2, A3, A4, A5, A6,
A7 and AB are
each hydrogen; R2 is selected from the group consisting of -R2o1 and -R2o2; X4
is -C(O)-; R4 is
selected from the group consisting of -R4a, -OR4a, and -NRaaRab; Raa is
selected from the group
consisting of hydrogen, alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the
R4a alkyl, cycloalkyl,
aryl, and heterocyclyl substituents may be optionally substituted as provided
in other
embodiments herein; R4b is selected from the group consisting of hydrogen and
alkyl, wherein
the R4b alkyl substituent may be optionally substituted as provided in other
embodiments herein;
R5 is selected from the group consisting of hydrogen, halogen, and alkyl,
wherein the R5 alkyl
substituent may be optionally substituted as provided in other embodiments
herein; R6 is
selected from the group consisting of -R6a and -OR6a; and R6a is selected from
the group
consisting of hydrogen, alkyl, cycloalkyl, aryl and heterocyclyl, wherein the
R6a alkyl, cycloalkyl,
aryl and heterocyclyl substituents may be optionally substituted as provided
in other
embodiments herein.
In another embodiment of the compounds of Formula (I), A', A2, A3, A4, A5, A6,
A7 and Aeare
each hydrogen; R2 is selected from the group consisting of -R2 ' and -R2c2; X4
is -C(O)-; R4 is -
Raa; Raa is selected from the group consisting of alkyl, cycloalkyl, aryl, and
heterocyclyl, wherein
the R4a alkyl, cycloalkyl, aryl and heterocyclyl substituents may be
optionally substituted as
provided in other embodiments herein; R5 is hydrogen; R6 is selected from the
group consisting
of -R6a and -OR6a; and R6a is selected from the group consisting of hydrogen,
alkyl and aryl,
wherein the R6a alkyl and aryl substituents may be optionally substituted as
provided in other
embodiments herein.
In another embodiment of the compounds of Formula (I), A', A2, A3, A4, A5, A6,
A7 and Aa are
each hydrogen; R2 is selected from the group consisting of -R2o1 and -R2o2; X4
is -C(O)-; R4 is -
OR4a; R4a is alkyl, wherein the R4a alkyl substituent may be optionally
substituted as provided in
other embodiments herein; R5 is hydrogen; R6 is selected from the group
consisting of -R6a and
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-ORsa; and R6a is selected from ttie group consisting of hydrogen,'alkyl and
aryl, wherein the R 6a
alkyl and aryl substituents may be optionally substituted as provided in other
embodiments
herein.
In another embodiment of the compounds of Formula (I), A', A2, A3, A4, A5, A6,
A' and A8are
5 each hydrogen; R2 is selected from the group consisting of -R2o1 and -R2o2;
X4 is -C(O)-; R4 is -
NRaaRab; Raa is alkyl and R4b is hydrogen, wherein the R4a alkyl substituent
may be optionally
substituted as provided in other embodiments herein; R5 is hydrogen; R6 is
selected from the
group consisting of -R6a and -OR6a; and R6a is selected from the group
consisting of hydrogen,
alkyl and aryl, wherein the R6a alkyl and aryl substituents may be optionally
substituted as
10 provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), A', A2, A3, A4, A5, A6,
A' and A8 are
each hydrogen; R2 is selected from the group consisting of -R2" and -R2o2; X4
is -C(O)-; R4 is -
Raa;Raa is selected from the group consisting of phenyl, oxadiazolyl,
thiazolyi, pyridinyl,
cyclopropyl, methyl, ethyl and fluorenyl, wherein the R4a substituents may be
optionally
15 substituted as provided in other embodiments herein; R5 is hydrogen; X6
represents a bond; R6 is
-R6a; and R6a is alkyl, wherein the R 6a alkyl substituent may be optionally
substituted as provided
in other embodiments herein.
In another embodiment of the compounds of Formula (I), A', A2, A3, A4, A5, A6,
A7 and A8are
each hydrogen; R2 is selected from the group consisting of -R2c1 and -R202; X4
is -C(O)-; R4 is -
20 ORaa; Raa is selected from the group consisting of methyl and ethyl,
wherein the R4a alkyl
substituents may be optionally substituted as provided in other embodiments
herein; R5 is
hydrogen; X6 represents a bond; R6 is -R6a; and R6a is alkyl, wherein the R6a
alkyl substituent
may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), A', A2, A3, A4, A5, A6,
A7 and Aa are
each hydrogen; R2 is selected from the group consisting of -R2c' and -R2o2; X4
is -C(O)-; R4 is
NRaaRab; Raa is selected from the group consisting of methyl, wherein the R4a
methyl may be
optionally substituted as provided in other embodiments herein; R4b is
hydrogen; R5 is hydrogen;
X6 represents a bond; R6 is -R6a; and R6a is alkyl, wherein the R 6a alkyl
substituent may be
optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), X6 represents a bond;
R6 is
-Rsa; and R6a is unsubstituted alkyl.
In another embodiment, the compound of Formula (I) has one of the structures
shown in Table B
below:
TABLE B - Formulae
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21
O~ /R4 O~ R4
. I I
N N
N N
(6 ~N s 4N
R6 3 6 ~ 3
~
S N OR2 H3C S N OR2
Formula I-A Formula I-B
O\Ra O\C/Ra
I
. N N
N N
s ~N O ~ ~N O
R6 6 7 T 3 3
1 % ~ 6 ~
s
N O R2a H3C S,
N O R2a
Formula I-C Formula 1-D ,
O\ R4 O\ / R4
N N
N N
s e-4
N S s 4
N S
R6 6 7 e 7 3 S N O R2a H3C S N1 O R2a
Formula I-E Formula I-F
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22
O\C/R4 Q\C/R4
(N)
N N
4 N O s '4N N 0
A6 3 3
6 I 6 I ~
~ R2a 7 1 31 R2a
S S
N O O H3C N O O
Formula I-G Formula 1-H
O\ C R4 Q\ R4
N N
N N
s 5 ~ N O s 4 3N 0
I~ 6 3 6
~ R2a 7 R2a
S
N O N H3C N O i
R2b R2b
Formula I-I Formula I-J
O~c~R4 Q~R4
N N
N N
S
~3N S
s 5 I 4 N S /--</66
I~ 6 3 II
~ I % \ Jj R2a ~ ~~ ll R2a
S /\ g
N O N H3C N O N
R2b R2b
Formula I-K Formula I-L
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23
O~C/R4 0 ~C1-1 R4
N N
N N
s 4 N Os ~ N
R6 6 36
7 3
R
S 2c1 7 R2c1
N O H3C S N O
Formula I-M Formula I-N
O\R4 O\C/R4
N N
N N
Rg N
s 3 6 \ n1 s 3 \
6
~ 1 3 R2c2 7 (~2c2
s N O H3C S N O
Formula 1-0 Formula I-P
wherein R2, R2b, R2 ', R2 2, R4, and R6 are as defined in any of the
embodiments described in this
application.
In another embodiment, the compound of Formula (I) has one of the structures
shown in Table B;
and R6 is -Rsa, wherein R6a is selected from the group consisting of alkyl and
phenyl. In still
another embodiment, the compound of Formula (I) has one of the structures
shown in Table B;
and R6 is -R6a, wherein R6a is unsubstituted alkyl. In still another
embodiment, the compound of
Formula (II) has one of the structures shown in Table B; and R6 is -R6a,
wherein Rsa is selected
from the group consisting of methyl, ethyl, propyl and isopropyl.
Another class of compounds of specific interest includes compounds, and
pharmaceutically
acceptable salts of the compounds, wherein the compounds have the structure of
Formula I1:
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24
R4
N
R5 N
4 3N
&/6
X6 6
OR2
Formula II
wherein:
R2 is selected from the group consisting of -R2c1 and -R2o2 wherein:
R2C1 is Cl-C6-alkyl, wherein the R2c1 Cl-C6-alkyl substituent is substituted
with one or
more substituents independently selected from the group consisting of alkenyl,
alkynyl,
cycloalkyl, aryl, heterocyclyl, -Cl, -Br, -I, -CN, =0, =S, -SR2d, -NO2,
-C(O)R2d, -C(S)R2d, -C(O)OR2d, -C(S)OR2d, -C(O)SR2d, -C(O)NRzdRze, -
C(S)NR2dR2e, -OR2d, -
OC(O)R2d, -OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e,
-NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e,
-NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(O)~R2d, -S(O)2NR2dR2e~ and -SC(O)R2d;
wherein the alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents
of the R2o1 Ci-
C6-alkyl substituent may be optionally substituted with one or more
substituents
independently selected from the group consisting of halogen, -CN, =0, =S, -
NO2, -R29,
-SR29, -C(O)R2g, -C(S)R29, -C(O)OR29, -C(S)OR29, -C(O)SR29, -C(O)NR29R2h,
-C(S)NR29R2h, -C(O)OC(O)R2g, -C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R29,
=OC(O)OR29,
-OC(O)NR29R2h, -OC(S)NR29R2h, -NR2gR2h, -NR29C(O)R2h, -NR29C(S)R2h, -
NR2gC(O)OR2",
-NR29C(S)OR2h, -NR29S(0)2R2h, -NR2gC(O)NR2hR2i, -S(O)PR2g, -S(O)2NR29R2h, and -
SC(O)R2g;
R 2C2 is selected from the group consisting of C7-C20-alkyl, alkenyl, alkynyl,
cycloalkyl, aryl
and heterocyclyl, wherein the R2o2 C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl,
aryl and
heterocyclyl substituents may be optionally substituted with one or more
substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl,
aryl, heterocyclyl, halogen, -CN, =0, =S, -SR2d, -NO2, -C(O)R2d, -C(S)R2d, -
C(O)OR2d, -
C(S)OR2d ,
-C(O)SR2d, -C(O)NR2dR28, -C(S)NR2dR2e, -OR2d, -OC(O)R2d, -OC(S)R2d, -
OC(O)OR2d,
-OC(O)NRzdR2e, -OC(S)NRadR2e, -NRzdRze, -NR2dC(O)R2e, -NRzdC(S)R2e, -
NR2dC(0)OR2e,
-NR2dC(S)ORZe, -NR2dS(O)2R2e, -NR2dC(O)NR2eRzt, -S(O),,R2d, -S(O)2NR2dR2e, and
-SC(O)R2d;
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wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl
substituents of the
R 2C2 substituents may be optionally substituted with one or more substituents
independently selected from the group consisting of halogen, -CN, =0, =S, -
NO2, -R29, -
SR29, -C(O)R2g,
5 -C(S)R29, -C(O)OR29, -C(S)OR29, -C(O)SR29, -C(O)NR29R2h, -C(S)NR29R2h, -
C(O)OC(O)R29, -
C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R29,-OC(O)OR29, -OC(O)NR2gR2h, -
OC(S)NR29R2h, -
NR29R2h, -NR29C(O)R2h, -NR29C(S)R2h, -NR29C(O)OR2h, -NR29C(S)OR2h,
-NR2gS(O)2R2h, -NR29C(O)NR2hR2', -S(O)PR29, -S(O)2NR29R2h, and -SC(O)R29;
n is 1 or 2;
10 R2d, R2e and R2f are independently selected from the group consisting of
hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
wherein the R2d, R2e and R2f alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
selected from the group consisting of halogen, -CN, =0, =S, -NO2, -R29, -SR29,
-C(O)R2g,
15 -C(S)R2g
-C(O)OR29, -C(S)OR2g, -C(O)SR29, -C(O)NR2gR2h, -C(S)NR2gR2h, -C(O)OC(O)R29,
-C(O)SC(O)R29, -OR2g, -OC(O)R2g, -OC(S)R29,-OC(O)OR29, -OC(O)NR29R2h, -
OC(S)NR29R2h, -
NR29R2h, -NR29C(O)R2h, -NR29C(S)R2h, -NR29C(O)OR2h, -NR29C(S)OR2h,
-NR29S(O)2R2h, -NR29C(O)NR2"R2', -S(O)pR2g, -S(O)2NR29R2h, and -SC(O)R29;
20 pislor2;
R29, R2h and R2i are independently selected from the group consisting of
hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
wherein the R29, R2h and R2i alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
25 selected from the group consisting of halogen and R 2m;
R2nt is selected from the group consisting of -CN, -NO2, -NH2, =0, =S, -SR2n,
alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyi, -C(O)R2", -C(S)R2n, -
C(O)OR2" ,
-C(S)OR2n, -C(O)SR2", -C(O)NR2nR2o, -C(S)NR2nR2o, -OR2n, -OC(O)R2", -OC(S)R2",
-OC(O)OR2n, -OC(O)NR2nR2o, _OC(S)NR2nRzo, -NR2nR2o, -NR2nC(O)R2o, -
NR2nC(S)Rzo,
-NR2nC(O)OR20, -NR2nC(S)OR2o, -NR2nS(0)2R2 , -NR2nC(O)NR2oR2P, -S(O)qR2n,
-S(O)2NR2"R2o, and -SC(O)R2n;
qisl or2;
R2n, R2 and R2p are independently selected from the group consisting of
hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
wherein the R2ni, R2n, R2o and R2p alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heterocyclyl
substituents may be optionally substituted with one or more substituents
independently
selected from the group consisting of halogen, -CN, -NO2, =0, =S, -SR2a -R24 -
C(O)R2q,
-C(S)R2q
-C(O)OR2q, -C(S)OR2q, -C(O)SR2q, -C(O)NR2qR2r, -C(S)NR2qR2' -OR2q, -OC(O)R2r,
-OC(S)R2q,-OC(0)OR2q,-OC(O)NR24R2,, -OC(S)NR2qR2r, -NR24R2r, -NR24C(O)R2r,
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26
-NR24C(S)R21, -NR24C(O)OR2r, -NR2qC(S)OR2,, -NR2qS(O)2R21, -NR2qC(O)NR2r R2s, -
S(O),R2q,
-S(0)2NR2qR2r, and -SC(O)R2Q;
risior2;
R24 R2r and R2S are independently selected from the group consisting of
hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;wherein the R24, R2r and
R2s alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be
optionally
substituted with one or more substituents independently selected from the
group
consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, amino, alkyl,
haloalkyl, carboxy,
alkoxy, alkylamino and alkoxycarbonyl;
R4 is selected from the group consisting of -R4j, -OR4', and -NR4'R4k,
wherein:
R41 and R4k are independently selected from the group consisting of hydrogen,
alkyl,
alkenyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl,
heterocyclylalkyl,
arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl,
cycloalkylheterocyclyl, arylaryl,
heterocyclylheterocyclyi, arylheterocyclyl, heterocyclylaryl,
cycloalkoxyalkyl,
heterocycloxyalkyl, aryloxyaryl, heterocycloxyheterocyclyl,
aryloxyheterocyclyl,
heterocycloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl,
aryloxyalkyl,
arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl,
heterocyclylcarbonylam inoalkyl, arylcarbonyl(aryl)am inoalkyl, and
heterocyclylcarbonyl(aryl)aminoalkyl; wherein
the R4j and R4k substituents may be optionally substituted with one or more
substituents
independently selected from the group consisting of halogen, haloalkyl,
hydroxyalkyl,
=0, =S,
-CN, -NO2, -R41, -SR41, -OR41, -C(O)R41, -C(O)OR41, -C(O)NR4'R4m, -OC(O)R41, -
ONR4'R4m-NR41R4m, -NRa1C(O)Ram, -NR41S(O)2R4m, -S(O)bR41, -SC(O)R41 and -
SC(O)NRMRam;
b is 1 or 2;
R41 and R4m are independently selected from the group consisting of hydrogen,
alkyl,
haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
R5 is selected from the group consisting of hydrogen, halogen, alkyl,
haloalkyl, alkoxy
and haloalkoxy;
X6 represents a bond or is -C(O)-; wherein:
(a) when X6 is -C(O)-, R 6 is selected from the group consisting of -R6a and -
OR6a;
(b) when X6 represents a bond, R 6 is selected from the group consisting of
halogen, -Rsa
and -OR6a;
R6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and
aryl; wherein:
the R6a alkyl, cycloalkyl and aryl substituent may be optionally substituted
with one or
more substituents independently selected from the group consisting of halogen,
=0, =S,
-CN, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl and heterocyclyl.
In another embodiment of the compounds of Formula (II), R5 is selected from
the group
consisting of hydrogen, halogen, alkyl, and haloalkyl; and R 6 is selected
from the group
consisting of -R6a and -ORsa, wherein R6a is defined as above. In still
another embodiment, R5 is
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selected from the group consisting of hydrogen and alkyl; R6 is selected from
the group
consisting of -R6a and -OR6a; and R6a is selected from the group consisting of
hydrogen, alkyl,
cycloalkyl and aryl, wherein the R6a alkyl, cycloalkyl and aryl substituents
may be optionally
substituted as above. In still another embodiment, R5 is hydrogen; X6
represents a bond; and R6
is -Rsa, wherein R6a is defined as provided in other embodiments herein. In
still another
embodiment, R6a is alkyl, wherein the R6a alkyl substituent may be optionally
substituted as
provided in other embodiments herein. In still another embodiment, R6a is
unsubstituted alkyl:
In another embodiment of the compounds of Formula (II), R4 is -NR4jR", wherein
the R4J and R 4k
substituents may be optionally substituted as provided in other embodiments
herein. In still
another embodiment, R4 is -NR41R4k, wherein R4j and R4k are independently
selected from the
group consisting of hydrogen, alkyl and aryl, and wherein the R4' and R4k
alkyl and aryl may be
optionally substituted as provided in other embodiments herein. In
still'another embodiment, R4'
and R4k are independently selected from the group consisting of hydrogen,
methyl, ethyl, propyl,
butyl, phenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylpropyl, and
phenylbutyl, wherein
the R''' and R4k methyl, ethyl, propyl, butyl, phenyl, phenyiphenyl,
phenylmethyl, phenylethyl,
phenylpropyl, and phenylbutyl may be optionally substituted as provided in
other embodiments
herein. In still another embodiment, R4 is -NR4jR4k, wherein R4j and R4k are
independently
selected from the group consisting of hydrogen, phenylmethyl and phenylphenyl,
and wherein
the R4' and R41 phenylmethyl and phenylphenyl may be optionally substituted as
provided in
other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4';
wherein R4j is
selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl,
heterocyclyl, arylaryl,
arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylalkyl, cycloalkylaryl,
arylheterocyclyl,
aryloxyaryl, heterocyclyloxyaryl, arylcarbonylaryl, and
arylcarbonylaminoalkyl; and wherein the
R4j substituents may be optionally substituted as provided in other
embodiments herein.
In still another embodiment of the compounds of Formula (II), R4 is -R4' or -
OR'''; wherein R 41 is
alkyl; and wherein the R4jsubstituent is further substituted with one or more
halogen
substituents. In still another embodiment of the compounds of Formula (II), R4
is -R4' or -OR4j
wherein R4J is alkyl; and wherein the R4j substituent is further substituted
with one or more
chlorine substituents. In still another embodiment of the compounds of Formula
(II), R4 is -R4j or
-OR4J; wherein R4j is alkyl; and wherein the R4j substituent is further
substituted with one or more
fluorine substituents.
In still another embodiment of the compounds of Formula (II), R4 is -R4' or -
OR41; wherein R4j is
alkyl; and wherein the R4j substituent is further substituted with one or more
haloalkyl
substituents. In still another embodiment of the compounds of Formula (II), R4
is -R4j or -OR4j;
wherein R41 is alkyl; and wherein the R4J substituent is further substituted
with one or more
fluoroalkyl substituents. In still another embodiment of the compounds of
Formula (II), R4 is -R 41
or -OR4j; wherein R4J is alkyl; and wherein the R4J substituent is further
substituted with one or
more chloroalkyl substituents:
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In still another embodiment of the compounds of Formula (II), R4 is -R4J or -
OR4j; wherein R4' is
alkyl; and wherein the R4j substituent is further substituted with one or more
trifluoroalkyl
substituents. In still another embodiment of the compounds of Formula (II), R4
is -R4j or -OR4j;
wherein R 41 is alkyl; and wherein the R4j substituent is further substituted
with one or more
trifluoromethyl substituents.
In another embodiment of the compounds of Formula (II), R4 is -R4J or -OR4J;
wherein R41 is.
selected from the group consisting of (Ci-C6)-alkyl, (C3-Cio)-aryl, (C3-C14)-
heterocyclyl, (C3-C10)-
aryl -(Ci-C6)-alkyl, (C3-C14)-heterocyclyl-(Ci-C6)-alkyl, (C3-Cio)-aryl-(C3-
C6)-cycloalkyl, (C3-C6)-
cycloalkyl-(C3-Cio)-aryl, (C3-Cio)-aryl-(C3-C14)-heterocyclyl, (C3-C10)-aryl-O-
(C3-C;o}-aryl, (C3-C10)-
aryl-(C3-Cio)-aryl, (C3-C14)-heterocyclyl-O-(C3-C10)-aryl, (C3-Cio)-aryl-C(O)-
(C3-C10)-aryl, (C3-C10)-
aryl-O-(Ci-C6)-alkyl, and (C3-Cio)-aryl-C(O)-amino-(Ci-C6)-alkyl; and wherein
the R4j substituents
may be optionally substituted as provided in other embodiments herein.
In another embodiment of Formula (II), R4 is -R4' or -OR4J; wherein R4j is
selected from the group
consisting of methyl, ethyl, propyl, butyl, phenyl, naphthyl, anthracenyl,
pyrrolidinyl, pyrrolinyl,
pyrrolyl, tetrahydrofuranyl, furanyl, dioxolanyl, imidazolidinyl,
imidazolynyl, imidazolyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-
oxadiazolyl, 1,3,4-oxadiazolyl,
thiophenyl, thiazolyl, thiadiazolyl, triazolyl, piperidinyl, pyridinyl,
piperazinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, triazinyl, morpholinyl, dioxanyl, tetrahydro-2H-pyranyl, 2H-
pyranyl, 4H-pyranyl,
thiomorpholinyl, indolyl, dihydrobenzofuranyl, quinolinyl and fluorenyl; and
wherein the R4j
substituents may be optionally substituted as provided in other embodiments
herein.
In another embodiment of the compounds of Formula (II), R4 is -R4j or -OR4j;
wherein R4' is
selected from the group consisting of phenylphenyl, phenylnaphthyl,
phenylanthracenyl,
naphthylphenyl, naphthylnaphthyl; naphthylanthracenyl, anthracenylphenyl,
anthracenylnaphthyl
and anthracenylanthracenyl; and wherein the R4jsubstituents may be optionally
substituted as
provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4j or -OR4';
wherein R4' is
selected from the group consisting of phenylmethyl, phenylethyl, phenylpropyl,
phenylbutyl,
naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl,
anthracenylmethyl,
anthracenylethyl, anthracenylpropyl, anthracenylbutyl, phenylcyclopropyl,
phenylcyclobutyl,
phenylcyclopentyl, phenylcyclohexyl, naphthylcyclopropyl, naphthylcyclobutyl,
naphthylcyclopentyl, naphthylcyclohexyl, anthracenylcyclopropyl,
anthracenylcyclobutyl,
anthracenylcyclopentyl, anthracenylcyclohexyl, cyclopropylphenyl,
cyclopropylnaphthyl,
cyclopropylanthracenyl, cyclobutylphenyl, cyclobutylnaphthyl,
cyclobutylanthracenyl,
cyclopentylphenyl, cyclopentyinaphthyl, cyclopentylanthracenyl,
cyclohexylphenyl,
cyclohexylnaphthyl, cyclohexylanthracenyl, phenylphenylmethyl,
phenylphenylethyl,
phenylphenylpropyl, phenylphenylbutyl, diphenylmethyl, diphenylethyl,
diphenylpropyl and
diphenylbutyl; and wherein the R41 substituents may be optionally substituted
as provided in other
embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4J or -OR4j;
wherein R4j is
selected from the group consisting of phenyloxymethyl, phenyloxyethyl,
phenyloxypropyl,
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phenyloxybutyl, naphthyloxymethyl, naphthyloxyethyl,-naphthyloxypropyl,
naphthyloxybutyl,
anthracenyloxymethyl, anthracenyloxyethyl, anthracenyloxypropyl,
anthracenyloxybutyl,
methoxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl, methoxynaphthyl,
ethoxynaphthyl,
propoxynaphthyl, butoxynaphthyl, phenyloxyphenyl, phenyloxynaphthyl,
phenyloxyanthracenyl,
naphthyloxyphenyl, naphthyloxynaphthyl, naphthyloxyanthracenyl,
anthracenyloxyphenyl,
anthracenyloxynaphthyl and anthracenyloxyanthracenyl; and wherein the R4J
substituents may be
optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R''j or -OR4j;
wherein R4' is
selected from the group consisting of phenylcarbonylphenyl,
phenylcarbonylnaphthyl,
phenylcarbonylanthracenyl, naphthylcarbonylphenyl, naphthylcarbonylnaphthyl,
naphthylcarbonylanthracenyl, anthracenylcarbonylphenyl,
anthracenylcarbonylnaphthyl,
anthracenylcarbonylanthracenyl, phenylcarbonylaminomethyl,
phenylcarbonylaminoethyl,
phenylcarbonylaminopropyl, phenylcarbonylaminobutyl, naphthylcarbonylam inom
ethyl,
naphthylcarbonylam inoethyl, naphthylcarbonylam inopropyl, naphthylcarbonylaam
inobutyl,
anth racenylcarbonylam inom ethyl, anthracenylcarbonylaminoethyl,
anthracenylcarbonylaminopropyl, anthracenylcarbonylaminobutyi,
phenylcarbonyl.(phenyl)am inom ethyl, phenylcarbonyl(phenyl)aminoethyl,
phenylcarbonyl(phenyl)aminopropyi and phenylcarbonyl(phenyl)aminobutyl; and
wherein the R4'
substituents may be optionally substituted as provided in other embodiments
herein.
In another embodiment of the compounds of Formula (II), R4 is -R4j or -OR4';
wherein R4' is
selected from the group consisting of pyrrolidinylmethyl, pyrrolidinylethyl,
pyrrolidinylpropyl,
pyrrolidinylbutyl, pyrrolinylmethyl, pyrrolinylethyl, pyrrolinylpropyl,
pyrrolinylbutyl, pyrrolylmethyl,
pyrrolylethyl, pyrrolylpropyl,. pyrrolylbutyl, tetrahydrofuranylmethyl,
tetrahydrofuranylethyl,
tetrahydrofuranylpropyl, tetrahydrofuranylbutyl, furanylmethyl, furanylethyl,
furanylpropyl,
furanylbutyl, dioxolanylmethyl, dioxolanylethyl, dioxolanylpropyl,
dioxolanylbutyl,
imidazolidinylmethyl, imidazolidinylethyl, imidazolidinylpropyl,
imidazolidinylbutyl,
im idazo lynylm ethyl, imidazolynylethyl, imidazolynylpropyl,
imidazolynylbutyl, im idazolylm ethyl,
imidazolylethyl, imidazolylpropyl, imidazolylbutyl, pyrazolidinylmethyl,
pyrazolidinylethyl,
pyrazolidinylpropyl, pyrazolidinylbutyl, pyrazolinylmethyl, pyrazolinylethyl,
pyrazolinylpropyl,
pyrazolinylbutyl, pyrazolylmethyl, pyrazolylethyl, pyrazolylpropyl,
pyrazolylbutyl, oxazolylmethyl,
oxazolyiethyl, oxazolylpropyl, oxazolylbutyl, isoxazolylmethyl,
isoxazolylethyl, isoxazolylpropyl,
isoxazolylbutyl, 1,2,3-oxadiazolylmethyl, 1,2,3-oxadiazolylethyl, 1,2,3-
oxadiazolylpropyl, 1,2,3-
oxadiazolylbutyl, 1,3,4-oxadiazolylmethyl, 1,3,4-oxadiazolylethyl, 1,3,4-
oxadiazolyipropyl, 1,3,4-
oxadiazolylbutyl, thiophenylmethyl, thiophenylethyl, thiophenylpropyl,
thiophenylbutyl,
thiazolylmethyl, thiazolylethyl, thiazolylpropyl, thiazolylbutyl,
thiadiazolylmethyl, thiadiazolylethyl,
thiadiazolylpropyl, thiadiazolylbutyl, triazolylmethyl, triazolylethyl,
triazolyipropyl, triazolylbutyl,
piperidinylmethyl, piperidinylethyl, piperidinylpropyl, piperidinylbutyl,
pyridinylmethyl,
pyridinylethyl, pyridinylpropyl, pyridinylbutyl, piperazinylmethyl,
piperazinylethyl,
piperazinylpropyl, piperazinylbutyl, pyrazinylmethyl, pyrazinylethyl,
pyrazinylpropyl,
pyrazinylbutyl, pyrim id inyl m ethyl, pyrimidinylethyl, pyrimidinylpropyl,
pyrimidinylbutyl,
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pyridazinylmethyl, pyridazinylethyl, pyridazinylpropyl, pyridazinylbutyl,
triazinylmethyl,
triazinylethyl, triazinylpropyl, triazinylbutyl, m orphol inylm ethyl,
morpholinylethyl,
morpholinylpropyl, morpholinylbutyl, dioxanylmethyl, dioxanylethyl,
dioxanylpropyl, dioxanylbutyl,
tetrahydro-2H-pyranylmethyl, tetrahydro-2H-pyranylethyl, tetrahydro-2H-
pyranylpropyl,
5 tetrahydro-2H-pyranylbutyl, 2H-pyranylmethyl, 2H-pyranylethyl, 2H-
pyranylpropyl, 2H-
pyranylbutyl, 4H-pyranylmethyl, 4H-pyranylethyl, 4H-pyranylpropyl, 4H-
pyranylbutyl,
thiomorpholinylmethyl, thiomorpholinylethyl, thiomorpholinylpropyl,
thiomorpholinylbutyl,
quinolinylmethyl, quinolinylethyl, quinolinylpropyl, quinolinylbutyl,
fluorenylmethyl, fluorenylethyl,
fluorenylpropyl and fluorenylbutyl; and wherein the R4j substituents may be
optionally substituted
10 as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4j or -OR4';
wherein R4' is
selected from the group consisting of phenylpyrrolidinyl,
naphthylpyrrolidinyl,
anthracenylpyrrolidinyl, phenylpyrrolinyl, naphthylpyrrolinyl,
anthracenylpyrrolinyl, phenylpyrrolyl,
naphthylpyrrolyl, anthracenylpyrrolyl, phenyltetrahydrofuranyl,
naphthyltetrahydrofuranyl,
15 anthracenyltetrahydrofuranyl, phenylfuranyl, naphthylfuranyl,
anthracenylfuranyl,
phenyldioxolanyl, naphthyldioxolanyl, anthracenyldioxolanyl,
phenyiimidazolidinyl,
naphthylimidazolidinyl, anthracenylimidazolidinyl, phenylimidazolynyl,
naphthylimidazolynyl,
anthracenylimidazolynyl, phenylimidazolyl, naphthylimidazolyl,
anthracenylimidazolyl,
phenylpyrazolidinyl, naphthylpyrazolidinyl, anthracenylpyrazolidinyl,
phenylpyrazolinyl,
20 naphthylpyrazolinyl, anthracenylpyrazolinyl, phenylpyrazolyl,
naphthylpyrazolyl,
anthracenylpyrazolyl, phenyloxazolyl, naphthyloxazolyl, anthracenyloxazolyl,
phenylisoxazolyl,
naphthylisoxazolyl, anthracenylisoxazolyl, phenyl-1,2,3-oXadiazolyl, naphthyl-
1,2,3-oxadiazolyl,
anthracenyl-1,2,3-oxadiazolyl, phenyl-1,3,4-oxadiazolyl, naphthyl-1,3,4-
oxadiazolyi, anthracenyl-
1,3,4-oxadiazolyi, phenylthiophenyl, naphthylthiophenyl,
anthracenylthiophenyl, phenylthiazolyl,
25 naphthylthiazolyl, anthracenylthiazolyl, phenylthiadiazolyl,
naphthylthiadiazolyl,
anthracenylthiadiazolyl, phenyltriazolyi, naphthyltriazolyl,
anthracenyltriazolyl, phenylpiperidinyl,
naphthylpiperidinyl, anthracenylpiperidinyl, phenylpyridinyl,
naphthylpyridinyl,
anthracenylpyridinyl, phenylpiperazinyl, naphthylpiperazinyl,
anthracenylpiperazinyl,
phenylpyrazinyl, naphthylpyrazinyl, anthracenylpyrazinyl, phenylpyrimidinyl,
naphthylpyrimidinyl,
30 anthracenylpyrimidinyl, phenylpyridazinyl, naphthylpyridazinyl,
anthracenylpyridazinyl,
phenyltriazinyl, naphthyltriazinyl, anthracenyltriazinyl, phenylmorpholinyl,
naphthylmorpholinyl,
anthracenylmorpholinyl, phenyldioxanyl, naphthyidioxanyl, anthracenyidioxanyl,
phenyltetrahydro-2H-pyranyl, naphthyltetrahydro-2H-pyranyl,
anthracenyltetrahydro-2H-pyranyl,
phenyl-2H-pyranyl, naphthyl-2H-pyranyl, anthracenyl-2H-pyranyl, phenyl-4H-
pyranyl, naphthyl-
4H-pyranyl, anthracenyl-4H-pyranyl, phenylthiomorpholinyl,
naphthylthiomorpholinyl,
anthracenylthiomorpholinyl, phenylquinolinyl, naphthylquinolinyl,
anthracenylquinolinyl,
phenylfluorenyl, naphthylfluorenyl and anthracenylfluorenyl; and wherein the
R4J substituents may
be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4J or -OR41 ;
wherein R4j is
selected from the group consisting of pyrrolidinyloxyphenyl,
pyrrolidinyloxynaphthyl,
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-pyrrolidinyloxyanthracenyl;-pyrrolinyloxyphenyl, pyrrolinyloxynaphthyl,
pyrrolinyloxyanthracenyl,
pyrrolyloxyphenyl, pyrrolyloxynaphthyl, pyrrolyloxyanthracenyl,
tetrahydrofuranyloxyphenyl,
fetrahydrofuranyloxynaphthyl, tetrahydrofuranyloxyanthracenyl,
furanyloxyphenyl,
furanyloxynaphthyl, furanyloxyanthracenyl, dioxolanyloxyphenyl,
dioxolanyloxynaphthyl,
dioxolanyloxyanthracenyl, imidazolidinyloxyphenyl,
imidazolidinyloxynaphthyl,imidazolidinyloxyanthracenyl, imidazolynyloxyphenyl,
imidazolynyloxynaphthyl, imidazolynyloxyanthracenyl, imidazolyloxyphenyl,
imidazolyloxynaphthyl, imidazolyloxyanthracenyl, pyrazolidinyloxyphenyl,
pyrazolidinyloxynaphthyl, pyrazolidinyloxyanthracenyl, pyrazolinyloxyphenyl,
pyrazolinyloxynaphthyl, pyrazolinyloxyanthracenyl, pyrazolyloxyphenyl,
pyrazolyloxynaphthyl,
pyrazolyloxyanthracenyl, oxazolyloxyphenyl, oxazolyloxynaphthyl,
oxazolyloxyanthracenyl,
isoxazolyloxyphenyl, isoxazolyloxynaphthyl, isoxazolyloxyanthracenyl, 1,2,3-
oxadiazolyloxyphenyl, 1,2,3-oxadiazolyloxynaphthyl, 1,2,3-
oxadiazolyloxyanthracenyl, 1,3,4-
oxadiazolyloxyphenyl, 1,3,4-oxadiazolyloxynaphthyl, 1,3,4-
oxadiazolyloxyanthracenyl,
thiophenyloxyphenyl, thiophenyloxynaphthyl, thiophenyloxyanthracenyl,
thiazolyloxyphenyl,
thiazolyloxynaphthyl, thiazolyloxyanthracenyl, thiadiazolyloxyphenyl,
thiadiazolyloxynaphthyl,
thiadiazolyloxyanthracenyl, triazolyloxyphenyi, triazolyloxynaphthyl,
triazolyloxyanthracenyl,
piperidinyloxyphenyl, piperidinyloxynaphthyl, piperidinyloxyanthracenyl,
pyridinyloxyphenyl,
pyridinyloxynaphthyl, pyridinyloxyanthracenyl, piperazinyloxyphenyl,
piperazinyloxynaphthyl,
piperazinyloxyanthracenyl, pyrazinyloxyphenyl, pyrazinyloxynaphthyl,
pyrazinyloxyanthracenyl,
pyrimidinyloxyphenyl, pyrimidinyloxynaphthyl, pyrimidinyloxyanthracenyl,
pyridazinyloxyphenyl,
pyridazinyloxynaphthyl, pyridazinyloxyanthracenyl, triazinyloxyphenyl,
triazinyloxynaphthyl,
triazinyloxyanthracenyl, morpholinyloxyphenyl, morpholinyloxynaphthyl,
morpholinyloxyanthracenyl, dioxanyloxyphenyl, dioxanyloxynaphthyl,
dioxanyloxyanthracenyl,
tetrahydro-2H-pyranyloxyphenyl, tetrahydro-2H-pyranyloxynaphthyl, tetrahydro-
2H-
pyranyloxyanthracenyl, 2H-pyranyloxy phenyl, 2H-pyranyloxy naphthyl, 2H-
pyranyloxy
anthracenyl, 4H-pyranyloxyphenyl, 4H-pyranyloxynaphthyl, 4H-
pyranyloxyanthracenyl,
thiomorpholinyloxyphenyl, thiomorpholinyloxynaphthyl,
thiomorpholinyloxyanthracenyl,
quinolinyloxyphenyl, quinolinyloxynaphthy.l, quinolinyloxyanthracenyl,
fluorenyloxyphenyl,
fluorenyloxynaphthyl and fluorenyloxyanthracenyl; and wherein the
R4jsubstituents may be
optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4j or -QR41;
wherein R4' is
selected from the group consisting of pyrrolidinylphenyl,
pyrrolidinyinaphthyl,
pyrrolidinylanthracenyl, pyrrolinylphenyl, pyrrolinyinaphthyl,
pyrrolinylanthracenyl, pyrrolylphenyl,
pyrrolylnaphthyl, pyrrolylanthracenyl, tetrahydrofuranylphenyl,
tetrahydrofuranylnaphthyl,
tetrahydrofuranylanthracenyl, furanylphenyl, furanylnaphthyl,
furanylanthracenyl,
dioxolanylphenyl, dioxolanylnaphthyl, dioxolanylanthracenyl,
imidazolidinylphenyl,
imidazolidinylnaphthyl, imidazolidinylanthracenyl, imidazolynylphenyl,
imidazolynyinaphthyl,
imidazolynylanthracenyl, imidazolylphenyl, imidazolyinaphthyl,
imidazolylanthracenyl,
pyrazolidinylphenyl, pyrazolidinyinaphthyl, pyrazolidinylanthracenyl,
pyrazolinylphenyl,
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pyrazolinylnaphthyl, pyrazolinylanthracenyl, pyrazolylphenyl,
pyrazolylnaphthyl,
pyrazolylanthracenyl, oxazolylphenyl, oxazolylnaphthyl, oxazolylanthracenyl,
isoxazolylphenyl,
isoxazolylnaphthyl, isoxazolylanthracenyl, 1,2,3-oxadiazolylphenyl,1,2,3-
oxadiazolylnaphthyl,
1,2,3-oxadiazolylanthracenyl, 1,3,4-oxadiazolylphenyl, 1;3,4-
oxadiazolylnaphthyl, 1,3,4-
oxadiazolylanthracenyl, thiophenylphenyl, thiophenyinaphthyl,
thiophenylanthracenyl,
thiazolylphenyl, thiazolyinaphthyl, thiazolylanthracenyl, thiadiazolylphenyl,
thiadiazolylnaphthyl,
thiadiazolylanthracenyl, triazolylphenyl, triazolylnaphthyl,
triazolylanthracenyl, piperidinylphenyl,
piperidinylnaphthyl, piperidinylanthracenyi, pyridinylphenyl,
pyridinyinaphthyl,
pyridinylanthracenyl, piperazinylphenyl, piperazinylnaphthyl,
piperazinylanthracenyl,
pyrazinylphenyl, pyrazinyinaphthyl, pyrazinylanthracenyl, pyrimidinylphenyl,
pyrimidinyinaphthyl,
pyrimidinylanthracenyl, pyridazinylphenyl, pyridazinylnaphthyl,
pyridazinylanthracenyl,
triazinylphenyl, triazinylnaphthyl, triazinylanthracenyl, morpholinylphenyl,
morpholinyinaphthyl,
morpholinylanthracenyl, dioxanyiphenyl, dioxanyinaphthyl, dioxanylanthracenyl,
tetrahydro-2H-
pyranyiphenyl, tetrahydro-2H-pyranylnaphthyl, tetrahydro-2H-
pyranylanthracenyl, 2H-pyranyl
phenyl, 2H-pyranyl naphthyl, 2H-pyranyl anthracenyl, 4H-pyranylphenyl, 4H-
pyranyinaphthyl, 4H-
pyranylanthracenyl, thiomorpholinylphenyl, thiomorpholinylnaphthyl,
thiomorpholinylanthracenyl,
quinolinylphenyl, quinolinyinaphthyl, quinolinylanthracenyl, fluorenylphenyl,
fluorenyinaphthyl and
fluorenylanthracenyl; and wherein the R4j substituents may be optionally
substituted as provided
in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4j or -OR4';
wherein R4j is
selected from the group consisting of butyl, phenyl, fluorenyl, phenylphenyl,
phenylmethyl,
phenylethyl, phenylphenylmethyl, diphenylethyl, phenyloxymethyl,
phenyloxyethyl,
phenyloxyphenyl, naphthyloxymethyl, phenylcyclopropyl, phenylcarbonylphenyl,
phenylcarbonylaminoethyl, phenylcarbonyl(phenyl)aminoethyl, thiophenylmethyl,
phenyl-1,2,3-
oxadiazolyl, phenyl-1,3,4-oxadiazolyl, 1,3,4-oxadiazolylphenyl,
thiazolylphenyl, phenylthiazolyl,
phenylpyridinyl, phenylpyrimidinyl, pyridinylphenyl and pyrimidinylphenyl; and
wherein the R4j
substituents may be optionally substituted as provided in other embodiments
herein.
In another embodiment of the compounds of Formula (II), R4 is selected from
the group
consisting of -R4j, -OR4' and -NR4'R4k; wherein R4J and R4k are independently
selected from the
groups shown in Table C below:
TABLE C - Formulae
N
\ I I I
I I I N
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33
IN I I
I I /
N
I ( II
N \ ~N \ \ N
I / I
LOcH3 F \ II ~ I F
N-O H / ~~ CHa
nN
O CH3
. ..
F N..==N \
\ \ I / ~ S
F
I / ''LL, \ \ N ~õ \
N O I I /
~ J N
CH3 N
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--- N~-
\ I \ \ \ I
F
F
F
H
I / I \
/ I
\ OCH3 F
'~ I /CH3
F
F
\ I I /
Br
Z?, F I I
N
3 /
( \ I I
'2'L, \ O\/CH3
H3C%% CH3 0 O
N IOI N",~CH3
N N
N'K NOIICH3
I
CH3
ON, CH3 F F
~ I I ~
\ I \ (kF c~. / N/CH3
/ CH3
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CH3 CH3 F
F F
CH3
O F F 0
~ Q I
F CH3
S \ F o \
/ I I
F ~
N--N S
N
\ I I
0
I I \
N
\ \ H
o
\ \ \ I
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36
N
0
CH
o
N O1"'CH3
o CH
CH3 'L-L
O p
fLCH3 L,CH3
H3 HsC p
CH3 CH3
CH3 CH3 p
HsC CH3
F O~
c-~F and CHa
"L .
F
wherein the R4J and R4k substituents shown in Table C may be optionally
substituted as provided
in other embodiments herein. In one illustrative embodiment, the R4j and R4k
substituents shown
in Table C each may be optionally substituted with one or more substituents
independently
selected from the group consisting of =0, -CN, -Cl, -Br, -F, methyl, ethyl,
propyl, butyl, phenyl,
methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy,
dimethylamino, carboxy,
methoxycarbonyl, and aminocarbonyl.
In another embodiment, the compound of Formula (II) has one of the structures
shown in Table
D below:
TABLE D - Formulae
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37
0 \CR4 0 \CR4
N N
N N
s 4 3 N /s 4R6 6 N
I -I 6 3
~ 0 R2c1 I
7 R2c1
S
N O H3C S N O
Formula II-A Formula II-B
0 ~CR4 O\C/R4
N N
N N
s 4 N s 4 N
R6 6 3 3
~ R2c2 7 I 3 R2c2
S
N O H3C S N O
Formula II-C Formula II-D
wherein R2o1, R2c2, R4, and R6are as defined in any of the embodiments
described in this
application.
In another embodiment, the compound of Formula (II) has one of the structures
shown in Table
D and R 6 is -R6a, wherein R6a is selected from the group consisting of
hydrogen, halogen, alkyl,
phenyl and haloalkyl; wherein the alkyl or phenyl substituent may be
optionally substituted as
provided in other embodiments herein. In still another embodiment, the
compound of Formula
(II) has one of the structures shown in Table D and R6 is -R6a, wherein R6a is
selected from the
group consisting of alkyl and phenyl. In still another embodiment, the
compound of Formula (II)
has one of the structures shown in Table D; and R6 is -R6a, wherein R 6a is
unsubstituted alkyl.
In still another embodiment, the compound of Formula (II) has one of the
structures shown in
Table D; and R6 is -R6a, wherein R6a is selected from the group consisting of
methyl, ethyl, propyl
and isopropyl.
In another embodiment, the compound of Formula (II) has one of the structures
shown in Table
D; R4 is selected from the group consisting of -R4j, -OR4j and -NR4jR4k,
wherein R4j and R4k are
independently selected from the groups shown in Table D; and wherein the R4j
and R4k
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38
substituents may be optionally substituted as provided in other embodiments
herein; and R6 is -
R6a, wherein R 6a is selected from the group consisting of alkyl and phenyl.
In another embodiment, the compound of Formula (II) has one of the structures
shown in Table
D; R4 is -R4j, wherein R4j is selected from the groups shown in Table D and
wherein the R4J
substituent may be optionally substituted as provided in other embodiments
herein; and R6 is -
R6a, wherein Rsa is unsubstituted alkyl.
In another embodiment, the compound of Formula (II) has one of the structures
shown in Table
D; R4 is -R4j, wherein R4' is selected from the groups shown in Table D and
wherein the R4'
substituent may be optionally substituted with one or more substituents
independently selected
from the group consisting of =0, -CN, -CI, -Br, -F, methyl, ethyl, propyl,
butyl, phenyl, methoxy,
trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino,
carboxy,
methoxycarbonyl, and aminocarbonyl; and R6 is -Rsa, wherein Rsa is selected
from the group
consisting of hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl
and fluoromethyl.
In another embodiment, the compound of Formula (II), R2 is -R2o1; -R2o1 is Ci-
C6-alkyl, wherein
the R2o1 C,-C6-alkyl substituent is substituted with one or more substituents
independently
selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl,
heterocyclyl, -Cl, -Br, -I, -
CN, =0, =S, -SR2d, -NO2, -C(O)R2d, -C(S)R2d, -C(O)OR2d ,
-C(S)OR2d, -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, -OR2d, -OC(O)R2d, -OC(S)R2d,
-OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -
NR2dC(S)R2e,
-NRZdC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, _NR2dC(O)NR2eR2t, -S(O)rR2d,
-S(O)2NR2dR2e, and,-SC(O)R2d; n is 1 or 2; and R2d, R2e and R2f are
independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
and heterocyclyl;
wherein the R2 ', R2d, R2e and R2f substituents may be optionally substituted
as provided in other
embodiments herein.
In another embodiment of the compound of Formula (II), R2 is -R20'; -R2o1 is
Cl-C6-alkyl, wherein
the R2c1 Cl-C6-alkyl substituent is substituted with one or more substituents
independently
selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl,
heterocyclyl, -Cl, -Br, -I, -
CN, =0, =S, -SR2d, -NO2, -C(O)R2tl, -C(S)R2d, -C(O)OR2d ,
-C(S)OR2d, -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, _OR2d, -OC(O)R2d, -OC(S)Rzd,
-
OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)
R2e, -
NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR21, -S(O),,R2d, -
S(O)2NR2dR2e,
and -SC(O)R2d; n is 1 or 2; and R2d, R2e and R2f are independently selected
from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and
heterocyclyl; and wherein the
R20, R2d, R2e and R2f substituents may be optionally substituted as provided
in other
embodiments herein.
In another embodiment of the compound of Formula (II), R2 is -R20; -R2 i is Ci-
C6-alkyl, wherein
the R20 Ci-Cs-alkyl substituent is substituted with one or more substituents
independently
selected from the group consisting of heterocyclyl, =0, -C(O)OR2d ,
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39
-C(O)NR2dR2e, -OR2d, -OC(O)R2d and -NR2dR2e; and R2d and R2e are independently
selected
from the group consisting of hydrogen, alkyl and heterocyclyl; and wherein the
R2cl, R2d and R2e
substituents may be optionally substituted as provided in other embodiments
herein.
In another embodiment of the compound of Formula (II), R2 is -R2 '; -R2o1 is
Cl-C6-alkyl, wherein
the R2o1 C1-C6-alkyl substituent is substituted with one or more substituents
independently
selected from the group consisting of heterocyclyl, =0, -C(O)OR2d,
-C(O)NR2dR2e, -OR2d, -OC(0)R2d and -NR2dR2e; R2d and R2e are independently
selected from
the group consisting of hydrogen, alkyl and heterocyclyl; wherein the R2c1,
R2d and R2e
substituents may be optionally substituted with one or more substituents
independently selected
from the group consisting of halogen, =0, -R29, -C(O)OR2g, C(O)NR29R2h, -OR2g
and -NR29R2h;
and R29 and R 2h are independently selected from the group consisting of
hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, and heterocyclyi, wherein the R29 and R2h alkyl,
alkenyl, alkynyl,
cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted
with one or more
substituents independently selected from the group consisting of halogen,
hydroxy, -CN, =0, =S,
-SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2o1 is
Ci-C6-alkyl, wherein
the R2c1 Cl-C6=alkyl substituent is substituted with one or more substituents
independently
selected from the group consisting of heterocyclyl, =0, -C(O)OR2d,-
C(O)NR2dR2e, -OR2d, -
OC(O)R2d and -NR2dR2e; R2d and R2e are independently selected from the group
consisting of
hydrogen, alkyl and heterocyclyl; wherein the R2c1, R2d and R2e substituents
may be optionally
substituted with one or more substituents independently selected from the
group consisting of
halogen, =0, -R29, -C(O)OR2g, C(O)NR2gR2ti, -OR29 and -NR2gR2h; and R2g and
R2h are
independently selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl,
aryl, and heterocyclyi.
In another embodiment of the compound of Formula (II), R2 is -R2o1; and -R20
is Ci-C6-alkyl,
wherein the R2o1 Ci-C6-alkyl substituent is substituted with one or more
substituents
independently selected from the group consisting of heterocyclyl, =0, -
C(O)OR2d,
-C(O)NR2dR2e, -OR2d, -OC(O)RZd and -NR2dR2e; R2d and R2e are independently
selected from
the group consisting of hydrogen, alkyl and heterocyclyi, and wherein the R2
', R2d and R2e
substituents may be optionally substituted with one or more substituents
independently selected
from the group consisting of halogen, =0, -R29, -C(O)OR29, -C(O)NR29R2h, -OR29
and
-NR29R2h; and R29 and R2h are independently selected from the group consisting
of hydrogen and
alkyl.
In another embodiment of the compound of Formula (II), R2 is -R2c'; -R2c' is
selected from the
group consisting of hydroxyalkyl, alkoxyalkyl, carboxyalkyl,
heterocyclylalkyl, aminoalkyl,
alkylaminoalkyl, aminocarbonylalkyl, oxoalkyl, alkylaminocarbonylalkyl,
hydroxyalkoxyalkyl,
aminocarbonylalkoxyalkyl and alkylcarbonylalkyl; wherein the R2o1
hydroxyalkyl, alkoxyalkyl,
carboxyalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl,
aminocarbonylalkyl, oxoalkyl,
alkylaminocarbonylalkyl, hydroxyalkoxyalkyl, aminocarbonylaikoxyalkyl and
alkylcarbonylalkyl
substituents may be optionally substituted with one or more substituents
independently selected
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from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2i alkyl,
haloalkyl, carboxy,
alkoxy and alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R20i is
selected from the
group consisting of hydroxyalkyl, alkoxyalkyl, carboxyalkyl,
heterocyclylalkyl, aminoalkyl,
5 alkylaminoalkyl, aminocarbonylalkyl and oxoalkyl; wherein the R2o1
hydroxyalkyl, alkoxyalkyl,
carboxyalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl,
aminocarbonylalkyl and oxoalkyl
substituents may be optionally substituted with one or more substituents
independently selected
from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl,
haloalkyl, carboxy,
alkoxy and alkoxycarbonyl.
10 In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c'
is selected from the
group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl,
methoxymethyl,
ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl,
butoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, butoxypropyl,
carboxymethyl,
carboxyethyl, carboxypropyl, carboxybutyl, aminoalkyl, aminomethyl,
aminoethyl, aminopropyl,
15 aminobutyl, alkylaminoalkyl, methylaminomethyl, methylaminoethyl,
methylaminopropyl,
methylaminobutyl, dimethylaminomethyl, dimethylaminoethyl,
dimethylaminopropyl,
dimethylaminobutyl, ethylam inom ethyl, ethylaminoethyl, ethylaminopropyl,
ethylaminobutyl,
diethylam inom ethyl, diethylaminoethyl, diethylaminopropyl,
diethylaminobutyl,
propylam inom ethyl, propylaminoethyl, propylaminopropyl, propylaminobutyl,
20 d ipropylam inom ethyl, dipropylaminoethyl, dipropylaminopropyl,
dipropylaminobutyl,
butylaminomethyl, butylaminoethyl, butylaminopropyl, butylaminobutyl,
dibutylaminomethyl,
dibutylaminoethyl, dibutylaminopropyl, dibutylaminobutyl, methylethylam inom
ethyl,
m ethyl propylam inom ethyl, m ethylbutylam inom ethyl, methylethylaminoethyl,
methylpropylaminoethyl, methylbutylaminoethyl, methylethylaminopropyl,
25 methylpropylaminopropyl, m ethyl butylam inopropyl, methylethylaminobutyl,
methylpropylaminobutyl, methylbutylaminobutyl, ethyl propylam inom ethyl,
ethylbutylam inom ethyl,
propylbutylam inom ethyl, ethylpropylaminoethyl, ethylbutylaminoethyl,
propylbutylaminoethyl,
ethyipropylaminopropyl, ethyl butylam inopropyl, propylbutylaminopropyl, ethyl
propylam inobutyl,
ethylbutylaminobutyl, propylbutylaminobutyl, aminocarbonylmethyl,
aminocarbonylethyl,
30 aminocarbonylpropyl, aminocarbonylbutyl, oxomethyl, oxoethyl, oxopropyl and
oxobutyl; wherein
the R2o1substituents may be optionally substituted with one or more
substituents independently
selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -
NO2, alkyl, haloalkyl,
carboxy, alkoxy and alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2c1 is
selected from the
35 group consisting of pyrrolidinylmethyl, pyrrolidinylethyl,
pyrrolidinylpropyl, pyrrolidinylbutyl,
pyrrolinylmethyl, pyrrolinylethyl, pyrrolinylpropyl, pyrrolinylbutyl,
pyrrolylmethyl, pyrrolylethyl,
pyrrolylpropyl, pyrrolylbutyl, tetrahydrofuranylmethyl,
tetrahydrofuranylethyl,
tetrahydrofuranylpropyl, tetrahydrofuranylbutyl, furanylmethyl, furanylethyl,
furanylpropyl,
furanylbutyl, dioxolanylmethyl, dioxolanylethyl, dioxolanylpropyl,
dioxolanylbutyl,
40 imidazolidinylmethyl, imidazolidinylethyl, imidazolidinylpropyl,
imidazolidinylbutyl,
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41
imidazolynylmethyl, imidazolynylethyl, imidazolynylpropyl, imidazolynylbutyl,
im idazolylm ethyl,
imidazolylethyl, imidazolylpropyl, imidazolylbutyl, pyrazolidinylmethyl,
pyrazolidinylethyl,
pyrazolidinylpropyl, pyrazolidinylbutyl, pyrazolinylmethyl, pyrazolinylethyl,
pyrazolinylpropyl,
pyrazolinylbutyl, pyrazolylmethyl, pyrazolylethyl, pyrazolylpropyl,
pyrazolylbutyl, oxazolylmethyl,
oxazolylethyl, oxazolyipropyl, oxazolylbutyl, isoxazolylmethyl,
isoxazolylethyl, isoxazolylpropyl,
isoxazolylbutyl, 1,2,3-oxadiazolylmethyl, 1,2,3-oxadiazolylethyl, 1,2,3-
oxadiazolyipropyl, 1,2,3-
oxadiazolylbutyl, 1,3,4-oxadiazolylmethyl, 1,3,4-oxadiazolyiethyl, 1,3,4-
oxadiazolylpropyl, 1,3,4-
oxadiazolylbutyl, oxetanylmethyl, oxetanylethyl, oxetanylpropyl,
oxetanylbutyl, oxiranylmethyl,
oxiranylethyl, oxiranylpropyl, oxiranylbutyl, thiophenylmethyl,
thiophenylethyl, thiophenylpropyl,
thiophenylbutyl, thiazolylmethyl, thiazolylethyl, thiazolylpropyl,
thiazolylbutyl, thiadiazolylmethyl,
thiadiazolylethyl, thiadiazolyipropyl, thiadiazolylbutyl, triazolylmethyl,
triazolylethyl, triazolyipropyl,
triazolylbutyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl,
piperidinylbutyl,
pyridinylmethyl, pyridinylethyl, pyridinylpropyl, pyridinylbutyl,
piperazinylmethyl, piperazinylethyl,
piperazinylpropyl, piperazinylbutyl, pyrazinylmethyl, pyrazinylethyl,
pyrazinylpropyl,
pyrazinylbutyl, pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl,
pyrimidinylbutyl,
pyridazinylmethyl, pyridazinylethyl, pyridazinylpropyl, pyridazinylbutyl,
triazinylmethyl,
triazinylethyl, triazinylpropyl, triazinylbutyl, morpholinylmethyl,
morpholinylethyl,
morpholinylpropyl, morpholinylbutyl, dioxanylmethyl, dioxanylethyl,
dioxanylpropyl, dioxanylbutyl,
tetrahydro-2H-pyranylmethyl, tetrahydro-2H-pyranylethyl, tetrahydro-2H-
pyranylpropyl,
tetrahydro-2H-pyranylbutyl, 2H-pyranylmethyl, 2H-pyranylethyl, 2H-
pyranylpropyl, 2H-
pyranylbutyl, 4H-pyranylmethyl, 4H-pyranylethyl, 4H-pyranylpropyl, 4H-
pyranylbutyl,
thiomorpholinylmethyl, thiomorpholinylethyl, thiomorpholinylpropyl,
thiomorpholinylbutyl,
quinolinylmethyl, quinolinylethyl, quinolinylpropyl, quinolinylbutyl,
fluorenylmethyl, fluorenylethyl,
fluorenylpropyl and fluorenylbutyl; wherein the R2o1 substituents may be
optionally substituted
with one or more substituents independently selected from the group consisting
of halogen,
hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and
alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2Q'; -R2c1 is
selected from the
group consisting of hydroxypropyl, hydroxybutyl, ethoxyethyl, carboxyethyl,
aminoethyl,
dimethylaminoethyl, am inocarbonylm ethyl, oxoethyl, tetrahydrofuranylmethyl,
oxetanylmethyl,
oxi ranylm ethyl, piperazinylethyl, morpholinylmethyl, morpholinylethyl,
morpholinylpropyl and
dioxanylmethyl; wherein the R2c'substituents may be optionally substituted
with one or more
substituents independently selected from the group consisting of halogen,
hydroxy, -CN, =0, =S,
-SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2 ' is
selected from the
group consisting of hydroxypropyl, hydroxybutyl, ethoxyethyl, carboxyethyl,
aminoethyl,
dimethylaminoethyl, aminocarbonylmethyl, oxoethyl, tetrahydrofuranylmethyl,
oxetanylmethyl,
oxiranylmethyl,piperazinylethyl, m orphol inylm ethyl, morpholinylethyl,
morpholinylpropyl and
dioxanyimethyl; wherein the R2o1 substituents may be optionally substituted
with one or more
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42
substituents independently selected from the group consisting of methyl,
hydroxy, methoxy and
ethoxy.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2o1 is
Cl-C6-alkyl; wherein
the R2c1 Ci-C6-alkyl is substituted with at least one hydroxyl substituent.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2c1 is
Cl-Cs-alkyl; wherein
the R20i Cl-C6-alkyl is substituted'with at least two hydroxyl substituents.
In another embodiment of the compound of Formula (II), R2 is -R2a1; -R2o1 is
C1=C6-alkyl; wherein
the R2c1 Ci-C6-alkyl is substituted with one hydroxyl substituent.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c' is
Cl-Cs-alkyl; wherein
the R2o1 C1-C6-alkyl is substituted with two hydroxyl substituents.
In another embodiment of the compound of Formula (II), R2 is -R2Q1; -R2o1 is
Cl-C6-alkyl; wherein
the R2c1 Ci-C6-alkyl is substituted with at least one hydroxyl substituent; R4
is selected from the
group consisting of -R4j, -OR4' and -NR4'R4k, wherein R4' and R4k are
independently selected
from the groups shown in Table C and wherein the R4' and R4k substituents may
be optionally
substituted as provided in other embodiments herein; and R6 is -R6a, wherein
R6a is selected
from the group consisting of alkyl and phenyl.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2c1 is
Ci-C6-alkyl; wherein
the R2o1 C,-C6-alkyl is substituted with at least one hydroxyl substituent; R4
is -R4j, wherein R4' is
selected from the groups shown in Table C and wherein the R4j substituent may
be optionally
substituted as provided in other embodiments herein; and R 6 is -R6a, wherein
R6a is
unsubstituted alkyl.,
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is
Ci-C6-alkyl; wherein
the R2c1 Ci-C6-alkyl is substituted with at least one hydroxyl'substituent; R4
is -R4j, wherein R4j-is
selected from the groups shown in Table C and wherein the R4j substituent may
be optionally
substituted with one or more substituents independently selected from the
group consisting of
=0, -CN, -CI, -Br, -F; methyl, ethyl, propyl, butyl, phenyl, methoxy,
trifluoromethyl,
trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy,
methoxycarbonyl, and
aminocarbonyl; and R6 is -Rsa, wherein R6a is selected from the group
consisting of methyl, ethyl,
propyl and isopropyl.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2c1 is
Cl-C6-alkyl; wherein
the R2o1 Cl -C6-alkyl is substituted with at least two hydroxyl substituents;
RA is selected from the
group consisting of -R4J, -OR4j and -NR4jR4k, wherein R4j and R4k are
independently selected
from the groups shown in Table C and wherein the,R4j and R4k substituents may
be optionally
substituted as provided in other embodiments herein; and R6 is -R6a, wherein
R6a is selected
from the group consisting of alkyl and phenyl.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2c1 is
Ci-C6-alkyl; wherein
the R2o1 CI-C6-alkyl is substituted with at least two hydroxyl substituents;
R4 is -R4~, wherein R4j is
selected from the groups shown in Table C and wherein the R4J substituent may
be optionally
substituted as provided in other embodiments herein; and R6 is -R6a, wherein
Rsa is
unsubstituted alkyl.
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43
In'another embodiment of the compound of Formula (II)2 R2 is -R2oi; -R2o1 is
Ci-Cs-alkyl; wherein
the R2c1 Ci-C6-alkyl is substituted with at least two hydroxyl substituents;
R4 is -R4j, wherein R4j is
selected from the groups shown in Table C and wherein the R4jsubstituent may
be optionally
substituted with one or more substituents independently selected from the
group consisting of
=0, -CN, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy,
trifluoromethyl,
trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy,
methoxycarbonyl, and
aminocarbonyl; and R6 is -R6a, wherein R6a is selected. from the group
consisting of methyl, ethyl,
propyl and isopropyl.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2c1 is
Ci-C6-alkyl; wherein
the RZC' Ci-C6-alkyl is substituted with one hydroxyl substituent; R4 is
selected from the group
consisting of -R4j, -OR4J and -NR4jR4k, wherein R41 and R4k are independently
selected from the
groups shown in Table C and wherein the R 41 and R4k substituents may be
optionally substituted
as provided in other embodiments herein; and R6 is -R6a, wherein R6a is
selected from the group
consisting of hydrogen, halogen, alkyl, haloalkyl and phenyl.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2o1 is
C1-C6-alkyl; wherein
the R20 C,-C6-alkyl is substituted with one hydroxyl substituent; R4 is -R4j,
wherein R4' is selected
from the groups shown in Table C and wherein the R4'substituent.may be
optionally substituted
as provided in other embodiments herein; and R6 is -R6a, wherein R6a
is'unsubstituted alkyl.
In another embodiment of the compound of Formula (II), R2 is -R2o1; -R2c1 is
Ci-C6-alkyl; wherein
the R2c1 Cl-C6-alkyl is substituted with one hydroxyl substituent; R4 is -R4J,
wherein R4' is selected
from the groups shown in Table C and wherein the R4'substituent may be
optionally substituted
with one or more substituents independently selected from the group consisting
of =0, -CN, -Cl,
-Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl,
trifluoromethoxy, ethoxy,
propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl, and aminocarbonyl;
and R6 is -Rsa,
wherein Rsa is selected from the group consisting of hydrogen, fluorine,
chlorine, methyl, ethyl,
propyl, isopropyl and fluoromethyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c' is
Cl-Cs-alkyl; wherein
the R2o1 C1-C6-alkyl is substituted with two hydroxyl substituents; R4 is
selected from the group
consisting of -R4j, -OR4j and -NR4'R41, wherein R4j and R4k are independently
selected from the
groups shown in Table C and wherein the R4j and R4k substituents may be
optionally substituted
as provided in other embodiments herein; and R6 is -R6a, wherein R6a is
selected from the group
consisting of alkyl and phenyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2o1 is
Cl-C6-alkyl; wherein
the R2 ' Ci-C6-alkyl is substituted with two hydroxyl substituents; R4 is -
R4J, wherein R4j is
selected from the groups shown in Table C and wherein the R4j substituent may
be optionally
substituted as provided in other embodiments herein; and R6 is -R6a, wherein
R6a is
unsubstituted alkyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2 ' is
Cl-C6-alkyl; wherein
the R2o1 Ci-C6-alkyl is substituted with two hydroxyl substituents; R4 is -
R4j, wherein R4J is
selected from the groups shown in Table C and wherein the R4j substituent may
be optionally
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44
substituted with one or more substituents independently -selected -f rom the
group consisting of
=0, -CN, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy,
trifluoromethyl,
trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy,
methoxycarbonyl, and
aminocarbonyl; and R 6 is -R6a, wherein R6a is selected from the group
consisting of methyl, ethyl,
propyl and isopropyl.
In another embodiment of the compound of Formula (II), R2 is -R2e2; -R2e2 is
selected from the
group consisting of C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and
heterocyclyl, wherein the
R2o2 C,-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl
substituents may be optionally
substituted with one or more substituents independently selected from the
group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halogen, -CN, =0, =S,
-SR2d, -NO2, -C(O)R2d,
-C(S)R2d, -C(O)OR2d, -C(S)OR2d, -C(O)SR2d, -C(O)NR2dR2e-C(S)NR2dR2e, -ORZd, -
OC(O)R2d, -OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e-NR2dR2e, -
NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NRZdS(O)2R2e,
-NR2dC(O)NR2eR2f, -S(O)õR2d, -S(O)2NR2dR2e, and -SC(O)R2d; n is 1 or 2; and
R2d, R2e and R2f
are independently selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl,
cycloalkyl, aryl, and heterocyclyl; wherein the R2 2, R2d, R2e and R2f
swbstituents may be
optionally substituted as provided in other embodiments herein.
In another embodiment of the compound of Formula (11), R2 is -R2 2; -R2 2 is
selected from the
group consisting of C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and
heterocyclyl, wherein the
R 2C2 C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl
substituents may be optionally
substituted with one or more substituents independently selected from the
group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halogen, -CN, =0, =S,
-SR2d, -NO2, -C(O)R2d,
-C(S)R2d, -C(O)OR2d, -C(S)OR2d, -C(O)SRZd, -C(O)NR2dR2e-C(S)NR2dR2e, -OR2d, -
OC(O)R2d, -OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e,
-NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -
NR2dS(O)2R2e,
-NR2dC(O)NR2eR2f, -S(O)õR2d, -S(O)2NR2dR2e, and -SC(O)R2d; n is 1 or 2; and
R2d, R2e and R2f
are independently selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl,
cycloalkyl, aryl, and heterocyclyl; wherein the R2 2, R2d, R2e and R21
substituents may be
optionally substituted as provided in other embodiments herein.
In another embodiment of the compound of Formula (II), R2 is -RZ 2; -R2 2 is
selected from the
group consisting of cycloalkyl and heterocyclyl, wherein the R2o2 cycloalkyl
and heterocyclyl
substituents may be optionally substituted with one or more substituents
independently selected
from the group consisting of =0, -C(O)OR2d, -C(O)NR2dR2e and -OR2d; and R2d
and R2e are
independently selected from the group consisting of hydrogen and alkyl;
wherein the R2c2, R2d
and R2e substituents may be optionally substituted as provided in other
embodiments herein.
In another embodiment of the compound of Formula (II), R2 is -R2 2; -R21 is
selected from the
group consisting of cycloalkyl and heterocyclyl, wherein the R2 2 cycloalkyl
and heterocyclyl
substituents may be optionally substituted with one or more substituents
independently selected
from the group consisting of =0, -C(O)OR2d ,-C(O)NR2dR2e and -OR2d; R2d and
R2e are
independently selected from the group consisting of hydrogen and alkyl;
wherein the R2 2, R2d
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and R2e substituents may be optionally substituted with one or more -OR2g; and
R29 is hydrogen
or alkyl, wherein the R 29 alkyl substituent may be optionally substituted
with one or more
substituents independently selected from the group consisting of halogen,
hydroxy, -CN, =0, =S,
-SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl.
5 In another embodiment of the compound of Formula (II), R2 is -R2o2; -R2c2 is
selected from the
group consisting of cycloalkyl and heterocyclyl, wherein the R 2C2 cycloalkyl
and heterocyclyl
substituents may be optionally substituted with one or more substituents
independently selected
from the group consisting of =0, -C(O)OR2d, -C(O)NR2dR2e and -OR2d; R2d and
R2e'are
independently selected from the group consisting of hydrogen and alkyl;
wherein the R2 2, R2d
10 and R2e substituents may be optionally substituted with one or more -OR29;
and R29 is hydrogen
or alkyl, wherein the R29 alkyl substituent may be optionally substituted with
one or more hydroxy
substituents.
In another embodiment of the compound of Formula (II), R2 is -R2c2; and -R2o2
is selected from
the group consisting of heterocyclyl, hydroxyheterocyclyl, cycloalkyl,
carboxycycloakyl,
15 aminocarbonylcycloalkyl and oxoheterocyclyl; wherein the R2o2heterocyclyl,
hydroxyheterocyclyl,
cycloalkyl, carboxycycloakyl, aminocarbonylcycloalkyl and oxoheterocyclyl
substituents may be
optionally substituted with one or more substituents independently selected
from the group
consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl,
carboxy, alkoxy and
alkoxycarbonyl.
20 In another embodiment of the compound of Formula (II), R2 is -R2o2; and -
R2o2 is heterocyclyi;
wherein the R 2C2 heterocyclyl substituent may be optionally substituted with
one or more
substituents independently selected from the group consisting of halogen,
hydroxy, -CN, =0, =S,
-SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2C2; and -R2o2
is selected from
25 the group consisting of pyrrolidinyl, pyrrolinyl, pyrrolyl,
tetrahydrofuranyl, furanyl, dioxolanyl,
imidazolidinyl, imidazolynyl, imidazolyl, pyrazolidinyl, pyrazolinyl,
pyrazolyl, oxazolyl, isoxazolyi,
1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, oxadiazolyi, oxetanyl, oxiranyl,
thiophenyl, thiazolyl,
thiadiazolyl, , triazolyl, piperidinyl, pyridinyl, piperazinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, ,
triazinyl, morpholinyl, dioxalanyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-
pyranyl, thiomorpholinyl,
30 quinolinyl and fluorenyl;
wherein the R 2C2 substituents may be optionally substituted with one or more
substituents
independently selected from the group consisting of halogen, hydroxy, -CN, =0,
=S, -SH,
-NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2c2; and -
R2olis
35 tetrahydrofuranyl; wherein the R2o2 tetrahydrofuranyl may be optionally
substituted with one or
more substituents independently selected from the group consisting of
inethyl', hydroxy, methoxy
and ethoxy.
Another class of compounds of specific interest includes compounds, and
pharmaceutically
acceptable salts of the compounds, wherein the compounds have the structure of
Formula III:
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46
O R4
N
N
\N
6
R6 7
S N/ OR2
Formula III
wherein:
R2 is selected from the group consisting of hydroxyalkyl, oxoalkyl,
aminoalkyl,
5 carboxyalkyl, cycloalkyl, carboxycycloalkyl, heterocyclyl,
heterocyclylalkyl, alkoxyalkyl,
alkylaminoalkyl, aminocarbonylalkyl, alkylcarbonylalkyl,
alkylaminocarbonylalkyl, and
aminocarbonylcycloalkyl; .
wherein the R2 substituent may be optionally substituted with one or more
substituents
independently selected from the group consisting of hydroxy, oxo, carboxy,
alkyl, hydroxyalkyl,
aminoalkyl, alkoxy, and aminocarbonyl; and
R4 is -R4j or -OR4';
wherein R4j is selected from the group consisting of alkyl, aryl,
heterocyclyl, arylaryl,
arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl,
arylheterocyclyl, aryloxyaryl,
heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl;
wherein the R4j and R4k substituents each may be optionally substituted with
one or more
substituents independently selected from the group consisting of =0, -CN,
halogen, alkyl, phenyl,
alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and
aminocarbonyl; and
R6 is alkyl.
In another embodiment of Formula (II), R2 is selected from the group
consisting of hydroxyalkyl,
oxoalkyl, aminoalkyl, carboxyalkyl, heterocyclyl, heterocyclylalkyl,
alkoxyalkyl, alkylaminoalkyl
and aminocarbonylalkyl, wherein the R2 substituent-may be optionally
substituted with one or
more substituents independently selected from the group consisting of hydroxy,
oxo, carboxy,
alkyl, hydroxyalkyl, aminoalkyl, alkoxy, and aminocarbonyl; R4 is -R41; R4j is
selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl,
arylaryl, arylalkyl,
heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl,
aryloxyaryl, heterocycloxyaryl,
arylcarbonylaryl, and arylcarbonylaminoalkyl, wherein the R 41 substituent may
be optionally
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47
substituted with one or more-substituents independently selected frorri the
group consisting of
=0, -CN, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino,
carboxy,
alkoxycarbonyl, and aminocarbonyl; and R6 is alkyl.
In another embodiment of the compound of Formula (II), R2 is hydroxyalkyl,
wherein the R2
hydroxyalkyl may be optionally substituted with one or more substituents
independently selected
from the group consisting of hydroxy, oxo, carboxy, alkyl, hydroxyalkyl,
aminoalkyl, alkoxy, and
aminocarbonyl; R4 is -R4j; R4j is selected from the group consisting of alkyl,
aryl, heterocyclyl,
arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl,
arylheterocyclyl, aryloxyaryl,
heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl, wherein the
R4j substituent may
be optionally substituted with one or more substituents independently selected
from the group
consisting of =0, -CN, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy,
alkylamino, carboxy,
alkoxycarbonyl, and aminocarbonyl; and R6 is selected from the group
consisting of hydrogen,
halogen, alkyl and haloalkyl.
In another embodiment of the compound of Formula (II), R2 is
heterocyclylalkyl, wherein the R2
heterocyclylalkyl may be optionally substituted with one or more substituents
independently
selected from the group consisting of hydroxy, oxo, carboxy, alkyl,
hydroxyalkyl, aminoalkyl,
alkoxy, and aminocarbonyl; R4 is -R4', R4' is selected from the group
consisting of alkyl, aryl,
heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl,
cycloalkylaryl, arylheterocyclyl,
aryloxyaryl, heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl,
wherein the R4j
substituent may be optionally substituted with one or more substituents
independently selected
from the group consisting of =0, -CN, halogen, alkyl, phenyl, alkoxy,
haloalkyl, haloalkoxy,
alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl; and R6 is hydrogen,
halogen, alkyl and
haloalkyl.
In another embodiment of the compound of Formula (II), R2 is selected from the
group consisting
of hydroxypropyl, hydroxybutyl, ethoxyethyl, carboxyethyl, aminoethyl,
dimethylaminoethyl,
am inocarbonylm ethyl, oxoethyl, tetrahydrofuranylmethyl, oxetanylmethyl,
oxiranylmethyl,piperazinylethyl, morpholinylmethyl, morpholinylethyl,
morpholinylpropyl,
dioxanylmethyl and tetrahydrofuranyl, wherein the R2 substituent may be
optionally substituted
with one or more substituents independently selected from the group consisting
of hydroxy, oxo,
carboxy, alkyl, hydroxyalkyl, aminoalkyl, alkoxy, and aminocarbonyl; R4 is -
R4j; R41 is selected
from the group consisting of butyl, phenyl, fluorenyl, phenylphenyl,
phenylmethyl, phenylethyl,
phenylphenylmethyl, diphenylethyl, phenyloxymethyl, phenyloxyethyl,
phenyloxyphenyl,
naphthyloxymethyl, phenylcyclopropyl, phenylcarbonylphenyl,
phenylcarbonylaminoethyl,
phenylcarbonyl(phenyl)aminoethyl, thiophenylmethyl, phenyl-1,2,3-oxadiazolyl,
phenyl-1,3,4-
oxadiazolyl, 1,3,4-oxadiazolylphenyl, thiazolylphenyl, phenylthiazolyl,
phenylpyridinyl,
phenylpyrimidinyl, pyridinylphenyl and pyrimidinylphenyl, wherein the R 41
substituent may be
optionally substituted with one or more substituents independently selected
from the group
consisting of =0, -CN, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy,
alkylamino, carboxy,
alkoxycarbonyl, and aminocarbonyl; and R6 is selected from the group
consisting of hydrogen,
methyl, ethyl, propyl, butyl and trifluoromethylmethyl.
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In another embodiment of the compound of Formula (II), R2 is selected from the
group consisting
of hydroxypropyl, hydroxybutyl, ethoxyethyl, carboxyethyl, aminoethyl,
dimethylaminoethyl,
am inocarbonylm ethyl, oxoethyl, tetrahydrofuranylmethyl, oxetanylmethyl,
oxiranylmethyl,piperazinylethyl, morpholinylmethyl, morpholinylethyl,
morpholinylpropyl,
dioxanylmethyl and tetrahydrofuranyl, wherein the R2 substituent may be
optionally substituted
with one or more substituents independently selected from the group consisting
of hydroxy,
methyl methoxy and ethoxy; R4 is -R4j; R4' is selected from the group
consisting of butyl, phenyl,
fluorenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylphenylmethyl,
diphenylethyl,
phenyloxymethyl, phenyloxyethyl, phenyloxyphenyl, naphthyloxymethyl,
phenylcyclopropyl,
phenyicarbonylphenyl, phenylcarbonylaminoethyl,
phenylcarbonyl(phenyl)aminoethyl,
thiophenylm ethyl, phenyl-1,2,3-oxadiazolyl, phenyl-1,3,4-oxadiazolyl, 1,3,4-
oxadiazolylphenyl,
thiazolylphenyl, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl,
pyridinylphenyl and
pyrimidinylphenyl, wherein the R4j substituent may be optionally substituted
with one or more
substituents independently selected from the group consisting of =0, -CN, -Cl,
-Br, -F, methyl,
ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy,
ethoxy, propoxy, butoxy,
dimethylamino, carboxy, methoxycarbonyl, and aminocarbonyl; and R 6 is ethyl.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
tert-butyl 4-[2-(2,2-diethoxyethoxy)-6-ethylthieno[2,3-d]pyrim idin-4-
yl]piperazine-1-carboxylate;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-(2,2-diethoxyethoxy)-6-
ethylthieno[2,3-
d]pyrimidine;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-ethylthieno[2,3-d]pyrimidine;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yi]-2-{[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-ethylthieno[2,3-d]pyrim idine;
(2R)-3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol;
(2S)-3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yi}oxy)propane-1,2-diol;
({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrim
idin-2-yl}oxy)acetic
acid;
({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylth ieno[2,3-d]pyrim
idin-2-
yl}oxy)acetaldehyde;
N-[2-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrim idin-2-
yl}oxy)ethyl]-N,N-dimethylamine;
3-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrim idin-4-
yl)piperazin-l-
yl]carbonyl}benzonitrile;
(2R)-3-[(6-ethyl-4-{4-[(5-phenyl-1,3,4-oxadiazol-2-yl)carbonyl]piperazin-1-
yl}thieno[2,3-
d]pyrim idin-2-yl)oxy]propane-1,2-diol;
(2R)-3-[(6-ethyl-4-{4-[(2-phenyl-1,3-thiazol-4-yl)carbonyl]piperazin-1-
yl}thieno[2,3-d]pyrim idin-2-
yl)oxy]propane-1,2-diol;
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4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-(2-ethoxyethoxy)-6-
ethylthieno[2,3-d]pyrim idine;
2-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1--yl]-6-ethylthieno[2,3-
d]pyrim idin-2-
yI}oxy)acetam ide;
(2R)-3-({4-[4-(1,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylth ieno[2,3-
d]pyrim idin-2-
yl}oxy)propane-1,2-diol;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(tetrahydrofuran-2-
ylmethoxy)thieno[2,3-
d]pyrimidine;
(2R)-3-({4-[4-(3-bromobenzoyl)piperazin-1_-yl]-6-ethylthieno[2,3-d]pyrimidin-2-
yl}oxy)propane-1,2-
diol;
(2S)-4-({4-[4-(1,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy) b utane-1,2-d iol;
3'-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-
yl)piperazin-1-
yl]carbonyl}-1,1'-biphenyl-4-carboxylic acid; and
2-({4-[4-(1,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy)ethanamine;
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
3-({4-[4-(1,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy)propanoic acid;
(2R)-3-[(6=ethyl-4-{4-[(4-phenylpyridin-2-yl)carbonyl]piperazin-1-
yl}thieno[2,3-d]pyrimidin-2-
yl)oxy]propane-1,2-diol;
(2R)-3-({6-ethyl-4-[4-(3-pyridin-3-ylbenzoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol;
(2R)-3-[(6-ethyl-4-{4-[(3'-fluoro-1,1'-biphenyl-3-yl)carbonyl]piperazin-1-
yl}th ieno[2,3-d]pyrim idin-2-
yI)oxy]propane-1,2-diol;
(2R)-3-({6-ethyl-4-[4-(3-pyrimidin-5-ylbenzoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol;
(2R)-3-[(4-{4-[(3',4'-difluoro-1,1'-biphenyl-3-yl)carbonyl]piperazin-1-yl}-6-
ethylthieno[2,3-
d]pyrim idin-2-yl)oxy]propane-1,2-d iol;
(2R)-3-[(6-ethyl-4-{4-[(4'-methyl-1,1'-biphenyl-3-yl)carbonyl]piperazin-1-
yl}thieno[2,3-d]pyrimidin-
2-yI)oxy]propane-1,2-diol;
(2R)-3-[(6-ethyl-4-{4-[3-(6-methoxypyridin-3-yl)benzoyl]piperazin-l-yl}th
ieno[2,3-d]pyrim idin-2-
yl)oxy]propane-1,2-diol;
3'-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-
yl)piperazin-1-
yl]carbonyl}-1,1'-biphenyl-3-carbonitrile;
4-[4-(1,1'-biphenyl-4-yicarbonyl)piperazin-1-yl]-6-ethyl-2-(2-morpholin-4-
ylethoxy)thieno[2,3-
d]pyrimidine;
(2R)-3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-yl}oxy)propane-
1,2-diol;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(2-piperazin-1-
ylethoxy)thieno[2,3-
d]pyrimidine;
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(2S)-4-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrim idin-2-
yI}oxy)butane-1,2-diol;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(morpholin-2-
ylmethoxy)thieno[2,3-
d]pyrimidine;
5 4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(3-morpholin-4-
ylpropoxy)thieno[2,3-
d]pyrimidine;
2-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrim
idin-2-
yl}oxy)ethanamine; -
(2R)-3-[(6-ethyl-4-{4-[(2-phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-
d]pyrimidin-2-
10 yl)oxy]propane-1,2-diol;
(2R)-3-({6-ethyl-4-[4-(phenylacetyl)piperazin-1 -yl]th ieno[2,3-d]pyrim idin-2-
yl}oxy)propane-1,2-
diol;
3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrim
idin-2-yl}oxy)propan-
1-ol; and
15 (2R)-3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-
phenylthieno[2,3-d]pyrimidin-2-
yl}oxy)propane-1,2-diol.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-[(3-methyloxetan-3-
yl)methoxy]thieno[2,3-d]pyrimidine;
20 4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(tetrahydrofuran-
3-yloxy)thieno[2,3-
d]pyrimidine; 4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-[(2R)-
oxiran-2-ylmethoxy]thieno[2,3-
d]pyrimidine;
(2R)-3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-methylthieno[2,3-
d]pyrim idin-2-
25 yI}oxy)propane-1,2-diol;
(2R)-4-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-l-yl]-6-ethylthieno[2,3-
d]pyrim idin-2-
yl}oxy)butane-1,2-diol; (2R)-3-[(4-{4-[(3',4'-difluoro-1,1'-biphenyl-4-
yl)carbonyl]piperazin-1-yl}-6-ethylthieno[2,3-
d]pyrim idin-2-yl)oxy]propane-1,2=diol;
30 (2R)-3-[(6-ethyl-4-{4-[4-(6-methoxypyridin-3-yl)benzoyl]piperazin-1-
yl}thieno[2,3-d]pyrimidin-2-
yl)oxy]propane-1,2-diol;
(2R)-3-{[6-ethyl-4-(4-{[4'-(trifluoromethyl)-1,1'-biphenyl-4-
yl]carbonyl}piperazin-1-yl)thieno[2,3-
d]pyrim idin-2-yl]oxy}propane-1,2-diol;
(2R)-3-({6-ethyl-4-[4-(4-pyridin-3-ylbenzoyl)piperazin-1 -yl]thieno[2,3-
d]pyrimidin-2-
35 yl}oxy)propane-1,2-diol;
2-[({4-[4-(1,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yi]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy)methyl]propane-1,3-diol;
(2R)-3-({6-ethyl-4-[4-(phenoxyacetyl)piperazin-1 -yl]thieno[2,3-d]pyrimidin-2-
yl}oxy)propane-1,2-
diol;
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(2R)-3-({6-ethyl-4-[4-(3-phenoxypropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-yl}oxy)propane-
1,2-diol;
- 4-({4=[4-(1,1'=biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrim idin-2-yl}oxy)-2-
methylbutan-2-ol;
(2R)-3-({6-ethyl-4-[4-(4-pyrimidin-5-ylbenzoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol;
(2R)-3-[(4-{4-[(3',5'-difluoro-1,1'-biphenyl-4-yl)carbonyl]piperazin-1-yl}-6-
ethylthieno[2,3-
d]pyrim idin-2-yl)oxy]propane-1,2-diol;
(2R)-3-[(4-{4-[(3,4-difluorophenyl)acetyl]piperazin-1-yl}-6-ethylthieno[2,3-
d]pyrimidin-2-
yl)oxy]propane-1,2-diol;
(2S)-5-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-l-yl]-6-ethylth ieno[2,3-
d]pyrim idin-2-
yI}oxy)pentane-1,2-diol;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yi]-2-{[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-propylthieno[2,3-d]pyrimidine;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-isopropylthieno[2,3-d]pyrimidine; and
(2R)-3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-propylthieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
(2R)-3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-
isopropylthieno[2,3-d]pyrimidin-2-
yI}oxy)propane-1,2-diol;
N-1,1'-biphenyl-4-y1-4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-
d]pyrim idin-4-
yl)piperazine-l-carboxamide;
N-(3-(4-(2-((R)-2,3-dihydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-
yl)piperazin-l-yl)-3-
oxopropyl)-N-phenylbenzamide;
N-(3-(4-(2-(((S)-2,2-d im ethyl- 1,3-d ioxolan-4-yl)m ethoxy)-6-ethylth
ieno[2,3-d]pyrim idin-4-
yl)piperazin-1-yl)-3-oxopropyl)-N-phenyl benzam ide;
(3-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-
yl)piperazin-1-
yI]carbonyl}phenyl)(phenyl)methanone;
(3-{[4-(2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethylthieno[2,3-
d]pyrim idin-4-
yl)piperazin-1 -yl]carbonyl}phenyl)(phenyl)methanone;
2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(thien-2-
ylacetyl)piperazin-1-
yl]thieno[2,3-d]pyrim idine;
(2R)-3-({6-ethyl-4-[4-(thien-2-ylacetyl)piperazin-1-yl]thieno[2,3-d]pyrim idin-
2-yl}oxy)propane-1,2-
diol;
2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3-
phenoxybenzoyl)piperazin-1 -
yl]thieno[2,3-d]pyrimidine;
2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-4-[4-(3,3-
diphenylpropanoyl)piperazin-1-yl]-6-
ethylthieno[2,3-d]pyrim idine;
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2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(1-
phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidine;
3-{[4-(2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethylthieno[2,3-
d]pyrim idin-4-
yl)piperazin-1-yI]carbonyl}-9H-fluoren-9-one;
2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(2-
naphthyloxy)acetyl]piperazin-1-
yI}thieno[2,3-d]pyrim idine;
2-{[(4S)-2,2-d imethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(4'-ethyl-1,1'-
biphenyl-4-
yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrim idine;
(2R)-3-({4-[(3R)-4-(1,1'-biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-6-
ethylthieno[2,3-
d]pyrimidin-2-yl}oxy)propane-1,2-diol;
(2R)-3-({4-[(3S)-4-(1,1'-biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-6-
ethylthieno[2,3-
d]pyrimidin-2-yl}oxy)propane-1,2-diol;
(2R)-3-({4-[(2R)-4-(1,1'-biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-6-
ethylthieno[2,3-
d] pyrim id i n-2-yl}oxy) p ropan e-1,2-d iol;
(2R)-3-({4-[(2S)-4-(1,1'-biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-6-
ethylthieno[2,3-
d]pyrimidin-2-yl}oxy)propane-1,2-diol;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-phenylthieno[2,3-d]pyrim idine;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]m ethoxy}-
6-methylthieno[2,3-d]pyrimidine; and
4-(2-{[(2R)-2,3-d i hydroxypropyl]oxy}-6-ethylth ieno[2,3-d]pyrim idin-4-yl)-N-
(3-
methoxybenzyl)piperazine-l-carboxamide.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
piperazine, 1-[2-(3-amino-2-hydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-
yl]-4-([1,1'-
biphenyl]-4-ylcarbonyl)-;
piperazine, 1-[2-(3-amino-2-hydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-
yl]-4-([1,1'-
biphenyl]-3-ylcarbonyl)-;
piperazine, 1-[2-(3-amino-2-hydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-
yl]-4-(phenylacetyl)-;
acetic acid, [[4-[4-([1,1'-biphenyl]-3-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-2-
yl]oxy]-;
acetic acid, [[6-ethyl-4-[4-(phenylacetyl)-1-piperazinyl]thieno[2,3-
d]pyrimidin-2-yl]oxy]-;
acetam ide, 2-[[4-[4-([1,1'-biphenyl]-3-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrim idin-2-
yl]oxy]-;
acetamide, 2-[[6-ethyl-4-[4-(phenylacetyl)-1-piperazinyl]thieno[2,3-
d]pyrimidin-2-yl]oxy]-;
acetamide, 2-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
methylthieno[2,3-d]pyrimidin-2-
yl]oxy]-;
acetic acid, [[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
methylthieno[2,3-d]pyrimidin-2-
yl]oxy]-;
acetamide, 2-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-2-
yl]oxy]-N-methyl-;
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acetamide, 2-[[4-[4-([1,1'-biphenyl]-3-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-2-
yl]oxy]-N-methyl-;
acetam ide, 2-[[6-ethyl-4-[4-(phenylacetyl)-1-piperazinyl]thieno[2,3-d]pyrim
idin-2-yl]oxy]-N-methyl-
propanoic acid, 3-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-
2-yl]oxy]-;
propanamide, 3-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-2-
yl]oxy]-;
propanamide, 3-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-2-
yl]oxy]-N-methyl-;
propanamide, 3-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-2-
yl]oxy]-N, N-dim ethyl-;
piperazine, 1-[2-(3-aminopropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-yl]-4-([1,1'-
biphenyl]-4-
ylcarbonyl)-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[3-(methylam
ino)propoxy]thieno[2,3-
d]pyrimidin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[2-
(methylamino)ethoxy]thieno[2,3-
d]pyrimidin-4-yI]-; and
piperazine, 1-([1,1'-biphenyl]-3-ylcarbonyl)-4-[6-ethyl-2-[2-hydroxy-l-
(hydroxymethyl)ethoxy]thieno[2,3-d]pyrimidin-4-yl]-.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
piperazine, 1-[6-ethyl-2-[2-hydroxy-l-(hydroxymethyl)ethoxy]thieno[2,3-
d]pyrimidin-4-yl]-4-
(phenylacetyl)-;
propanoic acid, 2-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrim idin-
2-yl]oxy]-2-methyl-;
propanoic acid, 2-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-
2-yI] oxy]-3-h yd roxy-;
propanamide, 2-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-2-
yl]oxy]-2-methyl-;
propanamide, 2-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrimidin-2-
yl]oxy]-3-hydroxy-N-m ethyl-;
propanamide, 2-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-d]pyrim idin-2-
yl]oxy]-3-hydroxy-; cyclopropanecarboxylic acid, 1-[[4-[4-([1,1'-biphenyl]-4-
ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-d]pyrim idin-2-yl]oxy]-;
cyclopropanecarboxam ide, 1-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-
d]pyrim idin-2-yl]oxy]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[(tetrahydro-4-
hydroxy-3-
furanyl)oxy]thieno[2,3-d]pyrim idin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[2-[[(1 R,2R,3R)-2,3-
dihydroxycyclopentyl]oxy]-6-
ethylthieno[2,3-d]pyrimidin-4-yl]-;
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piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[2-[(2,3-
dihydroxycyclopentyl)oxy]-6-ethylthieno[2,3-
d]pyrimidin-4-yi]-;
piperazine, 1=([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[[(1 R,2R,3R,4S)-
2,3,4-
trihydroxycyclopentyl]oxy]thieno[2,3-d]pyrim idin-4-yl]-;
1-piperazinecarboxaldehyde, 4-[6-ethyl-2-[(2,3,4-
trihydroxycyclopentyl)oxy]thieno[2,3-
d]pyrimidin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[2-[[(1 R,2R,3S,4S)-2,3-
dihydroxy-4-(2-
hydroxyethoxy)cyclopentyl]oxy]-6-ethylth ieno[2,3-d]pyrim idin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[2-[[2,3-dihydroxy-4-(2-
hydroxyethoxy)cyclopentyl]oxy]-6-ethylthieno[2,3-d]pyrimidin-4-yl]-;
cyclopentanecarboxamide, 4-
[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-ethylthieno[2,3-
d]pyrimidin-2-yl]oxy]-2,3- -
dihydroxy-, (1S,2R,3R,4R)-; cyclopentanecarboxamide, 4-[[4-[4-([1,1'-biphenyl]-
4-ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2-yi]oxy]-2,3-dihydroxy-;
piperazine, 1-([1,1'-biphenyl]-
4-ylcarbonyl)-4-[6-ethyl-2-[2-(2-hydroxyethoxy)ethoxy]thieno[2,3-d]pyrimidin-4-
yl]-; acetic acid, [2-
[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-ethylthieno[2,3-
d]pyrimidin-2-yl]oxy]ethoxy]-;
and acetam ide, 2-[2-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-
ethylthieno[2,3-
d]pyrim idin-2-yl]oxy]ethoxy]-.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[(5-oxo-3-
pyrrolidinyl)oxy]thieno[2,3-
d]pyrimidin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-(3-
pyrrolidinyloxy)thieno[2,3-d]pyrimidin-
4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[(2-oxo-3-
pyrrolidinyl)oxy]thieno[2,3-
d]pyrimidin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-(4-
piperidinyloxy)thieno[2,3-d]pyrimidin-4-
yq-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[(tetrahydro-2H-
pyran-4-yl)oxy]thieno[2,3-
d]pyrimidin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[[(2S,3R)-2,3,4-
trihydroxybutyl]oxy]thieno[2,3-d]pyrimidin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[[(2S,3S)-2,3,4-
trihydroxybutyl]oxy]thieno[2,3-d]pyrim idin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[[(2R,3R)-2,3,4-
trihyd roxybutyl]oxy]th ieno[2,3-d]pyrim idin-4-yl]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[[(2R,3S)-2,3,4-
trihydroxybutyl]oxy]thieno[2,3-d]pyrim idin-4-yi]-;
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-(3-
oxobutoxy)thieno[2,3-d]pyrimidin-4-yl]-;
and
piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-(2-
oxopropoxy)thieno[2,3-d]pyrimidin-4-
.
-40 yl]-.
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-Inanotherembodiment of the-compound-of Formuia-(II) is selected -from the
group consisting of:
(2S)-3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol;-
(2S)-3-({6-(1,1-difluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]th ieno[2,3-d]pyrim idin-2-
5 yl}oxy)propane-1,2-diol;
(2R)-3-({6-(1,1-difluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
yi}oxy)propane-1,2-diol;
2-({6-(1,1-difluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
yl}oxy)ethylam ine;
10 (2S)-3-({6-(2,2,2-trifluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-
1-yl]thieno[2,3-d]pyrimidin-
2-yl}oxy)propane-1,2-diol;
(2R)-3-({6-(2,2,2-trifluoroethyi)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yI]thieno[2,3-d]pyrim idin-
2-yl}oxy)propane-1,2-diol;
(2S)-3-({6- (trifluoromethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
15 yl}oxy)propane-1,2-diol;
(2R)-3-({6-(trifluoromethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-2-
yl}oxy)propane-1,2-diol;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-yl}oxy)propan-1-
ol;
20 2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)ethanol;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-l-yl]thieno[2,3-d]pyrim
idin-2-
yl}oxy)ethylamine;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)propane-
1,3-diol;
25 ({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)acetic acid;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-l-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)acetam ide;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yi}oxy)-N-
methylacetamide;
N-(tert-butyl)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-2-
30 yl}oxy)acetamide;
1-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)acetone;
4-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)butan-2-
one;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)propanoic
35 acid; and
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-
yl}oxy)propanamide.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
6-ethyl-2-(1 H-tetrazol-5-ylmethoxy)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-
1-yl]thieno[2,3-
40 d]pyrimidine;
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(4R)-4-[({6-ethyl-4-[4-(3;3,3=trifluoropropanoyl)piperazin-l=yl]th
ieno[2,3=d]pyrim idin-2-
yi}oxy)methyl]isoxazolidin-3-one;
(4S)-4-[({6-etliyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]th ieno[2,3-
d]pyrirri idin-2-
yi}oxy)methyl]isoxazolidin-3-one;
(3S)-3-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-
yI}oxy)methyl]dihydrofuran-2(3H)-one;
(3R)-3-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]thieno[2,3-
d]pyrim idin-2-
yl}oxy)methyl]dihydrofuran-2(3H)-one;
(4R)-4-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]thieno[2,3-
d]pyrimidin-2-
yl}oxy)isoxazolidin-3-one;
(4S)-4-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-
yl}oxy)isoxazolidin-3-one;
4-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-
yi}oxy)methyl]isoxazol-3(2H)-one;
(2S)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)-3-
hydroxypropanoic acid; -
(2R)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)-3-
hydroxypropanoic acid;
(2S)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)-3-
hydroxypropanamide;
(2R)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)-3-
hydroxypropanamide;
(2S)-3-am ino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin=2=
yl}oxy)propanamide;
(2R)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-2-
yl}oxy)propanamide;
(2S)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
yl}oxy)propanoic acid;
(2R)-3-am ino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
yl}oxy)propanoic acid;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-
yl}oxy)ethanesulfonamide; and
6-ethyl-2-[2-(methylsulfonyl)ethoxy]-4-[4-(3,3,3-trifluoropropanoyl)piperazin-
1-yl]thieno[2,3-
d]pyrimidine.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
(2S)-3-({6-(1,1-difluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-2-
yl}oxy)propane-1,2-diol;
(2R)-3-({6-(1,1-difluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-2-
yl}oxy)propane-1,2-diol;
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2-({6-(1,1-difluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
yl}oxy)ethylamine;
(2S)-3-({6-(2,2,2-trifluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-
2-yl}oxy)propane-1,2-diol;
(2R)-3-({6-(2,2,2-trifluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-
2-yl}oxy)propane-1,2-diol;
(2S)-3-({6-(trifluoromethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
yl}oxy)propane-1,2-diol;
(2R)-3-({6-(trifluoromethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-2-
yl}oxy)propane-1,2-diol;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-yl}oxy)propan-l-
ol;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-yl}oxy)ethanol;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-
yl}oxy)ethylamine; .
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-yl}oxy)propane-
1,3-diol;
({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]thieno[2,3-d]pyrim
idin-2-yl}oxy)acetic acid;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)acetam ide;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)-N-
methylacetamide;
N-(tert-butyl)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
yl}oxy)acetam ide;
1-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)acetone;
4-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yI]thieno[2,3-
d]pyrimidin-2-yl}oxy)butan-2-
one;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-yl}oxy)propanoic
acid;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-
yl}oxy)propanamide; and
6-ethyl-2-(1 H-tetrazol-5-ylmethoxy)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-
1-yl]thieno[2,3-
d]pyrimidine.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
(4R)-4-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrim idin-2-
yl}oxy)methyl]isoxazolidin-3-one;
(4S)-4-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrim idin-2-
yl}oxy)methyl]isoxazolidin-3-one;
(3S)-3-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazi n-1-yl]th ieno[2,3-
d]pyrim idin-2-
yl}oxy)methyl]dihydrofuran-2(3H)-one;
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-(3R)=3=[({6-ethyl-4=[4-
(3;3,3=trifluoropropanoyl)piperazin=l=yI]thieno[2,3=d]pyrimidin-2-
yI}oxy)methyl]dihydrofuran-2(3H)-one;
(4R)-4-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrim idin-2-
yi}oxy)isoxazolidin-3-one;
(4S)-4-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrim idin-2-
yl}oxy)isoxazolidin-3-one;
4-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-
yl}oxy)methyl]isoxazol-3(2H)-one;
(2S)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrim idin-2-yl}oxy)-3-
hydroxypropanoic acid;
(2R)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrim idin-2-yl}oxy)-3-
hydroxypropanoic acid;
(2S)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)-3-
hydroxypropanamide;
(2R)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]thieno[2,3-
d]pyrimidin-2-yl}oxy)-3-
hydroxypropanamide;
(2S)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-2-
yl}oxy)propanamide;
(2R)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yi]thieno[2,3-d]pyrimidin-2-
yI}oxy)propanamide;
(2S)-3-am ino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
yI}oxy)propanoic acid;
(2R)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrimidin-2-
yl}oxy)propanoic acid;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-
yl}oxy)ethanesulfonamide; and
6-ethyl-2-[2-(methylsulfonyl)ethoxy]-4-[4-(3,3,3-trifluoropropanoyl)piperazin-
1-yl]thieno[2,3-
d]pyrimidine.
In another embodiment of the compound of Formula (II) is selected from the
group consisting of:
2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3,3,3-
trifluoropropanoyl)piperazin-
1-yl]thieno[2,3-d]pyrimidine and
(2R)-3-({6-Ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol. -
C. Isomers
When an asymmetric center is present in a compound of Formulae (I) through
(III) the compound
may exist in the form of optical isomers (enantiomers). In one embodiment, the
present invention
comprises enantiomers and mixtures, including racemic mixtures of the
compounds of Formulae
(I) through (III). In another embodiment, for compounds of Formulae (I)
through (III) that contain
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more than one asymmetric center, the present invention comprises-
diastereomeric forms
(individual diastereomers and mixtures thereof) of compounds. When a compound
of Formulae
(I) through (III) contains an alkenyl group or moiety, geometric isomers may
arise.
D. Tautomeric Forms
The present invention comprises the tautomeric forms of compounds of Formulae
(I) through (I11).
Where structural isomers are interconvertible via a low energy barrier,
tautomeric isomerism
('tautomerism') can occur. This can take the form of proton tautomerism in
compounds of formula
I containing, for example, an imino, keto, or oxime group, or so-called
valence tautomerism in
compounds which contain an aromatic moiety. It follows that a single compound
may exhibit
more than one type of isomerism. The various ratios of the tautomers in solid
and liquid form is
dependent on the various substituents on the molecule as well as the
particular crystallization
technique used to isolate a compound.
E. Salts
The compounds of this invention may be used in the form of salts derived from
inorganic or
organic acids. Depending on the particular compound, a salt of the compound
may be
advantageous due to one or more of the salt's physical properties, such as
enhanced
pharmaceutical stability in differing temperatures and humidities, or a
desirable solubility in water
or oil. In some instances, a salt of a compound also may be used as an aid in
the isolation,
purification, and/or resolution-of the compound.
Where a salt is intended to be administered to a patient (as opposed to, for
example, being used
in an in vitro context), the salt preferably is pharmaceutically acceptable.
The term
"pharmaceutically acceptable salt" refers to a salt prepared by combining a
compound of
Formulae (I) -(III) with an acid whose anion, or a base whose cation, is
generally considered
suitable for human consumption. Pharmaceutically acceptable salts are
particularly useful as
products of the methods of the present invention because of their greater
aqueous solubility
relative to the parent compound. For use in medicine, the salts of the
compounds of this
invention are non-toxic "pharmaceutically acceptable salts." Salts encompassed
within the term
"pharmaceutically acceptable salts" refer to non-toxic salts of the compounds
of this invention
which are generally prepared by reacting the free base with a suitable organic
or inorganic acid.
Suitable pharmaceutically acceptable acid addition salts of the compounds of
the present
invention when possible include those derived from inorganic acids, such as
hydrochloric,
hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric,
nitric, carbonic,
sulfonic, and sulfuric acids, and organic acids such as acetic,
benzenesulfonic, benzoic, citric,
ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic,
maleic, malic,
methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic,
tartaric, and trifluoroacetic
acids. Suitable organic acids generally include, for example, aliphatic,
cycloaliphatic, aromatic,
araliphatic, heterocyclylic, carboxylic, and sulfonic classes of organic
acids.
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-Specific-examples of suitable organic acids-include acetate,-
trifluoroacetate,-formate, propionate,
succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid,
citrate, ascorbate,
glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate,
anthranilic acid,
mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate,
embonate
5 (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate,
pantothenate,
toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,
cyclohexylaminosulfonate, algenic acid,
(3-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate,
butyrate, camphorate,
camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate,
glycerophosphate,
heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate,
pectinate,
10 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and
undecanoate.
In another embodiment, examples of suitable addition salts formed include the
acetate,
aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate,
borate, camsyate,
citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,
glucuronate,
hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,
15 hydroiodide/iodide, isethionate, lactate, malate, maleate, nitrate,
orotate, oxalate, paimitate,
pamoate, phosphate/hydrogen phosphate/dihidrogen phosphate, saccharate,
stearate,
succinate, tartrate, tosylate and trifluoroacetate salts. In another
embodiment, representative
salts include benzenesulfonate, hydrobromide and hydrochloride.
Furthermore, where the compounds of the invention carry an acidic moiety,
suitable
20 pharmaceutically acceptable salts thereof may include alkali metal salts,
e.g., sodium or
potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts;
and salts formed
with suitable organic ligands, e.g., quaternary ammonium salts. In another
embodiment, base
salts are formed from bases which form non-toxic salts, including aluminum,
arginine,
benzathine, choline, diethylamine, diolamine, glycine, lysine, megiumine,
olamine, tromethamine
25 and zinc salts.
Organic salts may be made from secondary, tertiary or quaternary amine salts,
such as
tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine,
choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
Basic
nitrogen-containing groups may be quaternized with agents such as lower alkyl
(Cl-C6) halides
30 (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),
dialkyl sulfates (e.g.,
dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g.,
decyl, lauryl, myristyl, and
stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and
phenethyl bromides),
and others.
In one embodiment, hemisalts of acids and bases may also be formed, for
example,
35 hemisulphate and hemicalcium salts.
The compounds of the invention may exist in both unsolvated and solvated
forms. The term
'solvate' is used herein to describe a molecular complex comprising the
compound of the
invention and a stoichiometric amount of one or more pharmaceutically
acceptable solvent
molecules, for example, ethanol. The term 'hydrate' is employed when said
solvent is water.
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Included within the scope-of the-invention are complexes such as clathrates,
drug-host inclusion
complexes wherein, in contrast to the aforementioned solvates, the drug and
host are present in
stoichiometric or non-stoichiometric amounts. Also included are complexes of
the drug containing
two or more organic and/or inorganic components which may be in stoichiometric
or non-
stoichiometric amounts. The resulting complexes may be ionised, partially
ionised, or non-
ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288,
by Haleblian
(August 1975).
F. Prodrugs
Also within the scope of the present invention are so-called "prodrugs" of the
compounds of
Formulae (I) through (III).= Thus, certain derivatives of compounds of any of
Formulae (I) through
(III) which may have little or no pharmacological activity themselves can,
when administered into
or onto the body, be converted into compounds of any of Formulae (I) through
(III) having the
desired activity, for example, by hydrolytic cleavage. Such derivatives are
referred to as
"prodrugs." Further information on the use of prodrugs may be found in "Pro-
drugs as Novel
Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and
"Bioreversible
Carriers in Drug Design," Pergamon Press, 1987 (ed. E B Roche, American
Pharmaceutical
Association). Prodrugs in accordance with the invention can, for example; be
produced by
replacing appropriate functionalities present in the compounds of any of
Formulae (I) through (III)
with certain moieties known to those skilled in the art as "pro-moieties'.' as
described, for
example, in "Design of Prodrugs" by H Bundgaard (Elseview, 1985).
G. Methods of Treatment
The present invention further comprises methods for treating a condition in a
subject having or
susceptible to having such a condition, by administering to the subject a
therapeutically-effective
amount of one or more compounds of Formulae (I) through (III) as described
above. In one
embodiment, the treatment is preventative treatment. In another embodiment,
the treatment is
palliative treatment. In another embodiment, the treatment is restorative
treatment.
1. Conditions
The conditions that can be treated in accordance with the present invention
include platelet
aggregation mediated conditions such as atherosclerotic cardiovascular
conditions,
cerebrovascular conditions and peripheral arterial conditions, particularly
those related to
thrombosis. In another embodiment, platelet aggregation mediation conditions
may be treated.
In one embodiment, the compounds of the invention can be used to treat acute
coronary
syndrome. Acute coronary syndrome includes, but is not limited to, angina
(such as unstable
angina) and myocardial infarction (such as non-ST-segment elevation myocardial
infarction, non-
Q-wave myocardial infarction and Q-wave myocardial infarction).
In another embodiment, the compounds of the invention can be used to treat
stroke (such as
thrombotic stroke, ischemic stroke, embolic stroke and transient ischemic
attack).
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-In another- embodiment,-the-compounds of the invention-carrbe used to treat a
subject who has
suffered from at least one event selected from the group consisting of
myocardial infarction and
stroke.
In another embodiment, the compounds of the present invention can be used to
treat thrombotic
and restenotic complications or treat reocclusion following invasive
procedures including, but not
limited to, angioplasty, percutaneous coronary intervention, carotid
endarterectomy, coronary
arterial bypass graft ("CABG") surgery, vascular graft surgery, stent
placements, lower limb
arterial graft, prosthetic heart valve placement, hemodialysis and insertion
of endovascular
devices and prostheses.
In another embodiment, the compounds of the present invention. can be used to
treat
hypertension.
In another embodiment, the compounds of the present invention can be used to
treat
angiogenesis.
2. Administration and Dosing
Typically, a compound described in this specification is administered in an
amount effective to
inhibit ADP mediated platelet aggregation. The compounds of the present
invention are
administered by any suitable route in the form of a pharmaceutical composition
adapted to such
a route, and in a dose effective for the treatment intended. Therapeutically
effective doses -of the
compounds required to prevent or arrest the progress of or to treat the
medical condition are
readily ascertained by one of ordinary skill in the art using preclinical and
clinical approaches
familiar to the medicinal arts.
The compounds of the invention may be administered orally. Oral administration
may involve
swallowing, so that the compound enters the gastrointestinal tract, or buccal
or sublingual
administration may be employed by which the compound enters the blood stream
directly from
the mouth.
In another embodiment, the compounds of the invention may also be administered
directly into
the blood stream, into muscle, or into an internal organ. Suitable means for
parenteral
administration include intravenous, intraarterial, intraperitoneal,
intrathecal, intraventricular,
intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
Suitable devices for
parenteral administration include needle (including microneedle) injectors,
needle-free injectors
and infusion techniques.
In another embodiment, the compounds of the invention may also be administered
topically to
the skin or mucosa, that is, dermally or transdermally. In another embodiment,
the compounds of
the invention can also be administered intranasally or by inhalation. In
another embodiment, the
compounds of the invention may be administered rectally or vaginally. In
another embodiment,
the compounds of the invention may also be administered directly to the eye or
ear.
The dosage regimen for the compounds and/or compositions containing the
compounds is based
on a variety of factors, including the type, age, weight, sex and medical
condition of the patient;
the severity of the condition; the route of administration; and the activity
of the particular
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compound employed.- Thus the-dosage regimen-;may vary widely. Dosage levels-of
the order
from about 0.01 mg to about 100 mg per kilogram of body weight per day are
useful in the
treatment of the above-indicated conditions. In one embodiment, the total
daily dose of a
compound of Formulae (I) through (III) (administered in single or divided
doses) is typically from
about 0.01 to about 100 mg/kg. In another embodiment, total daily dose of the
compound of
Formulae (I) through (III) is from about 0.1 to about 50 mg/kg, and in another
embodiment, from
about 0.5 to about 30 mg/kg (i.e., mg compound of Formulae (I) through (III)
per kg body weight).
In one embodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment,
dosing is from
0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain such amounts or
submultiples
thereof to make up the daily dose. In many instances, the administration of
the compound will be
repeated a plurality of times in a day (typically no greater than 4 times).
Multiple doses per day
typically may be used to increase the total daily dose, if desired.
For oral administration, the compositions may be provided in the form of
tablets containing 0.01,
0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150,
175, 200, 250 and 500
milligrams of the active ingredient for the symptomatic adjustment of the
dosage to the patient to
be treated. A medicament typically contains from about 0.01 mg to about 500 mg
of the active
ingredient, or in another embodiment, from about 1 mg to about 100 mg of
active ingredient. =
Intravenously, doses may range from about 0.1 to about 10 mg/kg/minute during
a constant- rate
infusion.
Suitable subjects to be treated according to the present invention include
mammalian subjects.
Mammals according to the present invention include, but are not limited to,
canine, feline, bovine,
caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like,
and encompass
mammals in utero. In one embodiment, humans are suitable subjects. Human
subjects may be
- of either gender and at any stage of development.
H. Use in the Preaaration of a Medicament
In one embodiment, the present invention comprises methods for the preparation
of a
pharmaceutical composition. (or "medicament) comprising the compounds of
Formulae (I)
through (III) in combination with one or more pharmaceutically-acceptable
carriers and/or other
active ingredients for use in treating a platelet aggregation mediated
condition.
In another embodiment, the invention comprises the use of one or more
compounds of Formulae
(I) through (III) in the preparation of a medicament for the treatment of
acute coronary syndrome.
In another embodiment, the invention comprises the use of one or more
compounds of Formulae
(I) through (III) in the preparation of a medicament for the reduction of
atherosclerotic events.
In another embodiment, the invention comprises the use of one or more
compounds of Formulae
(I) through (III) in the preparation of a medicament for the treatment of
thrombosis.
In another embodiment, the invention comprises the use of one or more
compounds of Formulae
(I) through (III) in the preparation of a medicament to be co-administered
before, during or after
revascularization procedures, including, but not limited to, lower limb
arterial graft, carotid
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64
-~ endarterectomy; coronary arterybypass-surgery,-atrial fibrillation,
prosthetic heart valve
placement, hemodialysis and placement of mechanical devices.
1. Pharmaceutical Compositions
For the treatment of the conditions referred to above, the compounds of
Formulae (I) through (III)
can be administered as compound perse. Alternatively, pharmaceutically
acceptable salts are
suitable for medical applications because of their greater aqueous solubility
relative to the parent
compound.
In another embodiment, the present invention comprises pharmaceutical
compositions. Such
pharmaceutical compositions comprise compounds of Formulae (I) through (III)
presented with a
pharmaceutically-acceptable carrier. The carrier can be a solid, a liquid, or
both, and may be
formulated with the compound as a unit-dose composition, for example, a
tablet, which can
contain from 0.05% to 95% by weight of the active compounds. Compounds of
Formulae (I)
through (III) may be coupled with suitable polymers as targetable drug
carriers. Other
pharmacologically active substances can also be present.
The active compounds of the present invention may be administered by any
suitable route,
preferably in the form of a pharmaceutical composition adapted to such a
route, and in a dose
effective for the treatment intended. The active compounds and compositions,
for example, may
be administered orally, rectally, parenterally, or topically.
Oral administration of a solid dose form.may be, for example, presented in
discrete units, such as
hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a
predetermined
amount of at least one compound of the present invention. In another
embodiment, the oral
administration may be in a powder or granule form. In another embodiment, the
oral dose form
is sub-lingual, such as, for example, a lozenge. In such solid dosage forms,
the compounds of
Formulae (I) through (III) are ordinarily combined with one or more adjuvants.
Such capsules or
tablets may contain a controlled-release formulation. In the case of capsules,
tablets, and pills,
the dosage forms also may comprise buffering agentsor may be prepared with
enteric coatings.
In another embodiment, oral administration may be in a liquid dose form.
Liquid dosage forms
for oral administration include, for example, pharmaceutically acceptable
emulsions, solutions,
suspensions, syrups, and elixirs containing inert diluents commonly used in
the art (e.g., water).
Such compositions also may comprise adjuvants, such as wetting, emulsifying,
suspending,
flavoring (e.g., sweetening), and/or perfuming agents.
In another embodiment, the present invention comprises a parenteral dose form.
"Parenteral
administration" includes, for example, subcutaneous injections, intravenous
injections,
intraperitoneally, intramuscular injections, intrasternal injections, and
infusion. Injectable
preparations (e.g., sterile injectable aqueous or oleaginous suspensions) may
be formulated
according to the known art using suitable dispersing, wetting agents, and/or
suspending agents.
In another embodiment, the present invention comprises a topical dose form.
"Topical
administration" includes, for example, transdermal administration, such as via
transdermal
patches or iontophoresis devices, intraocular administration, or intranasal or
inhalation
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-administration.-Compositions-for topical-administration also include; for
example, topical gels,
sprays, ointments, and creams. A topical formulation may include a compound
which enhances
absorption or penetration of the active ingredient through the skin or other
affected areas. When
the compounds of this invention are administered by a transdermal device,
administration will be
5 accomplished using a patch either of the reservoir and porous membrane type
or of a solid
matrix variety. Typical formulations for this purpose include gels, hydrogels,
lotions, solutions,
creams, ointments, dusting powders, dressings, foams, films, skin patches,
wafers, implants,
sponges, fibres, bandages and microemulsions. Liposomes may also be used.
Typical carriers
include alcohol, water, mineral oil, liquid petrolatum, white petrolatum,
glycerin, polyethylene
10 glycol and propylene glycol. Penetration enhancers may be incorporated -
see, for example, J
Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
Formulations suitable for topical administration to the eye include, for
example, eye drops
wherein the compound of this invention is dissolved or suspended in suitable
carrier. A typical
formulation suitable for ocular or aural administration may be in the form of
drops of a micronised
15 suspension or solution in isotonic, pH-adjusted, sterile saline. Other
formulations suitable for
ocular and aural administration include ointments, biodegradable (e.g.
absorbable gel sponges,
collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and
particulate or
vesicular systems, such as niosomes or liposomes. A polymer such as crossed-
linked polyacrylic
acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,
20 hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose,
or a
heteropolysaccharide polymer, for example, gelan gum, may be incorporated
together with a
preservative, such as benzalkonium chloride. Such formulations may also be
delivered by
iontophoresis.
For intranasal administration or administration by inhalation, the active
compounds of the
25 invention are conveniently delivered in the form of a solution or
suspension from a pump spray
container that is squeezed or pumped by the patient or as an aerosol spray
presentation from a
pressurized container or a nebulizer, with the use of a suitable propellant.
Formulations suitable
for intranasal administration are typically administered in the form of a dry
powder (either alone,
as a mixture, for example, in a dry blend with lactose, or as a mixed
component particle, for
30 example, mixed with phospholipids, such as phosphatidylcholine) from a dry
powder inhaler or as
an aerosol spray from a pressurised container, pump, spray, atomiser
(preferably an atomiser
using electrohydrodynamics to produce a fine mist), or nebuliser, with or
without the use of a
suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-
heptafluoropropane. For
intranasal use, the powder may comprise a bioadhesive agent, for example,
chitosan or
35 cyclodextrin.
In another embodiment, the present invention comprises a rectal dose form.
Such rectal dose
form may be in the form of, for example, a suppository. Cocoa butter is a
traditional suppository
base, but various alternatives may be used as appropriate.
Other carrier materials and modes of administration known in the
pharmaceutical art may also be
40 used. Pharmaceutical compositions of the invention may be prepared by any
of the well-known
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66
techniques of pharmacy, such as effective formulation and administration
procedures. The
above considerations in regard to effective formulations and administration
procedures are well
known in the art and are described in standard textbooks. Formulation of drugs
is discussed in,
for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack
Publishing Co.,
Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage
Forms, Marcel
Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of
Pharmaceutical Excipients
(3rd Ed.), American Pharmaceutical Association, Washington, 1999.
J. Co-administration
The compounds of the present invention can be used, alone or in combination
with other
therapeutic agents, in the treatment of various conditions or disease states.
The compound(s) of
the present invention and other therapeutic agent(s) may be may be
administered simultaneously
(either in the same dosage form or in separate dosage forms) or sequentially.
The administration of two or more compounds "in combination" means that the
two compounds
are administered closely enough in time that the presence of one alters the
biological effects of'
the other. The two or more compounds may be administered simultaneously,
concurrently or
sequentially. Additionally, simultaneous administration may be carried out by
mixing the
compounds prior to administration or by administering the compounds at the
same point in time
but at different anatomic sites or using different routes of administration.
The phrases "concurrent administration," "co-administration," "simultaneous
administration," and
"administered simultaneously" mean that the compounds are administered in
combination.
In one embodiment, compounds of Formulae (I) through (III) may be co-
administered with an oral
antiplatelet agent, including, but not limited to, aspirin, dipyridamole,
cilostazol and anegrilide
hydrochloride. In still another embodiment, compounds of Formulae (I) through
(III) may be co-
administered with aspirin.
In another embodiment, compounds of Formulae (I) through (III) may be co-
administered with a
glycoprotein IIb/Illa inhibitor, including, but not limited to, abciximab,
eptifibatide and tirofiban. In
still another embodiment, compounds of Formulae (I) through (III) may be co-
administered with
eptifibatide.
In another embodiment, compounds of Formulae (I) through (III) may be co-
administered with a
heparin or heparinoid, including, but not limited to, heparin sodium,
enoxaparin sodium,
dalteparin sodium, ardeparin sodium, nadroparin calcium, reviparin sodium,
tinzaparin sodium
and fondaparinux sodium.
In another embodiment, compounds of Formulae (I) through (III) may be co-
administered with a
direct thrombin inhibitor, including, but not limited to, danaparoid, hirudin,
bivalirudin and
lepirudin.
In another embodiment, compounds of Formulae (I) through (III) may be co-
administered with an
anti-coagulant including, but not limited to, warfarin, warfarin sodium, 4-
hydroxycoumarin,
dicoumarol, phenprocoumon, anisindione, acenocoumerol and phenindione. In
still another
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67
embodiment, compounds of Formulae (I) through (III)-may be co-administered
with warfarin
sodium.
-In another embodiment, compounds of Formulae (I) through (1II) may be co-
administered with an
oral factor Xa inhibitor including, but not limited to, ximelagatran,
melagatran, dabigatran etexilate
and argatroban. In still another embodiment, compounds of Formulae (I) through
(III) may be co-
administered with ximelagatran.
In another embodiment, compounds of Formulae (I) through (III) may be co-
administered with a
fibrinolytic including, but not limited to, streptokinase, urokinase, tissue
plasminogen activator,
tenecteplase, reteplase, alteplase and aminocaproic acid.
In another embodiment, compounds of Formulae (I) through (Ili) may be co-
administered with an
investigational compound useful in treating platelet aggregation including,
but not limited to, BAY
59-7939, YM-60828, M-55532, M-55190, JTV-803 and DX-9065a.
K. Kits
The present invention further comprises kits that are suitable for use in
performing the methods
of treatment or prevention described above. In one embodiment, the kit
contains a first dosage
form comprising one or more of the compounds of the present invention and a
container for the
dosage, in quantities sufficient to carry out the methods of the present
invention.
In another embodiment, the kit of the present invention comprises one or more
compounds of
Formulae (I) through (III) and an oral antiplatelet agent, including, but not
limited to, aspirin,
dipyridamole, cilostazol and anegrilide hydrochloride. In still another
embodiment, the kit of the
present invention comprises one or more compounds of Formulae (I) through
(111) and aspirin.
In another embodiment, the kit of the present invention comprises one or more
compounds of
Formulae (I) through (III) and a glycoprotein Iib/Illa inhibitor, including,
but not limited to;
abciximab, eptifibatide and tirofiban. In still another embodiment, the kit of
the present invention
comprises one or more compounds of Formulae (I) through (III) and
eptifibatide.
In another embodiment, the kit of the present invention comprises one or more
compounds of
Formulae (I) through (III) and a heparin or heparinoid, including, but not
limited to, heparin
sodium, enoxaparin sodium, dalteparin sodium, ardeparin sodium, nadroparin
calcium, reviparin
sodium, tinzaparin sodium and fondaparinux sodium.
In another embodiment, the kit of the present invention comprises one or more
compounds of
Formulae (I) through (III) and a direct thrombin inhibitor, including, but not
limited to, danaparoid,
hirudin, bivalirudin and lepirudin.
In another embodiment, the kit of the present invention comprises one or more
compounds of
Formulae (I) through (111) and an anti-coagulant including, but not limited
to, warfarin, warfarin
sodium, 4-hydroxycoumarin, dicoumarol, phenprocoumon, anisindione,
acenocoumerol and
phenindione. In still another embodiment, the kit of the present invention
comprises one or more
compounds of Formulae (I) through (III) and warfarin sodium.
In another embodiment, the kit of the present invention comprises one or more
compounds of
Formulae (I) through (I11) and an oral factor Xa inhibitor including, but not
limited to, ximelagatran,
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68
melagatran, dabigatran etexilate and argatroban. In still another embodiment,
the kit of the
present invention comprises one or more compounds of Formulae (I) through
(III) and
ximelagatran.
In another embodiment, the kit of the present invention comprises one or more
compounds of
Formulae (I) through (III) and a fibrinolytic including, but not limited to,
streptokinase, urokinase,
tissue plasminogen activator, tenecteplase, reteplase, alteplase and
aminocaproic acid.
In another embodiment, the kit of the present invention comprises one or more
compounds of
Formulae (I) through (III) and an investigational compound useful in treating
platelet aggregation
including, but not limited to, BAY 59-7939, YM-60828, M-55532, M-55190, JTV-
803 and DX-
9065a.
L. Intermediates
In another embodiment, the invention relates to the novel intermediates useful
for preparing the
thieno[2,3-djpyrimidine compounds of Formulas (I)-(III).
M. General Synthetic Schemes
The starting materials used herein are commercially available or may prepared
by routine
methods known in the art (such as those methods disclosed in standard
reference books such as
the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-
Interscience)). The compounds of the present invention may be prepared using
the methods
illustrated in the general synthetic schemes and experimental procedures
detailed below. The
general synthetic schemes are presented for purposes of illustration and are
not intended to be
limiting.
Scheme A
0 R5 O
R5
R5 O
sulfar xOCN or NH
Rs + N-C R2 R Urea R6 HO
base R6 S NH2 acid S
H
1 2 3 4
rR4
~ N
N~A R4
~ 0~ ~
R5 N R5 CI
6
R6 N N
R6
~
S N/ CI S M 'CI
7
5
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69
-Scheme A. Thienopyrimidines may be prepared by various methods-One-method for
the
preparation of thienopyrimidine 7 is depicted in Scheme A. Commercially
available
aldehyde/ketone 1 and esters 2 are combined in the presence of sulfur to give
thiophene 3 using
the general method of Tinney et al. (J. Med. Chem. (1981) 24, 878-882).
Thiophene 3 is then
treated with potassium cyanate or urea in the presence of water and an acid
such as acetic acid
to give dione 4. Dione 4 is then treated with a chloride source such as
phosphorous oxychloride,
thionyl chloride, or phosphorous pentachloride with or without the presence of
a tertiary amine or
concentrated HCI and with or without added inert solvent such as
dimethylformamide at
temperatures ranging from 75 C to 175 C, optionally with an excess of
phosphorous
oxychloride in a sealed vessel at 130-175 C, to give dichloropyrimidine 5.
Dichloropyrimidine 5
is then treated with piperazine 6 (see Scheme B) in the presence of a base
such as trialkylamine,
pyridine, potassium carbonate, sodium carbonate, cesium carbonate, and other
bases well
known to those versed in the art and in the presence of a solvent such as THF,
acetonitrile,
dichloromethane, dialkyl ether, toluene, DMF, N-methyl pyrrolidinone and the
like at
temperatures ranging from room temperature to the reflux temperature of the
solvent to give
thienopyrimidine 7.
Scheme B
A O A 0
Protecting Protecting
//
Group -N N + R4C(O)X ~ Group N N--~(// -- HN N-~(
~~ ~-~ \Ra ~j \R
8 9 10 6
Scheme B. Scheme B depicts the preparation of intermediate 6. Protected
piperazine 8 is
commercially available or carr be prepared by (1) attaching a suitable
protecting group including,
but not limited to, Boc, Cbz, Fmoc and benzyl, to one of the nitrogen ring
atoms of the piperazine
and (2) reacting with alkylOCOCI or (alkylOCO)20). Protected piperazine 8 is
then acylated
using acyl reagent 9, where acyl reagent 9 is used in its acid form (X = OH)
in the presence of a
coupling agent. Suitable coupling agents include, but are not limited to, DCC,
EDC, DEPC,
HATU, HBTU and CDI. In an alternative preparation of intermediate 6, acyl
reagent 9 is used in
the form of an acid halide (X = Cl, Br, F) or anhydride (X = O(COR4))in the
presence of a base,
including, but not limited to, a trialkylamine, pyridine, or an alkaline earth
metal carbonate and in
the presence of inert solvents such as THF, d ich lorom ethane, acetonitrile,
toluene, dialkyl ether,
DMF, N-methylpyrrolidinone, dimethylacetamide and the like at temperatures
ranging between
ice/water temperature to the reflux temperature of the solvent, to give
bisamide 10. Bisamide 10
is converted to piperazine 6 using methods well know to those versed in the
art, many of which
are discussed by Greene and Wuts in Protective Groups in Organic Synthesis,
Third Ed., Wiley-
Interscience, pp. 502-550. When the protecting group of bisamide 10 is a
benzyl group, then
removal of the benzyl group to give intermediate 6 is accomplished using
standard methods
known in the art (e.g., those discussed by Greene and Wuts in Protective
Groups in Organic
Synthesis, Third Ed., Wiley- I nterscience, pp. 502-550).
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Scheme C
Protectin A Protecting
Grou g~, Groupl H Oy R4
p-N N I
R5 CI N A N A R cc0)x N. A
( l
Rs I N~CI Rs Rs N 9 > e N
S R
4D R
5 R6 S %~ R6 S I\ N R6 N
N CI N~CI
11 12 7
5 Scheme C. The order of addition of various functionalities to the
thienopyrimidine can be
changed to take advantage of commercially available materials or in order to
avoid reactivities at
other parts of the molecule. An alternative method for the preparation of
thienopyrmidine 7 using
an order of addition differing from that of Scheme A is shown in Scheme C.
Dichloropyrimidine 5
(Scheme A) is aminated with 8 (Scheme B) in inert solvents at temperatures
ranging from room
10 temperature to the boiling point of the solvent to give pyrimidine 11. The
amination may be done
using excess 8 or in the presence of a base, including but not limited to, a
trialkylamine, pyridine,
or an alkaline earth metal carbonate. Removal of the protecting group to give
pyrimidine-
piperazine 12 is achieved using standard deprotection method, such as those
discussed by
Greene and Wuts in Protective Groups in Organic Synthesis, Third Ed., Wiley- I
nterscience, pp.
15 502-550. Thienopyrimidine 7 is obtained upon combining acyl reagent 9 (X =
OH) with
pyrimidine-piperazine 11 using coupling reagents, many of which are well known
to those versed
in the art and include but are not limited to DCC, EDC, DEPC, HATU, HBTU and
CDI.
Alternatively, 9 is used in the form of an acid halide X = Cl, Br, F) or
anhydride (X = O(COR4)) in
the presence of a base, preferably a trialkylamine, pyridine, or an alkaline
earth metal carbonate
20 and in the presence of inert solvents including, but not limited to, THF,
dichloromethane,
acetonitrile, toluene, dialkyl ether, DMF, N-methylpyrrolidinone and the like
at temperatures
ranging between ice/water temperature to the ref lux temperature of the
solvent.
Scheme D
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71
~- R4-
0 Ra
c N 1 13 ~N/
R5 N H aR R 5 N
0 1-B(OH)2 R6 / l N base
R6 I/N
S N CI S N OR
2
az
14 Yl-B(alkoxy)2 7 14
or
aryl-B(alkenyloxy) base H-ORZ'Protected
deprotection de rotection
or 13A p
heteroaryl-B(alkenyloxy)
p R4protected or p R4 p R4
~ heteroaryl-B(OH)2 ~ ~
N, N, N
~ or ~
C~ heteroaryl-B(alkoxy)Z 5~
R5 N E R N R5 N
R6 / ~\N R6 N R6 N
S N pR2protected S N OR2protected S N OR2protected
14C 14A 14B
Scheme D. Elaboration of thienopyrimidine 7 to substituted thienopyrimidine 14
is accomplished
by treating thienopyrimidine 7 with H-OR2 (13), and where H-OR2 is
commercially available or
may be prepared by methods well-known to those versed in the art. Regaent 13
is combined
with thienopyrimidine 7 in the presence of a base and an inert solvent.
Reagent 13 may be
treated with a strong base and is then added to thienopyrimdine 7.
Alternatively,
thienopyrimidine 7 may be added to reagent 13 after the addition of strong
base. Whichever the
order of addition, in one example, reagent 13 is first treated with a strong
base to form an anion.
Suitable strong include, but are not limited to, alkali metal hydrides (such
as sodium hydride). In
one embodiment, the addition of the strong base to reagent 13, or addition of
reagent 13 to
strong base, is done at temperatures ranging from -30 C to room temperature.
In another
embodiment, the addition of the strong base to reagent 13, or addition of
reagent 13 to strong
base, is done at a temperature from 0 C to room temperature.
To reduce undesired reactions, reagent 13 can be protected first (i.e. R2 is
in a protected form)
namely reagent 13A, to give substituted thienopyrimidine 14A, wherein the
protecting group may
be removed at a later stage to give substituted thienopyrimidine 14. Reagent
13A is
commercially available or may be prepared by methods well known to those
versed in the art.
For example, when R7 is desired to be an alkyl diol, the diol of H-Y-R2 may be
protected using
methods known in the art. Methods for the synthesis and removal diol
protecting groups are
discussed by Greene and Wuts in "Protective Groups in Organic Synthesis,"
Third Ed., Wiley-
Interscience, pp. 201-245.
Alternatively, R2 in 14A may be an alkyl aldehyde or alkyl ketone in its
protected form. Many
protected aldehydes and ketones 13A are commercially available. Conventional
procedures for
the synthesis and removal of aidehyde and ketone protecting groups are known
in the art (e.g.
the procedures discussed by Greene and Wuts in "Protective Groups in Organic
Synthesis,"
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72
Third Ed., Wiley-Interscience, pp. 201-245.) After removal of the aidehyde or
ketone protecting
group to give substituted thienopyrimidine 14B, the aldehyde or ketone may be
further
manipulated. For example, treatment of an aldehyde with an oxidizing agent
such as 3-
chloroperoxbenzoic acid and the like gives substituted thienopyrimidine 14
where R2contains a
carboxylic acid. Treatment of an aldehyde or ketone with an amine in the
presence of a reducing
agent such as sodium cyanoborohydride, sodium triacetoxyborohydride,
tri(trifluoroacetoxy)borohydride, or hydrogen gas and a metal catalyst give
substituted
thienopyrimidine 14 where R2 contains an amino group.
When R4 is phenyl or heteroaryl substituted with Br, I, Cl, and 0-triflate,
then additional
manipulations of R4 may be carried out using standard methods known in the
art. For example,
aryl- or heteroaryl-boronic acids or esters, many of which are commercially
available, may be
reacted, in the presence of a metal catalyst, with substituted
thienopyrimidine 14A to give biaryl
substituted thienopyrimidine 14C. Thus, treatment with an aryl or heteroaryl
boronic acid or
heteroaryl or aryl boronic acid ester such as [(aryl or heteroaryl)-B(OH)2] or
[(aryl or heteroaryl)-
B(ORa)(ORb) (where Ra and Rb are each C1-C6 alkyl, or when taken together, Ra
and Rb are
C2-C12 alkylene)] in the presence of a metal catalyst with or without a base
in an inert solvent
yields biaryl substituted thienopyrimidine 14C. Metal catalysts in these
transformations include,
but are not limited to, salts or phosphine complexes of Cu, Pd, or Ni (for
example, Cu(OAc)2,
PdC12(PPh3)2, NiC12(PPh3)2). Bases may include, but are not limited to,
alkaline earth metal
carbonates, alkaline earth metal bicarbonates, alkaline earth metal
hydroxides, alkali metal
carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal
hydrides, alkali metal
alkoxides, alkaline earth metal hydrides, alkali metal dialkylamides, alkali
metal
bis(trialkylsilyl)amides, trialkyl amines or aromatic amines.
In one embodiment, the alkali.metal hydride is sodium hydride. In another
embodiment, the
alkali metal alkoxide is sodium methoxide. In another embodiment, the alkali
metal alkoxide is
sodium ethoxide. In another embodiment, the alkali metal dialkylamide is
lithium
diisopropylamide. In another embodiment, the alkali metal
bis(trialkylsilyl)amide is sodium
bis(trimethylsilyl)arnide. In another embodiment, the trialkyl amine is
diisopropylethylamine. In
another embodiment, the trialkylamine is triethylamine. In another embodiment,
the aromatic
amine is pyridine.
Inert solvents may include, but are not limited to, acetonitrile, dialkyl
ethers, cyclic ethers, N,N-
dialkylacetam ides (dimethylacetamide), N,N-dialkylformamides,
dialkylsulfoxides, aromatic
hydrocarbons or haloalkanes.
In one embodiment, the dialkyl ether is diethyl ether. In another embodiment,
the cyclic ether is
tetrahydrofuran. In another embodiment, the cyclic ether is 1,4-dioxane. In
another embodiment
the N,N-dialkylacetamide is dimethylacetamide. In another embodiment, the N,N-
dialkylformamide is dimethylformamide. In another embodiment, the
dialkylsulfoxide is
dimethylsulfoxide. In another embodiment, the aromatic hydrocarbon is benzene.
In another
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embodiment, the aromatic hydrocarbon is toluene. In another embodiment, the
haloalkane is
methylene chloride.
Exemplary reaction temperatures range from room temperature up to the boiling
point of the
solvent employed. Non-commercially available boronic acids or boronic acid
esters may be
obtained from the corresponding optionally substituted aryl halide as
described in Tetrahedron,
50, 979-988 (1994). Alternatively, as described in Tetrahedron, 50, 979-988
(1994), one may
convert the R4 substituent to the corresponding boronic acid or boronic acid
ester (OH)2B- or
(ORa)(ORb)B- and obtain the same products set forth above by treating with a
suitable aryl or
heteroaryl halide or triflate. The protecting group on R'2 of 14C is then
removed using conditions
discussed above to give 14.
Scheme E
Protecting Protecting
Group I Group
H Ozj_R4
CN J H-OR2 ~ rN~ RqC(O)X rN~
R5 N -t= R5 N R5 'N RS
R6 S NCI 13 R6 S I NOR2 R6 S N 9 R6 I~~ z
OR2 S N OR
11 15 16 14
H-ORz ' -~
13 Ozz~-R4
H H N=~I
R5 N H_OR2pmtected 5 CN~ R5 N
CNS N,
' R R
R6 6 N
N 13A R6 ' N S i' N ORzprotcct
S N Cl S N~OR2protectcd 14A
12 12
Scheme E. The order of addition of various functionalities of the
thienopyrimidine can be
changed in the preparation of substituted thienopyrimidine 14 in order to take
advantage of
commercially available materials or in order to avoid reactivities at other
parts of the molecule.
Another method for the preparation of substituted thienopyrimidine 14 is shown
in Scheme E,
where piperazinyl pyrimidine 11 is combined with reagent 13 where H-OW is
commercially
available or may be prepared by methods well-known to those versed in the art,
to give di-
substituted thienopyrimidine 15. Reagent 13 is first treated with a strong
base and is then added
to piperazinyl pyrimidine 11. Alternatively, piperazinyl pyrimidine 11 may be
added to reagent 13
after the addition of strong base. Whichever the order of addition, in one
embodiment, reagent
13 is first treated with a strong base to form an anion. Suitable strong bases
include an alkali
metal hydride. In another embodiment, the strong base is sodium hydride. In
one embodiment,
the additiori of the strong base to reagent 13, or addition of reagent 13 to
strong base, is done at
temperatures ranging from -30 C to room temperature. In another embodiment,
the addition of
strong base to reagent 13, or addition of reagent 13 to strong base is done at
0 C to room
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--temperature. Disubstituted thienopyrmidine 15-is then combined with a
reagent suitable for the
removal of the protecting group to give amine 16. Suitable means for removal
of the protecting
- group depends on the nature of the group: For example, in one embodiment,
the protecting
group Boc is removed by dissolving disubstituted thienopyrimidine in a
trifluoroacetic
acid/dichloromethane mixture. Annother method for removing the protecting
group Boc is the
addition of hydrogen chloride gas dissolved in an alcohol or ether such as
methanol or dioxane.
When complete, the solvents are removed under reduced pressure to give the
corresponding
amine as the corresponding salt, i.e. trifluoroacetic acid or hydrogen
chloride salt. If desired, the
amine can be purified further, for example by recrystallization or other
standard techniques
known in the art. Further, if the non-salt form is desired that also can be
obtained by means
known to those skilled in the art, such as for example, preparing the free
base amine via
treatment of the salt with mild basic conditions. Additional deprotection
conditions and
deprotection conditions for other protecting groups can be found in T.W. Green
and P.G.M. Wuts
in "Protective Groups in Organic Chemistry," John Wiley and Sons, 1999, pp.
502-550.
Thienopyrimidine 14 is obtained upon combining acyl reagent 9 (X = OH) with
amine 16 using
coupling reagents, many of which are well known to those versed in ttie art
and include but are
not limited.to DCC, EDC, DEPC, HATU, HBTU and CDI. In another embodiment, 9 is
used in
the form of an acid halide (X = Cl, Br, F) or anhydride (X = O(COR4)) in the
presence of a base,
including, but not limited to, a trialkylamine, pyridine, or an alkaline earth
metal carbonate, and in
the presence of inert solvents such as THF, dichloromethane, acetonitrile,
toluene, dialkyl ether,
DMF, N-methylpyrrolidinone and the like at temperatures ranging between
ice/water temperature
to the reflux temperature of the solvent.
Depending upon the nature of the various substituents, it may be desirable to
change the order
of addition of the substituents. For example, the protecting group of 11 may
be removed to give
12 as described in Scheme C. Pyrimidine-piperazine 12 may then be reacted with
13 in the
same manner as described for the conversion of 7 to 14 in Scheme D to give 16.
Alternatively,
pyrimidine-piperazine 12 may be reacted with a protected form of 13, namely
13A, to give 17.
Addition of R4C(O)X (9) to 17 gives 14A, which then may be further manipulated
as described for
Scheme D. Alternatively, amine 17 may be converted to 16 by methods described
for the
conversion of 14A to 14 in Scheme D.
N. Workinp Examples
The following illustrate the synthesis of various compounds of the present
invention. Additional
compounds within the scope of this invention may be prepared using the methods
illustrated in
these Examples, either alone or in combination with techniques generally known
in the art.
EXAMPLE 1
Methyl 2-am ino-5-ethylth iophene-3-carboxylate
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O--
O
\CH3
H3C
S NH2
To a mixture of sulfur (6.4 g) in DMF (25 mL) were added methyl cyanoacetate
(19.8 g) and
triethylamine (15 mL) under nitrogen. The mixture was stirred for 10 minutes
at which time
butyraldehyde (18 mL) was added drop-wise at a sufficient rate to maintain a
temperature of 50
5 C. The mixture was then stirred at room temperature for 20 hours. The
mixture was partitioned
between brine and ethyl acetate. The layers were separated and the organic
layer washed three
times with brine, dried over anhydrous magnesium sulfate and concentrated. The
residue was
chromatographed on silica gel (150 mL) using 10% ethyl acetate in hexanes to
give a yellow
solid. The solid was slurried in hexanes and collected and dried under reduced
pressure to give
10 25.74 g of the title compound. MS (ESI+) for C8H11N02S m/z 186.0598 (M+H)+.
'H NMR (300
MHz, CDCI3) 51.22 (t, 3 H), 2.6 (q, 2 H), 3.79 (s, 3 H), 5.79 (s, 2 H), 6.62
(s, 1 H).
EXAMPLE 2
6-Ethyl-4a, 7a-dihydrothieno[2,3-d] pyrimidine-2, 4-diol
OH
N
H3C S N'K OH
To a mixture of the carboxylate of Example 1 (25.2 g) in glacial acetic acid
(450 mL) and water
(45 mL) was added drop-wise a solution of potassium cyanate (30.9 g) in water
(150 mL). The
mixture exothermed to 33 C and some gas was evolved. A white precipitate
formed during
addition. The mixture was stirred at room temperature for 20 hours. Ice water
(300 mL) was
added to the mixture and the solids were collected by filtration and washed
with water (200 mL).
The solids were transferred to a round bottom flask to which was added 6%
aqueous sodium
hydroxide (500 mL). The mixture was refluxed for 2 hours and then cooled to
room temperature.
The temperature was further lowered to 5 C in an ice bath. The pH was adjusted
to
approximately 6 with concentrated hydrochloric acid. The resulting solids were
collected,
washed with water and dried under reduced pressure to give 16.39 g of the
title compound. The
material was subsequently azeotroped using THF/toluene to remove any residual
water: MS
(ESI+) for C8H8N202S m/z 197.0 (M+H)+; 'H NMR (300 MHz, DMSO-ds) 81.24 (t, 3
H), 2.74 (q,
2 H), 6.85 (s, 1 H), 11.1 (s, 1 H), 11.8 (s, 1 H).
EXAMPLE 3
2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine
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CI
i
HsC S N~Ci
The diol of Example 2 (4.0 g) was placed into a pressure vessel with
phosphorus oxychloride
.(35 mL). The mixture was heated to 150 C for 1.5 hours. The mixture was
cooled to room
temperature and concentrated under reduced pressure. The mixture was twice
azeotroped with
toluene (50 mL) to remove any residual phosphorus oxychloride under reduced
pressure. The
residue was partitioned between saturated sodium bicarbonate and
dichloromethane. The
resulting layers were separated and decolorizing carbon (1 g) was added to
organic layer.
Organic layer was filtered through anhydrous magnesium sulfate and
concentrated to dryness
under reduced pressure to give 3.96 g of the title compound: MS (ESI+) for
C8H6CI2N2S m/z
233.0 (M+H)+; iH NMR (300 MHz, CDCI3) 51.4 (t, 3 H), 3.0 (q, 2 H), 7.1 (s, 1
H).
EXAMPLE 4
Tert-butyl 4-(phenylacetyl)piperazine-1 -carboxylate
N N
\-/
0 H3C0
H3C CH3
To a mixture of Boc-piperazine (4.2 g) in dry THF (30 mL) in a round bottom
flask in an ice bath
was added triethylamine (3.14 mL). Phenyl acetyl chloride (2.9 mL) was added
drop wise
keeping temperature below 15 C. Once addition was complete removed the
mixture from the
ice bath and allowed to stir at room temperature for 2 hours. The solvents
were removed under
reduced pressure and the residue partitioned between brine and ethyl acetate.
The layers were
separated and the organic layer washed with brine. The organic layer was then
dried over
anhydrous magnesium sulfate and concentrated. Hexanes were added to the
resulting solids
and collected via filtration to give 6.24 g of the title compound. MS (ES1+)
for C17H24N203 m/z
327.0 (M+H+Na)+; 'H NMR (300 MHz, CDCI3) S 1.44 (s, 9 H), 3.2 (m, 2 H), 3.4
(m, 4 H), 3.6 (m,
2 H), 7.25 (m, 3 H), 7.33 (m, 2 H).
EXAMPLE 5
1 -(Phenylacetyl)piperazine
O N NH
--/
To a mixture of the carboxylate of Example 4 (6.0 g) in dichloromethane (5 mL)
was added
trifluoroacetic acid (5.0 mL). The mixture was stirred at room temperature for
8 hours. The
solvents were removed under reduced pressure and the residue partitioned
between saturated
sodium bicarbonate and dichloromethane. The layers were separated and the
aqueous layer
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extracted with dichloromethane. The combined dichloromethane extracts were
dried using
anhydrous magnesium sulfate and concentrated. The residue was chromatographed
on silica
gel (100 mL) using 8% methanol in dichloromethane with 0.1% ammonium hydroxide
to give
2.01 g of the title compound: iH NMR (300 MHz, CDCI3) S 1.75 (s, 1 H), 2.66
(t, 2 H), 2.8 (t, 2
H), 3.4 (t, 2 H), 3.6 (t, 2 H), 3.7 (s, 2 H), 7.2 (m, 3 H), 7.3 (m, 2 H).
EXAMPLE 6
2-Chloro-6-ethyl-4-[4-(phenylacetyl)piperazin-1 -yl]thieno[2,3-d]pyrim idine
O
N~::
"T:,
N
(N)
H3C
S N"CI
To a mixture of the pyrimidine of Example 3 (1.53 g) in dry THF (60 mL) was
added
diisopropylethylamine (4.6 mL) and 1-(phenylacetyl)piperazine (1.35 g; EXA 5).
The mixture was
stirred at room temperature for 2.5 hours, at which time the mixture was
partitioned between
brine and ethyl acetate. The layers were separated and the organic layer
washed with brine,
dried over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed
on silica gel (100 mL) using 2% methanol in dichloromethane to give 2.28 g of
the title
compound: MS (ESI+) for C20H21CIN40S m/z401.0 (M+H)+; 'H NMR (300 MHz, CDCI3)
8 1.35
(t, 3 H), 2.85 (q, 2 H), 3.63 (m, 2 H), 3.74 (m, 2 H), 3.80 (s, 2 H), 3.85 (m,
2 H), 3.89 (m, 2 H), 6.9
(s, 1 H), 7.27 (m, 3 H), 7.34 (m, 2 H).
EXAMPLE 7
Methyl 2-am ino-5-phenylth iophene-3-carboxylate
0 0'~'
H NH2
S
Methyl cyanoacetate (15.0 g) and elemental sulfur (4.85 g) were suspended in
DMF (30 mL)
followed by addition of triethylamine (22 mL). Phenyl acetaldehyde (33.8 mL)
was added such
that the temperature was maintained at 50 C. The mixture was stirred for an
additional 20 min
at 50 C followed by stirring at room temperature overnight. The mixture was
poured into water
(100 mL) and the aqueous solution was extracted with ethyl acetate (3 x 80
mL). The organic
layers were washed with brine, separated, dried over MgSO4, filtered and
concentrated. The
residue was triturated with diethyl ether containing a few drops of
acetonitrile and the resulting
solid was collected to give the title compound (20.8 g). iH NMR (400 MHz,
CDCI3) S 7.41-7.43
(m, 2H), 7.29-7.34 (m, 2H), 7.22 (s, 1 H), 7.18-7.21 (m, 1 H).
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EXAMPLE 8
6-Phenylthieno[2,3-d]pyrim idine-2,4(1 H,3H)-dione
0
N
S NO
Methyl 2-amino-5-phenylthiophene-3-carboxylate (Example 7, 3.0 g) and urea
(6.8 g) were
combined in a thick-walled glass sealed tube and heated to 200 C for 2 hours.
The mixture was
then cooled to room temperature and DMF (45 mL) was added and the mixture
refluxed for one
hour. Ice water (120 mL) was added and the resulting precipitate was collected
and dried under
reduced pressure to give 1.6 g of the title compound, which was used in the
next step without
further purification. LCMS (ESI+) for C12H8N202S m/z245.11 (M+H)+.
EXAMPLE 9
2,4-Dichloro-6-phenylthieno[2,3-d]pyrimidine
CI
N
S N~CI
6-Phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 8, 1.2 g) and
POCI3(10 mL) were
placed in a thick-walled glass sealed tube and heated to 150 C for 2 hours.
The mixture was
cooled to room temperature and the POCI3 was evaporated under reduced
pressure. The
residue was partitioned between dichloromethane and aqueous saturated sodium
bicarbonate.
The aqueous layer was extracted twice with dichloromethane. The organic layers
were
combined and dried over MgSO4, filtered, and concentrated. The crude residue
was triturated
with acetonitrile and the resulting solid was collected to give 0.71 g of the
title compound. 1H
NMR (400 MHz, CDCI3) 5 7.72-7.69 (m, 2H), 7.55 (s, 1 H), 7.50-7.44 (m, 3H).
EXAMPLE 10
6-Methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione
O
N
S N O
2-Amino-5-methyl-thiophene-3-carboxylic acid (4.0 g) and urea (8.4 g) were
placed in a sealed
tube and heated to 200 C for 2 hours. The mixture was cooled to room
temperature and DMF
was added (50 mL) and the mixture was refluxed for 1 hour. After cooling to
room temperature,
ice water was added to the mixture. The resulting solid was collected and
dried under reduced
pressure to give 2.47 g of the title compound, which was used in the next step
without further
purification. MS (ESI+) for C7H6N202S m/z 183.1 (M+H)+.
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EXAMPLE 11
2-Chloro-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine dihydrochloride
N
HCI
H3C / ~ ~~ HCI
S N CI
HCI gas was bubbled through dry 1,4-dioxane (400 mL) for 15 minutes. The
mixture was cooled
to room temperature and added to the carboxylate of Example 12 (22.1 g) in dry
1,4-dioxane.
The mixture was stirred at room temperature overnight. 1,4-Dioxane was removed
under
reduced pressure and dichloromethane was added. The resulting solids were
collected via
filtration to give 19.22 g of the title compound: 'H NMR (300 MHz, DMSO-d6) S
1.28 (t, 3 H), 2.90
(q, 2 H), 3.23 (m, 4 H), 4.05 (m, 4 H), 7.39 (s, 1 H), 9.47 (s, 2 H).
EXAMPLE 12
tert-Butyl 4-(2-chloro-6-ethylthieno[2,3-d]pyrim idin-4-yl)piperazine-l-
carboxylate
Boc
CNJ
N
H3C / . N
~
S NCI
To a mixture of the pyrimidine of Example 3 (10.38 g) in dry THF (300 mL) was
added
diisopropylethylamine (19.4 mL) and Boc-piperazine (9.9 g). The mixture was
stirred at room
temperature 6 hours at which time the solvents were removed under reduced
pressure and the
residue partitioned between brine and dichloromethane. The layers were
separated and the
organic layer washed with brine, dried over anhydrous magnesium sulfate and
concentrated to
dryness to give 15.35 g of the title compound. 'H NMR (300 MHz, CDCI3) S 1.36
(t, 3 H), 1.49 (s,
9 H), 2.89 (q, 2 H), 3.62 (m, 4 H), 3.91 (m, 4 H), 6.95 (s, 1 H).
EXAMPLE 13
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-ethylthieno[2,3-
d]pyrim idine
il
i
0 ~~
CN)
N
H3C / I ~~
S N CI
To a mixture of the pyrimidine dihydrochloride salt of Example 11 (1.02 g) in
DMF (5.0 mL) was
added diisopropylethylamine (2.0 mL) and 4-biphenyl carbonyl chloride (0.63
g). The mixture
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was stirred at room temperature for 2 hours. The mixture was partitioned
between ethyl acetate
and water. The layers were separated and the organic layer washed four times
with brine, dried
over anhydrous magnesium sulfate and concentrated. The residue was dissolved
in ethyl
acetate, adsorbed to silica gel and placed on top of a~/2 inch silica gel plug
in a 60 mL sintered
5 glass funnel. The silica gel plug was eluted with dichloromethane to remove
impurities. The
silica gel plug was then washed with ethyl acetate. The ethyl acetate
filtrates were concentrated
to give 0.966 g of the title compound. MS (ESI+) for C25H23CIN40S m/z465.14
(M+H)+; 'H NMR
(300 MHz, CDCI3) S 1.36 (t, 3 H), 2.9 (q, 2 H), 3.98 (m, 8 H), 6.95 (s, 1 H),
7.37-7.68 (m, 9 H).
10 EXAMPLE 14
tert-Butyl 4-(1,1'-biphenyl-4-ylcarbonyl)piperazine-l-carboxylate
O
(N)
N
O" O CH3
H3C~CH3
To a mixture of Boc-piperazine (5.0 g) in THF (100 mL) was added 4-biphenyl
carbonyl chloride
(3.9 g) and diisopropylethylamine (6.0 g). The mixture was stirred at room
temperature
15 overnight. The mixture was partitioned between brine and ethyl acetate. The
layers were
separated and the organic layer washed with brine, dried over anhydrous
magnesium sulfate and
concentrated to give 6.0 g of the title compound. ' H NMR (400 MHz, CDC13) S
1.47 (s, 9 H), 3.4-
3.8 (m, 8 H), 7.39 (m, 1 H), 7.43-7.48 (m, 4 H), 7.57-7.64 (m, 4 H).
20 EXAMPLE 15
1-(1,1'-Biphenyl-4-ylcarbonyl)piperazine hydrochloride
O
(N)
N
H
HCI
HCI gas was bubbled through methanol (100 mL) for 20 minutes then cooled to
room
temperature. The carboxylate of Example 14 was added(6.0 g). The mixture was
stirred at room
25 temperature for 20 hours. The solvents were removed under reduced pressure
and hexanes
added to the residue. The resulting solids were collected via filtration to
give 4.8 g of the title
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compound. 'H NMR (400 MHz, DMSO-d6) S 3.14 (m, 4 H), 4.14 (m, 4 H), 7.36 (m, 1
H), 7.45 (m,
2 H), 7.54 (m, 2 H), 7.68 (d, 2 H), 7.73 (d, 2 H), 9.64 (s, 1 H).
EXAMPLE 16
2,4-Dichloro-6-methylthieno[2,3-d]pyrimidine
CI
N
H3C
S N/ CI
6-Methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (Example 10, 2.0 g) and
POCI3 were heated
together in a sealed tube at 150 C for 3 hours. The mixture was then cooled
and concentrated
under reduced pressure and the residue was partitioned between dichloromethane
and aqueous
saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered
and
concentrated. The residue was triturated with diethyl ether containing a small
amount of
acetonitrile and the resulting solid was collected and dried under reduced
pressure to give the
title compound (1.75 g). MS (ESI+) m/z219.05 (M+H)+.
EXAMPLE 17
6-Propylthieno[2,3-d]pyrim idine-2,4(1 H,3H)-dione
O
H3C NH
S N~O
H
Methyl 2-amino-5-propylthiophene-3-carboxylate (8.1 g) and urea (15.0 g) were
heated together
in a sealed tube to 200 C for 3 hours and then stirred at room temperature
overnight. The
resulting mixture was poured into ice water (250 mL) and the resulting solid
was collected. The
solid was washed with diethyl ether and dried under reduced pressure to give
3.1 g of the title
compound. MS (ESI+) m/z 219.05 (M+H)+.
EXAMPLE 18
2,4-Dichloro-6-propylthieno[2,3-d]pyrimidine
CI
H3C N
S
6-Propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 17, 2.0 g) and POCI3
were heated in
a sealed tube for 1.5 hours at 150 C. The mixture was then allowed to cool to
room temperature
and concentrated. The residue was partitioned between dichloromethane and
aqueous
saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered
and
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concentrated under reduced pressureFto give 1.1 g of the title compound: MS
(ESI+) for
C9H8ChN2S m/z 247.09 (M+H)+.
EXAMPLE 19
4-[4-(1,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-2-chloro-6-ethylthieno[2,3-
d]pyrim idine
N
N
H3C N
S I
N ~CI
To biphenyl-3-carboxylic acid (0.489 g) in dichloromethane (10 mL) was added
1,1'-
carbonyldiimidazole. The mixture was stirred for 45 min, at which time a
slurry of 2-chloro-6-
ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine dihydrochloride (0.750 g) and
triethylamine (0.33
mL) in dichloromethane.(15 mL) and DMF (1 mL) was added. The mixture was
stirred overnight
and then partitioned between d ichlorom ethane, aqueous sodium bicarbonate,
and brine. The
organic layer was dried over sodium sulfate and concentrated under reduced
pressure.
Crystallization from dichloromethane and hexane gave 0.914 g of the title
compound. MS [m+H]
463.27; 'H NMR (400 MHz, CDCI3) 8 1.34 (3H), 2.88 (2H), 3.6-4.1 (8 H), 6.93 (1
H), 7.36-7.53
(5H), 7.58 (2H), 7.67 (2H).
EXAMPLE 20
Tert-butyl 4-(2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]m ethoxy}-6-
ethylthieno[2,3-d]pyrim id in-4-
yl)piperazine-1 -carboxylate
H3C CH3
)"~-'CH3
OyO
(N)
N
H3C N
S N- O'-1('O
O_/-CH3
H3C
Sodium hydride 60% in mineral oil (0.16 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (10 mL) was added and the
mixture stirred for
5 minutes. (S)-(+)-2,2-Dimethyl-1,3-dioxolane-4-methanol (0.502 g) was added
and the mixture
stirred for 15 minutes. The carboxylate of Example 12 (1.46 g) was dissolved
in NMP (15 mL)
and added drop-wise to the chilled mixture. Once the addition was complete
removed from the
ice/acetone bath and stirred at room temperature for 30 hours. The mixture was
then partitioned
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between saturated sodium bicarbonate and ethyl acetate. The layers were
separated and the
organic layer washed three times with brine, dried over anhydrous magnesium
sulfate and
concentrated. The residue was chromatographed on silica gel (100 mL) using
ethyl acetate-
hexanes (20/80) to give 1.346 g of the title compound. 'H NMR (400 MHz, CDCI3)
S 1.32 (t, 3 H),
1.38 (s, 3 H), 1.46 (s, 3 H), 1.48 (s, 6 H), 1.58 (s, 3 H), 2.84 (q, 2 H),
3.58 (m, 4 H), 3.84 (m, 4 H),
3.92 (m, 1 H), 4.15 (m, 1 H), 4.31 (m, 1 H), 4.45-4.55 (m, 2 H), 6.86 (s, 1
H).
EXAMPLE 21
6-Isopropylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione
0
H3C NH
H3C S N__~p
H
Methyl 2-amino-5-isopropylthiophene-3-carboxylate (8.0 g) and urea (14.4 g)
were heated
together in a sealed tube to 200 C for 3 hours and then cooled to room
temperature and stirred
overnight. The mixture was poured into ice cold water (250mL) and the
resulting solid was
collected, washed with diethyl ether and dried under reduced pressure to give
7.9 g of the title
compound. MS (ESI+) for C9HIoN202S m/z212.19 (M+H)+.
EXAMPLE 22
(2R)-3-[(6-Ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidin-2-yl)oxy]propane-1,2-
diol hydrochloride
H
(N)
N
H3C N
S NO""J~OH
OH
HCI
HCI gas was bubbled through methanol (75 mL) for 10 minutes, then cooled to
room
temperature. The carboxylate of Example 20 (1.34 g) was then added. The
mixture was stirred at
room temperature for 2 hours. The solvents were removed under reduced pressure
and the
residue dried under high vacuum for 48 hours. Ethyl acetate was added to
residue and refluxed
for 1 hour. The resulting solids were collected via filtration and dried under
reduced pressure to
give 0.93 g of the title compound. 'H NMR (400 MHz, DMSO-d6) 5 1.25 (t,. 3 H),
2.82 (q, 2 H),
3.20 (m, 4 H), 3.6 (m, 2 H), 3.77 (m, 1 H), 4.03 (m, 4 H), 4.15 (m, 1 H), 4.3
{m, 1 H), 7.24 (s, 1
H), 9.54 (s, 1 H).
EXAMPLE 23
2-Chloro-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine
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N
H3C
N_ CI
HCI gas was bubbled through a solution of the carboxylate of Example 12 (6.36
g) dissolved in
methanol (100 mL) for 1 minute. The mixture was stirred at room temperature
for 1 hour. The
mixture was concentrated under reduced pressure. The residue was partitioned
between
saturated sodium bicarbonate and ethyl acetate. The layers were separated and
the organic
layer washed with brine, dried over anhydrous magnesium sulfate and
concentrated to dryness
under reduced pressure to give 3.65 g of the title compound: 'H NMR (400 MHz,
CDCI3) S 1.34
(t, 3 H), 2.87 (q, 2 H), 3.05 (m, 4 H), 3.96 (m, 4 H), 6.93 (s, 1 H).
EXAMPLE 24
2-(2-Ethoxyethoxy)-6-ethyl-4-piperazin-1-yithieno[2,3-d]pyrimidine
H
CN~
N
H3C I ~ ~t
S Ni \0~/oCH3
Sodium hydride 60% in mineral oil (0.024 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1.0 mL) was added and the
mixture stirred for
5 minutes. 2-Ethoxyethanol (0.05 g) was added and the mixture stirred for 5
minutes. The
mixture was removed from the ice/ acetone bath for 30 minutes then placed back
in ice bath. The
pyrimidine of Example 23 (0.15 g) was dissolved in NMP (1 mL) and added drop-
wise to the
chilled mixture. Once the addition was complete removed from the ice/acetone
bath and stirred
at room temperature for 18 hours. The mixture was then partitioned between
saturated sodium
bicarbonate and ethyl acetate. The layers were separated and the organic layer
washed three
times with brine, dried over anhydrous magnesium sulfate and concentrated to
dryness to give
0.116 g of the title compound: 'H NMR (400 MHz, CDCI3) S 1.21 (t, 3 H), 1.32
(t, 3 H), 2.3 (m, 1
H), 2.36 (m, 1 H), 2.83 (m, 2 H), 3.00 (m, 4 H), 3.37 (m, 1 H), 3.58 (q, 2 H),
3.78-3.83 (m, 4 H),
4.48 (m, 1 H), 6.86 (s, 1 H).
EXAMPLE 25
2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-piperazin-1-
ylthieno[2,3-d]pyrimidine
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H-
(N)
N
H3C N
S NO"~O
O_/-CH3
H3C
Sodium hydride 60% in mineral oil (0.042 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1.0 mL) was added and the
mixture stirred for
5 minutes. (S)-(+)-2,2-Dimethyi-1,3-dioxolane-4-methanol (0.14 g) was added
and the mixture
5 stirred for 5 minutes. The mixture was removed from the ice/ acetone bath
for 30 minutes then
placed back in ice bath. The pyrimidine of Example 23 (0.15 g) was dissolved
in NMP (1 mL) and
added drop-wise to the chilled mixture. Once the addition was complete removed
frorri the
ice/acetone bath and stirred at room temperature for 4 hours. The mixture was
then partitioned
between saturated sodium bicarbonate and ethyl acetate. The layers were
separated and the
10 organic layer washed three times with brine, dried over anhydrous magnesium
sulfate and
concentrated to dryness to give 0.1234 g of the title compound: 'H NMR (400
MHz, CDCI3) b
1.32 (t, 3 H), 1.37 (s, 3 H), 1.46 (s, 3 H), 2.84 (q, 2 H), 2.99 (in, 4 H),
3.83 (m, 4 H), 3.91 (m, 1 H),
4.15 (m, 1 H), 4.28 (m, 1 H), 4.44-4.53 (m, 2 H), 6.87 (s, 1 H).
15 EXAMPLE 26
4-[4-(1,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-ethy{thieno[2,3-d]pyrim idine
(NN)
H3C N
S N~O,)(-",\,o
O
H3C CH3
To a mixture of the pyrimidine of Example 25 (0.123 g) in THF (4.0 mL) in a
round bottomed flask
20 was added diisopropylethylamine (0.088 g), 3-biphenyl carboxylic acid
(0.071 g), and HATU
(0.136 g). The mixture was stirred at room temperature for 20 hours at which
time the mixture
was partitioned between brine and ethyl acetate. The layers were separated and
the organic
layer washed three times with brine, dried over anhydrous magnesium sulfate
and concentrated.
The residue was chromatographed on silica gel using acetone:hexanes (20:80) as
eluent to give
25 0.15 g of the title compound: 'H NMR (400 MHz, CDCI3) 8 1.32 (t, 3 H), 1.37
(s, 3 H), 1.45 (s, 3
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H), 2.84 (q, 2 H), 3.6-4.0 (m, 9 H), 4.14 (m, 1 H), 4.29 (m, 1 H), 4.42-4.52
(m, 2 H), 6.85 (s, 1 H),
7.38-7.53 (m, 5 H), 7.6 (d, 2 H), 7.66 (m, 2 H).
EXAMPLE 27
2,4-Dichloro-6-isopropylthieno[2,3-d]pyrimidine
ci
H3C N
H3C S
6-Isopropylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 21, 2.1 g) and
POCI3 were heated
together in a sealed tube to 150 C for 1.5 hours. The mixture was cooled to
room temperature
and stirred overnight. The mixture was concentrated and the residue was
partitioned between
dichloromethane and aqueous saturated sodium bicarbonate. The organic layer
was dried over
MgSO4, filtered and concentrated under reduced pressure to give 1.0 g of the
title compound.
MS (ESI+) for C9H8ChN2S m/z 247.01 (M+H)+.
EXAMPLE 28
4-[4-(3-Bromobenzoyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-
yl]methoxy}-6-
ethylthieno[2,3-d]pyrim idine
O aBr
CNJ
N
H3C ~ = N
S I N0--'~0
O
H3C CH3
To a mixture of the pyrimidine of Example 25 (2.5 g) in THF (50.0 mL) and NMP
(25 mL) in a
round bottom flask were added diisopropylethylamine (1.8 g), 3-bromobenzoic
acid (1.35 g), and
HATU (2.54 g). The mixture was stirred at room temperature for 4 hours at
which time the
mixture was partitioned between brine and ethyl acetate. The layers were
separated and the
organic layer washed four times with brine, dried over anhydrous magnesium
sulfate and
concentrated to dryness to give 2.8 g of the title compound: 'H NMR (400 MHz,
CDCI3) S 1.34 (t,
3 H), 1.37 (s, 3 H), 1.45 (s, 3 H), 2.85 (q, 2 H), 3.6 (m, 2 H), 3.8-4.0 (m, 7
H), 4.12 (m, 1 H), 4.31
(m, I H), 4.42-4.52 (m, 2 H), 6.85 (s, 1 H), 7.28-7.37 (m, 2 H), 7.59 (m, 2
H).
EXAMPLE 29
.2-{2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]ethoxy}-6-ethyl-4-piperazin-1-
ylthieno[2,3-d]pyrim idine
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H
CN
N H3C
H3C / ~ N o~CH3
I '~ ' O
S N/p~.~
Sodium hydride 60% in mineral oil (0.057 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1.5 mL) was added and the
mixture stirred for
15 minutes. (S)-(+)-4-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (0.205 g)
was added and the
mixture stirred for 30 minutes. The pyrimidine of Example 23 (0.2 g) was
dissolved in NMP (2.5
mL) and added drop-wise to the chilled mixture. Once the addition was
complete, the flask was
removed from the ice/acetone bath and the mixture stirred at room temperature
for 3 hours. The
mixture was then partitioned between saturated sodium bicarbonate and ethyl
acetate. The
layers were separated and the organic layer washed three times with brine,
dried over anhydrous
magnesium sulfate and concentrated to dryness to give 0.222 g of the title
compound: 'H NMR
(400 MHz, CDCI3) 51.32 (m, 6 H), 1.41 (s, 3 H), 2.07 (m, 2 H), 3.00 (m, 4 H),
3.61 (m, 1 H), 3.83
(m, 4 H), 4.11 (m, 1 H), 4.33 (m, 1 H), 4.44 (m, 1 H), 6.86 (s, 1 H).
EXAMPLE 30
2-(3,3-Diethoxypropoxy)-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine
H
(N)
N CH3
H3C _~ O
S N O~~O
~CH3
Sodium hydride 60% in mineral oil (0.084 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1.0 mL) was added and the
mixture stirred for
15 minutes. 3,3-Diethoxy-l-propanoi (0.33 g) was added and the mixture stirred
for 30 minutes.
2-Chloro-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine (Example 23, 0.3 g)
was dissolved in
NMP (1.5 mL) and added drop-wise to the chilled mixture. Once the addition was
complete
removed from the ice/acetone bath and stirred at room temperature for 3 hours.
The mixture
was then partitioned between saturated sodium bicarbonate and ethyl acetate.
The layers were
separated and the organic layer washed three times with brine, dried over
anhydrous magnesium
sulfate and concentrated to dryness to give 0.435 g of the title compound: 'H
NMR (400 MHz,
CDCI3) S 1.22 (m, 6 H), 1.34 (t, 3 H), 1.89 (m, 1 H), 2.12 (m, 1 H), 2.84 (m,
2 H), 3.0 (m, 4 H),
3.39 (m, 1 H), 3.53 (m, 2 H), 3.84 (m, 4 H), 4.4 (m, 1 H), 4.6-4.8 (m, 1 H),
6.86 (m, 1 H).
EXAMPLE 31
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3'-{[4-(2-{[(4S)-2,2-Dim ethyl-1,3-d ioxolan-4-yl]m ethoxy}-6-ethylth ieno[2,3-
d] pyrim idin-4-
yl)piperazin-1-yl]carbonyl}-1,1'-biphenyl-4-carboxylic acid
0
N LoH
C,).
0
N
H3C N
S
N I- O"'~O
O-E.-CH3
CH3
To a mixture of the pyrimidine of Example 28 (0.15 g) in NMP (3.0 mL) was
added 5M K3PO4
(1.0 mL), trans-dichloro-bis triphenylphosphine palladium II (0.019 g) and 4-
carboxyphenyl
boronic acid (0.049 g). The mixture was heated at 90 C overnight then cooled
to room
temperature. The mixture was then partitioned between 1 N HCI and ethyl
acetate. The layers
were separated and the organic layer washed three times with 1 N HCI, dried
over anhydrous
magnesium sulfate and concentrated. The residue was chromatographed on silica
gel (75 mL)
using 5% methanol in methylene chloride with 0.5% glacial acetic acid to give
0.0868 g of the title
compound: MS (ESI+) for C32H34N4O6S m/z 603.35 (M+H)+. 'H NMR (400 MHz, CDCI3)
S 1.32
(t, 3 H), 1.37 (s, 3 H), 1.45 (s, 3 H), 2.84 (q, 2 H), 3.67 (m, 2 H), 3.8-4.0
(m, 7 H), 4.14 (m, 1 H),
4.31 (m, 1 H), 4.4-4.6 (m, 2 H), 6.85 (s, 1 H), 7.16 (m, 1 H), 7.46 (m, 1 H),
7.71 (m, 1 H), 7.71 (d,
2 H), 8.18 (d, 2 H).
EXAMPLE 32
4-[4-(1,1'-Biphenyl-3-ylcarbonyl)piperazin-1-yl]-2-(3,3-diethoxypropoxy)-6-
ethylth ieno[2,3-
d]pyrimidine
O
N
)
N CH
C
H3C / O I 3
I J
S N O" v 'O
'CH3
To a mixture of the pyrimidine of Example 30 (0.43 g) in DMF (5 mL) was added
diisopropylethylamine (0.284 g), 3-biphenyl carboxylic acid (0.218 g), and
HATU (0.418 g). The
mixture was stirred at room temperature for 18 hours at which time the mixture
was partitioned
between brine and ethyl acetate. The layers were separated and the organic
layer washed three
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times with brine, dried over anhydrous magnesium sulfate and concentrated. The
residue was
chromatographed on silica gel (100 mL) using 20% ethyl acetate in hexanes to
give 0.380 g of -
the title compound: 'H NMR (400 MHz, CDCI3) S 1.19 (t, 6 H), 1.32 (t, 3 H),
2.08 (m, 2 H), 2.83
(q, 2 H), 3.48 (m, 2 H), 3.66 (m, 2 H), 3.8-4.0 (m, 8 H), 4.4 (m, 2 H), 4.46
(m, 1 H), 6.84 (s, 1 H),
7.38-7.49 (m, 5 H), 7.58 (d, 2 H), 7.66 (m, 2 H).
EXAMPLE 33
3-({4-[4-(1,1'-Biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylth ieno[2,3-
d]pyrim idin-2-
yl}oxy)propanal
O
N
N
H3C / I N O
S N~o~
To a mixture of the pyrimidine of Example 32 (0.36 g) in methylene chloride (4
mL) was added p-
toluenesufonic acid (0.131 g). The mixture was stirred at room temperature for
6 hours. The
mixture was washed twice with brine, dried over anhydrous magnesium sulfate
and
chromatographed on silica gel (75 mL) using 2% methanol in methylene chloride
to give 0.168 g
of the title compound: 'H NMR (400 MHz, CDCI3) 81.32 (t, 3 H), 2.84 (q, 2 H),
2.92 (m, 2 H),
3.67 (m, 2 H), 3.8-4.0 (m, 6 H), 4.68 (m, 2 H), 6.85 (s, 1 H), 7.36-7.53 (m, 5
H), 7.6 (d, 2 H), 7.66
(m, 2 H), 9.88 (s, 1 H).
EXAMPLE 34
Trans-2-chloro-6-ethyl-4-{4-[(2-phenylcyclopropyl)carbonyl]piperazin-1-
yl}thieno[2,3-d]pyrim idine
O
CN)
N
H3C / I N
S N~Ci
To a mixture of the pyrimidine of Example 23 (0.202 g) in DMF (5 mL) was added
diisopropylethylamine (0.194 g), trans-2-phenyl-1-cyclopropyl carboxylic acid
(0.123 g), and
HATU (0.285 g). The mixture was stirred at room temperature for 4 days. The
mixture was
partitioned between brine and ethyl acetate. The layers were separated and the
organic layer
washed six times with brine, dried over anhydrous magnesium sulfate and
concentrated to give
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0.27 g of the title compound: 'H NMR (400 MHz, CDCI3) 81.34 (m, 4 H), 1.72 (m,
1 H), 1.98 (m,
1 H), 2.52 (m, 1 H), 2.88 (q, 2 H), 3.85 (m, 4 H), 3.97 (m, 4 H), 6.95 (s, 1
H), 7.13 (m, 2 H), 7.2-
7.31 (m, 3 H).
5 EXAMPLE 35
Trans-2-{[(4S)-2,2-dim ethyl-l,3-dioxolan-4-yl]m ethoxy}-6-ethyl-4-{4-[(2-
phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidine
I~
~
O
C ~
N
H3C ~ ~ '~
S N O~~O
H ~CH3
Sodium hydride 60% in mineral oil (0.028 g) was placed into a round bottom
flask, washed with
10 hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture was stirred
for 15 minutes. (S)-(+)-2,2-Dim.ethyl-1,3-dioxolane-4-methanol (0.093 g) was
added and the
mixture stirred for 30 minutes. The pyrimidine of Example 34 (0.15 g) was
dissolved in NMP (2.0
mL) and added drop-wise to the chilled mixture. Once the addition was complete
removed from
the ice/acetone bath and stirred at room temperature for 3 hours. The mixture
was then
15 partitioned between saturated sodium bicarbonate and ethyl acetate. The
layers were separated
and the organic layer washed three times with brine, dried over anhydrous
magnesium sulfate
and concentrated. The residue was dissolved in ethyl acetate and passed
through a~/2 inch
silica gel plug in a 30 mL scintered glass funnel. The filtrates were
concentrated to dryness to
give 0.177 g of the title compound: 'H NMR (400 MHz, CDCI3) S 1.34 (t, 3 H),
1.37 (s, 3 H), 1.44
20 (m, 3 H), 1.7-1.81 (m, 1 H), 2.0 (m, 1 H), 2.3-2.55 (m, 1 H), 2.84 (m, 3
H), 3.3-3.8 (m, 1 H), 3.7-
4.0 (m, 9 H), 4.0-4.2 (m, 1 H), 4.2-4.35 (m, 1 H), 4.4-4.58 (m, 1 H), 6.87 (s,
1 H), 7.13 (d, 1 H),
7.2-7.35 (m, 4 H).
EXAMPLE 36
25 4-[4-(4-Bromobenzoyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-
yl]methoxy}-6-
ethylthieno[2,3-d]pyrim idine
Br
O ~I
CNJ
H3C ~ I IN
S NC")f-\O
H C~CH3
3
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To a mixture of the pyrimidine of Exarnple 25 (1.08 g) in NMP (5 mL) in a
round bottom flask was
added diisopropylethylamine (0.039 g), 4-bromobenzoic acid (0.603 g), and HATU
(1.14 g). The
mixture was stirred at room temperature overnight at which time the mixture
was partitioned
between brine and ethyl acetate. The layers were separated and the organic
layer washed four
times with brine, dried over anhydrous magnesium sulfate and concentrated. The
residue was
chromatographed on silica gel (100 mL) using ethyl acetate as eluent to give
0.9 g of the title
compound: 'H NMR (400 MHz, CDCI3) 51.25 (t, 3 H), 1.37 (s, 3 H), 1.45 (s, 3
H), 2.84 (q, 2 H),
3.6 (m, 2 H), 3.8-4.0 (m, 7 H), 4.14 (m, 1 H), 4.29 (m, 1 H), 4.46 (m, 1 H),
4.5 (m, 1 H), 6.84 (s, 1
H), 7.32 (d, 2 H), 7.58 (d, 2 H).
EXAMPLE 37
(2,2-Dim ethyl-1,3-d ioxan-5-yl)m ethanol
H3C ~0' OH
ICHO
3
To a mixture of 2-(hydroxymethylpropane-1,3-diol (0.953 g) in THF (5 mL) was
added 2,2-
dimethoxypropane (1.28 mL) and p-toluenesulfonic acid monohydrate (0.053 g).
The mixture
was stirred at room temperature for 18 hours. Triethyl amine (0.028 g) was
added and the
mixture was concentrated under reduced pressure. The residue was
chromatographed on silica
gel (100 mL) using 10% methanol in methylene chloride as eluent to give 0.963
g of the title
compound: 'H NMR (CDCI3) 51.39 (s, 3 H), 1.44 (s, 3 H), 1.57 (m, 1 H), 1.83
(m, 1 H), 3.75 (m,
4 H), 4.01 (dd, 2 H).
EXAMPLE 38
N-Benzoyl-N-phenyl-beta-alanine
i I
o O
O~ N ~
~ NH CI' v OH O' H ~/ O~~N I~
2 OH
A mixture of aniline (0.858 g, 9.22 mmol), 3-chloropropionic acid (1.00 g,
9.22 mmol),
triethylamine (1.86 g, 18.4 mmol), sodium iodide (0.05 g), and THF (10 mL) was
stirred at reflux
for 2 days, at which time it was cooled. Benzoyl chloride (1.42 g, 10.1 mmol)
and additional
triethylamine (1.41 mL) and THF (3 mL) were added. The mixture was stirred for
3 hours, at
which time it was partitioned between ethyl acetate and 1 N HCI. The organic
layer was dried
over magnesium sulfate and the crude product was chromatographed on silica gel
using
methanol:dichloromethane (5:95) with 0.005% acetic acid added to give 0.47 g
of the title
compound. MS [m+H] 270.2;'H NMR (400 MHz, CDCI3) 6 2.76 (2H), 4.23 (2H), 7.0-
7.3 (10H).
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EXAMPLE 39
Thieno[2,3-d]pyrimidine-2,4(1 H, 3H)-dione
0
/ I ,,,,
S N~0
H
Methyl 2-amino thiophene-3-carboxylate (1.0 g) and urea (2.2 g) were heated in
sealed tube for
3.5 hours at 200 C and then cooled to room temperature. DMF (20 mL) was added
and the
mixture was refluxed for 1 hour. Ice water (50 ml) was added and the solid
thus precipitated was
collected and dried to give 0.5 g of the title compound after 1 hour. The
compound was used in
the next step without further purification. MS (ESI+) for C6H402N2S m/z (M+H)+
169.05.
EXAMPLE 40
2,4-Dichlorothieno[2,3-d]pyrimidine
cl
N
S I
NCI
The dione of Example 39 (2.6 g) was placed into a pressure vessel with
phosphorus oxychloride
(15 mL). The mixture was heated at 200 C for 2.3 hours and then cooled to
room temperature
and concentrated under reduced pressure. Residual phosphorus oxychloride was
azeotroped
twice with toluene (30 mL) under reduced pressure. The residue was partitioned
between
saturated aqueous sodium bicarbonate and dichloromethane. The resulting layers
were
separated and the organic layer was filtered through anhydrous magnesium
sulfate and
concentrated to dryness under reduced pressure to give 1.06 g of the title
compound: MS (ESI+)
for C6H2N2CI2S m/z205.0 (M+H)+. 'H NMR (400 MHz, CDCI3) 8 7.42 (d,1 H), 7.61
(d,1 H).
EXAMPLE 41
4-[4-(1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl]-2-
chlorothieno[2,3d]pyrimidine
S NCI
To a mixture of 2,4-dichlorothieno[2,3-d]pyrimidine (Example 40, 0.4 g) in
THF/DMF (20/8 mL)
was added diisopropylethylamine (0.44mL) and (1,1'-biphenyl-4-yl)piperazine
trifluoroacetate
(0.780 g). The mixture was stirred overnight at room temperature. The mixture
was then
partitioned between ethyl acetate and brine. The layers were separated and the
organic layer
was washed four times with brine, dried over anhydrous magnesium sulfate and
concentrated.
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-The resulting crude mixture was stirred in hot MeOH to remove impurities and
the remaining
solid was collected and dried to give 0.34 g of the title compound: MS (ESI+)
for C23H19CIN401S1
m/z435.25 (M+H)+.'H NMR (400 MHz, CDCI3). S 3.6 to 4.2 (m, 8H) 7.3 to 7.67
(m.11 H). To a
mixture of the pyrimidine of Example 40 (0.4 g) in THF/DMF (20/8 mL) was added
diisopropylethylamine (0.44 mL) and the TFA salt of Example 15 (0.780 g). The
mixture was
stirred overnight at room temperature. The mixture was then partitioned
between ethyl acetate
and brine. The layers were separated and the organic layer was washed four
times with brine,
dried over anhydrous magnesium sulfate and concentrated. The resulting crude
mixture was
stirred in hot methanol to remove impurities and the remaining solid was
collected and dried to
give 0.34 g of the title compound: MS (ESI+) for C23H19CIN4OS m/z435.25
(M+H)+. 'H NMR
(400 MHz, CDCI3). S 3.6-4.2 (m, 8H) 7.3-7.67 (m, 11 H).
EXAMPLE 42
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-
yl]methoxy}thieno[2,3-d]pyrimidine
/ I
/ \
O \ I
(N)
N
DI N
S N~O 1 O
O 'Ci
H3C
Hg
Sodium hydride (0.277 g, 60% in hexane) was washed with hexane. The flask was
cooled in an
ice bath and then NMP (2 mL) and (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol
(0.9 mL) were
added to the flask. The solution was slowly allowed to warm to room
temperature and stirred for
an additional 30 min. The mixture was cooled to 0 C and a solution of the
pyrimidine of Example
41 (1.5 g) in NMP (10 mL) was added slowly. The mixture was stirred at room
temperature for 3
h and then diluted with ethyl acetate. The organic layer was washed with
saturated aqueous
sodium bicarbonate and brine and dried over magnesium sulfate and concentrated
to give the
title compound (2.3 g). The compound was used in the next step without further
purification. MS
(ESI+) for C23H30N404Sj m/z 531.36 (M+H)+.
EXAMPLE 43
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yi]-2-chloro-6-phenylthieno[2,3-
d]pyrimidine
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\ ~
O I /
N
N
C
JI
S N" CI
2,4-Dichloro-6-phenylthieno[2,3-d]pyrimidine (Example 9, 0.69 g) was dissolved
in a mixture of
THF/DMF (20 mU3 mL). Diisopropylethylamine (0.42 g) and 1-(1,1'-biphenyl-4-
ylcarbonyl)piperazine (0.98 g) were added. The mixture was stirred overnight
at room
temperature. The mixture was partitioned between ethyl acetate and brine. The
organic layer
was separated and washed four times with brine then separated, dried over
MgSO4, filtered and
concentrated. The resulting residue was stirred with hot acetonitrile
containing a few drops of
methanol. The resulting solid was collected and dried under reduced pressure
to give 0.99 g of
the title compound. MS (ESI+) m/z511.27 (M+H)+.'H NMR (400 MHz, CDCI3) S 7.37-
7.67 (m,
15H), 3.6-4.2 (m, 8H).
EXAMPLE 44
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-methylthieno[2,3-
d]pyrimidine
o
()
N
~N
H3C ~ ~ ~
S N 15 2,4-Dichloro-6-methylthieno[2,3-d]pyrimidine (Example 16, 0.80 g) was
dissolved in a mixture of
THF/DMF (10 mU6 mL) followed by addition of 1-(1,1'-biphenyl-4-
ylcarbonyl)piperazine (1.45 g,
3.65 mmol) and diisopropylethylamine (0.61 g, 4.7 mmol). The mixture was
stirred at room
temperature overnight. The mixture was partitioned between ethyl acetate and
brine. The
organic layer was separated and washed additional four times with brine. The
organic layer was
dried over MgSO4, filtered and concentrated. The resulting residue was stirred
in hot acetonitrile
with a few drops of methanol. The resulting solid was collected and dried
under reduced
pressure to give 1.41 g of the title compound. MS (ESI+) for C24H21CIN40S1 m/z
449.242
(M+H)+. 1H NMR (400 MHz, CDCI3) S 7.66 to 7.36 (m, 9H), 6.93 (s, 1H), 3.95 (br
s, 8H), 2.54 (s,
3H).
EXAMPLE 45
Methyl 2-am ino-5-propylth iophene-3-carboxylate
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0
~ CH3
S NH2
_jr H3C
To a mixture of sulfur (5.5 g) in DMF (30 mL) was added methyl cyanoacetate
(17.0 g) and
triethylamine (24 mL,) under nitrogen. The mixture was stirred for 10 minutes
at which time
valeraldehyde (29.55 g) was added dropwise at a sufficient rate to maintain a
temperature of 50
5 C. The mixture was then stirred at room temperature for 20 hours. The
mixture was partitioned
between brine and ethyl acetate. The layers were separated and the organic
layer washed with
brine three times, dried over anhydrous magnesium sulfate and concentrated.
The residue was
dried on vacuum line. Crude residue was purified on silica gel using hexanes
and ethyl acetate
(95:5) to give 33.0 g of the title compound. MS (ESI+) m/z200.16 (M+H)+. 'H
NMR (CDCI3) S
10 6.60 (s, 1 H), 3.77 (s, 3H), 2.53 (t, 3H), 1.59 (t, 3H), 0.93 (t, 3H).
EXAMPLE 46
Methyl 2-am ino-5-isopropylth iophene-3-carboxylate
O
H3
H $C
NH2
H3
15 To a mixture of sulfur (5.5 g) in DMF (30 mL) was added methyl cyanoacetate
(17.0 g) and
triethylamine (24 mL,) under nitrogen. The mixture was stirred for 10 minutes
at which time
isovaleraidehyde (29.55 g) was added dropwise at a sufficient rate to maintain
a temperature of
50 C. The mixture was then stirred at room temperature for 20 hours. The
mixture was
partitioned between brine and ethyl acetate. The layers were separated and the
organic layer
20 washed with brine three times, dried over anhydrous magnesium sulfate and
concentrated. The
residue was dried on vacuum line. The crude residue was purified on silica gel
using hexanes
and ethyl acetate (95:5) to give 29.1 g of the title compound. MS (ESI+)
200.01 (M+H)+. 'H
NMR (400 MHz, CDCI3) S 6.61 (s, 1 H), 3.77 (s, 3H), 2.91 (s, 1 H), 1.22 (d,
6H).
25 EXAMPLE 47
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-propylthieno[2,3-
d]pyrimidine
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O ~I
0
N
N
S N
HgC
2,4-Dichloro-6-propylthieno[2,3-d]pyrimidine (Example 18, 0.68 g) was
dissolved in a mixture of
THF/DMF (5 mU2 mL) followed by addition of 1-(1,1'-biphenyl-4-
ylcarbonyl)piperazine (1.1 g)
and DIEA (0.46 g). The mixture was stirred overnight at room temperature and
then partitioned
between ethyl acetate and brine. The ethyl acetate layer was washed an
additional four times
with brine. The organic layer was dried over MgSO4, filtered and concentrated.
The resulting
residue was treated with acetonitrile containing a few drops of methanol and
the resulting solid
was collected and dried under reduced pressure to give 0.85 g of the title
compound. MS (ESI+)
m/z477.22 (M+H)+.'H NMR (400 MHz, CDCI3) S 7.66-7.38 (m, 9H), 6.93 (s, 1 H),
3.96 (br s, 8H),
2.82 (t, 2H), 1.74 (m, 2H), 1.00 (t, 3H).
EXAMPLE 48
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-
isopropylthieno[2,3-d]pyrimidine
o
N
1N
H3C N~CI
S
H3C
2,4-Dichloro-6-isopropylthieno[2,3-d]pyrimidine (Example 27, 1.0 g) was
dissolved in a mixture of
THF/DMF (5 mU2 mL) followed by addition of 1-(1,1'-biphenyl-4-
ylcarbonyl)piperazine (1.6 g, 4.0
mmol) and DIEA (0.68 g). The mixture was stirred overnight at room temperature
and then was
partitioned between ethyl acetate and brine. The ethyl acetate layer was then
washed an
additional four times with brine. The organic layer was dried over MgSO4,
filtered and
concentrated. The resulting residue was treated with acetonitrile containing a
few drops of
methanol and the resulting solid was collected and dried under vacuum to give
1.26 g of the title
compound. MS (ESI+) m/z477.029 (M+H)+. 'H NMR (400 MHz, CDCI3) S 7.66 to 7.36
(m, 9H),
6.92 (s, 1 H), 3.77 (br s, 8H), 3.18 (m, 1 H), 1.40 (d, 6H).
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EXAMPLE 49
tert-Butyl (3R)-4-(1,1'-biphenyl-4-ylcarbonyl)-3-methylpiperazine-1-
carboxylate
CH3 O
N
O N' J ~ \
~H3v
O,,, ~CH3
CH3
tert-Butyl (3R)-3-methylpiperazine-l-carboxylate (332 mg) and 1,1'-biphenyl-4-
carbonyl chloride
(300 mg) were placed in a flask with 2.5 mL of NMP and DIEA (0.5 mL). The
mixture was stirred
at room temperature overnight. The mixture was then diluted with ethyl acetate
and washed with
brine. The ethyl acetate layer was dried over MgSO4, filtered and
concentrated. The resulting
residue was purified by silica gel chromatography, eluting with 30:70 ethyl
acetate-hexanes, to
give 0.387 g of the title compound. MS (ESI+) for C23H28N2O3 m/z381.2192
(M+H)+. 'H NMR
(400 MHz, CDCI3) S 7.61 (d, 2H), 7.56-7.58 (m, 2H), 7.42-7.46 (m, 4H), 7.34-
7.38 (m, 1 H), 3.88-
4.13 (m, 4H), 2.84-3.21 (m, 3H), 1.45 (s, 9H), 1.26 (d, 3H).
EXAMPLE 50
tert-Butyl (3S)-4-(1,1'-biphenyl-4-ylcarbonyl)-3-methylpiperazine-l-
carboxylate
CH3 0
N
O NJ
OCH
~/bH3
ICH3
tert-Butyl (3S)-3-methylpiperazine-l-carboxylate (332 mg) and 1,1'-biphenyl-4-
carbonyl chloride
(300 mg) were placed in a flask with 2.5 mL of NMP and DIEA (0.5 mL). The
mixture was stirred
at room temperature overnight and then was diluted with ethyl acetate and
washed with brine.
The ethyl acetate layer was dried over MgSO4, filtered and concentrated. The
residue was
purified by silica gel chromatography, eluting with 30/70 ethyl
acetate/hexanes, to give 0.466 g of
the title compound. MS (ESI+) for C23H28N203 m/z (M+H)+ 381.41. 'H NMR (400
MHz,
CDCI3) 5 7.61 (d, 2H), 7.56-7.58 (m, 2H), 7.44 (t, 4H), 7.25-7.39 (m, 1 H),
3.88-4.13 (m, 4H), 2.84-
3.20 (m, 3H), 1.45 (s, 9H), 1.25 (d, 3H).
EXAMPLE 51
(2R)-1-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazine hydrochloride
CH3O
fJC N
HNJ
=HCl
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The carboxylate of Example 49 was placed in a flask and cooled to 0 C (ice
bath). 4N HCI in
dioxane (2 mL) was added. The mixture was stirred and gradually warmed to room
temperature.
After 90 minutes the mixture was diluted with ether. The resulting precipitate
was collected,
washed with ether, and dried to give 0.197g of the title compound. MS (ESI+)
for C18H20N20 m/z
281.1627 (M+H)+. 'H NMR (400 MHz, CD30D) 5 7.73-7.76 (m, 2H), 7.63-7.66 (m,
2H), 7.53-7.56
(m, 2H), 7.44-7.48 (m, 2H), 7.36-7.40 (m, 1 H), 4.73 (br s, 1 H), 4.23 (br s,
1 H), 3.45-3.53 (m, 1 H),
3.33-3.39 (m, 3H), 3.15-3.22 (m, 1 H), 1.44 (d, 3H).
EXAMPLE 52
(2S)-1-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazine hydrochloride
CH3o
~N I \
HNJ
=HC1
The carboxylate of Example 50 was placed in a flask and cooled to 0 C (ice
bath). 4N HCI in
dioxane (2 mL) was added. The reaction was stirred and gradually warmed to
room
temperature. After 90 minutes the mixture was diluted with ether. The
resulting precipitate was
collected, washed with ether, and dried to give 0.212 g of the title compound.
'H NMR (400
MHz, CD30D) 5 7.74-7.76 (m, 2H), 7.63-7.66 (m, 2H), HRMS (ESI+) for C18H2ON20
m/z
(M+H)+ 281.16047.53-7.56 (m, 2H), 7.44-7.48 (m, 2H), 7.36-7.40 (m, 1 H), 4.73
(br s, 1 H), 7.24
(br s, 1 H), 3.46-3.53 (m, 1 H), 3.29-3.39 (m, 3H), 3.15-3.22 (m, 1 H), 1.44
(d, 3H).
EXAMPLE 53
4-[(3R)-4-(1,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-2-chloro-6-
ethylthieno[2,3-
d]pyrimidine
~I
~ ~
o ~I
H3C N
NJ
~ I~~
H3C S N N CI
2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine (Example 3, 125.8 mg) was
dissolved in NMP
(2.5mL). To this was added (2R)-1-(1,1'-biphenyl-4-ylcarbonyl)-2-
methylpiperazine (170 mg)
followed by DIEA (0.19 mL). The mixture was stirred at room temperature
overnight and then
diluted with ethyl acetate and washed with brine. The ethyl acetate layer was
dried over MgS04,
filtered, and concentrated. The residue was purified by silica gel
chromatography (30:70 ethyl
acetate/hexanes) to give 0.234 g of the title compound. MS (ESI+) for
C26H25CIN4OS m/z477.14
(M+H)+. 'H NMR (400 MHz, CDCI3) 5 7.62-7.65 (m, 2H), 7.57-7.59 (m, 2H), 7.43-
7.49 (m, 4H),
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7.24-7.39 (m, 1 H), 6.92 (s, 1 H), 4.30-4.51 (m, 4H), 3.31-3.56 (m, 3H), 2.87
(q, 2H), 1.31-1.35 (m,
6H).
EXAMPLE 54
4-[(3S)-4-(1,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-2-chloro-6-
ethylthieno[2,3-
d]pyrimidine
i~
i ~
o ~~
H3CiCN~
N
/ N
H3C S N CI
2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine (Example 3, 0.126 g) was dissolved
in NMP (2.5mL).
To this was added (2S)-1-(1,1'-biphenyl-4-ylcarbonyl)-2-methylpiperazine (170
mg) followed by
DIEA (0.19 mL). The mixture was stirred at room temperature overnight and then
diluted with
ethyl acetate and washed with brine. The ethyl acetate layer was dried over
MgSO4, filtered, and
concentrated. The residue was purified by silica gel chromatography (30:70
ethyl
acetate:hexanes) to give 0.203 g of the title compound. MS (ESI+) for
C26H25CIN40S m/z
477.1484 (M+H)+. 'H NMR (400 MHz, CDCI3) 5 7.62-7.65 (m, 2H), 7.56-7.59 (m,
2H), 7.44-7.49
(m, 4H), 7.24-7.39 (m, 1 H), 6.92 (s, 1 H), 4.30-4.51 (m, 4H), 3.31-3.57 (m,
3H), 2.87 (q, 2H),
1.32-1.35 (m, 6H).
EXAMPLE 55
4-[(3R)-4-(1,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-2-{[(4S)-2,2-
dimethyl-1,3-dioxolan-
4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine
~I
H3C~N
NJ
/ tE)'
H3C S N 0'~O
O
3 CH3
(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (133 mg) was placed in a flask along
with 2.5 mL of
NMP. The mixture was cooled to 0 C and NaH (0.024 g of 60% dispersion in oil)
was added.
After stirring for 15 minutes at 0 C, the pyrimidine of Example 53 was added
as a solution in
NMP (2 mL). The mixture was allowed to warm to room temperature and was
stirred for an
additional 90 minutes. The mixture was then diluted with ethyl acetate and
washed with brine.
The ethyl acetate layer was dried over MgSO4, filtered and concentrated. The
resulting residue
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was purified by silica gel chromatography (35:65 ethyl acetate/hexanes) to
give 0.129 g of the
title compound. MS (ESI+) for C32H36N404S m/z573.2578 (M+H)+. 'H NMR (400 MHz,
CDCI3) S
7.62-7.64 (m, 2H), 7.57-7.59 (m, 2H), 7.43-7.48 (m, 4H), 7.35-7.39 (m, 1 H),
6.84 (s, 1 H), 4.11-
4.52 (m, 8H), 3.88-3.92 (m, 1 H), 3.49 (br s, 2H), 3.24-3.31 (m, 1 H), 2.83
(q, 2H), 1.58 (s, 3H),
1.29-1.44 (m, 9H).
EXAMPLE 56
4-[(3S)-4-(1,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-2-{[(4S)-2,2-
dimethyl-1,3-dioxolan-
4-yl]methoxy}-6-ethylthieno[2,3-d]pyrim idine
il
H3C/(N
N)
s ~N
H3C S ( N'..-J'0--)r0
O
H C CH3
3
(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (133 mg) was placed in flask along
with 2.5 mL of
NMP. The solution was cooled to 0 C and NaH (0.024 g of 60% dispersion in oil)
was added.
After stirring for 15 min at 0 C, the pyrimidine of Example 54 (0.160 g) was
added as a solution
in NMP (2 mL). The mixture was allowed to warm to room temperature and was
stirred for an
additional 90 min, after which the mixture was diluted with ethyl acetate and
washed with brine.
The ethyl acetate layer was dried over MgSO4, filtered and concentrated. The
resulting residue
was purified by silica gel chromatography (35:65 ethyl acetate/hexanes) to
give 0.137 g of the
title compound. MS (ESI+) for C32H36N404S m/z573.2532 (M+H)+. 'H NMR (400 MHz,
CDCI3) S
7.62-7.65 (m, 2H), 7.58-7.60 (m, 2H), 7.43-7.48 (m, 4H), 7.35-7.39 (m, 1 H),
6.84 (s, 1 H), 4.25-
4.52 (m, 6H), 4.11-4.15 (m, 2H), 3.88-3.92 (m, 1 H), 3.49 (br s, 2H), 3.24-
3.31 (m, 1 H), 2.83 (q,
2H), 1.44 (s, 3H), 1.36 (s, 3H), 1.29-1.36 (m, 6H).
EXAMPLE 57
tert-Butyl (3R)-4-(2-chloro-6-ethylthieno[2,3-d]pyrimidin-4-yi)-3-
methylpiperazine-l-carboxylate
O O CH~H3
~ t
C N ) CH3
,,.
H3C N
N
H3C S N CI
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2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine (Example 3, 0.300 g) and tert-
butyl (3R)-3-
methylpiperazine-l-carboxylate (0.307 g) were dissolved in NMP (2.5 mL)
followed by addition of
DIEA (0.5mL). The mixture was heated to 80 C and stirred at this temperature
overnight. The
mixture was then cooled to room temperature and diluted with ethyl acetate and
washed with
brine. The ethyl acetate layer was dried over MgSO4, filtered and
concentrated. The resulting
residue was purified by silica gel chromatography (20/80 ethyl
acetate/hexanes) to give 0.420 g
of the title compound. MS (ESI+) for C18H25CIN402S m/z397.1438 (M+H)+. 'H NMR
(300 MHz,
CDCI3) S 6.89 (s, 1 H), 4.77 (br s, 1 H), 4.37 (d, 1 H), 3.87-4.12 (m, 2H),
3.47 (t, 1 H), 3.06-3.24 (m,
2H), 2.86 (q, 2H), 1.47 (s, 9H), 1.33 (t, 6H).
EXAMPLE 58
tert-Butyl (3S)-4-(2-chloro-6-ethylthieno[2,3-d]pyrimidin-4-yl)-3-
methylpiperazine-l-carboxylate
O yO~ CHH3
N CH3
)
H3C N
I N
~
H3C N" 'CI
2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine (Example 3, 0.300 g) and tert-
butyl (3S)-3-
methylpiperazine-l-carboxylate (0.307 g) were dissolved in NMP (2.5 mL)
followed by addition of
DIEA (0.5mL). The mixture was heated to 80 C and stirred at this temperature
overnight. The
mixture was then cooled to room temperature and diluted with ethyl acetate and
washed with
brine. The ethyl acetate layer was dried over MgSO4, filtered and
concentrated. The resulting
residue was purified by silica gel chromatography (20:80 ethyl
acetate:hexanes) to give 0.409 g
of the title compound. MS (ESI+) for C1 H25CIN402S m/z397.1423 (M+H)+. 'H NMR
(400 MHz,
CDCI3) 5 6.90 (s, 1 H), 4.78 (br s, 1 H), 4.37 (d, 1 H), 3.89-4.14 (m, 2H),
3.47 (t, 1 H), 3.02-3.23 (m,
2H), 2.87 (q, 2H), 1.47 (s, 9H), 1.33 (t, 6H).
EXAMPLE 59
2-Chloro-6-ethyl-4-[(2R)-2-methylpiperazin-1-yl]thieno[2,3-d]pyrimidine
hydrochloride
H
N
,,..C) H3C N HCI
N
~
HaC S N 'CI
To tert-butyl (3R)-4-(2-chloro-6-ethylthieno[2,3-d]pyrimidin-4-yl)-3-
methylpiperazine-1-
carboxylate (Example 57, 0.350 g) was added 4N HCI in dioxane (2 mL) at 0 C.
The mixture
was allowed to warm to room temperature and stir for 90 min. The mixture was
then diluted with
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diethyl ether and the resulting solid was collected, washed with diethyl
ether, and dried under
reduced pressure to give 0.245 g of the title compound. MS (ESI+) for
C13H17CIN4S m/z
297.0900 (M+H)+. ' H NMR (400 MHz, CD3OD) S 7.23 (s, 1 H), 5.09-5.15 (m, 1 H),
4.69-4.73 (m,
1 H), 3.64-3.72 (m, 1 H), 3.48-3.52 (m, 1 H), 3.41 (d, 2H), 3.23-3.30 (m, 1
H), 2.93-2.99 (m, 2H),
1.52 (d, 3H), 1.36 (t, 3H).
EXAMPLE 60
2-Chloro-6-ethyl-4-((S)-2-methylpiperazin-1-yl)thieno[2,3-djpyrimidine
H
~ N
= HC1
H3C N
H3C / ~ '~
S N CI
To tert-butyl (3S)-4-(2-ch loro-6-ethylthieno[2,3-d]pyrim idin-4-yl)-3-m ethyl
piperazine-1 -carboxylate
(Example 58, 0.350 g) was added 4N HCI in dioxane (2 mL) at 0 C. The mixture
was allowed to
warm to room temperature and stir for 90 min, at which time the mixture was
diluted with diethyl
ether and the resulting solid was collected, washed with diethyl ether, and
dried under reduced
pressure to give 0.241 g of the title compound. MS (ESI+) for C13H17CIN4S
m/z297.0896
(M+H)+. 1 H NMR (400 MHz, CD3OD) 5 7.24 (s, 1 H), 5.11-5.14 (m, 1 H), 4.69-
4.73 (m, 1 H), 3.64-
3.72 (m, 1 H), 3.48-3.51 (m, 1 H), 3.41 (d, 2H), 3.23-3.30 (m, 1 H), 2.96 (q,
2H), 1.52 (d, 3H), 1.36
(t, 3H).
EXAMPLE 61
4-[(2R)-4-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-2-chloro-6-
ethylthieno[2,3-
d]pyrimidine
O
N
H3c~.~ N
N
H3C S N~CI
2-Chloro-6-ethyl-4-[(2R)-2-methylpiperazin-1-yl]thieno[2,3-d]pyrimidine
(Example 59, 0.210 g)
was dissolved in NMP (4 mL) and 1,1'-biphenyl-4-carbonyl chloride (204 mg,
0.94 mmol) was
added followed by DIEA (0.23 mL). The mixture was stirred at room temperature
overnight. The
mixture was diluted with ethyl acetate and washed with brine. The ethyl
acetate layer was dried
over MgSO4, filtered and concentrated and the resulting residue was purified
by silica gel
chromatography, eluting with 30/70 ethyl acetate/hexanes, to give 0.211 g of
the title compound.
MS (ESI+) for C26H25CIN4OS m/z477.1497 (M+H)+. 1H NMR (400 MHz, CDC13) 8 7.63-
7.65 (m,
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2H), 7.57-7.60 (m, 2H), 7.50 (d, 2H), 7.43-7.47 (m, 2H), 7.36-7.40 (m, 1 H),
6.90 (s, 1 H), 4.44-
4.86 (m, 3H), 3.1-4.0 (m, 4H), 2.87 (q, 2H), 1.31-1.61 (m, 6H).
EXAMPLE 62
4-[(2S)-4-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-2-chloro-6-
ethylthieno[2,3-
d]pyrimidine
o 4I
O'ec N
H3C N
N
~
HsC M 'CI
2-Chloro-6-ethyl-4-[(2S)-2-methylpiperazin-1-yl]thieno[2,3-dJpyrimidine
(Example 60, 0.210 g)
was dissolved in NMP (4 mL) and 1,1'-biphenyl-4-carbonyl chloride (204 mg,
0.94 mmol) was
added followed by DIEA (0.23 mL). The mixture was stirred at room temperature
overnight. The
mixture was then diluted with ethyl acetate and washed with brine and the
ethyl acetate layer
was dried over MgSO4, filtered and concentrated. The resulting residue was
chromatographed
on silica gel (30/70 Othyl acetate/hexanes) to give 0.165 g of the title
compound. MS (ESI+) for
C26H25CIN40S m/z477.1501 (M+H)+. iH NMR (400 MHz, CDCI3) S 7.63-7.65 (m, 2H),
7.57-7.61
(m, 2H), 7.51 (d, 2H), 7.45-7.48 (m, 2H), 7.36-7.40 (m, 1 H), 6.90 (s, 1 H),
4.44-4.85 (m, 3H), 3.0-
4.0 (m, 4H), 2.87 (q, 2H), 1.1.31-1.61 (m, 6H).
EXAMPLE 63
4-[(2R)-4-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-2-{[(4S)-2,2-
dimethyl-1,3-dioxolan-
4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine
~I
o ~I
rNl
H30 N
,~
H3C S N O--g-\O
~C CH3
((S)-2,2- Dim ethyl-1,3-d ioxolan-4-yl)m ethanol (0.133 g) was placed in flask
along with 2.5 mL of
NMP. The mixture was cooled to 0 C and NaH (0.024 g of 60% dispersion in oil)
was added.
After stirring for 15 min at 0 C, 4-[(2R)-4-(1,1'-biphenyl-4-ylcarbonyl)-2-
methylpiperazin-1-yl]-2-
chloro-6-ethylthieno[2,3-d]pyrimidine (Example 61, 0.160 g) was added as a
mixture in NMP (2
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mL). The mixture was allowed to warrn to-room temperature and was stirred for
an additional 90
min. The mixture was diluted with ethyl acetate and washed with brine. The
ethyl acetate layer
was dried over MgSO4, filtered and concentrated. Silica gel chromatography
(40/60 ethyl
acetate/hexanes) gave 0.098 g of the title compound. MS (ESI+) for C32H36N404S
m/z 573.2523
(M+H)+. 'H NMR (400 MHz, CDCI3) 8 7.64 (d, 2H), 7.59 (d, 2H), 7.50 (d, 2H),
7.45 (t, 2H), 7.35-
7.39 (m, 1 H), 6.83 (s, 1 H), 4.40-4.82 (m, 5H), 4.24-4.29 (m, 1 H), 4.11-4.15
(m, 1 H), 3.88-3.91
(m, 1 H), 3.20-3.70 (m, 4H), 2.82 (q, 2H), 1.43 (s, 3H), 1.35 (s, 3H), 1.29-
1.36 (m, 6H).
EXAMPLE 64
4-[(2S)-4-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-2-{[(4S)-2,2-
dimethyl-1,3-dioxolan-
4-yl]methoxy}-6-ethylthieno[2,3-d]pyrim idine
il .
i ~
O
~N
H3C N
I,~
HsC S N 0'-g~O
OC CH3
((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (0.133 g) was placed in flask
along with 2.5 mL of
NMP. The mixture was cooled to 0 C and NaH (0.024 mg of 60% dispersion in oil)
was added.
After stirring for 15 min at 0 C, 4-[(2S)-4-(1,1'-biphenyl-4-ylcarbonyl)-2-
methylpiperazin-l-yl]-2-
chloro-6-ethylthieno[2,3-d]pyrimidine (Example 62, 0.120 g) was added as a
mixture in NMP (2
mL). The mixture was allowed to warm to room temperature and was stirred for
an additional 90
min. The mixture was diluted with ethyl acetate and washed with brine. The
ethyl acetate layer
was dried over MgSO4, filtered and concentrated. Silica gel chromatography
(40/60 ethyl
acetate/hexanes) gave 0.079 g of the title compound. MS (ESI+) for C32H36N404S
m/z 573.2538
(M+H)+. 'H NMR (400 MHz, CDCI3) S 7.64 (d, 2H), 7.58-7.60 (m, 2H), 7.50 (d,
2H), 7.43-7.47 (m,
2H), 7.36-7.39 (m, 1 H), 6.83 (s, 1 H), 4.40-4.57 (m, 5H), 4.25-4.29 (m, 1 H),
4.11-4.15 (m, 1 H),
3.87-3.91 (m, 1 H), 3.20-3.80 (m, 4H), 2.82 (q, 2H), 1.55 (s, 3H), 1.36-1.43
(m, 6H), 1.31 (t, 3H).
EXAMPLE 65
4-[4-(1,1'-biphenyl-3-ylcarbonyl)piperazin-1 -yl]-2-chloro-6-ethylthieno[2,3-
d]pyrimidine
O
CN~
N
I'N
H3C S N-J, CI
To the carboxylate of Example 12 (1.22 g) in dichloromethane (10 mL) was added
HCI/MeOH
(50 mL, prepared by the addition of 1.25 g of acetyl chloride to 50 mL of
MeOH). The mixture
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was stirred at room temperature-overnight, after which an additional 5
equivalents of HCI/MeOH
(prepared as above) was added. After stirring for 4.5 hours, the mixture was
concentrated to
near dryness and diethyl ether was added. The resulting solid was collected
and dried to give
1.08 g of the hydrochloride salt of Example 23. To biphenyl-3-carboxylic acid
(0.49 g) in
dichloromethane (10 mL) was added 1,1'-carbonyldiimidazole (0.40 g). The
mixture was stirred
for 45 min, after which a slurry prepared from the hydrochloride salt of
Example 23 (0.75 g),
triethylamine (0.33 mL), dichloromethane (15 mL), and DMF (1 mL) was added.
The mixture
was stirred at room temperature overnight, after which it was partitioned
between
dichloromethane and saturated aq. sodium bicarbonate. The organic layer was
dried over
sodium sulfate and concentrated. Crystallization from dichloromethane-hexane
gave 0.91 g of
the title compound. MS [m+H] 463.3;'H NMR (400 MHz, CDCI~,) S 1.34 (3H), 2.88
(2H), 3.6-4.1
(8H), 6.93 (1 H), 7.36-7.53 (5H), 7.58-7.69 (4H).
EXAMPLE 66
(2R)-3-[(6-Ethyl-4-{4-[(5-phenyl-1,3,4-oxadiazol-2-yl)carbonyl]piperazin-1-
yl}thieno[2,3-
d]pyrim idin-2-yl)oxy]propane-1,2-diol
N.N
(N)
N
H3C N
S N O-*-~OH
OH
To a mixture of the diol hydrochloride salt of Example 22 (0.103 g) in THF
(3.0 mL) were added
diisopropylethylamine (0.087 g) and 5-phenyl-1,3,4-oxadiazole-2-carbonyl
chloride (0.057 g).
The mixture was stirred at room temperature for 18 hours. The solvents were
removed under
reduced pressure and the residue chromatographed on silica gel (100 mL) using
5% methanol in
ethyl acetate to give 0.0238 g of the title compound: 'H NMR (400 MHz, CDCI3)
S 1.35 (t, 3 H),
2.87 (q, 2 H), 3.73 (m, 2 H), 4.0-4.13 (m, 6 H), 4.46 (m, 2 H), 4.50 (m, 2 H),
6.91 (s, 1 H), 7.52-
7.60 (m, 3 H), 8.16 (d, 2 H).
EXAMPLE 67
(2R)-3-[(6-Ethyl-4-{4-[(2-phenyl-1,3-thiazol-4-yl)carbonyl]piperazin-1-
yl}thieno[2,3-d]pyrim idin-2-
yl)oxy]propane-1,2-diol
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S
(N)
N
H3C N
S NO"')rOH
OH
To a mixture of the diol hydrochloride salt of Example 22 (0.1 g) in THF (5
mL) and NMP (2 mL)
was added diisopropylethylamine (0.116 g), HATU (0.114 g), and 2-phenyl-1,3-
thiazole-4-
carboxylic acid (0.055 g). The mixture was stirred at room temperature for 18
hours. The mixture
was partitioned between brine and ethyl acetate. The layers were separated and
the organic
layer washed three times with brine, dried over anhydrous magnesium sulfate
and concentrated.
The residue was chromatographed on silica gel (100 mL) using 5% methanol in
ethyl acetate to
give 0.0446 g of the title compound: MS (ESI+) for C25H27N504S2 m/z526.18
(M+H)+. 'H NMR
(400 MHz, CDCI3) S 1.34 (t, 3 H), 2.85 (q, 2 H), 3.67-3.77 (m, 2 H), 3.98-4.1
(m, 6 H), 4.29 (m, 2
H), 4.51 (m, 2 H), 6.92 (s, 1 H), 7.47 (m, 3 H), 7.95 (m, 2 H), 8.03 (s, 1 H).
EXAMPLE 68
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-(2-ethoxyethoxy)-6-
ethylthieno[2,3-d]pyrim idine
O
N'
CJl
N
H3C I
S N- O~iO~CH3
To a mixture of the pyrimidine of Example 24 (0.116 g) in THF (3 mL) were
added
diisopropylethylamine (0.098 g), and 4-biphenyl carbonyl chloride (0.082 g).
The mixture was
stirred at room temperature for 3.5 hours. The mixture was partitioned between
brine and ethyl
acetate. The layers were separated and the organic layer washed three times
with brine, dried
over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed on
silica gel (100 mL) using ethyl acetate-hexanes (30/70) to give 0.0603 g of
the title compound:
MS (ESI+) for C29H32N403S m/z517.37 (M+H)+. 'H NMR (400 MHz, CDCI3) 51.21 (t,
3 H), 1.32
(t, 3 H), 2.84 (q, 2 H), 3.58 (q, 2 H), 3.6-4.0 (m, 10 H), 4.49 (m, 2 H), 6.85
(s, 1 H), 7.38 (m, 1 H),
7.46 (m, 2 H), 7.52 (d, 2 H), 7.60 (d, 2 H), 7.65 (d, 2 H).
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EXAMPLE 69 -
(2R)-3-({4-[4-(1,1'-Biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol
O
N
(N)
H3C / . N
s I
N~O-'J"OH
OH
HCI gas was bubbled through methanol (50 mL) for 1 minute then cooled to room
temperature.
The pyrimidine of Example 26 (0.15 g) was added. The mixture was stirred at
room temperature
for 15 minutes. The solvents were removed under reduced pressure and the
residue was
partitioned between saturated sodium bicarbonate and ethyl acetate. The layers
were separated
and the organic layer dried over anhydrous magnesium sulfate and concentrated
to dryness to
give 0.0868 g of the title compound: 'H NMR (400 MHz, CDCI3) S 1.32 (t, 3 H),
2.84 (q, 2 H),
3.6-3.8 (m, 3 H), 3.94 (m, 6 H), 4.08 (m, 1 H), 4.48 (m, 2 H), 6.87 (s, 1 H),
7.36-7.53 (m, 5 H),
7.59 (d, 2 H), 7.66 (m, 2 H).
EXAMPLE 70
(2R)-3-({4-[4-(3-Bromobenzoyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-
yl}oxy)propane-1,2-
diol
O a Br
(N)
N
~
H3C / I -
S N O"~OH
OH
HCI gas was bubbled through methanol (15 mL) for 1 minute then cooled to room
temperature
and added to the pyrimidine of Example 28 (0.4 g). The mixture was stirred at
room temperature
for 2.5 hours. The solvents were removed under reduced pressure and the
residue was
triturated in ethyl acetate. The resulting solids were collected via
filtration to give 0.298 g of the
title compound: MS (ESI+) for C22H25BrN4O4S mIz523.17 (M+H)+. 'H NMR (400 MHz,
DMSO-
ds) S 1.13 (t, 3 H), 2.8 (q, 2 H), 3.4-4.0 (m, 11 H), 4.14 (m, 1 H), 4.'30 (m,
1 H), 7.24 (s, 1 H), 7.45
(m, 2 H), 7.65 (m, 2 H).
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EXAMPLE 71
(2S)-4-({4-[4-(1,1'-Biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrim idin-2-
yl}oxy)butane-1,2-diol
o
N
N
H3C ~ I~ N OH
s N~o~~OH
To a mixture of 2-{2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}-6-ethyl-4-
piperazin-l-
ylthieno[2,3-d]pyrimidine (Example 29, 0.222 g) in NMP (5 mL) were added 3-
biphenyl carboxylic
acid (0.112 g), HATU (0.215 g), and diisopropylethylamine (0.155 g). The
mixture was stirred at
room temperature for 2.5 hours at which time the mixture was partitioned
between brine and
ethyl acetate. The layers were separated and the organic layer washed three
times with brine,
dried over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed
on silica gel (100 mL) using ethyl acetate as eluent. The residue was
dissolved in HCI/methanol
(10 mL) and stirred at room temperature for 2 hours. The solvents were removed
under reduced
pressure and the residue dried under reduced pressure to give 0.1136 g of the
title compound:
MS (ESI+) for C29H32N4O4S m/z533.31 (M+H)+.'H NMR (400 MHz, CDCI3) 6 1.23 (t,
3 H), 1.8
(m, 1 H), 1.9 (m, 1 H), 2.76 (q, 2 H), 3.4-3.6 (m, 2 H), 3.8-4.4 (m, 9 H), 4.6
(m, 2 H), 6.99 (s, 1 H);
7.3 (m, 1 H), 7.4 (m, 4 H), 7.38 (d, 2 H), 7.54 (d, 1 H), 7.66 (s, 1 H).
EXAMPLE 72
3-{[4-(2-{[(2R)-2,3-Dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrim idin-4-
yl)piperazin-1-
yl]carbonyl}benzonitrile
O ~I
(N) N
N
H30 I N
S N~p"~~'OH
OH
To a mixture of the diol hydrochloride salt of Example 22 (0.1 g) in NMP (5
mL) was added
diisopropylethylamine (0.076 g), HATU (0.102 g), and 3-cyanobenzoic acid (0.04
g). The mixture
was stirred at room temperature for 3.5 hours. The mixture was partitioned
between brine and
ethyl acetate. The layers were separated and the organic layer washed three
times with brine,
dried over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed
on silica gel (100 mL) using 10% ethyl acetate in hexanes to give 0.0386 g of
the title compound:
MS, (ESI+) for C23H25N504S m/z468.31 (M+H)+. 1 H NMR (400 MHz, CDCI3) 8 1.33
(t, 3 H), 2.85
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(q, 2 H), 3.6-4.0 (m, 10 H), 4.08 (m, 1 H), 4.48 (m, 2 H), 6.86 (s, 1 H), 7.58
(t, 1 H), 7.69 (d, 1 H),
7.75 (m, 2 H).
EXAMPLE 73
3'-{[4-(2-{[(2R)-2,3-Dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrim idin-4-
yl)piperazin-1-
yl]carbonyl}-1,1'-biphenyl-4-carboxylic acid
/ I .
O
N OH
CN~ O
H3C I ~ N
S N~O"*--J'OH
OH
To a mixture of the carboxylic acid of Example 31 (0.0868 g) in dioxane (4.0
mL) and water (0.7
mL) was added 4N HCI in dioxane (1 mL). The mixture was stirred at room
temperature for 1
hour. The solvents were removed under reduced pressure. Toluene (10 mL) was
added then
removed under reduced pressure three times. The solids were triturated in
diethyl ether and
filtered to give 0.0675 g of the title compound: MS (ESI+) for C29H30N406S m/z
563.35 (M+H)+.
'H NMR (400 MHz, DMSO-ds) S 1.23 (t, 3 H), 2.8 (q, 2 H), 3.4 (m, 2 H), 3.58
(m, 2 H), 3.77 (m, 2
H), 3.89 (m, 2 H), 4:0 (m, 2 H), 4.3 (m, 2 H), 7.24 (s, 1 H), 7.4-7.6 (m, 4
H), 7.83 (d, 2 H), 8.0 (d,
2 H).
EXAMPLE 74
3-({4-[4-(1,1'-Biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylth ieno[2,3-
d]pyrim idin-2-
yl}oxy)propanoic acid
N I /
N
H3C N O
S N~O" OH
To a mixture of the propanal of Example 33 (0.168 g) in methylene chloride (5
mL) was added m-
chloroperoxybenzoic acid (0.078 g). The mixture was stirred at room
temperature for 4 hours
then chromatographed on silica gel (100 mL) using 2% methanol and 0.1% glacial
acetic acid in
hexanes to give 0.0708 g of the title compound: MS (ESI+) for C28H28N404S m/z
517.25 (M+H)+.
'H NMR (400 MHz, CDCI3) S 1.31 (t, 3 H), 2.87 (m, 4 H), 3.67 (m, 2 H), 3.8-4.0
(m, 6 H), 4.61 (m,
2 H), 6.84 (s, 1 H), 7.37-7.52 (m, 5 H), 7.58 (d, 2 H), 7.67 (m, 2 H).
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EXAMPLE 75
(2R)-3-({6-Ethyl-4-[4-(3-pyridin-3-ylbenzoyl)piperazin-1 -yl]thieno[2,3-
d]pyrim idin-2-
yl}oxy)propane-1,2-diol
o
N (N) NH3C IN
S N~O11_~OH
OH
To a mixture of the pyrimidine of Example 28 (0.1 g) and NMP (2 mL) in a 2
dram screw capped
vial were added pyridine-3-boronic acid (0.033 g), 5M K3P04 (1 mL), palladium
II acetate (0.006
g) and, tri-o-tolyl phosphine (0.046 g). The vial was placed into a Lab-Line
MAX Q2000 orbital
shaker at 80 C for 8 hours. The mixture was partitioned between brine and
ethyl acetate,
separated the layers and washed the organic layer three times with brine. The
organic layer was
dried over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed
on silica gel (100 mL) using ethyl acetate as eluent. The resulting residue
was dissolved in
methanol (3 mL) and 4N HCI in dioxane was added. The mixture was stirred at
room
temperature for 1 hour. The mixture was partitioned between saturated sodium
bicarbonate and
ethyl acetate. The layers were separated and the organic layer dried over
anhydrous
magnesium sulfate and concentrated to dryness to give 0.0253 g of the title
compound: MS
(ESI+) for C27H29N504S m/z520.33 (M+H)+. 'H NMR (400 MHz, CDCI3) S 1.32 (t, 3
H), 2.84 (q, 2
H), 3.7 (m, 4 H), 3.9 (m, 6 H), 74.08 (m, 1 H), 4.47 (rn, 2 H), 6.86 (s, 1 H),
7.42 (m, 1 H), 7.48 (m,
1 H), 7.56 (m, 1 H), 7.66 (m, 2 H), 7.71 (d, 1 H), 8.62 (s, 1 H), 8.86 (s, 1
H).
EXAMPLE 76
(2R)-3-[(6-Ethyl-4-{4-[(3'-fluoro-1,1'-biphenyl-3-yl)carbonyl]piperazin-l-
yl}thieno[2,3-d]pyrimidin-2-
yl)oxy]propane-1,2-diol
NJ
N F
H3C N
S N~O1'~~OH
OH
To a mixture of pyrimidine of Example 28 (0.1 g) and NMP (2 mL) in a 2 dram
screw capped vial
were added 3-fluorophenyl boronic acid (0.038 g), 5M K3P04 (1 mL), palladium
II acetate (0.006
g) and, tri-o-tolyl phosphine (0.046 g). The vial was placed into a Lab-Line
MAX Q2000 orbital
shaker at 80 C for 8 hours. The mixture was partitioned between brine and
ethyl acetate,
separated the layers and washed the organic layer three times with brine. The
organic layer was
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dried over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed
on silica gel (100 mL) using 1:1 ethyl acetate : hexanes as eluent. The
resulting residue was
dissolved in methanol (3 mL) and 4N HCI in dioxane was added. The mixture was
stirred at
room temperature for 1 hour. The mixture was partitioned between saturated
sodium
bicarbonate and ethyl acetate. The layers were separated and the organic layer
dried over
anhydrous magnesium sulfate and concentrated to dryness to give 0.0558 g of
the title
compound: MS (ESI+) for C28H29FN404S m/z 537.34 (M+H)+. 'H NMR (400 MHz,
CDCI3) S 1.32
(t, 3 H), 2.84 (q, 2 H), 3.69 (m, 4 H), 3.94 (m, 6 H), 4.08 (m, 1 H), 4.47 (m,
2 H), 6.86 (s, 1 H),
7.05 (m, 1 H), 7.28 (m, 1 H), 7.37 (m, 1 H), 7.41 (m, 2H), 7.52 (m, 2H), 7.64
(m, 2H).
EXAMPLE 77
(2R)-3-({6-Ethyl-4-[4-(3-pyrim idin-5-ylbenzoyl)piperazin-1-yl]thieno[2,3-
d]pyrim idin-2-
yl}oxy)propane-1,2-diol
O N
N INJ
CNJ
H3C N
S N~O-"j-"OH
OH
To a mixture of pyrimidine of Example 28 (0.1 g) and NMP (2 mL) in a 2 dram
screw capped vial
were added pyrimidine-5-boronic acid (0.033 g), 5M K3PO4 (1 mL), palladium II
acetate (0.006 g)
and, tri-o-tolyl phosphine (0.046 g). Placed the vial into a Lab-Line MAX
Q2000 orbital shaker at
80 C for 8 hours. The mixture was partitioned between brine and ethyl
acetate, separated the
layers and washed the organic layer three times with brine. The organic layer
was dried over
anhydrous magnesium sulfate and concentrated. The residue was chromatographed
on silica
gel (100 mL) using ethyl acetate as eluent. The resulting residue was
dissolved in methanol (3
mL) and 4N HCI in dioxane was added. The mixture was stirred at room
temperature for 1 hour.
The mixture was partitioned between saturated sodium bicarbonate and ethyl
acetate. The
layers were separated and the organic layer dried over anhydrous magnesium
sulfate and
concentrated to dryness to give 0.0101 g of the title compound: MS (ESI+) for
C26H28N604S m/z
521.34 (M+H)+. 'H NMR (400 MHz, CDCI3) 81.33 (t, 3 H), 2.85 (q, 2 H), 3.6-3.8
(m, 4 H), 3.8-
4.05 (m, 6 H), 4.08 (m, 1 H), 4.47 (m, 2 H), 6.87 (s, 1 H), 7.53 (m, 1 H),
7.63 (m, 1 H), 7.69 (m, 2
H), 8.97 (s, 2 H), 9.24 (s, 1 H).
EXAMPLE 78
(2R)-3-[(4-{4-[(3',4'-Difluoro-1,1'-biphenyl-3-yl)carbonyl]piperazin-1-yl}-6-
ethylthieno[2,3-
d]pyrim idin-2-yl)oxy]propane-1,2-diol
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O
N F
N F
N
H3C / I
S N~O__~OH
OH
To a mixture of pyrimidine of Example 28 (0.1 g) and NMP (2 mL) in a 2 dram
screw capped vial
were added 3,4-difluorophenyl boronic acid (0.042 g), 5M K3P04 (1 mL),
palladium II acetate
(0.006 g) and, tri-o-tolyl phosphine (0.046 g). The vial was placed into a Lab-
Line MAX 02000
orbital shaker at 80 C for 8 hours. The mixture was partitioned between brine
and ethyl acetate,
separated the layers and washed the organic layer three times with brine. The
organic layer was
dried over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed
on silica gel (100 mL) using 1:1 ethyl acetate:hexanes as eluent. The
resulting residue was
dissolved in methanol (3 mL) and 4N HCI in dioxane was added. The mixture was
stirred at
room temperature for 1 hour. The mixture was partitioned between saturated
sodium
bicarbonate and ethyl acetate. The layers were separated and the organic layer
dried over
anhydrous magnesium sulfate and concentrated to dryness to give 0.009 g of the
title compound:
MS (ESI+) for C28H28F2N404S m/z555.29 (M+H)+. 'H NMR (400 MHz, CQCI3) 5 1.32
(t, 3 H),
2.85 (q, 2 H), 3.6-3.8 (m, 4 H), 3.8-4.0 (m, 6 H), 4.08 (m, 1 H), 4.48 (m, 2
H), 6.87 (s, 1 H), 7.2-
7.35 (m, 2 H), 7.38-7.744 (m, 2 H), 7.51 (m, 1 H), 7.6 (m, 2 H).
EXAMPLE 79
(2R)-3-[(6-Ethyl-4-{4-[(4-phenylpyridin-2-yl)carbonyl]piperazin-1-yl}th
ieno[2,3-d]pyrim idin-2-
yl)oxy]propane-1,2-diol
N~
O ~I \
N
CNJ
H3C N
S N~O"-~OH
OH
To a mixture of diol hydrochloride salt of Example 22 (0.15 g) in NMP (2 mL)
was added
diisopropylethylamine (0.155 g), 4-phenylpyridine-2-carboxylic acid (0.08 g),
and HATU (0.152
g). The mixture was stirred at room temperature for 4 hours at which time the
mixture was
partitioned between brine and ethyl acetate. The layers were separated and the
organic layer
washed five times with brine, dried over anhydrous magnesium sulfate and
concentrated to give
0.0651 g of the title compound: MS (ESI+) for C27H29N504S m/z520.33 (M+H)+. 'H
NMR (400
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113
MHz, CDCI3) 51.33 (t, 3-H), 2:85 (q;-2 H); 3.6-3.8 (m, 2 H), 3.92 (m, 2 H),
3.96 (m, 4 H), 4.07 (m,
3 H), 4.49 (m, 2 H), 6.9 (s, 1 H), 7.47 (m, 3 H), 7.6 (m, 1 H), 7.67 (m, 2 H),
7.97 (s, 1 H), 8.64 (d,
2 H).
EXAMPLE 80
(2R)-3-[(6-Ethyl-4-{4-[(4'-methyl-1,1'-biphenyl-3-yl)carbonyl] piperazin-1-
yl}th ieno[2,3-d]pyrim idin-
2-yl)oxy]propane-1,2-diol
O
N
CH3
NJ
H3C N
S I
N ~O"-~OH
OH
To a mixture of pyrimidine of Example 28 (0.1 g) and NMP (2 mL) in a 2 dram
screw capped vial
were added p-tolylboronic acid (0.037 g), 5M K3P04 (1 mL), palladium 11
acetate (0.004 g) and,
tri-o-tolyl phosphine (0.008 g). The vial was placed into a Lab-Line MAX Q2000
orbital shaker at
80 C for 8 hours. The mixture was partitioned between brine and ethyl
acetate, separated the
layers and washed the organic layer three times with brine. The organic layer
was dried over
anhydrous magnesium sulfate and concentrated. The residue was chromatographed
on silica
gel (100 mL) using 1:1 ethyl acetate:hexanes as eluent. The resulting residue
was dissolved in
methanol (3 mL) and 4N HCI in dioxane was added. The mixture was stirred at
room
temperature for 1 hour. The mixture was partitioned between saturated sodium
bicarbonate and
ethyl acetate. The layers were separated and the organic layer dried over
anhydrous
magnesium sulfate and concentrated to dryness to give 0.0249 g of the title
compound: MS
(ESI+) for C29H32N404S m/z 533.37 (M+H)+. 'H NMR (400 MHz, CDCI3) S 1.31 (t, 3
H), 2.39 (s, 3
H), 2.83 (q, 2 H), 3.6-3.8 (m, 4 H), 3.8-4.0 (m, 6 H), 4.07 (m, 1 H), 4.46 (m,
2 H), 6.85 (s, 1 H),
7.15 (m, 1 H), 7.25 (m, 2 H), 7.38 (m, 1 H), 4.48 (m, 2 H), 7.64 (m, 2 H).
EXAMPLE 81
(2R)-3-[(6-Ethyl-4-{4-[3-(4-methoxypyridin-3-yl)benzoyl]piperazin-l-
yl}thieno[2,3-d]pyrimidin-2-
yl)oxy]propane-1,2-diol
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114
/
0 \ I ~N
N1 I / O
C J
N CH3
H3C N
S N- C11"'~OH
OH
To a mixture of pyrimidine of Example 28 (0.114 g) and NMP (2 mL) in a 2 dram
screw capped
vial were added 2-methoxy-5-pyridyl boronic acid (0.037 g), 5M K3P04 (0.5 mL),
palladium 11
acetate (0.012 g) and, tri-o-tolyl phosphine (0.047 g). The vial was placed
into a Lab-Line MAX
Q2000 orbital shaker at 80 C for 8 hours. The mixture was partitioned between
brine and ethyl
acetate, separated the layers and washed the organic layer three times with
brine. The organic
layer was dried over anhydrous magnesium sulfate and concentrated. The residue
was
chromatographed on silica gel (100 mL) using 1:1 ethyl acetate : hexanes as
eluent. The
resulting residue was dissolved in methanol (3 mL) and 4N HCI in dioxane was
added. The
mixture was stirred at room temperature for 1 hour. The mixture was
partitioned between
saturated sodium bicarbonate and ethyl acetate. The layers were separated and
the organic
layer dried over anhydrous magnesium sulfate and concentrated to dryness to
give 0.0437 g of
the title compound: MS (ESI+) for C28H31N505S m/z550.38 (M+H)}. 'H NMR (400
MHz, CDCI3)
51.3 (t, 3 H), 2.82 (q, 2 H), 3.68 (m, 4 H), 3.95 (m, 6 H), 4.07 (m, 1 H),
4.45 (m, 2 H), 6.83 (m, 2
H), 7.39 (d, 1 H), 7.5 (t, 1 H), 7.58 (m, 2H), 7.77 (dd, 1 H), 8.37 (m, 1 H).
EXAMPLE 82
3'-{[4-(2-{[(2R)-2,3-Dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-
yl)piperazin-1-
yl]carbonyl}-1,1'-biphenyl-3-carbonitrife
0 I N
N
N
H3C N
S ,C'OH
OH
To a mixture of the pyrimidine of Example 28 (0.135 g) and NMP (2 mL) in a 2
dram screw
capped vial were added 3-cyanophenyl boronic acid (0.053 g), 5M K3PO4 (0.5
mL), palladium fi
acetate (0.005 g) and, tri-o-tolyl phosphine (0.015 g). The vial was placed
into a Lab-Line MAX
Q2000 orbital shaker at 90 C for 8 hours. The mixture was partitioned between
brine and ethyl
acetate, separated the layers and washed the organic layer three times with
brine. The organic
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115
layer was dried over anhydrous magnesium sulfate and concentrated. The residue
was
chromatographed on silica gel (100 mL) using 1:1 ethyl acetate : hexanes as
eluent. The
resulting residue was dissolved in methanol (3 mL) and 4N HCI in dioxane was
added. The
mixture was stirred at room temperature for 1 hour. The mixture was
partitioned between
saturated sodium bicarbonate and ethyl acetate. The layers were separated and
the organic
layer dried over anhydrous magnesium sulfate and concentrated to dryness to
give 0.00271 g of
the title compound: MS (ESI+) for C29H29N504S m/z544.33 (M+H)+. 'H NMR (400
MHz, CDCI3)
S 1.31 (t, 3 H), 2.83 (q, 2 H), 3.69 (m, 4 H), 3.8-4.0 (m, 6 H), 4.07 (m, 1
H), 4.44 (m, 2 H), 6.85 (s,
1 H), 7.46 (d, 1 H), 7.56 (m, 2 H), 7.65 (m, 3 H), 7.81 (d, 1 H), 7.86 (s, 1
H).
EXAMPLE 83
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(2-morpholin-4-
ylethoxy)thieno[2,3-
d]pyrimidine
O ~ I
(N)
N
H3C rO
S NN
Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
15 minutes. 4-(2-Hydroxyethyl)morpholine (0.08 mL) was added and the mixture
stirred for 30
minutes. The pyrimidine of Example 13 (0.15 g) was dissolved in NMP (2.0 mL)
and added drop-
wise to the chilled mixture. Once the addition was complete the mixture was
removed from the
ice/acetone bath and stirred at room temperature for 3 hours. The mixture was
then partitioned
between saturated sodium bicarbonate and ethyl acetate. The layers were
separated and the
organic layer washed three times with brine, dried over anhydrous magnesium
sulfate and
concentrated to dryness to give 0.0938 g of the title compound: MS (ESI+) for
C31H35N5O3S m/z
558.44 (M+H)+. 1H NMR (400 MHz, CDCI3) S 1.32 (t, 3 H), 2.57 (m, 4 H), 2.83
(m, 4 H), 3.71 (m,
4 H), 3.91 (m, 4 H), 4.48 (m, 2 H), 6.86 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2
H), 7.53 (d, 2 H), 7.61
(d, 2 H), 7.65 (d, 2 H).
EXAMPLE 84
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(2-piperazin-1-
ylethoxy)thieno[2,3-
d]pyrimidine
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116
O I
(N)
N
H3C N rNH
S N~N.,)
Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
15 minutes. 1-(2-Hydroxyethyl) piperazine (0.08 mL) was added and the mixture
stirred for 30
minutes. The pyrimidine of Example 13 (0.15 g) was dissolved in NMP (2.0 mL)
and added drop-
wise to the chilled mixture. Once the addition was complete the mixture was
removed from the
ice/acetone bath and stirred at room temperature for 3 hours. The mixture was
then partitioned
between saturated sodium bicarbonate and ethyl acetate. The layers were
separated and the
organic layer washed three times with brine, dried over anhydrous magnesium
sulfate and
concentrated. Water (20 mL) was added,to the residue. The resulting solids
were filtered and
dried under high vacuum to dryness to give 0.109 g of the title compound: MS
(ESI+) for
C31H36N602S m/z557.43 (M+H)+. 'H NMR (400 MHz, CDCI3) S 1.32 (t, 3 H), 2.6 (m,
4 H), 2.8
(m, 4 H), 2.95 (m, 4 H), 3.6-4.0 (m, 8 H), 4.46 (m, 2 H), 6.85 (s, 1. H), 7.36
(m, 1 H), 7.46 (m, 2
H), 7.52 (d, 2 H), 7.59 (d, 2 H), 7.64 (d, 2 H).
EXAMPLE 85
(2S)-4-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-y1]-6-ethylthieno[2,3-
d]pyrim idin-2-
yl}oxy) butane-1,2-diol
I
O I
(N)
N
H3C / ( N OH
S N~p~~~OH
To a mixture of 2-{2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}-6-ethyl-4-
piperazin-1-
ylthieno[2,3-d]pyrimidine (Example 29, 0.270 g) in DMF (5 mL) were added
diisopropylethylamine (0.196 g), and 4-biphenyl carbonyl chloride (0.150 g).
The mixture was
stirred at room temperature for 3.5 hours. The mixture was partitioned between
brine and ethyl
acetate. The layers were separated and the organic layer washed three times
with brine, dried
over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed on
silica gel (100 mL) using ethyl acetate-hexanes (40/60). The residue was then
dissolved in
methanol (4 mL) and 4N HCI in dioxane (2 mL) was added. The mixture was
stirred at room
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117
temperature for 2.5 hours, at which time the mixture was partitioned between
saturated sodium
bicarbonate and ethyl acetate. The layers were separated and the organic layer
dried over
anhydrous magnesium sulfate and concentrated to dryness under reduced pressure
to give
0.019 g of the title compound: MS (ESI+) for C29H32N404S m/z533.37 (M+H)+. 'H
NMR (400
MHz, CDCI3) S 1.32 (t, 3 H), 2.8 (q, 2 H), 3.48 (m, 2 H), 3.63 (m, 2 H), 3.8-
4.0 (m, 8 H), 4.21 (m, 1
H), 4.62 (m, 2 H), 6.99 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.58 (m, 4 H),
7.65 (m, 2 H).
EXAMPLE 86
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(morpholin-2-
ylmethoxy)thieno[2,3-
d]pyrimidine
il
(N)
H3C "Z N
S N"j' O O
~N~
H
Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred 15
for minutes. 2-Hydroxymethyl morpholine (0.076 mL) was added and the mixture
stirred for 30
minutes. The pyrimidine of Example 13 (0.15 g) was dissolved in NMP (2.0 mL)
and added drop-
wise to the chilled mixture. Once the addition was complete the mixture was
removed from the
ice/acetone bath and stirred at room temperature for 20 hours. The mixture was
then partitioned
between saturated sodium bicarbonate and ethyl acetate. The layers were
separated and the
organic layer washed three times with brine, dried over anhydrous magnesium
sulfate and
concentrated. Water (20 mL) was added to the residue. The resulting solids
were filtered and
dried under high vacuum to dryness to give 0.0073 g of the title compound: 'H
NMR (400 MHz,
CDCI3) 5 1.32 (t, 3 H), 2.85 (m, 3 H), 2.96 (m, 2 H), 3.15 (d, 1 H), 3.6-3.8
(m, 3 H), 3.8-4.1 (m, 8
H), 4.28 (m, 1 H), 4.41 (m, 1 H), 6.85 (s, 1 H), 7.38 (m, 1 H), 7.44 (m, 2 H),
7.53 (d, 2 H), 7.6 (d,
2 H), 7.66 (d, 2 H).
EXAMPLE 87
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yi]-6-ethyl-2-(3-morpholin-4-
ylpropoxy)thieno[2,3-
d]pyrimidine
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118
i I
0
~N~
H3C ~ I ~~
S N O'-~N
00
Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
15 minutes. 4-(3-Hydroxypropyl) morpholine (0.094 g) was added and the mixture
stirred for 30
minutes. The pyrimidine of Example 13 (0.15 g) was dissolved in NMP (2.0 mL)
and added drop-
wise to the chilled mixture. Once the addition was complete the mixture was
removed from the
ice/acetone bath and stirred at room temperature for 96 hours. The mixture was
then partitioned
between saturated sodium bicarbonate and ethyl acetate. The layers were
separated and the
organic layer washed three times with brine, dried over anhydrous magnesium
sulfate and
concentrated. Water (20 mL) was added to the residue. The resulting solids
were filtered and
dried under high vacuum to dryness to give 0.0574 g of the title compound: MS
(ESI+) for
C32H37N5O3S m/z572.42 (M+H)+. 'H NMR (400 MHz, CDCI3) 5 1.32 (t, 3 H), 2.0 (m,
4 H), 2.38
(m, 2 H), 2.54 (m, 2 H), 2.83 (m, 4 H), 3.37 (m, 2 H), 3.8-4.0 (m, 8 H), 4.39
(m, 2 H), 6.85 (s, 1
H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.52 (d, 2 H), 7.59 (d, 2 H), 7.65 (d, 2 H).
EXAMPLE 88
Trans-(2R)-3-[(6-ethyl-4-{4-[(2-phenylcyclopropyl)carbonyl]piperazin-1-
yl}thieno[2,3-d]pyrimidin-
2-yl)oxy]propane-1,2-diol
I~
~
0
C ~
N
H3C ~ I .~
S N O"*'~OH
OH
To a mixture of the cyclopropane of Example 35 (0.197 g) in methanol (4 mL)
was added 4N HCI
in dioxane (1 mL). The mixture was stirred at room temperature for 1 hour. The
mixture was
partitioned between saturated sodium bicarbonate and ethyl acetate. The layers
were separated
and the organic layer dried over anhydrous magnesium sulfate and concentrated
to dryness to
give 0.0674 g of the title compound: 'H NMR (400 MHz, CDCI3) 5 1.31 (t, 3 H),
1.69 (m, 1 H),
1.96 (m, 1 H), 2.51 (m, 1 H), 2.83 (q, 2 H), 3.6-4.0 (m, 10 H), 4.09 (m, 1 H),
4.44 (m, 2 H), 6.86
(s, 1 H), 7.1 (m, 2 H), 7.2 (m, 1 H), 7.26 (m, 2 H).
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EXAMPLE 89
(2R)-3-({6-Ethyl-4-[4-(phenylacetyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-
yl}oxy)propane-1,2-diol
O
(N)
N
H3C S N O'_)rOH
OH
To-a mixture of the diol hydrochloride salt of Example 22 (0.190 g) in DMF (5
mL) was added
diisopropylethylamine (0.197 g), and phenyl acetyl chloride (0.067 mL). The
mixture was stirred
at room temperature for 2.0 hours. The mixture was partitioned between brine
and ethyl acetate.
The layers were separated and the organic layer washed three times with brine,
dried over
anhydrous magnesium sulfate and concentrated. The residue was chromatographed
on silica
gel (100 mL) using 5% methanol in ethyl acetate as eluent to give 0.059 g of
the title compound:
MS (ESI+) for C23H28N404S m/z457.29 (M+H)+. 'H NMR (400 MHz, CDCI3) S 1.32 (t,
3 H), 2.85
(q, 2 H), 3.61 (m, 2 H), 3.71 (m, 4 H), 3.78 (s, 2 H), 3.81 (m, 2 H), 3.84 (m,
2 H), 4.07 (m, 1 H),
4.46 (m, 2 H), 6.83 (s, 1 H), 7.27 (m, 3 H), 7.35 (m, 2 H).
EXAMPLE 90
3-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-yl}oxy)propan-
1-ol
/ I . . . .
(N)
N
H3C ~ . N
S I N-,O'~OH
Sodium hydride 60% in mineral oil (0.052 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
15 minutes. 3-[(tert-Butyldimethyl-silyl)oxy]propanoi (0.28 mL) was added and
the mixture stirred
for 30 minutes. The pyrimidine of Example 13 (0.3 g) was dissolved in NMP (2.0
mL) and added
drop-wise to the chilled mixture. Once the addition was complete, the mixture
was removed from
the ice/acetone bath and stirred at room temperature for 18 hours. The mixture
was then
partitioned between saturated sodium bicarbonate and ethyl acetate. The layers
were separated
and the organic layer washed three times with brine, dried over anhydrous
magnesium sulfate
and concentrated. The residue was chromatographed on silica gel (100 mL) using
ethyl acetate
as eluent to give 0.13 g of the title compound: MS (ESI+) for C28H30N403S m/z
503.33 (M+H)+.
'H NMR (400 MHz, CDCI3) 8 1.32 (t, 3 H), 2.02 (m, 2 H), 2.66 (m, 1 H), 2.84
(q, 2 H), 3.75 (m, 4
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H), 3.92 (m, 6 H), 4.54 (m, 2 H), 6.86 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H),
7.53 (d, 2 H), 7.61 (d,
2 H), 7.65 (d, 2 H).
EXAMPLE 91
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-{2-[(2S)-oxiran-2-
yl]ethyl}thieno[2,3-
d]pyrimidine
/ I
O \I
(N)
N
H3C a~yj N NO
Sodium hydride 60% in mineral oil (0.035 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
15 minutes. (S)-(-)-Glycidol (0.057 mL) was added and the mixture stirred for
30 minutes. The
pyrimidine of Example 13 (0.2 g) was dissolved in NMP (2.0 mL) and added drop-
wise to the
chilled mixture. Once the addition was complete, the mixture was removed from
the ice/acetone
bath and stirred at room temperature for 18 hours. The mixture was then
partitioned between
saturated sodium bicarbonate and ethyl acetate. The layers were separated and
the organic
layer washed three times with brine, dried over anhydrous magnesium sulfate
and concentrated.
The residue was chromatographed on silica gel (100 mL) using ethyl acetate-
hexanes (50/50)as
eluent to give 0.0464 g of the title compound: MS (ESI+) for C28H2BN4O3S m/z
501.37 (M+H)+.
'H NMR (400 MHz, CDCI3) S 1.33 (t, 3 H), 2.73 (m, 1 H), 2.85 (m, 3 H), 3.4 (m,
1 H), 3.6-4.0 (m,
8 H), 4.36 (m, 1 H), 4.51 (dd, 1 H), 6.87 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 1
H), 7.51 (d, 2 H), 7.61
(d, 2 H), 7.66 (d, 2 H).
EXAMPLE 92
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(tetrahydrofuran-3-
yloxy)thieno[2,3-
d]pyrimidine
i I
i ~
CNJ
N
H3C ~ ~ ~ N
'CO
S N 0
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121
Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
15 minutes. 3-Hydroxytetrahydrofuran (0.057 g) was added and the mixture
stirred for 30
minutes. The pyrimidine of Example 13 (0.15 g) was dissolved in NMP (2.0 mL)
and added drop-
wise to the chilled mixture. Once the addition was complete, the mixture was
removed from the
ice/acetone bath and stirred at room temperature for 18 hours. The mixture was
then partitioned
between saturated sodium bicarbonate and ethyl acetate. The layers were
separated and the
organic layer washed three times with brine, dried over anhydrous magnesium
sulfate and
concentrated. The residue was chromatographed on silica gel (100 mL) using
ethyl acetate as
eluent to give 0.0711 g of the title compound: MS (ESI+) for C29H30N403S
m1z515.36 (M+H)+.
'H NMR (400 MHz, CDCI3) S 1.33 (t, 3 H), 2.22 (m, 2 H), 2.86 (q, 2 H), 3.6-4.0
(m, 11 H), 4.11
(m, 1 H), 5.53 (m, 1 H), 6.86 (s, 1 H), 7.39 (m, 1 H), 7.46 (m, 1 H), 7.52 (d,
2 H), 7.60 (d, 2 H),
7.66 (d, 2 H).
15' EXAMPLE 93
(2R)-4-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrim idin-2-
yl}oxy)butane-1,2-diol
~I
i ~
(N)
N
H3C eS N-,J,O,,XOH
Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
15 minutes. (4R)-4-(2-Hydroxyethyl)-2,2-dim ethyl- 1, 3-dioxoiane (0.066 mL)
was added and the
mixture stirred for 30 minutes. The pyrimidine of Example 13 (0.15 g) was
dissolved in NMP (2.0
mL) and added drop-wise to the chilled mixture. Once the addition was
complete, the mixture
was removed from the ice/acetone bath and stirred at room temperature for 18
hours. The
mixture was then partitioned between saturated sodium bicarbonate and ethyl
acetate. The
layers were separated and the organic layer washed three times with brine,
dried over anhydrous
magnesium sulfate and concentrated. The residue was chromatographed on silica
gel (100 mL)
using ethyl acetate as eluent. The residue was dissolved in methanol (2.0 mL)
and 4N HCI in dioxane (0.5 mL) was added. The mixture was stirred at room
temperature for 2 hours, at which
time the mixture was partitioned between saturated sodium bicarbonate and
ethyl acetate. The
layers were separated and the organic layer washed three times with brine,
dried over anhydrous
magnesium sulfate and concentrated to dryness to give 0.077 g of the title
compound: MS
(ESI+) for C29H32N404S m1z533.37 (M+H)+. iH NMR (400 MHz, CDCI3) 5 1.33 (t, 3
H), 1.84 (m,
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1 H), 1.96 (m, 1 H), 2.12 (m, 1 H), 2.84 (q, 2 H), 3.52-4.0 (m, 10 H), 4.4 (m,
1 H), 4.75 (m, 1 H),
6.87 (s, 1 H), 7.4 (m, 1 H), 7.46 (m, 2 H), 7.53 (d, 2 H), 7.61 (d, 2 H), 7.66
(d, 2 H).
EXAMPLE 94
(2R)-3-[(4-{4-[(3',4'-Difluoro-1,1'-biphenyl-4-yl)carbonyl]piperazin-1-yl}-6-
ethylthieno[2,3-
d]pyrimidin-2-yl)oxy]propane-1,2-diol
~ F
F
O ~
(N)
N
H3C . N
S NO'-Ir'OH
OH
To a mixture of the pyrimidine of Example 36 (0.1 g) and NMP (2 mL) in a 2
dram screw capped
vial was added 3,4-difluorophenyl boronic acid (0.056 g), 5M K3P04 (0.5 mL),
palladium II
acetate (0.004 g) and, tri-o-tolyl phosphine (0.011 g). The vial was placed
into a Lab-Line MAX
Q2000 orbital shaker at 80 C overnight. The mixture was partitioned between
brine and ethyl
acetate, the layers were separated and the organic layer washed three times
with brine. The
organic layer was dried over anhydrous magnesium sulfate and concentrated. The
residue was
chromatographed on silica gel (100 mL) using 1:1 ethyl acetate:hexanes as
eluent. The resulting
residue was dissolved in methanol (2 mL) and 4N HCI in dioxane (0.5 mL) was
added. The
mixture was stirred at room temperature for 1 hour. The mixture was
partitioned between
saturated sodium bicarbonate and ethyl acetate. The layers were separated and
the organic
layer dried over anhydrous magnesium sulfate and concentrated to dryness to
give 0.029 g of
the title compound: MS (ESI+) for C28H2BF2N404S m1z555.42 (M+H)+. 'H NMR (400
MHz,
CDCI3) S 1.33 (t, 3 H), 2.85 (q, 2 H), 3.6-4.1 (m, 11 H), 4.48 (m, 2 H), 6.87
(s, 1 H), 7.23 (m, 1 H),
7.30 (m, 1 H), 7.39 (m, 1 H), 7.52 (d, 2 H), 7.58 (d, 2 H).
EXAMPLE 95
(2R)-3-[(6-Ethyl-4-{4-[4-(6-methoxypyridin-3-yl)benzoyl]piperazin-1-
yl}thieno[2,3-d]pyrimidin-2-
yl)oxy]propane-1,2-diol
O'(',H3
N
O
(N)
N
H3C / ' ' N
S N'O-"~OH
OH
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123
To a mixture of the pyrimidine of Example 36 (0.1 g) and NMP (2 mL) in a 2
dram screw capped
vial was added 2-methoxy-5-pyridine boronic acid (0.054 g), 5M K3PO4 (1.0 mL),
palladium II
acetate (0.004 g) and, tri-o-tolyl phosphine (0.011 g). The vial was placed
into a Lab-Line MAX
Q2000 orbital shaker at 80 C overnight. The mixture was partitioned between
brine and ethyl
acetate, the layers were separated and the organic layer washed three times
with brine. The
organic layer was dried over anhydrous magnesium sulfate and concentrated. The
residue was
chromatographed on silica gel (100 mL) using 60% ethyl acetate in hexanes as
eluent. The
resulting residue was dissolved in methanol (2 mL) and 4N HCI in dioxane (0.5
mL) was added.
The mixture was stirred at room temperature for 3 hours. The mixture was
partitioned between
saturated sodium bicarbonate and ethyl acetate. The layers were separated and
the organic
layer dried over anhydrous magnesium sulfate and concentrated to dryness to
give 0.0226 g of
the title compound: MS (ESI+) for C28H31N505S m/z550.37 (M+H)+. 'H NMR (400
MHz, CDCI3)
5 1.32 (t, 3 H), 2.57 (m, 1 H), 2.85 (q, 2 H), 3.46 (m, 1 H), 3.70 (m, 4 H),
3.9 (m, 4 H), 3.99 (s, 3
H), 4.08 (m, 1 H), 4.47 (m, 2 H), 6.84 (d, 1 H), 6.87 (s, 1 H), 7.53 (d, 2 H),
7.59 (d, 2 H), 7.8 (dd,
1 H), 8.4 (m, 1 H).
EXAMPLE 96
(2R)-3-{[6-Ethyl-4-(4-{[4'-(trifluoromethyl)-1,1'-biphenyl-4-
yl]carbonyl}piperazin-1-yl)thieno[2,3-
d]pyrimidin-2-yl]oxy}propane-1,2-dioi
F
F F
/ ~ .
O ~~ .
(N)
N
H3C N
S N~O"~~OH
OH
To a mixture of the pyrimidine of Example 36 (0.1 g) and NMP (2 mL) in a 2
dram screw capped
vial was added 4-trifluoromethyl phenyl boronic acid (0.068 g), 5M K3P04 (1.0
mL), palladium II
acetate (0.004 g) and, tri-o-tolyl phosphine (0.011 g). The vial was placed
into a Lab-Line MAX
Q2000 orbital shaker at 80 C overnight. The mixture was partitioned between
brine and ethyl
acetate, the layers were separated and the organic layer washed three times
with brine. The
organic layer was dried over anhydrous magnesium sulfate and concentrated. The
residue was
chromatographed on silica gel (100 mL) using 60% ethyl acetate in hexanes as
eluent. The
resulting residue was dissolved in methanol (2 mL) and 4N HCI in dioxane (0.5
mL) was added.
The mixture was stirred at room temperature for 2 hours. The mixture was
partitioned between
saturated sodium bicarbonate and ethyl acetate. The layers were separated and
the organic
layer dried over anhydrous magnesium sulfate and concentrated to dryness to
give 0.062 g of
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the title compound: MS (ESI+) for C29H29F3N404S m/z587.38 (M+H)+. 'H NMR (400
MHz,
CDCI3) 5 1.33 (t, 3 H), 2.45 (m, 1 H), 2.85 (q, 2 H), 3.4 (m, 1 H), 3.69 (m, 4
H), 3.95 (m, 4 H),
4.08 (m, 1 H), 4.49 (m, 2 H), 6.88 (s, 1 H), 7.56 (d, 2 H), 7.67 (d, 2 H),
7.71 (m, 4 H).
EXAMPLE 97
(2R)-3-({6-Ethyl-4-[4-(4-pyridin-3-ylbenzoyl)piperazin-l-yl]thieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol
i)
N
H3C e
N ,
S N0''~OH
OH
To a mixture of the pyrimidine of Example 36 (0.1 g) and NMP (2 mL) in a 2
dram screw capped
vial was added pyridine-3-boronic acid (0.044 g), 5M K3PO4 (1.0 mL), palladium
II acetate (0.004
g) and, tri-o-tolyl phosphine (0.011 g). The vial was placed into a Lab-Line
MAX Q2000 orbital
shaker at 80 C overnight. The mixture was partitioned between brine and ethyl
acetate, the
layers were separated and the organic layer washed three times with brine. The
organic layer
was dried over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed on silica gel (100 mL) using ethyl acetate as eluent. The
resulting residue was
dissolved in methanol (2 mL) and 4N HCI in dioxane (0.5 mL) was added. The
mixture was
stirred at room temperature for 2 hours. The mixture was partitioned between
saturated sodium
bicarbonate and ethyl acetate. The layers were separated and the organic layer
dried over
anhydrous magnesium sulfate and concentrated to dryness to give 0.0078 g of
the title
compound: MS (ESI+) for C27H29N504S m/z520.28 (M+H)+. 'H NMR (400 MHz, CDCI3)
S 1.33
(t, 3 H), 2.85 (q, 2 H), 3.69 (m, 4 H), 3.94 (m, 6 H), 4.08 (m, 1 H), 4.49 (m,
2 H), 6.88 (s, 1 H),
7.43 (m, 1 H), 7.58 (d, 2 H), 7.66 (d, 2 H), 7.92 (d, 1 H), 8.64 (m, 1 H),
8.87 (m, 1 H).
EXAMPLE 98
2-[({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy)methyl]propane-1,3-diol
ip, I ~ I
O ~I
C ~
N
H3C ~ I .~
S N O~OH
OH
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Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
15 minutes. (2,2-Dimethyl-1,3-dioxan-5-yl)methanol (Example 37, 0.095 g) was
added and the
mixture stirred for 30 minutes. The pyrimidine of Example 13 (0.15 g) was
dissolved in NMP (2.0
mL) and added drop-wise to the chilled mixture. Once the addition was complete
the mixture
was removed from the ice/acetone bath and stirred at room temperature for 18
hours. The,
mixture was then partitioned between saturated sodium bicarbonate and ethyl
acetate. The
layers were separated and the organic layer washed three times with brine,
dried over anhydrous
magnesium sulfate and concentrated. The residue was chromatographed on silica
gel (100 mL)
using ethyl acetate as eluent. The residue was dissolved in methanol (2.0 mL)
and 4N HCI in
dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 1
hour, at which
time the mixture was partitioned between saturated sodium bicarbonate and
ethyl acetate. The
layers were separated and the organic layer washed three times with brine,
dried over anhydrous
magnesium sulfate and concentrated to dryness to give 0.019 g of the title
compound: MS
(ESI+) for C29H32N404S m/z533.31 (M+H)+.'H NMR (400 MHz, CDCI3) S 1.33 (t, 3
H), 2.18 (m, 1
H), 2.85 (q, 2 H), 3.6-4.1 (m, 13 H), 4.61 (m, 2 H), 6.88 (s, 1 H), 7.39 (m, 1
H), 7.47 (m, 2 H),
7.53 (d, 2 H), 7.6 (d, 2 H), 7.66 (d, 2 H).
EXAMPLE 99
(2R)-3-({6-Ethyl-4-[4-(phenoxyacetyl)piperazin-1-yl]th ieno[2,3-d]pyrim idin-2-
yl}oxy)propane-1,2-
diol ,
i
O~.O ~~
(N)
N
H3C ~ ~ ~~
S N O"X'OH
OH
To a mixture of the pyrimidine of Example 25 (0.15 g) in NMP (3 mL) was added
diisopropylethylamine (0.109 g), phenoxy acetic acid(0.064 g), and HATU (0.16
g). The mixture
was stirred at room temperature for 4 hours. The mixture was partitioned
between brine and
ethyl acetate. The layers were separated and the organic layer washed three
times with brine,
then dried over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed on silica gel (100 mL) using ethyl acetate as eluent.
Fractions containing
product were combined and concentrated. The residue was dissolved in methanol
(2 mL) and
4M HCI in dioxane (0.5 mL) was added. The mixture was stirred at room
temperature for 2
hours. The mixture was partitioned between saturated sodium bicarbonate and
ethyl acetate.
The layers were separated ant the aqueous layer extracted with ethyl acetate.
The ethyl acetate
extracts were combined, dried over anhydrous magnesium sulfate and
concentrated to dryness.
The residue was chromatographed on silica gel (100 mL) using ethyl
acetate:acetone:methanol
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(50:45:5) as eluent to give 0.0957 g-of the title compound: MS (ESI+) for
C23H28N405S m/z
473.28 (M+H)+. 'H NMR (400 MHz, CDCI3) S 1.33 (t, 3 H), 2.85 (q, 2 H), 3.73
(m, 2 H), 3.79 (m,
4 H), 3.9 (m, 4 H), 4.08 (m, 1 H), 4.48 (m, 2 H), 4.74 (s, 2 H), 6.86 (s, 1
H), 6.95 (d, 2 H), 6.97 (m,
1 H), 7.31 (m, 1 H).
EXAMPLE 100
(2R)-3-({6-Ethyl-4-[4-(3-phenoxypropanoyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-
yl}oxy)propane-1,2-diol
0'.~~0
(JL
H3C e N
S N.-,O'X'OH
OH
To a mixture of the pyrimidine of Example 25 (0.158 g) in NMP (10 mL) was
added
diisopropylethylamine (0.107 g), 3-phenoxy propionic acid(0.074 g), and HATU
(0.171 g). The
mixture was stirred at room temperature for 3 hours. The mixture was
partitioned between brine
and ethyl acetate. The layers were separated and the organic layer washed
three times with
brine, dried over anhydrous magnesium sulfate and concentrated. The residue
was
chromatographed on silica gel (100 mL) using ethyl acetate as eluent.
Fractions containing
product were combined and concentrated. The residue was dissolved in methanol
(2 mL) and
4M HCI in dioxane (0.5 mL) was added. The mixture was stirred at room
temperature for 2
hours. The mixture was partitioned between saturated sodium bicarbonate and
ethyl acetate.
The layers were separated and the aqueous layer extracted with ethyl acetate.
The ethyl acetate
extracts were combined, dried over anhydrous magnesium sulfate and
concentrated to dryness
to give 0.0945 g of the title compound: MS (ESI+) for C24HaoN4OsS m/z487.33
(M+H)+. 'H NMR
(400 MHz, CDCI3) 8 1.34 (t, 3 H), 2.87 (m, 4 H), 3.67-3.8 (m, 4 H), 3.83 (m, 2
H), 3.92 (m, 2 H),
3.98 (m, 2 H), 4.09 (m, 1 H), 4.35 (m, 2 H), 4.49 (m, 2 H), 6.89 (m, 3 H),
6.95 (m, 1 H), 7.25 (m, 2
H).
EXAMPLE 101
(2R)-3-({6-Ethyl-4-[4-(4-pyrim idin-5-ylbenzoyl)piperazin-1-yl]thieno[2,3-
d]pyrim id in-2-
yl}oxy)propane-1,2-diol
N
N
CN~ .
N
H3C ~ I ~~
S N O---,C-OH
OH
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To a mixture of the pyrimidine of Example 36 (0.1 g) in NMP (1 mL) was added
tri-o-
tolylphosphine (0.011 g), palladium (II) acetate (0.004 g), 5M K3PO4 (1 mL),
and pyrimidine-5-
boronic acid (0.044 g). The mixture was placed in a 20 mL screw cap vial and
place in a Lab-
Line MAX Q2000 orbital shaker at 80 C overnight. The mixture was removed from
heat and
cooled to room temperature. The mixture was partitioned between brine and
ethyl acetate. The
layers were separated and the organic layer washed three times with brine,
dried over anhydrous
magnesium sulfate and concentrated. The residue was chromatographed on silica
gel (100 mL)
using ethyl acetate as eluent. The resulting residue was dissolved in methanol
(2 mL) and
chilled in an ice bath. 4M HCI in dioxane was added and the mixture placed in
4 C refrigerator
overnight. The mixture was partitioned between saturated sodium bicarbonate
and ethyl acetate.
The layers were separated and the organic layer dried over anhydrous magnesium
sulfate and
concentrated to dryness to give 0.015 g of the title compound: MS (ESI+) for
C26H28N604S m/z
521.40 (M+H)+. 'H NMR (400 MHz, CDCI3) 5 1.33 (t, 3 H), 2.85 (q, 2 H), 3.72
(m, 4 H), 3.95 (m,
6 H), 4.08 (m, 1 H), 4.49 (m, 2 H), 6.88 (s, 1 H), 7.61 (d, 2 H), 7.67 (d, 2
H), 8.97 (s, 2 H), 9.25 (s,
1H).
EXAMPLE 102
(2R)-3-[(4-{4-[(3',5'-Difluoro-1,1'-biphenyl-4-yl)carbonyl]piperazin-1-yl}-6-
ethylthieno[2,3-
d]pyrimidin-2-yl)oxy]propane-1,2-dioi
F
F
Q ~I
CN~
N
H3C s ~ \~
S N O'~~OH
OH
To a mixture of the pyrimidine of Example 36 (0.105 g) in NMP (2 mL) was added
tri-o-
tolylphosphine (0.011 g), palladium (II) acetate (0.004 g), 5M K3PO4 (1 mL),
and 3,5-
difluorophenyl boronic acid (0.059 g). The mixture was placed in a 20 mL screw
cap vial and
place in a Lab-Line MAX Q2000 orbital shaker at 80 C overnight. The mixture
was removed
from heat and cooled to room temperature. The mixture was partitioned between
brine and ethyl
acetate. The layers were separated and the organic layer washed three times
with brine, dried
over anhydrous magnesium sulfate and concentrated. The residue was
chromatographed on
silica gel (100 mL) using (60:40) hexanes:ethyl acetate as eluent. The
resulting residue was
dissolved in methanol (2 mL) and chilled in an ice bath. 4M HCI in dioxane was
added and the
mixture refrigerated at 4 C overnight. The mixture was partitioned between
saturated sodium
bicarbonate and ethyl acetate. The layers were separated and the organic layer
dried over
anhydrous magnesium sulfate and concentrated to dryness. Hexanes: diethyl
ether (90:10) was
added to the residue and the solids collected via filtration to give 0.0277 g
of the title compound:
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MS (ESI+) for C28H28N404S rn/2555.35 (M+H)+. iH-NMR (400 MHz, CDCI3) S 1.27
(t, 3 H), 2.80
(q, 2 H), 3.66 (m, 4 H), 3.89 (m, 6 H), 4.03 (m, 1 H), 4.39 (d, 2 H), 6.78 (m,
1 H), 6.83 (s, 1 H),
7.06 (d, 2 H), 7.49 (d, 2 H), 7.57 (d, 2 H).
EXAMPLE 103
4-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylth ieno[2,3-
d]pyrim idin-2-yl}oxy)-2-
methylbutan-2-ol
/ I
0 \ I
(N)
N
H3C N
~ H3C CH3
S N~O'OH
Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
minutes. 3-Methyl-1,3-butanediol (0.069 mL) was added and the mixture stirred
for 30
minutes. The pyrimidine of Example 13 (0.15 g) was dissolved in NMP (2.0 mL)
and added drop-
wise to the chilled mixture. Once the addition was complete, the mixture was
removed from the
ice/acetone bath and stirred at room temperature for 18 hours. The mixture was
then partitioned
15 between saturated sodium bicarbonate and ethyl acetate. The layers were
separated and the
organic layer washed three times with brine, dried over anhydrous magnesium
sulfate and
concentrated. The residue was chromatographed on silica gel (100 mL) using
ethyl acetate as
eluent to give 0.1018 g of the title compound: MS (ESI+) for C30H34N403S
m/z531.48 (M+H)+.
'H NMR (400 MHz, CDCI3) S 1.3 (s, 6 H), 1.31 (t, 3 H), 2.01 (m, 2 H), 2.84 (q,
2 H), 3.6-4.03 (m,
8 H), 4.54 (m, 2 H), 6.86 (s, 1 H), 7.39 (m, 1 H), 7.47 (m, 2 H), 7.53 (d, 2
H), 7.61 (d, 2 H), 7.65
(d, 2 H).
EXAMPLE 104
(2R)-3-[(4-{4-[(3,4-Difluorophenyl)acetyl]piperazin-1-yl}-6-ethylthieno[2,3-
d]pyrimidin-2-
yl)oxy]propane-1,2-diol
0 F
(N)
F
N
H3C ~ N
S N- O")('OH
OH
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To a mixture of the pyrimidine of Example 25 (0.159 g) in NMP (15 mL) was
added
diisopropylethylamine (0.109 g), 3,4-difluorophenyl acetic acid (0.077 g), and
HATU (0.171 g).
The mixture was stirred at room temperature for 1 hour. The mixture was
partitioned between
brine and ethyl acetate. The layers were separated and the organic layer
washed three times
with brine, dried over anhydrous magnesium sulfate and concentrated. The
residue was
chromatographed on silica gel (100 mL) using ethyl acetate as eluent. The
residue was
dissolved in methanol (2 mL) and chilled in an ice bath. 4M HCI in dioxane
(0.5 mL) was added
and the mixture was refrigerated at 4 C overnight. The mixture was partitioned
between
saturated sodium bicarbonate and ethyl acetate. The layers were separated ant
the aqueous
layer extracted with ethyl acetate. The ethyl acetate extracts were combined,
dried over
anhydrous magnesium sulfate and concentrated to dryness to give 0.0646 g of
the title
compound: MS (ESI+) for C23H26N404S m/z493.37 (M+H)+. 'H NMR (400 MHz, CDCI3)
S 1.32
(t, 3 H), 2.84 (q, 2 H), 3.64 (m, 2 H), 3.71 (m, 4 H), 3.82 (m, 4 H), 3.87 (m,
2 H), 4.08 (m, 1 H),
4.47 (m, 2 H), 6.85 (s, 1 H), 6.97 (m, 1 H), 7.1 (m, 2 H).
EXAMPLE 105
4-(2-{[(2R)-2,3-Dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yl)-N-(3-
methoxybenzyl)piperazine-l-carboxam ide
O N \ I O
I i
N CH3
(l'N Jl
H3C
S I
N" O--"~OH
OH
To a mixture of the pyrimidine of Example 25 (0.159 g) in pyridine (2 mL) was
added 3-
methoxybenzyl isocyanate (0.125 g). The mixture was heated at 80 C for 18
hours. The
mixture was cooled to room temperature and partitioned between brine and
dichloromethane.
The layers were separated and the organic layer washed three times with 1 N
HCI, dried over
anhydrous magnesium sulfate and concentrated. The residue was chromatographed
on silica
gel (100 mL) using hexanes-ethyl acetate (20/80) as eluent. The fractions
containing product
were concentrated under reduced pressure. The residue was dissolved in
methanol (5mL) and
refrigerated at 4 C for 30 minutes. 4N HCI in dioxane was added and the
mixture placed back in
refrigerator overnight. The mixture was then partitioned between saturated
sodium bicarbonate
and ethyl acetate. The layers were separated and the aqueous layer extracted
with ethyl
acetate. The ethyl acetate extracts were combined, dried over anhydrous
magnesium sulfate
and concentrated to dryness to give 0.0595 g of the title compound: MS (ESI+)
for C24H31N505S
m/z502.32 (M+H)+. 'H NMR (400 MHz, CDC13) 81.31 (t, 3 H), 2.82 (q, 2 H), 3.6
(m, 4 H), 3.65-
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3.8 (m, 6 H), 3.93 (m, 4 H), 4.06 (m, 1 H), 4.43 (m, 4 H), 4.96 (m, 1 H), 6.74-
6.88 (m, 4 H), 7.22
(m, 1 H).
EXAMPLE 106
(2S)-5-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yI}oxy)pentane-1,2-diol
N
H3C e N
S N.',O''~OH
OH
Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom
flask, washed with
hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the
mixture stirred for
15 minutes. 3-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]-propanol (0.102 g) was
added and the
mixture stirred for 30 minutes. The pyrimidine of Example 13 (0.15 g) was
dissolved in NMP (2.0
mL) and added drop-wise to the chilled mixture. Once the addition was complete
the mixture
was removed from the ice/acetone bath and stirred at room temperature for 22
hours. The
mixture was then partitioned between saturated sodium bicarbonate and ethyl
acetate. The
layers were separated and the organic layer washed three times with brine,
dried over anhydrous
magnesium sulfate and concentrated. The residue was chromatographed on silica
gel (100 mL)
using ethyl acetate. The resulting residue was dissolved in methanol (5 mL) to
which was added
4N HCI in dioxane (0.5 mL). The mixture was placed in a 4 C refrigerator for
18 hours. The
mixture was partitioned between saturated sodium bicarbonate and ethyl
acetate. The layers
were separated and the ethyl acetate layer dried over anhydrous magnesium
sulfate and
concentrated to dryness under reduced pressure to give 0.0145 g of the title
compound: MS
(ESI+) for C30H34N4O4S m/z547.42 (M+H)+. 1H NMR (400 MHz, CDCI3) S 1.32 (t, 3
H), 1.63 (m,
2 H), 1.95 (m, 2 H), 2.84 (q, 2 H), 3.46 (m, 1 H), 3.6-4.05 (m, 10 H), 4.39
(m, 2 H), 6.86 (s, 1 H),
7.39 (m, 1 H), 7.46 (m, 2 H), 7.53 (d, 2 H), 7.60 (d, 2 H), 7.65 (d, 2 H).
EXAMPLE 107
N-1,1'-Biphenyl-4-yi-4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-
d]pyrim idin-4-
yl)piperazine-1-carboxam ide
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H
Oy N
N
N
H3C e I ~ N
S NIJ1O"')COH
OH
To a mixture of the pyrimidine of Example 25 (0.24 g) in pyridine (5 mL) was
added 4-biphenyl
isocyanate (0.248 g). The mixture was heated at 80 C for 6 hours. The mixture
was cooled to
room temperature and partitioned between brine and d ich lorom ethane. The
layers were
separated and the organic layer washed three times with 1 N HCI, dried over
anhydrous
magnesium sulfate and concentrated. The residue was chromatographed on silica
gel (100 mL)
using ethyl acetate as eluent. The fractions containing product were
concentrated. The residue
was dissolved in methanol (5mL) and refrigerated at 4 C for 30 minutes. 4N HCI
in dioxane was
added and the mixture placed back in the refrigerator overnight. The mixture
was then
partitioned between saturated sodium bicarbonate and ethyl acetate. The layers
were separated
and the aqueous layer extracted with ethyl acetate. The ethyl acetate extracts
were combined,
dried over anhydrous magnesium sulfate and concentrated to dryness to give
0.0687 g of the title
compound: MS (ESI+) for C28H31N404S m/z534.38 (M+H)+. 'H NMR (400 MHz, CDCI3)
S 1.32
(t, 3 H), 2.84 (q, 2 H), 3.74 (m, 6 H), 4.01 (m, 4 H), 4.1 (m, 1 H), 4.49 (m,
2 H), 6.61 (s, 1 H), 6.9
(s, 1 H), 7.3 (m, 1 H), 7.38-7.5 (m, 4 H), 7.54 (m, 4 H).
EXAMPLE 108
tert-butyl 4-[2-(2,2-diethoxyethoxy)-6-ethylthieno[2,3-d]pyrim idin-4-
yl]piperazine-1-carboxylate
O yO~ CHH3
N) CH3
C
N
H3C ~ I ~ N
S N~p~CuCH3
O
CH3
To sodium hydride (60% by weight in mineral oil; 0.026 g) was added N-
methylpyrrolidinone (1
mL), followed by glycolaldehyde diethylacetal (0.087 g). After stirring the
mixture for 10 min, the
carboxylate of Example 12 (0.050 g) was added. The mixture was stirred for 30
min, after which
time the mixture was quenched with saturated aqueous sodium bicarbonate and
then extracted
with ethyl acetate. The ethyl acetate layer was washed with brine, dried over
magnesium sulfate,
concentrated, and the residue was chromatographed on silica gel using ethyl
acetate:hexane
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(20:80) to give 0.52 g of the title compound. MS [m+H] 481.22;'H NMR (400 MHz,
CDCI3) S
1.23 (t, 6H), 1.32 (t, 3H), 1.48 and 1.55 (s, s, 9H), 2.84 (q, 2H), 3.57 (m,
4H), 3.64 (m, 2H), 3.76
(m, 2H), 3.84 (m, 4H), 4.36 (d, 2H), 4.89 (t, 1 H), 6.86 (s, 1 H).
EXAMPLE 109
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-(2,2-diethoxyethoxy)-6-
ethylthieno[2,3-
d]pyrimidine
O ~I
C ~
N
H3C ~'
g Ni;kO,,,rOvCH3
O)
CH3
To sodium hydride (60% by weight in mineral oil; 0.0210 g) was added N-methyl
pyrrolidinone (1
mL), followed by glycolaidehyde diethylacetal (0.0706 g). After stirring the
mixture for 10
minutes, the pyrimidine of Example 13 (0.0487 g) was added. The mixture was
stirred for 35
minutes and then saturated aqueous sodium bicarbonate was added. The mixture
was extracted
with ethyl acetate and the ethyl acetate layer was washed with water and
brine. The organic
layer was dried over magnesium sulfate and concentrated and the residue was
chromatographed
on silica gel using m ethanol:dich lorom ethane (1:99) to give 0.045 g of the
title compound. MS
[m+H]561.3;'H NMR (400 MHz, CDCI3) 51.23 (t, 6H), 1.32 (t, 3H), 2.83 (q, 2H),
3.5-4.0 (m,
12H), 4.37 (m, 2H), 4.89 (m, 1 H), 6.85 (s, 1 H), 7.35-7.68 (m, 9H).
EXAMPLE 110
({4-[4-(1,1''-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy)acetaldehyde
~I .
O ~I
(N)
N
H3C N
S N OCHO
A mixture of the pyrimidine of Example 109 (0.353 g), pyridinium p-
toluenesulfonate (0.0009 g),
acetone (5 mL), and water (0.2 mL) was stirred at room temperature for 1 hour
and then heated
at reflux with the addition of pyridinium p-toluenesulfonate (0.35 g) in
portions over 4 days. After
cooling, the mixture was concentrated and partitioned between ethyl acetate,
saturated aqueous
sodium bicarbonate, and brine. The organic layer was dried over magnesium
sulfate,
concentrated, and the residue was cliromatographed on silica gel using ethyl
acetate:hexane
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(gradient of 50% to 67% ethyl acetate in hexane) to give 0.124 g of the title
compound. MS
[m+H] 487.16;'H NMR (400 MHz, CDCI3) S 1.33 (t, 3H), 2.85 (q, 2H), 3.62-4.0
(m, 8H), 4.77 (s,
2H), 6.88 (s, 1 H), 7.35-7.68 (m, 9H), 9.74 (s, 1 H).
EXAMPLE 111
({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin=1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-yl}oxy)acetic acid
O
(N)
N
H3C 91 N
S N OCOOH
To the acetaldehyde of Example 110 (0.1137 g) and dichloromethane (2 mL)
cooled in a cold
water bath was added 3-chloroperoxybenzoic acid (Aldrich 273031; 0.605 g). The
mixture was
stirred for 1 hour and then chromatographed on silica gel using
methanol:dichloromethane:acetic
acid (10:90:0.1). The product fractions were combined, concentrated, and
azeotroped with
toluene under reduced pressure to give 0.102 g of the title compound. MS [m+H]
503.14; 'H
NMR (400 MHz, CDCI3) S 1.30 (t, 3H), 2.82 (q, 2H), 3.6-4.0 (m, 8H), 4.84 (s,
2H), 6.85 (s, 1H),
7.13-7.65 (m, 9H).
EXAMPLE 112
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-ethylthieno[2,3-d]pyrimidine
O
(N)
N
H3C ~ I N
3
S NO~OO~CH
Sodium hydride (60% by weight in mineral oil; 0.0194 g) was washed twice with
hexane. To the
residue was added N-methylpyrrolidinone (0.6 mL). The mixture was cooled in a
cold water bath
and (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (0.0642 g) was added. After
stirring for 5 min,
ice was added to the cold water bath and the pyrimidine of Example 13 (0.150
g) was added,
followed by additional N-methylpyrrolidinone (0.2 mL). After stirring the
mixture for 1.5 hours at 0
C, saturated aqueous sodium bicarbonate was added and the mixture was
extracted with ethyl
acetate. The ethyl acetate layer was washed with brine and then dried over
magnesium sulfate.
After concentration, the residue was chromatographed on silica gel using ethyl
acetate:hexane
(50:50) to give 0.167 g of the title compound. MS [m+H] 559.26;'H NMR (400
MHz, CDCI3) 5
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1.33 (t, 3H), 1.37 (s, 3H), 1.45 (s, 3H), 2.84 (q, 2H), 3.83-4.0 (m, 9H), 4.15
(m, 1 H), 4.28 (m, 1 H),
4.48 (m, 2H), 6.86 (s, 1 H), 7.38-7.7 (m, 9H).
EXAMPLE 113
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-ethylthieno[2,3-d]pyrimidine
~I
~ ~
O ~I
(N)
N
HsC N
S NO~O~CFi
3
O
Sodium hydride (60% by weight in mineral oil; 0.0194 g) was washed twice with
hexane. To the
residue was added N-methylpyrrolidinone.(0.6 mL). The mixture was cooled in a
cold water bath
and (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol (0.0642 g) was added. After
stirring for 5
minutes, ice was added to the cold water bath and the pyrimidine of Example 13
(0.150 g) was
added, followed by additional N-methylpyrrolidinone (0.2 mL). After stirring
the mixture for 1.5
hours at 0 C, saturated aqueoussodium bicarbonate was added and the mixture
was extracted
with ethyl acetate. The ethyl acetate layer was washed with brine and then
dried over
magnesium sulfate. After concentration, the residue was chromatographed on
silica gel using
ethyl acetate:hexane (50/50) to give 0.150 g of the title compound. MS [m+H]
559.26;'H NMR
(400 MHz, CDCI3) S 1.33 (t, 3H), 1.37 (s, 3H), 1.45 (s, 3H), 2.83 (q, 2H),
3.83-4.0 (m, 9H), 4.13
(m, 1 H), 4.30 (m, 1 H), 4.48 (m, 2H), 6.86 (1 H), 7.35-7.70 (9H).
EXAMPLE 114
(2R)-3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylth ieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol
~I
O ~I
(N)
N
H3C ~ I ~~
S N O ~OH
OH
A mixture of the pyrimidine of Example 112 (0.16 g), pyridinium p-
toluenesulfonate (0.079 g), and
methanol (3 mL) was stirred at room temperature for 1.5 hours and then at 80
C for 19.5 hours.
After cooling and concentration under reduced pressure, the residue was
partitioned between
ethyl acetate and saturated aqueous sodium bicarbonate, water, and brine. The
organic layer
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was dried over magnesium sulfate and concentrated under reduced pressure. The
residue was
chromatographed on silica gel using methanol:dichloromethane (4:96) to give
0.129 g of the title
compound. MS [m+H] 519.16;'H NMR (400 MHz, CDCI3) S 1.33 (t, 3H), 2.46 (br s,
0.5H), 2.85
(q, 2H), 3.38 (br s, 0.5H), 3.65-4.12 (m, 12 H), 4.48 (m, 2H), 6.88 (s, 1 H),
7.37-7.67 (m, 9H).
EXAMPLE 115
(2S)-3-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrim idin-2-
yl}oxy)propane-1,2-diol
O ~I
(N)
N
H3C ~ I ~N
S N'O ~"tOH
OH
A mixture of the pyrimidine of Example 113 (0.144 g), pyridinium p-
toluenesulfonate (0.071 g),
and methanol (3 mL) was stirred at 80 C for 20 hours. After cooling and
concentration under
reduced pressure, the residue was partitioned between ethyl acetate and
saturated aqueous
sodium bicarbonate, water, and brine. The organic layer was dried over
magnesium sulfate and
concentrated under reduced pressure. The residue was chromatographed on silica
gel using
methanol:dichloromethane (4:96) to give 0.12 g of the title compound. MS [m+H]
519.18; iH
NMR (400 MHz, CDCI3) S 1.33 (t, 3H), 2.48 (br s, 0.5H), 2.85 (q, 2H), 3.40 (br
s, 0.5H), 3.65-4.15
(m, 12 H), 4.48 (m, 2H), 6.88 (s, 1 H), 7.38-7.68 (m, 9H).
EXAMPLE 116
N-[2-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy)ethyl]-N,N-dimethylamine hydrochloride
~I
O ~I
(N) =HC1
N
H3C / I . N CH3
S N0'~ =CH3
Sodium hydride (60% by weight in mineral oil; 0.022 g) was washed twice with
hexane. To the
residue was added N-methylpyrrolidinone (1 mL). The mixture was cooled in a
cold water bath
and N, N-dimethylethanolamine (0.049 g) was added. After stirring for 5
minutes, ice was added
to the cold water bath and the pyrimidine of Example 13 (0.150 g) was added.
The mixture was
allowed to warm to room temperature over 5.5 hours and then was stored in the
refrigerator over
the weekend, after which saturated aqueous sodium bicarbonate was added and
the mixture was
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extracted with ethyl acetate. The ethyl acetate layer was washed with brine
and then dried over
magnesium sulfate. The residue was concentrated to give 0.106 g of N-[2-({4-[4-
(1,1'-biphenyl-
4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)ethyl]-N,N-
dimethylamine. MS
[m+H] 516.2;'H NMR (400 MHz, CDCI3) 8 1.32 (t, 3H), 2.33 (s, 6H), 2.73 (m,
2H), 2.83 (q, 2H),
3.65-3.95 (m, 8H), 4.45 (m, 2H), 6.85 (s, 1 H), 7.38-7.70 (m, 9H). Addition of
HCI-methanol to N-
[2-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrim idin-2-yl}oxy)ethyl]-
N,N-dimethylamine gave the title compound.
EXAMPLE 117
2-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yi]-6-ethylth ieno[2,3-
d]pyrim idin-2-
yl}oxy)acetam ide
O ~I
(N)
N
H3C N
S NO"')rNH2
O
To the acetic acid of Example 111 (0.0196 g) in a mixture of dichloromethane
(1 mL) and
dioxane (0.1 mL) was added.1,1'-carbonyidiimidazole (0.0070 g). After stirring
for 1 hour,
ammonia in dioxane (0.5 M solution, 0.39 mL) was added and the mixture was
stirred for 4
hours, at which time an additional 0.35 mL of ammonia/dioxane was added. The
mixture was
stirred for an additional hour and then concentrated to dryness under reduced
pressure.
Chromatography on silica gel using methanol:Ethyl acetate (4:96) gave 0.0113 g
of the title
compound. MS [m+H] 502.3;'H NMR (400 MHz, CDCI3) S 1.33 (t, 3H), 2.86 (q, 2H),
3.6-4.0 (m,
8H), 4.83 (s, 2H), 5.51 (br s, 1 H), 6.51 (br s, 1 H), 6.89 (s, 1 H), 7.37-
7.67 (m, 9H).
EXAMPLE 118
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(tetrahydrofuran-2-
ylmethoxy)thieno[2,3-
d]pyrimidine
~I
O ~I
(N)
N
H3C ~ N
S N''LO~o~
Sodium hydride (60% by weight in mineral oil; 0.014 g) was washed twice with
hexane. To the
residue was added N-methylpyrrolidinone (0.75 mL). (+/-)-Tetrahydrofurfural
alcohol (0.0373 g)
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was added. After stirring for 5 min, the pyrimidine of Example 13 (0.0564 g)
was added. After
stirring the mixture for 1.2 hours, saturated aqueous sodium bicarbonate was
added and the
mixture was extracted with ethyl acetate. The ethyl acetate layer was washed
with brine and
then dried over magnesium sulfate. After concentration, the residue was
chromatographed on
silica gel using ethyl acetate:hexane (50:50) to give 0.0345 g of the title
compound. MS [m+H]
529.3;'H NMR (400 MHz, CDCI3) S 1,32 (t, 3H), 1.78 (m, 1H), 1.92 (m, 2H), 2.03
(m, 1H), 2.84
(q, 2H), 3.6-4.0 (m, 10H), 4.26-4.38 (m, 3H), 6.85 (s, 1 H), 7.38-7.66 (m,
9H).
EXAMPLE 119
2-({4-[4-(1,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-
d]pyrimidin-2-
yl}oxy)ethanamine hydrochloride
~I
O ~
~I
\= HCI
CN)
N
H3C ~ I ~ N
S Ni-,0,,,,NH2
Sodium hydride (60% by weight in mineral oil; 0.0194 g) was washed twice with
hexane. To the
residue was added N-methylpyrrolidinone (0.6 mL). The mixture was cooled in a
cold water bath
and ethanolamine (0.0341 g) was added. After stirring for 5 min, ice was added
to the cold water
bath and 4-[4-(1,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-2-chloro-6-
ethylthieno[2,3-d]pyrimidine
(Example 19, 0.0861 g) was added, followed by additional N-methylpyrrolidinone
(0.2 mL). After
stirring the mixture for 1.5 hours at 0 C, saturated aqueous sodium
bicarbonate was added and
the mixture was extracted with ethyl acetate. The ethyl acetate layer was
washed with brine and
then dried over magnesium sulfate. After concentration, the residue was
chromatographed on
silica gel using ethyl acetate:hexane (50:50) to give 0.018 g of the title
compound after addition
of HCI/methanol followed by concentration to dryness.
MS [m+H] 488.3;'H NMR (400 MHz, CDCI3) 5 1.32 (t, 3H), 2.83 (q, 2H), 3.08 (m,
2H), 3.6-4.0
(m, 8H), 4.36 (m, 2H), 6.85 (s, 1 H), 7.36-7.68 (m, 9H).
EXAMPLE 120
2-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrim
idin-2-
yl}oxy)ethanamine hydrochloride
o
N' =HCI
~ ~
H3C
NH2
S NCti
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Sodium hydride (60% in-oil) was washed three times with hexane to remove oil.
DMF (0.5 mL)
was added to the NaH, followed by ethanolamine (0.203 mL) in DMF (0.5 mL).
After stirring for
min, the pyrimidine of Example 13 (0.154 g) in DMF (1 mL) was added. The
mixture was
stirred for 4 hours, at which time it was partitioned between ethyl acetate
and brine. The organic
5 layer was dried over magnesium sulfate and concentrated to dryness. The
residue was
dissolved in methanol (0.3 mL) and HCI/methanol (0.35 mol) was added. After
standing
overnight at room temperature and then in the refrigerator for 4 hours, the
resulting solid was
collected, washed with a small amount of methanol, and dried to give 0.072 g
of the title
compound. MS [m+H] 488.3;'H NMR (400 MHz, CDCI3 + methanol-d4) S 1.26 (t, 3H),
2.81 (q,
10 2H), 3.26 (m, 2H), 3.3 (m, 2H), 3.7-4.1 (m, 8H), 4.72 (m, 2H), 6.99 (s, 1
H), 7.30-7.60 (m, 9H).
EXAMPLE 121
N-(3-(4-(2-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-ethylthieno[2,3-
d]pyrim idin-4-
yl)piperazin-1 -yl)-3-oxopropyl)-N-phenylbenzamide
/ /
N O \ ~ O \ I
CJ O~ N \
ON
N
O'H I / rN
H3C ~ 'N~
S N O"~-~O
O H3C 4 NI
H3 ~CH3 S I J~
N O",-rO
O
H3C CH3
A mixture of the beta-alanine of Example 38 (0.102 g, 0.378 mmol) and 1,1'-
carbonyl diimidazole
(0.0736 g, 0.454 mmol) in dichloromethane (0.25 mL) was stirred at room
temperature for 2.5
hours, at which time the pyrimidine of Example 25 (0.171 g, 0.454 mmol) was
added. After
stirring for 23 hours, dichloromethane was removed under reduced pressure and
the residue was
partitioned between ethyl acetate and 0.5 N HCI, saturated aqueous sodium
bicarbonate, and
brine. The organic layer was dried over magnesium sulfate and chromatographed
on silica gel
using methanol:ethyl acetate (4:96) to give 0.123 g of the title compound. MS
[m+H] 630.5; iH
NMR (400 MHz, CDCI3) 5 1.33 (3H), 1.38 (3H), 1.46 (3H), 2.84 (4H), 3.76 (4H),
3.85-3.95 (5H),
4.15 (1H), 4.22 (2H), 4.27 (1H), 4.44 (2H), 6.86 (1H), 7.05-7.30 (10H).
EXAMPLE 122
N-(3-(4-(2-((R)-2,3-dihydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-
yl)piperazin-1-yl)-3-
oxopropyl)-N-phenylbenzam ide
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/
O O \I
O N
~' v \
N
N~
CN CN'
H3C iN H3C ~ I\ N
S N~-O \~
---,CNO S N = O~~OH
O CH3 OH
H3C
A mixture of the phenylbenzamide of Example 121 (0.112 g, 0.178 mmol), 4M HCI-
dioxane (0.18
mL), THF (1 mL), and methanol (0.2 mL) was stirred at room temperature for 3
hours, then
stored overnight in the refrigerator. The solvents were then removed under
reduced pressure
and the residue was partitioned between ethyl acetate, saturated aqueous
sodium bicarbonate,
and brine. The organic layer was dried over magnesium sulfate and concentrated
to dryness to
give 0.082 g of the title compound. MS [m+H] 590.4;'H NMR (400 MHz, CDCI3) S
1.33 (3H),
2.85 (4H), 3.73 (3H), 3.77 (4H), 3.89 (2H), 3.96 (2H), 4.08 (1H), 4.21 (2H),
4.48 (2H), 6.88 (1H),
7.07-7.30 (10H).
EXAMPLE 123
(2R)-3-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]thieno[2,3-d]pyrim
idin-2-yl}oxy)propane-
1,2-diol
o
C J
N
N
S N~O---j-'OH
OH
To an ice cooled solution of the pyrimidine of Example 42 (2.3 g) in methanol
was added 4N HCI.
in dioxane (4 ml) and stirred for 2 hours. The solution was warmed to room
temperature and
stirred for additional 6 hours at room temperature and concentrated. The
residue was dissolved
in ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over
magnesium sulfate
and then concentrated under reduced pressure to give title compound: (0.39 g).
MS (ESI+) for
C26H26N404S m/z 491.27 (M+H)+.'H NMR (400 MHz, CD3OD) S 7.39-7.76 (m, 11 H),
4.7 (m, 1 H)
4.55 (m,1 H) 4.3 -4.01 (m,4H) 4.0 (m,3H), 3.9 (b,2H), 3.6 (m,2H), LCMS =
491.22 (M+).
EXAMPLE 124
(2R)-3-({4-[(2S)-4-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-6-
ethylthieno[2,3-
d]pyrimidin-2-yl}oxy)propane-1,2-diol
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~I
O
N
H3C~N
I I'N
H3C S N O'X~OH
OH
4-[(2S)-4-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-2-{[(4S)-2,2-
dimethyl-1,3-dioxolan-
4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine (Example 64, 0.066 g) was
dissolved in 4N
HCI/dioxane (2 mL) at 0 C. The mixture was allowed to warm to room temperature
and stir for 3
days. The solvent was evaporated under reduced pressure and the residue was
triturated with
ether. The resulting solid was collected, washed with diethyl ether and dried
under reduced
pressure to give 0.038 g of the title compound. HRMS (ESI+) for C29H32N404S
m/z 533.2202
(M+H)+,'H NMR (400 MHz, CD3OD) S 7.76 (d, 2H), 7.65-7.67 (m, 2H), 7.60 (d,
2H), 7.47 (t, 2H),
7.36-7.40 (m, 2H), 4.40-4.70 (m, 3H), 3.45-4.02 (m, 9H), 2.95 (q, 2H), 1.38-
1.61 (m, 3H), 1.35 (t,
3H).
EXAMPLE 125
3-{[4-(2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethylthieno[2,3-
d]pyrim idin-4-
yl)piperazin-1-yl]carbonyl}-9H-fluoren-9-one
0
O \ /
(N)
N
N
H3C S NO'Y~O
O-~-CH3
H3C
2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-piperazin-1-
ylthieno[2,3-d]pyrim idine
(Example 25, 0.106 g) was dissolved in THF. To this mixture was added HATU
(0.106 g) and
DIEA (0.072 g), followed by 9-oxo-9H-fluorene-3-carboxylic acid (0.063 g). The
mixture was
stirred at room temperature overnight. The solvent was evaporated under
reduced pressure and
the residue was purified by silica gel chromatography, eluting with ethyl
acetate/hexanes (70/30)
to give 0.11 g of the title compound. MS (ESI+) for C32H32N405S1 m/z585.44
(M+H)+. 'H NMR
(400 MHz, CDCI3) S 7.71 (d, 2H), 7.69 (m, 4H), 7.37 (t, 1 H), 6.85 (s, 1 H),
4.52 (m, 2H), 4.35 (m,
1 H), 4.16 (m, 2H), 3.92 (br m, 8H), 2.87 (m, 2H), 1.58 (s, 3H), 1.36 (s, 3H),
1.34 (t, 3H).
EXAMPLE 126
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4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethyl-2-[(3-methyloxetan-3-
yl)methoxy]thieno[2,3-d]pyrimidine
O
(N)
N
N
S NO~
O
Sodium hydride (0.026 g, 60% in mineral oil) was placed into a round bottomed
flask and then
washed with hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added
and the
mixture stirred for 15 minutes. 3-Methyl-3-oxetane methanol (0.064 mL) was
added and the
mixture was stirred for 30 minutes. The pyrimidine of Example 13 (0.15 g) was
dissolved in NMP
(2.0 mL) and added drop-wise to the chilled mixture. Once the addition was
complete removed
from the ice/acetone bath and stirred at room temperature for 18 hours. The
mixture was then
partitioned between saturated sodium'bicarbonate and ethyl acetate. The layers
were separated
and the organic layer washed three times with brine, dried over anhydrous
magnesium sulfate
and concentrated. The residue was chromatographed on silica gel (100 mL) using
ethyl acetate
as eluent to give 0.0787 g of the title compound: MS (ESI+) for C30 H32 N4 03
S, m/z 529.35
(M+H)+. 'H NMR (CDCI3) b 1.33 (t, 3 H), 1.59 (s, 3 H), 2.85 (q, 2 H), 3.6-4.0
(m, 8 H), 4.46 (m, 4
H), 4.62 (m, 2 H), 6.87 (s, 1 H), 7.39 (m, 1 H), 7.41 (m, 1 H), 7.53 (d, 2 H),
7.61 (d, 2 H), 7.66 (d,
2H).
EXAMPLE 127
(2R)-3-({6-Ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-
d]pyrim idin-2-
yl}oxy)propane-1,2-diol
O~CF3
CN)
N
H3C N
S
N O O H
OH
To an ice cooled solution of 2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-
6-ethyl-4-[4-(3,3,3-
trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidine (Example 145, 0.084
g) in 'methanol was
added 4N HCI in dioxane (5 mL) and the mixture was stirred for 2 hours. The
mixture was
warmed to room temperature and stirred for an additional 6 hours at room
temperature and
concentrated. The residue was dissolved in ethyl acetate, washed with
saturated sodium
bicarbonate, brine, and dried over magnesium sulfate and then concentrated
under reduced
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pressure to give 0.050 g of the title compound. MS (ESI+) for C18H23F3N404S
m/z449.24
(M+H)+. 'H NMR (400 MHz, CD3OD) S 6.87 (s, 1 H), 4.50 (m, 2H), 4.10 (m, 1 H);
3.98 (m, 4H),
3.91 (m, 2H), 3.71 (m, 4H), 3.33 (q, 2H), 2.88 (q, 2H), 1.99 (t, 3H).
EXAMPLE 128
(3-{[4-(2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethylth ieno[2,3-
d]pyrim idin-4-
yl)p iperazin-1-yl]carbonyl}phenyl)(phenyl)m ethanone
(N) O
N
H3C N
S NO'-rO
O-~-CH3
H3C
To a mixture of 2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-
piperazin-1-
ylthieno[2,3-d]pyrimidine (Example 25, 0.6 g) in THF (20 mL) was added
diisopropylethylamine
(0.6 mL), 3-benzoylbenzoic acid (0.375 g) and HATU (0.632 g). The mixture was
stirred
overnight at room temperature. The mixture was then partitioned between ethyl
acetate and
brine. The layers were separated and the organic layer was washed three times
with brine, dried
over anhydrous magnesium sulfate and concentrated. The resulting crude mixture
was purified
on silica gel using ethyl acetate and hexanes (40/60)'to give 0.98 g of the
title compound. MS
(ESI+) m1z587.36 (M+H)+. iH NMR (400 MHz, CDCI3). 5 7.87-7.50 (m, 9H), 6.86
(s, 1H) 4.51-
4.50 (m, 2H), 4.48 (q, 1 H), 4.16 (t, 1 H), 4.14-3.90 (br m, 7H), 3.60 (br s,
2H), 2.87 (q, 2H), 1.70
(s, 3H), 1.44 (s, 3H), 1.34 (t, 3H).
EXAMPLE 129
(3-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-
yl)piperazin-1-
yl]carbonyl}phenyl)(phenyl)m ethanone
o a o
(N) O
N
'N
H3C S I N~O O OH
To an ice cooled solution of the methanone of Example 128 (0.35 g) in methanol
was added 4N
HCI in dioxane (12 ml) and stirred for 2 hours. The solution was warmed to
room temperature
and stirred for additional 3 hours at room temperature and concentrated. The
residue was
dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine,
dried over
magnesium sulfate and then concentrated under reduced pressure to give 0.12 g
of the title
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compound. MS (ESI+) m/z547.30 (M+H)+. 'H NMR (400 MHz, CDCI3) S 7.83-7.30 (m,
9H), 6.9
(s, 1 H), 4.40 (m, 2H) 4.0 (m, 8H), 3.67 (b, 3H), 2.8 (t, 2H), 1.31 (t, 3H).
EXAMPLE 130
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-phenylthieno[2,3-d]pyrimidine
i~
i ~
N
l"~ ~'J1
~ S N O"~O
O-/- CH3
H3C
[(4S)-2,2-Dim ethyl- 1, 3-d ioxolan-4-yl]m ethanol (0.25 g) was dissolved in
NMP and cooled to 0 C.
To this solution was added sodium hydride (60% dispersion, 0.08 g). The
mixture was stirred for
10 minutes at 0 C and then for 30 minutes at room temperature. The mixture was
cooled back
to 0 C and 4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-
phenylthieno[2,3-
d]pyrimidine (Example 43, 0.5 g) was added as a solution in NMP (10 mL). After
15 minutes of
stirring the cooling bath was removed and the mixture was stirred an
additional 3 hours. The
mixture was then partitioned between ethyl acetate and aqueous saturated
sodium bicarbonate.
The organic layer was then washed with brine, separated, dried over MgSO4,
filtered and
concentrated. The resulting crude mixture was purified on silica gel using
ethyl acetate-hexanes
(40/60) to give 0.31 g of the title compound. MS (ESI+) m/z607.41 (M+H)+. 'H
NMR (400 MHz,
CDCI3) S 7.67-7.33 (m, 15H), 4.50 (m, 2H), 4.35 (m, 1 H) 4.20 (m, 1 H), 4.15-
3.91 (m, 9H), 1.46 (s,
3H), 1.38 (s, 3H).
EXAMPLE 131
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-m ethylth ieno[2, 3-d]pyrim idine
I
o
CNJ
~N
H3C / ~ ~
S Np~C
/_CH3
H3C
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[(4S)-2,2-Dimethyl-1,3-dioxolan=4-yl]methanol (0.17 g, 1.33 mmol) was-
dissolved in NMP (5 mL)
and cooled to 0 C. Hexane washed NaH (0.053 g) was added. The mixture was
stirred at 0 C
for 10 minutes followed by stirring at room temperature for 30 minutes. The
mixture was cooled
again to 0 C and 4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-
methylthieno[2,3-
d]pyrimidine (Example 44, 0.3 g) was added as a solution in NMP/DMF (8 mU5
mL). The
mixture was stirred at 0 C for 15 minutes followed by stirring at room
temperature overnight. The
mixture was partitioned between ethyl acetate and aqueous saturated sodium
bicarbonate. The
organic layer was dried over MgSO4, filtered, dried and concentrated. The
resulting residue was
purified by silica gel chromatography using ethyl acetate-hexanes (40/60) to
give 0.24 g of the
title compound. MS (ESI+) m/z545.38 (M+H)+. 'H NMR (400 MHz, CDCI3) S 7.66-
7.37 (m, 9H),
6.85 (s, 1 H), 4.52 (m, 2H), 4.28 (m, 1 H), 4.88 (m, 1 H), 3.95-3.89 (m, 9H),
2.25 (s, 3H), 1.57 (s,
3H), 1.44 (s, 3H).
EXAMPLE 132
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-propylth'ieno[2,3-d]pyrimidine
O
CN~
S N~O'~~O
H3C 01-CH3
3
[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol (0.17 g) was dissolved in NMP (5
mL) and cooled
to 0 C. Hexane washed NaH (0.05 g) was added. The mixture was stirred at 0 C
for 10
minutes followed by stirring at room temperature for 30 minutes. The mixture
was cooled again
to 0 C and 4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-
propylthieno[2,3-
d]pyrimidine (Example 47, 0.3 g) was added as a solution in NMP/DMF (8 mU5
mL). The
mixture was stirred at 0 C for 15 minutes followed by stirring at room
temperature overnight.
The mixture was partitioned between ethyl acetate and aqueous saturated sodium
bicarbonate
and the organic layer was dried over MgSO4, filtered, dried and concentrated.
The resulting
residue was purified by silica gel chromatography ethyl acetate-hexanes
(30/70) to give 0.18 g of
the title compound. MS (ESI+) m/z573.43 (M+H)+. 1H NMR (400 MHz, CDCI3) 5 7.66-
7.36 (m,
9H), 6.86 (s, 1 H), 4.50(m, 2H) 4.45 (m, 1 H), 4.14 (m, 1 H), 3.92 (br m, 9H),
2.76 (t, 2H), 1.74 (q,
2H),1.49 (s, 3H), 1.43 (s, 3H), 1.00 (t, 3H).
EXAMPLE 133
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-isopropylthieno[2,3-d]pyrimidine
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-~I
O ~I
N
H3C ~ I ~,
H3C S N O'-'C-O
OC CH3
3
[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol (0.17 g) was dissolved in NMP (6
mL) and cooled
to 0 C. Hexane washed NaH (0.05 g) was added. The mixture was stirred at 0 C
for 10
minutes followed by stirring at room temperature for 30 minutes. The mixture
was cooled again
to 0 C and 4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-
isopropylthieno[2,3-
d]pyrimidine (Example 48, 0.3 g) was added as a solution in NMP/DMF (8 mU5
mL). The
mixture was stirred at 0 C for 15 minutes followed by stirring at room
temperature overnight,
after which the mixture was partitioned between ethyl acetate and aqueous
saturated sodium
bicarbonate. The organic layer was dried over MgSO4, filtered, dried and
concentrated. The
resulting crude mixture was purified on silica gel using ethyl acetate and
hexanes (30:70) to give
0.21 g of the title compound. MS (ESI+) m/z573.43 (M+H)+. 'H NMR (400 MHz,
CDCI3) S 7.70-
7.36 (m, 9H), 6.85 (s, 1 H), 4.49 (m, 2H), 4.31 (m, 1 H), 4.09 (m, 1 H), 3.91
(br m, 9H), 3.74 (m,
1 H), 1.58 (s, 6H), 1.43 (s, 3H), 1.37 (s, 3H).
EXAMPLE 134
2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(thien-2-
ylacetyl)piperazin-1-
yl]thieno[2,3-d]pyrimidine
O
N
N
H3C S N O")g'O
O-~CH3
CH3
To a mixture of the pyrimidine of Example 25 (0.106 g) in THF (5 mL) was added
diisopropylethylamine (0.11 mL), HATU (0.106 g) and 2-thiophene acetic acid
(0.0398 g). The
mixture was stirred overnight at room temperature. The mixture was then
partitioned between
ethyl acetate and brine. The layers were separated and the organic layer was
washed four times
with brine, dried over anhydrous magnesium sulfate and concentrated. The
resulting crude
mixture was purified on silica gel using ethyl acetate and hexanes (70:30) to
give 0.096 g of the
title compound. MS (ESI+) m/z 503.32 (M+H)+. 'H NMR (400 MHz, CDCI3). S 7.40
(d, 1 H), 6.66
(m, 2H), 6.60 (s, 1 H), 4.51 (m, 2H), 4.30 (m, 1 H), 4.27 (m, 1 H), 3.95 (s,
2H), 3.88 (br m, 7H),
3.79 (br m, 2H), 2.84 (q, 2H), 1.62 (s, 3H), 1.34 (s, 3H), 1.32 (t, 3H).
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EXAMPLE 135
(2R)-3-({6-Ethyl-4-[4-(thien-2-ylacetyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-
2-yl}oxy)propane-1,2-
diol
O~, S
NI
N
'N
H3C S N O'-IC~OH
OH
To an ice cooled solution of the pyrimidine of Example 134 (0.090g) in
methanol was added 4N
HCI in dioxane (5 ml) and stirred for 2 hours. The solution was warmed to room
temperature and
stirred for additional 6 hours at room temperature and concentrated. The
residue was dissolved
in ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried
over magnesium
sulfate and then concentrated under reduced pressure to give 0.096 g of the
title compound. MS
(ESI+) m/z463.21 (M+H)+. iH NMR (400 MHz, CD3OD) 5 7.25 (d, 1 H), 6.96 (t, 2H)
6.84 (s, 1 H),
4.49 (m, 4H), 4.05 (m, 1 H), 3.95 (s, 1 H), 3.90-3.66 (m, 11 H), 2.83 (q, 2H),
1.32 (t, 3H).
EXAMPLE 136
2-{[(4S)-2,2-Dimethyl-1, 3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3-
phenoxybenzoyl)piperazin-l-
yl]thieno[2,3-d]pyrimidine
o ao o
N
ci
H3C N
S I N~-p----~O
O-~-CH3
H3C
To a mixture of the pyrimidine of Example 25 (0.106 g) in THF (5 mL) was added
diisopropylethylamine (0.11 mL), HATU (0.106 g) and 3-phenoxybenzoic acid
(0.06 g). The
mixture was stirred overnight at room temperature. THF was then removed under
reduced
pressure and the resulting crude mixture was purified on silica gel using
ethyl acetate and
hexanes (70/30) to give 0.13 g of the title compound. MS (ESI+) m/z 575.41
(M+H)+. ' H NMR
(400 MHz, CDCI3). S 7.40-7.36 (m, 3H), 7.25 (m, 2H), 7.15 (m, 4H), 6.84 (s, 1
H), 4.51 (m, 2H),
4.31 (m, 1 H), 4.15 (m, 1 H), 3.9-3.5 (br m, 9H), 2.85 (q, 2H), 1.59 (s, 3H),
1.37 (s, 3H), 1.32 (t,
3H).
EXAMPLE 137
(2R)-3-({6-Ethyl-4-[4-(3-phenoxybenzoyl)piperazin-1-yl]thieno[2,3-d]pyrim idin-
2-yl}oxy)propane-
1,2-diol
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O
N~
H3C N
S N O OHOH
To an ice cooled solution of 2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-
6-ethyl-4-[4-(3-
phenoxybenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidine (Example 136, 0.127g) in
methanol was
added 4N HCI in dioxane. The mixture was gradually warmed to room temperature
and stirred
for 3.5 hours. The mixture was partitioned between ethyl acetate and aqueous
saturated sodium
bicarbonate. The ethyl acetate layer was dried over MgSO4, filtered and
concentrated to give
0.070 g of the title compound. MS (ESI+) for C28H30N405S1 m/z535.29 (M+H)+. 'H
NMR (400
MHz, CD3OD) S 7.40 (m, 3H), 7.25 (m, 2H), 7.14 (m, 4H), 6.88 (s, 1 H), 4.48
(t, 2H), 4.07 (br, 7H),
3.69 (m, 4H), 2.86 (q, 2H), 1.34 (t, 3H).
EXAMPLE 138
2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-4-[4-(3,3-
diphenylpropanoyl)piperazin-1-yl]-6-
ethylthieno[2,3-d]pyrim idine
O
N
(N)
H3C N
S S N L O
O'**'J~,O
oCH3
3
To a mixture of the pyrimidine of Example 25 (0.106 g) in THF (5 mL) was added
diisopropylethylamine (0.11 mL), HATU (0.106 g) and 2,2-diphenylpropionic acid
(0.063 g). The
mixture was stirred overnight at room temperature. The mixture was then
partitioned between
ethyl acetate and brine. The layers were separated and the organic layer was
washed four times
with brine, dried over anhydrous magnesium sulfate and concentrated. The
resulting crude
mixture was purified on silica gel using ethyl acetate and hexanes (70:30) to
give 0.120 g of the
title compound. MS (ESI+) for C33H38N4O4S m/z587.35 (M+H)+.'H NMR (400 MHz,
CDCI3) S
7.55-7.23 (m, 10H), 6.70 (s, 1 H), 4.50 (m, 1 H), 4.40 (m, 1 H), 4.22 (m, 1
H), 4.11 (m, 1 H), 3.95 (br
m, 5H), 3.15 (br s, 4H), 2.75 (q, 2H), 2.30 (s, 1 H), 1.82 (s, 2H), 1.85 (s,
3H), 1.75 (t, 3H), 1.25 (t,
3H).
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EXAMPLE 139
2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(1-
phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrim idine
1;XO
CNJ
H3C N
S N ~0"'4~O
~C CH3
3
To a mixture of 2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-
piperazin-1-
ylthieno[2,3-d]pyrimidine (Example 25, 0.106 g) in THF (5 mL) was added
diisopropylethylamine
(0.11mL), HATU (0.106g) and phenyl-l-cyclopropane carboxylic acid (0.0454 g).
The mixture
was stirred overnight at room temperature. The mixture was then partitioned
between ethyl
acetate and brine. The layers were separated and the organic layer was washed
four times with
brine, dried over anhydrous magnesium sulfate and concentrated. The resulting
crude mixture
was purified on silica gel using ethyl acetate and hexanes (70/30) to give
0.13 g of the title
compound. MS (ESI+) for C28H34,N4O4S m/z523.34 (M+H)+. 1H NMR (400 MHz,
CDCI3). S 7.32
(t, 2H), 7.25 (m, 3H), 6.77 (s, 1 H), 4.51 (m, 4H), 4.24 (m, 1 H), 4.14 (m, 1
H), 3.90 (br m, 7H), 3.79
(br, 4H), 2.81 (q, 2H), 1.89 (s, 3H), 1.66 (s, 3H), 1.60 (t, 3H).
EXAMPLE 140
(2R)-3-[(6-Ethyl-4-{4-[(1-phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-
d]pyrimidin-2-
yI)oxy]propane-1,2-diol
O
N)
N
H3C ~ I . N
S N-'O OH
OH
To an ice cooled solution of the pyrimidine of Example 139 (0.127 g) in
methanol was added 4N
HCI in dioxane (5 mL) and the mixture was stirred for 2 hours. The solution
was warmed to room
temperature and stirred for additional 6 hours and concentrated. The residue
was dissolved in
ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over
magnesium
sulfate and then concentrated under reduced pressure to give 0.090 g of the
title compound. MS
(ESI+) for C25H30N404S m/z483.29 (M+H)+. 'H NMR (400 MHz, CDCI3). S 7.33 (t,
2H), 7.25 (m,
3H), 6.82 (s, 1 H), 4.49 (t, 2H), 4.24 (t, 1 H), 3.90 (br m, 11 H), 2.84 (q,
2H), 1.44 (t, 3H), 1.66 (br
m, 3H).
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EXAMPLE 141
2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(4'-ethyl-1,1'-
biphenyl-4-
yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidine
CiH3
0 \ I
CNJ
N
H3C S I NO~
O
O--~CH3
CH3
To a mixture of 2-{[(4S)-2,2-dimethyl-1,3-dioxoian-4-yl]methoxy}-6-ethyl-4-
piperazin-l-
ylthieno[2,3-d]pyrimidine (Example 25, 0.106 g) in THF (5 mL) was added
diisopropylethylamine
(0.11mL), HATU (0.106g) and 4'-ethyl-1,1'-biphenyl-4-carboxylic acid (0.056
g). The mixture.was
stirred overnight at room temperature. The mixture was then partitioned
between ethyl acetate
and brine. The layers were separated and the organic layer was washed four
times with brine,
dried over anhydrous magnesium sulfate and concentrated. The resulting crude
mixture was
purified on silica gel using ethyl acetate and hexanes (70/30) to give 0.15 g
of the title compound.
MS (ESI+) for C33H38N404S1 m/z587.35 (M+H)+. 'H NMR (400 MHz, CDCI3). S 7.65
(d, 2H),
7.53 (m, 4H), 7.30 (d, 2H), 6.86 (s, 1 H), 4.52 (m, 2H), 4.31 (m, 1 H), 4.88
(m, 1 H), 4.16 (br m,
9H), 2.87 (q, 2H), 2.71 (q, 2H), 1.43 (s, 3H), 1.33 (s, 3H), 1.31 (t, 3H),
1.26 (t, 3 H).
EXAMPLE 142
(2R)-3-[(6-Ethyl-4-{4-[(4'-ethyl-1,1'-biphenyl-4-yl)carbonyl]piperazin-1-yl}th
ieno[2,3-d]pyrim idin-2-
yl)oxy]propane-1,2-diol
CH3
~I
N
H3C S N O~'OH
OH
To an ice cold solution of 2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-
ethyl-4-{4-[(4'-
ethyl-1,1'-biphenyl-4-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidine
(Example 141) in
methanol was added 4N HCI in dioxane. The mixture was gradually warmed to room
temperature and stirred for 3.5 hours. The mixture was partitioned between
ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was separated, dried
over MgSO4,
filtered and concentrated to give 0.090 g of the title compound. MS for
C30H~N4O4S mlz 547.36
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(M+H)+. 'H NMR (400 MHz, CDCI3) S 7.65 (d, 2H), 7.53 (d, 4H), 7.30 (d, 2H),
6.98 (s, 1 H), 4.50
(t, 2H), 4.09-3.70 (br m,11 H), 2.88 (q, 2H), 2.73 (q, 2H), 1.27 (m, 6H).
EXAMPLE 143
2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(2-
naphthyloxy)acetyl]piperazin-1-
yl}thieno[2,3-d]pyrimidine
i i
O~O
(N)
N
N
H3C S NO
I-0
O~CH3
CH3
To a mixture of 2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-
piperazin-1-
ylthieno[2,3-d]pyrimidine (Example 25, 0.106 g) in THF (5 mL) was added
diisopropylethylamine
(0.11mL), HATU (0.106 g) and (2-naphthyloxy)acetic acid (0.056 g). The
reaction was stirred
overnight at room temperature. The mixture was then partitioned between ethyl
acetate and
brine. The layers were separated and the organic layer was washed four times
with brine, dried
over anhydrous magnesium sulfate and concentrated. The resulting crude mixture
was purified
on silica gel using ethyl acetate and hexanes (70/30) to give 0.13 g of the
title compouhd. MS
(ESI+) for C30H,,,AN4O5S m/z 563.39 (M+H)+. 'H NMR (400 MHz, CDCI3) S 8.25 (d,
1 H), 7.81 (d,
1 H), 7.35 (m, 3H), 7.20 (t, 1 H) 6.91(t, 1 H), 6.78 (s, 1 H), 4.94 (s, 2H),
4.50 (m, 2H), 4.27 (m; 1 H),
4.15 (m, 1 H) 3.91 (br m, 9H), 2.83 (q, 2H), 1.79 (s, 3H), 1.55 (s, 3H), 1.36
(t, 3H).
EXAMPLE 144
(2R)-3-[(6-Ethyl-4-{4-[(2-naphthyloxy)acetyl]piperazin-1-yl}thieno[2,3-
d]pyrirnidin-2-
yl)oxy]propane-1,2-diol
i ~
O'~"O IN IIN ~
N
.
H3C S I N JjlO
k'A~,OH
OH
To an ice cold solution of 2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-
ethyl-4-{4-[(2-
naphthyloxy)acetyl]piperazin-1-yl}thieno[2,3-d]pyrimidine (Example 143, 0.097
g) in methanol
was added 4N HCI in dioxane. The mixture was gradually warmed to room
temperature and
stirred for 3.5 hours, after which the mixture was partitioned between ethyl
acetate and aqueous
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saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered
and dried to
give 0.020 g of the title compound. MS (IESI+) for C27H30N405S m/z523.29
(M+H)+. 'H NMR
(400 MHz, CDCI3) S 8.25 (d, 1 H), 7.80 (d, 1 H), 7.45 (m, 3H), 7.38 (t, 1 H),
6.90 (d, 1 H), 6.80 (s,
1 H), 4.98 (s, 2H), 4.45 (t, 2H), 4.22 (t, 1 H), 3.88 (br s, BH), 3.66 (m,
2H), 2.80 (m, 2H), 1.33 (t,
3H).
EXAMPLE 145
2-{[(4S)-2,2-D im ethyl-1, 3-d ioxolan-4-yl]m ethoxy}-6-ethyl-4-[4-(3,3,3-
trifluoropropanoyl)piperazin-
1-yl]thieno[2,3-d]pyrimidine
0 ~'-'CF3
(N)
N
H3C eN
S N 0"'f--\O
C CH3
H3
To 2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-piperazin-1-
ylthieno[2,3-
d]pyrimidine (Example 25, 0.150 g) in THF (5 mL) was added
diisopropylethylamine (0.11 mL),
HATU (0.200 g) and 3,3,3-trifluoropropanoic acid (0.0659 g). The mixture was
stirred overnight
at room temperature. The mixture was then partitioned between ethyl acetate
and brine. The
layers were separated and the organic layer was washed four times with brine,
dried over
anhydrous magnesium sulfate and concentrated. The resulting crude mixture was
purified on
silica gel using ethyl acetate and hexanes (70/30) to give 0.090 g of the
title compound. MS
(ESI+) for C21H27F3N404S m/z489.22 (M+H)+.'H NMR (400 MHz, CDCI3). S 6.85 (s,
1H), 4.52
(m, 2H), 4.30 (m, 1 H), 4.16 (m, 1 H), 3.93 (m, 5H), 3.88 (m, 2H), 3.63 (br m,
2H), 3.32 (q, 2H),
2.85 (q, 2H), 1.45 (s, 3H), 1.34 (s, 3H), 1.24 (t, 3H).
EXAMPLE 146
(2R)-3-({4-[(3R)-4-(1,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-6-
ethylthieno[2,3-
d]pyrim idin-2-yl}oxy)propane-1,2-diol
O
H3C N
N
o I ;N
H3C S NI-O OHOH
4-[(3R)-4-(1,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-2-{[(4S)-2,2-
dimethyl-1,3-dioxolan-
4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine (Example 55, 0.090 g) was
dissolved in 3 mL of 4N
HCI in dioxane at 0 C. The mixture was gradually warmed to room temperature
and stirred for
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2.5 days. The solvent was evaporated and the solid was triturated with diethyl
ether and
collected, then washed with additional diethyl ether and dried under reduced
pressure to give
0.045 g of the title compound. HRMS (ESI+) for C29H32N404S m/z533.2194 (M+H)+.
1H NMR
(400 MHz, CD30D) 8 7.76 (d, 2H), 7.64-7.67 (m, 2H), 7.55-7.57 (m, 2H), 7.45-
7.49 (m, 2H), 7.42
(s, 1 H), 7.36-7.40 (m, 1 H), 4.53-4.72 (m, 5H), 3.99-4.05 (m, 2H), 3.82-3.86
(m, 1 H), 3.60-3.68
(m, 4H), 2.95 (q, 2H), 1.35 (t, 6H).
EXAMPLE 147
(2R)-3-({4-[(3S)-4-(1,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-6-
ethylthieno[2,3-
d]pyrimidin-2-yl}oxy)propane-1,2-diol
O
H3Cs N l
lNJ
e'l~
H3C S N O oHOH
H
4-[(3S)-4-(1,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-2-{[(4S)-2,2-
dimethyl-1,3-dioxolan-
4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine (Example 56, 0.090 g) was
dissolved in 3 mL of 4N
HCI in dioxane at 0 C. The mixture was gradually warmed to room temperature
and stirred for
2.5 days. The solvent was evaporated under reduced pressure and the solid was
triturated with
diethyl ether and collected, then washed with additional diethyl ether and
dried under reduced
pressusre to give 0.060 g of the title compound. HRMS (ESI+) for C29H32N404S
m/z533.2217
(M+H)+'H NMR (400 MHz, CD30D) S 7.76 (d, 2H), 7.65-7.67 (m, 2H), 7.56 (d, 2H),
7.45-7.57 (m,
2H), 7.41 (s, 1 H), 7.36-7.40 (m, 1 H), 4.51-4.72 (m, 5H), 3.99-4.05 (m, 2H),
3.82-3.87 (m, 2H),
3.60-3.68 (m, 3H), 2.95 (q, 2H), 1.35 (t, 6H).
EXAMPLE 148
(2R)-3-({4-[(2R)-4-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-6-
ethylthieno[2,3-
d]pyrim idin-2-yl}oxy)propane-1,2-diol
~I
O
rN
H30 l N
'N
H3C S N O-V-\OH
OH
4-[(2R)-4-(1,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-2-{[(4S)-2,2-
dimethyl-1,3-dioxolan-
4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine (Example 63, 0.036 g) was
dissolved in 4N
HCI/dioxane (2 mL) at 0 C. The mixture was allowed to warm to room
temperature and stir for 3
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days. The solvent was evaporated under reduced pressure and the residue was
triturated with
ether. The resulting solid was collected, washed with diethyl ether, and dried
under reduced
pressure to give 0.046 g of the title compound. HRMS (ESI+) for C29H32N404S
m/z533.2233
(M+H)+. iH NMR (400 MHz, CD3OD) b 7.76 (d, 2H), 7.65-7.67 (m, 2H), 7.59 (d,
2H), 7.45-7.49
(m, 2H), 7.37-7.41 (m, 1 H), 7.33 (s, 1 H), 4.41-4.69 (m, 3H), 3.45-4.04 (m,
9H), 2.95 (q, 2H), 1.42-
1.56 (m, 3H), 1.35 (t, 3H).
EXAMPLE 149
(2R)-3-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-phenylthieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol
i I
' J
N
c-cNAOOH
OH
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-phenylthieno[2,3-d]pyrimidine (Example 130, 0.21 g) was dissolved in 4N HCI
in dioxane at
0 C. The solution was then gradually warmed to room temperature and stirred
for 3 hours. The
mixture was partitioned between dichloromethane and aqueous saturated sodium
bicarbonate.
The organic layer was separated, dried over MgSO4, filtered and concentrated.
The resulting
residue was partitioned a second time between ethyl acetate and water. The
ethyl acetate was
dried over MgSO4, filtered, and concentrated then purified on silica gel (3%
methanol/ 97%
hexanes) to give 0.075 g of the title compound. MS (ESI+) m/z567.36 (M+H)+. 'H
NMR (400
MHz, CD3OD) 5 7.7-7.2 (m, 15H), 4.50 (m, 2H), 3.9-4.1 (m, 2H), 4.0 (br s, 6H),
3.7-3.8 (m, 3H).
EXAMPLE 150
(2R)-3-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-methylthieno[2,3-
d]pyrim idin-2-
yl}oxy)propane-1,2-diol
O
' J
N
~
HsC N
S N)'~O"Y'OH
oH
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-methylthieno[2,3-d]pyrimidine (Example 131, 0.20 g) was dissolved in 4N HCI
in dioxane (8
mL) and stirred at room temperature for 3 hours. The mixture was partitioned
between ethyl
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acetate and aqueous saturated sodium bicarbonate: The organic layer was-
separated, dried
over MgSO4i filtered and concentrated. The crude residue was purified on
silica gel using 5%
MeOH/ 95% hexanes to give 0.07 g of'the title compound. MS (ESI+) m/z505.26
(M+H)+. 1H
NMR (400 MHz, CD30D) S 2.5 (s, 3H), 3.65 (m, 4H), 3.85 (b, 8H), 4.1 (t, 1 H),
4.45 (d, 2H), 6.9 (s,
1 H), 7.4-7.7 (m, 9H).
EXAMPLE 151
(2R)-3-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-propylthieno[2,3-
d]pyrimidin-2-
yl}oxy)propane-1,2-diol
~I
~
~I
O ~
(N)
N
.N
H3C S N"'1'O'~%)r'OH
OH
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-,
6-propylthieno[2,3-d]pyrimidine (Example 132, 0.15 g) was dissolved in 4N HCI
in dioxane at
0 C. The solution was gradually warmed to room temperature and stirred for 8
hours. The
mixture was then partitioned between ethyl acetate and aqueous saturated
sodium bicarbonate.
The organic layer was separated, dried over MgSO4, filtered and concentrated.
The residue was
stirred with diethyl ether and a few drops of acetonitrile from which a white
solid precipitated.
The solid was collected and dried to give 0.090 g of the title compound. MS
(ESI+) m/z533.37
(M+H)+. 'H NMR (400 MHz, CD3OD) S 1.0 (t, 3H), 1.5 (m, 2H), 2.8 (t, 2H), 3.7
(rn, 2H), 3,9 (b,
8H), 4.05 (t, 1 H), 4.5 (d, 2H), 6.9 (s, 1 H), 7.4-7.7 (m, 9H).
EXAMPLE 152
(2R)-3-({4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-
isopropylthieno[2,3-d]pyrim idin-2-
yl}oxy)propane-1,2-diol
.~ .
N
H3C ~ I ' N
H3C g N~.IO--~OH
OH
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]methoxy}-
6-isopropylthieno[2,3-d]pyrimidine (Example 133, 0.17 g) was dissolved in 4N
HCI in dioxane at 0
C. The solution was gradually warmed to room temperature and stirred
overnight. The mixture
was partitioned between ethyl acetate and aqueous saturated sodium
bicarbonate. The organic
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layer was separated, dried over MgSO4, filtered and concentrated.--The crude -
residuewas-
stirred in diethyl ether with a few drops of acetonitrile and the resulting
solid was collected and
dried under reduced pressure to give 0.070g of th-e title compound. MS (ESI+)
m/z533.44
(M+H)+. 'H NMR (400 MHz, CD3OD) 81.34 (d, 6H), 3.2 (m, 1H), 3.7 (m, 2H), 3.95
(b, 8H), 4.1 (t,
1 H), 4.5 (m, 2H), 6.9 (s, 1 H), 7.4-7.7 (m, 9H).
Additional compounds of Formula I that can be prepared in accordance with the
synthetic
methods of the present invention include those compounds described in Table E.
TABLE E - Formulae
A,A,A,A,A,A,A,A and R=Hydrogen
X4=-CO-
Ex. R R X-R Compound Name
Ne%p ethyl piperazine, 1-[2-(3-amino-2-
~ hydroxypropoxy)-6-
0 NH2 ethylthieno[2,3-d]pyrimidin-4-yl]-4-
A-1 ([1,1'-biphenyl]-4-ylcarbonyl)-
Nf%P ethyl piperazine, 1 -[2-(3-am ino-2-
O OH hydroxypropoxy)-6-
ONH2 ethylthieno[2,3-d]pyrimidin-4-yl]-4-
A-2 ([1,1'-biphenyl]-3-yicarbonyl)-
ethyl piperazine, 1 -[2-(3-am ino-2-
OH
I hydroxypropoxy)-6-
O NH2 ethylthieno[2,3-d]pyrim idin-4-yl]-4-
A-3 (phenylacetyl)-
ethyl acetic acid, [[4-[4-([1,1'-biphenyl]-
3-ylcarbonyl)-1-piperazinyl]-6-
SSS-11, O OH I
~ ethylthieno[2,3-d]pyrimidin-2-
A-4 yl]oxy]-
ethyl acetic acid, [[6-ethyl-4-[4-
S.S"~O,,yOH (phenylacetyl)-1-
piperazinyl]thieno[2,3-d]pyrimidin-
A-5 O 2-yl]oxy]-
I ethyl
acetamide, 2-[[4-[4-([1,1'-
0 NH2 ~õ biphenyl]-3-ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-
A-6 O d]pyrimidin-2-yl]oxy]-
ethyl
~ NH2 acetamide, 2-[[6-ethyl-4-[4-
O~ (phenylacetyl)-1-
piperazinyl]thienoj2,3-d]pyrim idin-
A-7 O 2-yl]oxy]-
methyl
acetamide, 2-[[4-[4-([1,1'-
/11'0,,,yNH2 biphenYI]-4-YIcarbonYI)-1
-
piperazinyl]-6-methylthieno[2,3-
A-8 O d]pyrimidin-2-yl]oxy]-
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A,A,A,A,A-,A,A,-A and R=Hydrogen
X4=-CO-
4
Ex. R R
X-R Com ound Name
methyl acetic acid, [[4-[4-([1,1'-biphenyl]-
X0OH 4-ylcarbonyl)-1-piperazinyl]-6-
methylthieno[2,3-d]pyrimidin-2-
A-9 yl]oxy]-
CH3 ethyl acetamide, 2-[[4-[4-([1,1'-
O NH biphenyl]-4-ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-
A-10 0 d]pyrimidin-2-yl]oxy]-N-methyl-
SSSs CH3 ethyl acetamide, 2-[[4-[4-([1,1'-
O H \ biphenyl]-3-ylcarbonyl)-1-
N
~ piperazinyl]-6-ethylthieno[2,3-
A-11 0 d]pyrim idin-2-yl]oxy]-N-m ethyl-
CH3 ethyl acetamide, 2-[[6-ethyl-4-[4-
NH (phenylacetyl)-1-
piperazinyl]thieno[2,3-d]pyrimidin-
A-12 0 2-yl]oxy]-N-methyl-
~' ethyl propanoic acid, 3-[[4-[4-([1,1
O,,,,-),OH biphenyl]-4-ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-
A-13 O d rimidin-2- I]ox -
ethyl propanamide, 3-[[4-[4-([1,1'-
O NH2 biphenyl]-4-ylcarbonyl)-1-
~
~ piperazmyl]-6-ethylthieno[2,3-
A-14 0 d rimidin-2- I]ox -
CH3 ethyl propanamide, 3-[[4-[4-([1,1'-
~ biphenyl]-4-ylcarbonyl)-1-
NH I ~ piperazinyl]-6-ethylthieno[2,3-
A-15 0 d]pyrimidin-2-yl]oxy]-N-methyl-
~v+ CH3 ethyl propanamide, 3-[[4-[4-([1,1'-
0N biphenyl]-4-ylcarbonyl)-1-
~f CH3 piperazinyl]-6-ethylthieno[2,3-
A-16 0 d]pyrimidin-2-yl]oxy]-N,N-dimethyl-
w' ethyl piperazine, 1-[2-(3-aminopropoxy)-
NH2 6-ethylthieno[2,3-d]pyrimidin-4-yl]-
A-17 4-([1,1'-biphenyl]-4-ylcarbonyl)-
' CH3 ethyl piperazine, 1-([1,1'-biphenyl]-4-
~ ylcarbonyl)-4-[6-ethyl-2-[3-
NH 'I (methylamino)propoxy]thieno[2,3-
A-18 d rimidin-4- I -
ethyl piperazine, 1-([1,1'-biphenyl]-4-
O CH3 "I ylcarbonyl)-4-[6-ethyl-2-[2-
N (methylamino)ethoxy]thieno[2,3-
A-19 H d rimidin-4- I-
'V' ethyl piperazine, 1-([1,1'-biphenyl]-3-
ylcarbonyl)-4-[6-ethyl-2-[2-
OOH hydroxy-1-
(hydroxymethyl)ethoxy]thieno[2,3-
A-20 HO d rimidin-4- I-
~
~~'I''~' ethyl piperazine, 1-[6-ethyl-2-[2-
O OH '2 I hydroxy-1-
~ (hydroxymethyl)ethoxy]thieno[2,3-
A-21 HO d]pyrimidin-4-yl]-4-(phenylacetyl)-
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A,A;A,A,A,A,A,A andR-=Hydrogen ---
X4=-C O -
Ex. R R X-R Com ound Name
H3C CH3 \ ethyl propanoic acid, 2-[[4-[4-([1,1'-
411' O OH biphenyl]-4-ylcarbonyl)-1-
piperazinyl]-6-ethylth ieno[2,3-
A-22 0 d]pyrim idin-2-yl]oxy]-2-methyl-
OHOH ethyl propanoic acid, 2-[[4-[4-([1,1'-
~I biphenyl]-4-ylcarbonyl)-1-
~~Q piperazinyl]-6-ethylthieno[2,3-
A-23 0 d]pyrim idin-2-yl]oxy]-3-hydroxy-
OH \ ethyl propanamide, 2-[[4-[4-([1,1'-
I biphenyl]-4-ylcarbonyl)-1-
NH2 piperazinyl]-6-ethylthieno[2,3-
A-24 0 d]pyrim id in-2-yl]oxy]-2-m ethyl-
OH ethyl
CH3 propanamide, 2-[[4-[4-([1,1'-
~ biphenyl]-4-ylcarbonyl)-1-
O NH piperazinyl]-6-ethylthieno[2,3-
d]pyrim idin-2-yl]oxy]-3-hydroxy-N-
O methyl-
A-25
OH ethyl
propanamide, 2-[[4-[4-([1,1'-
NH2 biphenyl]-4-ylcarbonyl)-1-
0 piperazinyl]-6-ethylthieno[2,3-
A-26 O d]pyrimidin-2-yl]oxy]-3-hydroxy-
~.S ethyl cyclopropanecarboxylic acid, 1-[[4-
S''\O OH [4-([1,1'-biphenyl]-4-ylcarbonyl)-1-
\, piperazinyl]-6-ethylthieno[2,3-
A-27 O d]pyrimidin-2-yl]oxy]-
~S ethyl cyclopropanecarboxamide, 1-[[4-
S'\O NH2 [4-([1,1'-biphenyl]-4-ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-
A-28 O d]pyrim idin-2-yl]oxy]-
OH ethyl piperazine, 1-([1,1'-biphenyl]-4-
~'\ ylcarbonyl)-4-[6-ethyl-2-
Q ''~,~ [(tetrahydro-4-hydroxy-3-
furanyl)oxy]th ieno[2,3-d]pyrim idin-
A-29 O 4-yl]-
OH ethyl piperazine, 1-([1,1'-biphenyl]-4-
J'r = ylcarbonyl)-4-[2-[[(1 R,2R,3R) -2,3-
Owo-1I0H dihydroxycyclopentyl]oxy]-6-
A-30 ethylthieno[2,3-d]pyrim idin-4-yl]-
OH ethyl piperazine, 1-([1,1'-biphenyl]-4-
~ ylcarbonyl)-4-[2-[(2,3-
O OH dihydroxycyclopentyl)oxy]-6-
A-31 ethylthieno[2,3-d]pyrim idin-4-yl]-
OH I~ ethyl piperazine, 1-([1,1'-biphenyl]-4-
xj ylcarbonyl)-4-[6-ethyl-2-
O -iI OH [[(1 R,2R,3R,4S)-2,3,4-
trihydroxycyclopentyl]oxy]thieno[2,
A-32 OH 3-d]pyrimidin-4-yl]-
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A,A,A,A,A,A,A,A and R=Hydrogen
X4=-CO-
Ex. R R X-R Compound Name
OH ethyl 4-[6-
A-33 A1-piperazinecarboxaldehyde,
O OH ethyl-2-[(2,3,4-
~ trihydroxycyclopentyl)oxy]thieno[2,
H 3-d]pyrimidin-4-yl]-
oH ethyl piperazine, 1-([1,1'-biphenyl]-4-
o NII
ylcarbonyl)-4-[2-[[(1 R,2R,3S,4S)-
2,3-dihydroxy-4-(2-
O hydroxyethoxy)cyclopentyl]oxy]-6-
A-34 -~-OH ethylthieno[2,3-d]pyrim idin-4-yl]-
OH ethyl
0 oH piperazine, 1-([1,1'-biphenyl]-4-
ylcarbonyl)-4-[2-[[2,3-dihydroxy-4-
(2-hydroxyethoxy)cyclopentyl]oxy]-
0 6-ethylthieno[2,3-d]pyrimidin-4-yl]-
A-35 --\-OH
OH ethyl
cyclopentanecarboxamide, 4-[[4-
~~O ,,%~OH [4-([1,1'-biphenyl]-4-ylcarbonyl)-1-
piperazinyl]-6-ethylth ieno[2,3-
d]pyrim idin-2-yl]oxy]-2,3-
A-36 O NH2 dihydroxy-, (1 S,2R,3R,4R)-
OH ethyl
cyclopentanecarboxamide, 4-[[4-
s< 0 OH [4-([1,1'-biphenyl]-4-ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-
d]pyrim idin-2-yl]oxy]-2,3-
A-37 O NH2 dihydroxy-
ethyl piperazine, 1-([1,1'-biphenyl]-4-
I ylcarbonyl)-4-[6-ethyl-2-[2-(2-
hydroxyethoxy)ethoxy]thieno[2,3-
A-38 d rimidin-4- I -
h~o~~o~ OH ethyl acetic acid, [2-[[4-[4-([1,1'-
'a oj biphenyl]-4-ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-
A-39 d rimidin-2- I ox ]ethox -
NH, ethyl acetamide, 2-[2-[[4-[4-([1,11-
o, o biphenyl]-4-ylcarbonyl)-1-
piperazinyl]-6-ethylthieno[2,3-
A-40 d rimidin-2- I ox ethox -
ethyl
piperazine, 1 -([1,1'-biphenYI]-4
-
O NH ylcarbonyl)-4-[6-ethyl-2-[(5-oxo-3-
pyrrolidinyl)oxy]thieno[2,3-
d]pyrimidin-4-yl]-
A-41
, ethyl piperazine, 1-([1,1'-biphenyl]-4-
~ ylcarbonyl)-4-[6-ethyl-2-(3-
O NH pyrrolidinyloxy)thieno[2,3-
A-42 d]pyrim idin-4-yl]-
V~p O ethyl piperazine, 1-([1,1'-biphenyl]-4-
I ylcarbonyl)-4-[6-ethyl-2-[(2-oxo-3-
O NH pyrrolidinyl)oxy]thieno[2,3-
A-43 d]pyrimidin-4-yl]-
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A,A,A,A,A,A,A,A and R=Hydrogen
X4=-Ci O -
Ex. R X-R Com ound Name
ethyl piperazine, 1-([1,1'-biphenyl]-4-
p ylcarbonyl)-4-[6-ethyl-2-(4-
NH piperidinyloxy)thieno[2,3-
A-44 d]p rimidin-4- I]-
.N' ethyl piperazine, 1-([1,1'-biphenyl]-4-
0 NII ylcarbonyl)-4-[6-ethyl-2-
~ [(tetrahydro-2H-pyran-4-
A-45 yl)oxy]thieno[2,3-d]pyrimidin-4-yl]-
OH I~ ethyl piperazine, 1-([1,1'-biphenyl]-4-
~'~O~OH ylcarbonyl)-4-[6-ethyl-2-[[(2S,3R)-
2,3,4-
OH trihydroxybutyl]oxy]thieno[2,3-
A-46 d] rimidin-4- I -
OH I~ ethyl piperazine, 1-([1,1'-biphenyl]-4-.
.ss~O~OH I ~ ~ ylcarbonyl)-4-[6-ethyl-2-[[(2S,3S)-
2,3,4-
OH trihydroxybutyl]oxy]thieno[2,3-
A-47 d rimidin-4- I -
OH ethyl piperazine, 1-([1,1'-biphenyl]-4-
41~,O,,,~,~OH ylcarbonyl)-4-[6-ethyl-2-[[(2R,3R)-
2,3,4-
OH trihydroxybutyl1oxy]thieno[2,3-
A-48 d rimidin-4- I -
OH ethyl piperazine, 1-([1,1'-biphenyl]-4-
~'~O~OH ylcarbonyl)-4-[6-ethyl-2-[[(2R,3S)-
2,3,4-
OH trihydroxybutyl]oxy]thieno[2,3-
A-49 d rimidin-4- I -
O ethyl piperazine, 1-([1,1'-biphenyl]-4-
~.f\ ylcarbonyl)-4-[6-ethyl-2-(3-
O CH3 oxobutoxy)thieno[2,3-d]pyrimidin-
A-50 4- I -
ethyl piperazine, 1-([1,1'-biphenyl]-4-
0 CH3 ylcarbonyl)-4-[6-ethyl-2=(2-
11"Y oxopropoxy)thieno[2,3-d]pyrimidin-
A-51 O 4-yl]-
F~~ ethyl (2S)-3-({6-ethyl-4-[4-(3,3,3-
0oH ~ I/ F trifluoropropanoyl)piperazin-l-
~H yl]thieno[2,3-d]pyrimidin-2-
A-52 F yl}oxy)propane-1,2-d iol
F F F F (2S)-3-({6-(1,1-difluoroethyl)-4-[4-
(3,3,3-trifluoropropanoyl)piperazin-
CH3 1-yl]thieno[2,3-d]pyrimidin-2-
A-53 OH F ~ yl}oxy)propane-1,2-diol
ooH F F F F (2R)-3-({6-(1,1-difluoroethyl)-4-[4-
(3,3,3-trifluoropropanoyl)piperazin-
oH CH3 1-yl]thieno[2,3-d]pyrimidin-2-
A-54 F yl}oxy)propane-1,2-diol
F F 2-({6-(1,1-difluoroethyl)-4-[4-
NH2 F (3,3,3-trifluoropropanoyl)piperazin-
~~ CH3 1-yl]thieno[2,3-d]pyrim idin-2-
A-55 F yl}oxy)ethylamine
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A,A,A,A,A,A,A,A and R=Hydrogen
X4=-C O -
Ex. R R X-R Com ound Name
F ~F (2S)-3-({6-(2,2,2-trifluoroethyl)-4-
o~~OH F ~ [4-(3,3,3-
oH F trifluoropropanoyl)piperazin-l-
yl]thieno[2,3-d]pyrim idin-2-
A-56 F ylloxy) ro ane-1,2-diol
F F (2R)-3-({6-(2,2,2-trifluoroethyl)-4-
OH F "~v \~F [4-(3,3,3-
oH F trifluoropropanoyl)piperazin-1-
yl]thieno[2,3-d]pyrim idin-2-
A-57 F ylloxy)propane-1,2-diol
F F (2S)-3-({6-(trifluoromethyl)-4-[4-
0-"--~oH F F (3,3,3-trifluoropropanoyl)piperazin-
5H 1-yl]thieno[2,3-d]pyrimidin-2-
F F yl}oxy)propane-1,2-diol
A-58
~ F F (2R)-3-({6-(trifluoromethyl)-4-[4-
O/~~ \OH F F (3,3,3-trifluoropropanoyl)piperazin-
oH ~Ik 1 -yl]thieno[2,3d]pyrimidin 2
F F yl}oxy)propane-1,2-diol
A-59
,,sr F ethyl 3-({6-ethyl-4-[4-(3,3,3-
~o"~~~oH /~/ F trifluoropropanoyl)piperazin-1-
~, yl]thieno[2,3-d]pyrimidin-2-
A-60 F yl}oxy)propan-1-ol
F ethyl 2-({6-ethyl-4-[4-(3,3,3-
F trifluoropropanoyl)piperazin-1-
~, yl]thieno[2,3-d]pyrimidin-2-
A-61 F yl}oxy)ethanol
F ethyl 2-({6-ethyl-4-[4-(3,3,3-
0NH2 F trifluoropropanoyl)piperazin-1-
tl, yl]thieno[2,3-d]pyrimidin-2-
A-62 F yl}oxy)ethylamine
OH F ethyl 2-({6-ethyl-4-[4-(3,3,3-
F trifluoropropanoyl)piperazin-l-
SS' OH yl]thieno[2,3-d]pyrimidin-2-
A-63 O F yI}oxy)propane-1,3-diol
OH F F ethyl ({6-ethyl-4-[4-(3,3,3-
O~ trifluoropropanoyl)piperazin-1-
~, yl]thieno[2,3-d]pyrimidin-2-
O F yl}oxy)acetic acid
A-64
S.SS\ NH2 F F ethyl 2-({6-ethyl-4-[4-(3,3,3-
O~ trifluoropropanoyl)piperazin-l-
yI]thieno[2,3-d]pyrimidin-2-
O F yl}oxy)acetamide
A-65
H F ethyl 2-({6-ethyl-4-[4-(3,3,3-
'~ O N~CH F trifluoropropanoyl)piperazin-l-
~ 3 ~,~ yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-
0 F N-methylacetamide
A-66
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A,A,A,A,A,A,A,A and R=Hydrogen
X4 = -C O -
Ex. R R X-R Com ound Name
N~ 3 F ethyl N-(tert-butyl)-2-({6-ethyl-4-[4-
~ F (3,3,3-trifluoropropanoyl)piperazin-
o c"3 1-yl]thieno[2,3-d]pyrimidin-2-
A-67 IF yl}oxy)acetamide
5.S's~ CH3 F ethyl 1-({6-ethyl-4-[4-(3,3,3-
O~ F trifluoropropanoyl)piperazin-l-
~, yl]thieno[2,3-d]pyrimidin-2-
0 F yl}oxy)acetone
A-68
O F ethyl 4-({6-ethyl-4[4-(3,3,3-
/~~II ~I/F trifluoropropanoyl)piperazin-l-
O CH3 ' 'I~" yl]thieno[2,3 d]pyrimidin-2-
A-69 F yl}oxy)butan-2-one
O F ethyl 3-({6-ethyl-4-[4-(3,3,3-
F ~I/ trifluoropropanoyl)piperazin-l-
O/ \ OH yl]thieno[2,3 d]pyrimidin-2-
F yl}oxy)propanoic acid
A-70
O F ethyl 3-({6-ethyl-4-[4-(3,3,3-
/----'II c.~ F trifluoropropanoyl)piperazin-l-
O NH2 yl]thieno[2,3-d]pyrimidin-2-
A-71 F yl}oxy)propanamide
H F ethyl 6-ethyl-2-(1 H-tetrazol-5-
C5~ O N ~I/ F ylmethoxy)-4-[4-(3,3,3-
~N '," 7 trifluoropropanoyl)piperazin-l-
A-72 N~N IF yl]thieno[2,3-d]pyrimidine
O F ethyl (4R)-4-[({6-ethyl-4-[4-(3,3,3-
s=S, F trifluoropropanoyl)piperazin-l-
O NH yl]thieno[2,3-d]pyrimidin-2-
A-73 Cr F yl}oxy)methyl]isoxazolidin-3-one
O F ethyl (4S)-4-[({6-ethyl-4-[4-(3,3,3-
S1'1 Oc.~ ~ I /F trifluoropropanoyl)piperazin-l-
NH '"t.' ~II' yl]thieno[2,3-d]pyrimidin-2-
A-74 0 F yl}oxy)methyl]isoxazolidin-3-one
O F ethyl (3S)-3-[({6-ethyl-4-[4-(3,3,3-
F trifluoropropanoyl)piperazin-l-
O yl]thieno[2,3-d]pyrimidin-2-
F yljoxy)m
-75 one
O F ethyl (3R)=3-[({6-ethyl-4-[4-(3,3,3-
SS', F trifluoropropanoyl)piperazin-1=
O O 11, yl]thieno[2,3-d]pyrimidin-2-
F olxy)methyl]dihydrofuran-2(3H)-
A-76 one
O F ethyl (4R)-4-({6-ethyl-4-[4-(3,3,3-
~ F trifluoropropanoyl)piperazin-l-
-S.S: 2, yl]thieno[2,3-d]pyrimidin-2-
A-77 \O ONH F yl}oxy)isoxazolidin-3-one
0 F ethyl (4S)-4-({6-ethyl-4-[4-(3,3,3-
F trifluoropropanoyl)piperazin-l-
0' NH yl]thieno[2,3-d]pyrimidin-2-
A-78 O F yl}oxy)isoxazolidin-3-one
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A,A,A,A,A,A,A,A and R=Hydrogen
X4 = -C O -
Ex. R R 4 X-R Compound Name
O F ethyl 4-[({6-ethyl-4-[4-(3,3,3-
r ~ I / F trifluoropropanoyl)piperazin-l-
~~ ~-~,' 'II' yl]thieno[2,3-d]pyrimidin-2-
NH F yl}oxy)methyl]isoxazol-3(2H)-one
0
A-79
OH F ethyl (2S)-2-({6-ethyl-4-[4-(3,3,3-
F trifluoropropanoyl)piperazin-1-
-9~ 0 OH yl]thieno[2,3-d]pyrim idin-2-yl}oxy)-
F 3-hydroxypropanoic acid
A-80 0
--OH F ethyl (2R)-2-({6-ethyl-4-[4-(3,3,3-
~ F trifluoropropanoyl)piperazin-l-
~~O OH yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-
~ F 3-hydroxypropanoic acid
0
A-81
OH F ethyl (2S)-2-({6-ethyl-4-[4-(3,3,3-
F trifluoropropanoyl)piperazin-1-
"S,~, 0 NH2 yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-
2 3-hydroxypropanamide
F
A-82 0
--OH F ethyl (2R)-2-({6-ethyl-4-[4-(3,3,3-
__ F trifluoropropanoyl)piperazin-l-
"~. O NH2 yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-
F 3-hydroxypropanamide
A-83 O
NH2 F ethyl (2S)-3-amino-2-({6-ethyl-4-[4-
F (3,3,3-trifluoropropanoyl)piperazin-
O NH 1-yl]thieno[2,3-d]pyrimidin-2-
2 F yl}oxy)propanamide
A-84 0
--NH2 F ethyl (2R)-3-amino-2-({6-ethyl-4-[4-
__ ~ F (3,3,3-trifluoropropanoyl)piperazin-
"S,S:"~0NH 1 -yl]thieno[2,3-d]pyrimidin-2-
~ 2 yl}oxy)propanamide
F
A-85 O
NH2 F ethyl (2S)-3-amino-2-({6-ethyl-4-[4-
F (3,3,3-trifluoropropanoyl)piperazin-
"SI~10 OH 1-yl]thieno[2,3-d]pyrimidin-2-
F yl}oxy)propanoic acid
A-86 0
--NH2 F ethyl (2R)-3-amino-2-({6-ethyl-4-[4-
F (3,3,3-trifluoropropanoyl)piperazin-
-S.S~~ O OH 1-yl]thieno[2,3-d]pyrimidin-2-
~ F yl}oxy)propanoic acid
A-87 O
o F ethyl 2-({6-ethyl-4-[4-(3,3,3-
~/g \ F trifluoropropanoyl)piperazin-1-
0 lol NH2 '~~ yl]thieno[2,3-d]pyrimidin-2-
A-88 F yl}oxy)ethanesulfonamide
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A,A,A,A,A,A,A,A and R=Hydrogen
X4=-C O -
Ex. R R X-R Compound Name
O F F ethyl 6-ethyl-2-[2-
h (m ethylsulfonyl)ethoxy]-4-[4-
CH3 '2~ (3,3,3-trifluoropropanoyl)piperazin-
0 F 1 -yl]thieno[2,3-d]pyrimidine
A-89
0. Biological Protocols
In vitro assays
1. Inhibition of [33P]2MeS-ADP Binding to Washed Human Platelet Membranes.
The ability of a test compound to bind to the P2Y12 receptor was evaluated in
a platelet
membrane binding assay. In this competitive binding assay, the test compound
competed
against a radiolabelled agonist for binding to the P2Y1 2 receptor, which is
found on the surface
of platelets. Inhibition of binding of the labeled material was measured and
correlated to the
amount and potency of the test compound. Data from this assay are presented in
Table F.
Platelet rich plasma ("PRP") was obtained from the Interstate Blood bank,
Memphis, Tennessee.
Platelet rich plasma was prepared from blood units collected in ACD ((prepared
by (1)
combining: 2.5 g sodium citrate (Sigma S-4641); 1.5 g citric acid (Sigma C-
0706); and, 2.0 g
dextrose (Sigma G-7528); (2) bringing pH to 4.5; and (3) adding water to bring
volume to 100
mL) and using the light spin protocol; this protocol involves centrifugation
at room temperature for
approximately 20 minutes at speeds up to 160xg. Platelet rich plasma is
supplied in units of
approximately 200 ml. Each unit is distributed into four 50 mL polypropylene
conical tubes for
centrifugation. Blood from each donor is maintained separately.
The 50 mL tubes were centrifuged for 15 minutes at 1100 rpm in Sorvall RT6000D
(with H1000B
rotor). Internal centrifuge temperature was maintained at approximately room
temperature (22-
24 C). This spin pelleted cellular components remaining from the PRP
preparation.
The supernatant was decanted into fresh 50 mL tubes. To avoid carry over of
cellular
components following the room temperature centrifugation, approximately 5 mL
of PRP was left
in the tube and discarded. The tubes were capped and inverted 2-3 times and
allowed to stand
at room temperature for at least 15 minutes following inversion.
Optionally, a Coulter Counter may be used to count platelets from the resting
samples during the
resting phase. Normal human platelet counts are expected to range from 200,000
to 400,000
per pL of PRP supernatant.
The 50 mL tubes containing PRP supernatant were centrifuged for 15 minutes at
2300-2400 rpm
to loosely pellet the platelets. The supernatant from this spin was decanted
immediately into a
clean cell culture bottle (Corning bottle) and saved in case further
centrifugation was needed.
The pellet of each tube was resuspended in 2-4 mL of Wash buffer (pH 6.5) (1 L
prepared new
daily - 134 mM NaCI (Sigma S-5150); 3 mM KCI (Sigma P-9333); 1 mM CaCl2 (JT
Baker 1311-
01); 2 mM MgCI2 (Sigma M-2670); 5 mM glucose (EM 4074-2); 0.3 mM NaH2PO4
(Sigma S-
9638)/12 mM NaHCO3 (JT Baker 3506-01); 5 mM HEPES pH 7.4 (Gibco 12379-012);
0.35%
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BSA (Sigma A-7906); 330 mg Heparin (bovine lung, Sigma H-4898); and 30 mL of
ACD) by
repeated gentle aspiration using disposable polypropylene sample pipettes.
Wash buffer (pH 6.5) was added to each tube to bring the volume to
approximately 40 mL. Each
tube was incubated for at least 15 minutes at 37 C.
The tubes were then centrifuged again for 15 minutes at 2300-2400 rpm to
loosely pellet the
platelets. The supernatant was decanted and discarded. The pellet was
resuspended in 2-4 mL
of Assay buffer (pH 7.4) (1 L volume - 134 mM NaCI; 3 mM KCI; 1 mM CaC12; 2 mM
MgCI2i 5
mM glucose; 0.3 mM NaH2PO4/12 mM NaHCO3; 5 mM HEPES pH 7.4; and 0.35% BSA) by
repeated aspiration using disposable polypropylene sample pipettes. Tubes were
combined and
gently swirled to mix only when all pellets were successfully resuspended;
pellets that did not
resuspend or contained aggregates were not combined.
The pooled platelet preparation was counted using a Coulter Counter. The final
concentration of
platelets was brought to 1 x 106 per pL using Assay buffer pH 7.4. The
platelets were rested for a
minimum of 45 minutes at 37 C before use in the assay.
In one embodiment, the compounds were tested in 96-well microtiter
filterplates (Millipore
Multiscreen-FB opaque plates, #MAFBNOB50). These plates were used in the assay
and pre-
wet with 50 pL of Assay buffer pH 7.4 then filtered through completely with a
Millipore plate
vacuum. Next, 50 pL of platelet suspension was placed into 96-well
filterplates. 5 pL of 2MeS-
ADP (100 pM working stock concentration to give final concentration 5 pM in
well) and 20 pL
Assay buffer were added to background control wells. 25 pl Assay buffer were
added to set of
wells for total binding.
pL of 4X concentrated compound were added in duplicate to the 96-well
filterplates. Next, 25
NL [33P]2MeS-ADP (Perkin Elmer NEN custom synthesis, specific activity -
2100Ci/mmol) was
added to all wells. (1.6 nM working stock concentration to give 0.4 nM final
concentration in well).
25 The mixture was incubated for 60 minutes at room temperature and agitated
with gentle shaking.
The reaction was stopped by washing the 96-well filterplate three times with
100 pl/well of Cold
Wash buffer (1 L volume - 134 mM NaCI; 10 mM Hepes pH 7.4, stored at 4 C) on a
plate
vacuum. The plate was disassembled and allowed to air dry overnight with the
filter side up.
The filter plates were snapped into adapter plates and 0.1 mL of Microscint 20
Scintillation Fluid
(Perkin Elmer # 6013621) was added to each well. The top of the filterplate
was sealed with
plastic plate covers. The sealed filterplate was agitated for 30 minutes at
room temperature. A
Packard TopCount Microplate Scintillation Counter was used to measure counts.
The binding of
compound is expressed as a %binding decrease of the ADP samples after
correcting for
changes in unaggregated control samples.
2. Inhibition of Human Platelet Aggregation
The ability of a test compound to bind to the P2Y12 receptor was evaluated in
a platelet
aggregation assay. In this functional assay, the test compound competed
against an agonist for
binding to the P2Y1 2 receptor, which is found on the surface of platelets.
Inhibition of platelet
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aggregation was measured using standard techniques. Data from this assay are
presented in
Table F.
As an alternative to the binding assay which measures a candidate compound's
ability to bind to
the P2Y12 receptor, an assay may be used that measures the effect of the
candidate compound
on cellular function. The candidate compound competes with ADP, a known
agonist, for binding
at P2Y12. ADP is sufficient to induce platelet aggregation; the presence of an
effective
candidate compound inhibits aggregation. The inhibition of platelet
aggregation is measured
using standard techniques.
Whole blood was collected by Pfizer medical personnel from volunteers (100 mL
per volunteer)
in 20 mL syringes containing 2 mL of buffered Citrate. In one embodiment,
buffered Citrate is
0.105 M Citrate: 0.0840 M Na3-citrate and 0.0210 M citric acid. In another
embodiment, buffered
Citrate is 0.109 M Citrate: 0.0945 M Na3-citrate and 0.0175 M citric acid. The
contents of the
syringes were expelled into two 50 mL polypropylene conical tubes. Blood was
combined only
when collected from a single donor. The 50 mL tubes were centrifuged for 15
minutes at 1100
rpm in Sorvall RT6000D (with H1000B rotor). The internal centrifuges
temperature was
maintained between 22-24 C and was operating without using the centrifuge
brake. This spin
pelleted cellular components remaining from the PRP preparation. The PRP layer
was collected
from each tube and set aside. The supernatant was decanted into fresh 50 mL
tubes. To avoid
carry over of cellular components following the room temperature
centrifugation, approximately 5
mL of PRP was left in the tube and discarded.
The 50 mL tubes were placed back into the centrifuge and spun for 15 minutes
at 2800-3000 rpm
(with the brake on). This pelleted out most particulate blood constituents
remaining, leaving a
layer of Platelet Poor Plasma ("PPP"). The PPP was collected and the platelet
concentration
determined using a Coulter Counter. The PRP layer, previously set aside, was
diluted with PPP
to a final concentration of approximately 330,000 platelets/pi with the PPP.
The final preparation
was split into multiple 50 mL conical tubes, each filled with only 25-30 mL of
diluted PRP prep. In
one embodiment, the tube was filled with 5%CO2/95%O2 gas, to maintain the pH
of the prep.
Each tube was tightly capped and stored at room temperature.
The human platelet aggregation assay is performed is performed in 96-well
plate using microtiter
plate reader (SpectraMax Plus 384 with SoftMax Pro software from Molecular
Devices). The
instrument settings include: Absorbance at 626 nm and run time at 15 minutes
with readings in 1-
minute intervals and 45 seconds shaking between readings.
The reaction is incubated at 37 C. First 18 pl of test compound at lOx final
concentration in 5%
DMSO is mixed with 144 pl fresh PRP for 30 seconds and incubated at 37 C for 5
minutes.
Following that incubation period, 18 pl of 200 pM ADP is added to the reaction
mix. This addition
of ADP is sufficient to induce aggregation in the absence of an inhibitor.
Results of the assay are
expressed as % inhibition, and are calculated using absorbance values at 15
minutes.
3. Human P2Y12 Recombinant Cell Membrane Binding Assay with 33P 2MeS-ADP.
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The ability of a test compound to b-ind to the-P2Y12 receptor was-evaluated in
a recombinant cell
membrane binding assay. In this competitive binding assay, the test compound
competed
against a radiolabelled agonist for binding to the P2Y12 receptor, expressed
on the cell
membrane. Inhibition of binding of the labeled material was measured and
correlated to the
amount and potency of the test compound. Data from this assay are presented in
Table F.
This binding assay is a modification of the procedure in Takasaki, J. et. aI,
Mol. Pharmacol.,
2001, Vol. 60, pg. 432.
HEK cells were transfected with the pDONR201 P2Y12 vector and cultured in MEM
with
GlutaMAX I, Earle's salts, 25 mM HEPES (Gibco # 42360-032) containing 10%
dialyzed FBS
(Gibco # 26400-044), 100 M nonessential amino acids (Gibco # 11140-050), 1 mM
sodium
pyruvate (Gibco # 11360-070), 0.05% geneticin (Gibco #1 01 31-027), 3 g/mL
blasticidin (Fluka
brand from Sigma # 15205), and 0.5 g/mL puromycin (Sigma # P-8833).
Confluent cells were washed once with cold DPBS (Gibco # 14190-136). Fresh
DPBS was
added and the cells were scraped and centrifuged at 500 x g for 5 minutes at 4
C. The cell
pellets were resuspended in TEE buffer (25 mM Tris, 5 mM EDTA, 5 mM EGTA)
containing 1
protease inhibitor cocktail tablet (Roche # 1 873 580) per 50 mL (called TEE +
Complete) and
cari be flash frozen at this point.
In one embodiment, frozen cell pellets were used to prepare the membranes. In
that
embodiment, the frozen cell pellets were thawed on ice. In another embodiment,
cell pellets may
be used without flash freezing before moving on to the next step.
Cell pellets were resuspended in TEE buffer + Complete and homogenized in a
glass dounce for
12 strokes. The cell suspension was centrifuged at 500 x g for 5 minutes at 4
C. The
supernatant was saved and centrifuged at 20,000 x g for 20 minutes at 4 C.
This supernatant
was discarded and the cell pellet resuspended in TEE buffer + Complete and
homogenized in a
glass dounce for 12 strokes. This suspension was centrifuged at 20,000 x g for
20 minutes at 4
C and the supernatant discarded. The pellet was resuspended in assay buffer
(50 mM Tris, 100
mM NaCI, 1 mM EDTA) containing one protease inhibitor cocktail tablet per 50
mL, and can be
flash frozen as 1 mL aliquots at this point.
Dry compounds were diluted as 10 mM DMSO stocks and tested in a seven-point,
three-fold
dilution series run in triplicate beginning at 10 M, final concentration. A 1
mM DMSO
intermediate stock was made in a dilution plate and from this the seven
dilutions were made to
5X the final concentration in assay buffer containing 0.02% BSA.
To a polypropylene assay plate (Costar # 3365) the following were added: a) 30
L of assay
buffer containing one protease inhibitor cocktail tablet per 50 mL; b) 30 L
of 1 nM 33P 2MeS-
ADP made in assay buffer containing 0.02% BSA and 12.5 mg/mL ascorbic acid; 30
L of cold
1.5 M 2MeS-ADP for the positive control wells, or assay buffer containing
0.02% BSA and 12.5
mg/mL ascorbic acid for the negative control wells, or 5X drug dilution; and
60 L of 1 ug/well
membranes.
The plates were incubated at room temperature for 1 hour. The reaction was
stopped using a
cell harvester to transfer the reaction mixture onto GF/B UniFilter plates
(Perkin Elmer #
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167
6005177), and washed three times-with wash buffer (50 mM Tris)~ filtering
between each wash.
The filter plates were dried for approximately 20 minutes in an oven at 50 C.
Back seals were
adhered to the filter plates and 25 uL of Microscint 20 scintillation fluid
(Perkin Elmer # 6013621)
were added. The filter plates were sealed, shaken for 30 minutes, and counted
on a Top Count.
Data were analyzed using a four-parameter curve fit with a fixed minimum and
maximum
experimentally defined as the average positive and negative controls on each
plAte, and with a
hill slope equal to one.
4. Human P2Y12 Recombinant Cell Membrane Binding Assay With Human Serum
Albumin, Alpha-1 Acid Glycoprotein and 33P 2MeS-ADP
The ability of a test compound to bind to the P2Y12 receptor was evaluated in
a recombinant cell
membrane binding assay. In this competitive binding assay, the test compound
competed
against a radiolabelled agonist for binding to the P2Y1 2 receptor, expressed
on the cell
membrane. To simulate in vivo conditions, human protein is added to the assay
mixture.
Inhibition of binding of the labeled material was measured and correlated to
the amount and
potency of the test compound. Data from this assay are presented in Table F.
HEK cells were transfected with the pDONR201 P2Y12 vector and cultured in MEM
with
GlutaMAX I, Earle's salts, 25 mM HEPES (Gibco # 42360-032) containing
containing 10%
dialyzed FBS (Gibco # 26400-044), 100 M nonessential amino acids (Gibco # 1 1
1 40-050), 1
mM sodium pyruvate (Gibco # 11360-070), 0.05% geneticin (Gibco #10131-027), 3
g/mL
blasticidin (Fluka brand from Sigma # 15205), and 0.5 g/mL puromycin (Sigma #
P-8833).
Confluent cells were washed once with cold DPBS (Gibco # 14190-136). Fresh
DPBS was
added and the cells were scraped and centrifuged at 500 x g for 5 minutes at 4
C. The cell
pellets were resuspended in TEE buffer (25 mM Tris, 5 mM EDTA, 5 mM EGTA)
containing 1
protease inhibitor cocktail tablet (Roche # 1 873 580) per 50 mL (called TEE +
Complete) and
can be flash frozen at this point.
In one embodiment, frozen cell pellets were used to prepare the membranes. In
that
embodiment, the frozen cell pellets were thawed on ice. In another embodiment,
cell pellets may
be used without flash freezing before moving on to the next step.
Cell pellets were resuspended in TEE buffer + Complete and homogenized in a
glass dounce for
12 strokes. The cell suspension was centrifuged at 500 x g for 5 minutes at 4
C. The
supernatant was saved and centrifuged at 20,000 x g for 20 minutes at 4 C.
This supernatant
was discarded and the cell pellet resuspended in TEE buffer + Complete and
homogenized in a
glass dounce for 12 strokes. This suspension was centrifuged at 20,000 x g for
20 minutes at 4
C and the supernatant discarded. The pellet was resuspended in assay buffer
(50 mM Tris, 100
mM NaCI, 1 mM EDTA) containing one protease inhibitor cocktail tablet per 50
mL, and can be
flash frozen as 1 mL aliquots at this point.
Dry compounds were diluted as 10 mM DMSO stocks and tested in a seven-point,
three-fold
dilution series run in triplicate beginning at 10 M, final concentration. A 1
mM DMSO
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168
-intermediate stock was nrade in a dilution plate and from this the seven -
dilutionswere made to
5X the final concentration in assay buffer containing 0.02% BSA.
To a polypropylene assay plate (Costar # 3365)-the following were added: a) 30
L of assay
buffer containing one protease inhibitor cocktail tablet per 50 mL; b) 30 L
of 1 nM 33P 2MeS-
ADP made in assay buffer containing 0.02% BSA and 12.5 mg/mL ascorbic acid; c)
30 L of cold
1.5 M 2MeS-ADP for the positive control wells, or assay buffer containing
0.02% BSA and 12.5
mg/mL ascorbic acid for the negative control wells, or 5X drug dilution; and
d) 60 L of 1 ug/well
membranes containing 0.875% human serum albumin (Sigma # A-3782) and 0.0375%
alpha-1
acid glycoprotein (Sigma # G-9885).
The plates were incubated at room temperature for 1 hour. The reaction was
stopped using a
cell harvester to transfer the reaction mixture onto GF/B UniFilter plates
(Perkin Elmer #
6005177), and washed three times with wash buffer (50 mM Tris), filtering
between each wash.
The filter plates were dried for approximately 20 minutes in an oven at 50 C.
Back seals were
adhered to the filter plates and 25 uL of Microscint 20 scintillation fluid
(Perkin Elmer # 6013621).
were added. The filter plates were sealed, shaken for 30 minutes, and counted
on a Top Count
Scintillation Counter.
Data are analyzed using a four-parameter curve fit with a fixed minimum and
maximum,
experimentally defined as the average positive and negative controls on each
plate and with a
Hill slope equal to one.
The table below presents the IC50, K;, and percent inhibition values for
compounds tested in
either washed human platelets membrane binding assay (assay #1 above) or
recombinant cell
membrane binding assay (Assay #3, above). Example number refers to the
compound prepared
as described in the example noted in the section Working Examples, above. The
highest
concentration of candidate compound tested is listed for each experimental run
presented.
Multiple data sets indicate multiple experimental runs completed for a given
compound.
TABLE F - Data
Current [ P]-2MeS-ADP Binding to Recombinant Human [ P]-2MeS-ADP
Example P2Y12 Membranes (Assay 3) Binding to Washed
Number Platelets (Assay 1)
IC50 K1 % Hi hest % [Hi-ghestl
M M Inhibition M Inhibition M
66 0.186 0.11 90.26 10 -- --
0.123 0.07 87.11 10 -- --
67 0.09 0.054 81.70 10
68 0.083 0.053 98.45 10 -- --
0.022 0.014 98.11 10 -- --
0.024 0.014 91.43 1
0.07 0.04 89.26 10
69 0.048 0.028 92 1
70 2.43 1.45 68.52 10 -- --
71 0.046 0.027 97.24 10 -- --
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Current [ P]-2MeS=ADP-Binding to Recombinant Human --[ P]=2MeS=ADP-
Example P2Y12 Membranes (Assay 3) Binding to Washed
Number Platelets (Assay 1)
IC50 K; % Hi hest % Hi hest
M M Inhibition Li-M Inhibition
-- -- 20.54 10 -- --
9.77 5.87 30.66 10
-- -- 42.55 10
9.18 5.48 49.18 10
-- -- 22.6 10
72 5.59 3.22 10 1
73 7.32 4.13 61.20 10 -- --
74 0.058 0.031 91.05 1 -- --
0.472 0.248 86.71 10 -- --
5.63 3.22 30 10
75 2.56 1.49 72 10
76 0.148 0.078 95.88 10 -- --
77 2.8 1.47 73.69 10 -- --
78 0.089 0.047 96.07 10 -- --
0.062 0.033 98.8 10 -- --
79 0.053 0.031 83.63 10
80 0.169 0.089 96.28 10 -- --
81 0.1 0.053 95.90 110 -- --
82 0.333 0.175 94.61 10 -- --
83 0.344 0.181 92.61 10 -- --
84 0.091 0.054 89.52 10 -- --
0.011 0.006 94.74 10 -- --
7.19 4.09 80.73 10
0.02 0.01 86.05 1
0.038 0.022 93.20 1
85 0.048' 0.028 91 1
0.16 0.092 85.95 10 -- --
86 0.05 0.028 94.79 10
0.32 0.182 84.54 10 -- --
87 0.07 0.036 97.06 10
3.26 1.87 70.45 10 -- --
88 1.4 0.761 97.4 10
1.48 0.848 72.89 10 -- --
89 1.1 0.598 85.03 10
90 0.028 0.016 94.04 10 -- --
0.105 0.06 92 10 -- --
91 0.094 0.055 93 10
92 0.089 0.051 97 10 -- --
0.0293 0.017 91 10 -- --
93 0.0685 0.04 95 10
94 0.0094 0.005 91 10 -- --
95 0.0276 0.015 87 10 -- --
96 0.089 0.048 82 10 -- --
97 0.026 0.015 88 1 -- --
98 0.0053 0.003 94 1 -- --
2.859 1.55 64 10 -- --
99 1.53 0.83 76 10
0.919 0.495 75 10 -- --
0.906 0.491 79 10
100 1.11 0.624 77 10
101 0.365 0.187 85 10 -- --
102 0.015 0.007 90 10 -- --
103 0.071 0.037 84 10 -- --
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C[irrent- - [ P]-2MeS=ADP'Binding to Recombinant Human [ P]-2MeS-ADP
Example P2Y12 Membranes (Assay 3) Binding to Washed
Number Platelets Assa 1)
IC50 K; % Hi hest % Hi hest
M M Inhibition M Inhibition M
104 0.704 0.361 82 10 -- --
105 -- -- -- -- 17.0 100
106 0.042 0.024 95 10 -- --
107 0.301 0.176 88 10 -- --
2.4 1.3 82.08 10 -- --
108 1.4 0.82 83.95 10
.061 0.036 86.92 10 -- --
109 .093 0.053 88.17 10
0.026 0.015 92.8 10 -- --
110 0.022 0.012 93.74 1
0.016 0.0092 97.7 10 -- --
0.022 0.013 94.8 1
0.01 0.01 94.1 10
111 0.02 0.012 95 10
112 .088 0.051 94.2 10 -- --
113 .075 0.043 93.49 10 -- --
0.0058 0.0034 99.41 10 -- --
0.0052 0.0029 9169 1
0.0056 0.0029 89.53 0.1
0.01 0.0058 99.14 10
114 0.016 0.009 94 10
0.0092 0.0053 95.2 10 -- --
0.0063 0.0036 92.67 1
0.0078 0.004 83.97 0.1
0.01 0.01 96.61 10
115 0.026 0.015 96 10
0.03 0.019 97.04 10 -- --
0.045 0.028 5.5 10
0.042 0.022 92.89 1
0.04 0.03 88.97 10
116 0.065 0.038 91 1
0.018 0.011 99.34 10 -- --
117 0.0088 0.0049 93.79 1
118 0.148 0.088 89.92 10 -- --
0.202 0.114 57.74 10 -- --
0.08 0.044 97.27 10
0.15 0.09 88.48 10
119 0.134 0.077 91 1
0.09 0.054 89.84 10 -- --
0.05 0.025 90.76 10
0.0437 0.025 93.59 10
0.07 0.040 84.82 10
120 0.079 .046 88 1
121 2.31 1.35 74 10 -- --
122 0.834 0.487 83.5 10 -- --
123 0.129 0.076 90.49 10 -- --
124 0.424 0.239 81.70 10 -- --
125 0.321 0.181 83.60 10 -- --
126 2.47 1.43 68.30 10 -- --
127 4.19 2.43 60.70 10 -- --
3.99 2.19 54.2 10 -- --
128 36.8 1
129 0.619 0.340 90.7 10 -- --
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"Current "-" [ P]=2MeS=ADP-Bindingto Recombinant"Human --[ P]=2MeS-ADP
Example P2Y12 Membranes (Assay 3) Binding to Washed
Number Platelets (Assay 1)
IC50 Ki % Hi hest % Hi hest
M M Inhibition M Inhibition M
-- -- -- -- 36.7 100
130 47.7 100
-- -- -- -- 2.50 100
131 9.79 100
132 0.103 0.0560 82.6 10 -- --
133 0.159 0.0870 77.7 10 -- --
134 2.95 1.62 71.3 10 -- --
135 0.779 0.426 88 10 -- --
4.32 2.36 50.8 10 -- --
136 6.36 3.08 43.8 10
137 -- -- 8.85 10 -- --
138 -- -- 36 10 -- --
0.234 0.128 76 10 -- --
139 0.612 0.297 65 10
140 0.535 0.293 79 10 -- --
141 0.32 0.187 90 10 -- --
142 0.189 0.11 87 10 -- --
143 0.0749 0.044 85 10 -- --
144 0.0856 0.05 77 10 -- --
145 0.214 0.117 80 10 -- --
146 0.067 0.038 96 - 10 -- --
147 3.37 1.9 70.90 10 -- --
148 >10 >5.64 19.80 10 -- --
0.124 0.071 82.64 10 -- --
0.488 0.279 80 10
149 0.402 0.235 95 10 0.045 0.026 93 10 -- --
150 0.032 0.019 66 10
151 0.0186 0.01000 92.8 10 -- --
152 0.103 0.0560 85 10 -- --
AII mentioned documents are incorporated by reference as if here written. When
introducing elements of the present invention or the exemplary embodiment(s)
thereof, the
articles "a," "an," "the" and "said" are intended to mean that there are one
or more of the
elements. The terms "comprising," "including" and "having" are intended to be
inclusive and
mean that there may be additional elements other than the listed elements.
Although this
invention has been described with respect to specific embodiments, the details
of these
embodiments are not to be construed as limitations.
