Title of Invention

SUBSTITUTED ISOQUINOLINONE COMPOUNDS AND PHARMACEUTICAL COMPOSITION, COMPRISING THEM

Abstract The invention discloses a isoquinolinone compound having the formula: or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional double bond, and R1, R2, R3, R4 and R5 are as defined in the specification. The invention is also for a pharmaceutical composition comprising the said compound useful for the treatment of thrombosis and thrombosis related conditions or disorders.
Full Text CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of Provisional Application Serial No.
60/508,402, filed October 3,2003, the disclosure of which is incorporated herein by
reference.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER
FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0002] NOT APPLICABLE
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER
PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK.
[0003] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0004] Thrombotic complications are a major cause of death in the industrialized
world. Examples of these complications include acute myocardial infarction, unstable
angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease,
preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular
coagulation and thrombotic cytopenic purpura. Thrombotic and restenotic complications also
occur following invasive procedures, e.g., angioplasty, carotid endarterectomy, post CABG
(coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion
of endovascular devices and protheses. It is generally thought that platelet aggregates play a
critical role in these events. Blood platelets, which normally circulate freely in the
vasculature, become activated and aggregate to form a thrombus with disturbed blood flow
caused by ruptured atherosclerotic lesions or by invasive treatments such as angioplasty,
resulting in vascular occlusion. Platelet activation can be initiated by a variety of agents, e.g.,
exposed subendothelial matrix molecules such as collagen, or by thrombin which is formed in
the coagulation cascade.

[0005] An important mediator of platelet activation and aggregation is ADP
(adenosine 5'-diphosphate) which is released from blood platelets in the vasculature upon
activation by various agents, such as collagen and thrombin, and from damaged blood cells,
endothelium or tissues. Activation by ADP results in the recruitment of more platelets and
stabilization of existing platelet aggregates. Platelet ADP receptors mediating aggregation
are activated by ADP and some of its derivatives and antagonized by ATP (adenosine 5'-
triphosphate) and some of its derivatives (Mills, D.C.B. (1996) Thromb. Hemost. 76:835-
856). Therefore, platelet ADP receptors are members of the family of P2 receptors activated
by purine and/or pyrimidine nucleotides (King, B.F., Townsend-Nicholson, A. & Burnstock,
G. (1998) Trends Pharmacol. Sci. 19:506-514).
[0006] Recent pharmacological data using selective antagonists suggests that ADP-
dependent platelet aggregation requires activation of at least two ADP receptors (Kunapuli,
S.P. (1998), Trends Pharmacol. Sci. 19:391-394; Kunapuli, S.P. & Daniel, J.L. (1998)
Biochem. J. 336:513-523; Jantzen, H.M. et al. (1999) Thromb. Hemost. 81:111-117). One
receptor appears to be identical to the cloned P2Y1 receptor, mediates phospholipase C
activation and intracellular calcium mobilization and is required for platelet shape change.
The second platelet ADP receptor important for aggregation mediates inhibition of adenylyl
cyclase. Molecular cloning of the gene or cDNA for this receptor (P2Y12) has recently been
reported (Hollopeter, G. et. al. (2001) Nature 409:202-207). Based on its pharmacological
and signaling properties this receptor has been previously termed P2YADP (Fredholm, B.B. et
al. (1997) TIPS 18:79-82), P2TAC (Kunapuli, S.P. (1998), Trends Pharmacol. Sci. 19:391-
394) or P2Ycyc (Hechler, B. et al. (1998) Blood 92,152-159).
[0007] Various directly or indirectly acting synthetic inhibitors of ADP-dependent
platelet aggregation with antithrombotic activity have been reported. The orally active
antithrombotic thienopyridines ticlopidine and clopidogrel inhibit ADP-induced platelet
aggregation, binding of radiolabeled ADP receptor agonist 2-methylthioadenosine 5'-
diphosphate to platelets, and other ADP-dependent events indirectly, probably via formation
of an unstable and irreversible acting metabolite (Quinn, M.J. & Fitzgerald, D.J. (1999)
Circulation 100:1667-1667). Some purine derivatives of the endogenous antagonist ATP,
e.g., AR-C (formerly FPL or ARL) 67085MX and AR-C69931MX, are selective platelet
ADP receptor antagonists which inhibit ADP-dependent platelet aggregation and are effective
in animal thrombosis models (Humphries et al. (1995), Trends Pharmacol. Sci. 16,179;
Ingall, A.H. et al. (1999) J. Med. Chem. 42,213-230). Novel triazolo[4,5-d]pyrimidine

compounds have been disclosed as P2T - antagonists (WO 99/05144). Tricyclic compounds
as platelet ADP receptor inhibitors have also been disclosed in WO 99/36425. The target of
these antithrombotic compounds appears to be the platelet ADP receptor mediating
inhibition of adenylyl cyclase.
[0008] Despite these compounds, there exists a need for more effective platelet ADP
receptor inhibitors. In particular, there is a need for platelet ADP receptor inhibitors having
antithrombotic activity that are useful in the prevention and/or treatment of cardiovascular
diseases, particularly those related to thrombosis.
BRIEF SUMMARY OF THE INVENTION
[0009] In view of the above, the present invention provides, in one aspect,
compounds that are specifically substituted isoquinolinones. The compounds are represented
by the formula:

[0010] With respect to formula I, the dotted line represents an optional double bond;
the symbol R1 represents C1-6 alkyl, C1-6 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl or
benzyl; and the symbol R2 represents H, C1-6 alkyl or C1-6 haloalkyl. The symbol R3
represents H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C1-6
haloalkyl, C1-6 hydroxyalkyl, cyano or -C(O)R3a, wherein R3a is H, hydroxy, C1-6 alkyl, C1-6
alkoxy, amino, C1-6 alkylamino and di- C1-6 alkylamino; and R4 represents H or C1-6 alkyl.
[0011] Turning next to the substituents on the thiophene ring, R5 represents H,
halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, cyano or -C(O)R5a,
wherein R5a represents C1-6 alkoxy, amino, C1-6 alkylamino and di- C1-6 alkylamino.
[0012] The symbol Ar represents an aromatic ring selected from benzene, pyridine
and pyrimidine, each of which is optionally substituted with from 1-2 R6 substituents,
wherein each R6 is independently selected from halogen, cyano, hydroxy, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-5 cycloalkyl, C3-5

cycloalkyl-alkyl, C3.5 cycloalkyl-alkoxy, amino, C1-6 alkylamino, di-C1-6 alkylamino,
-C(O)R6a, -O(CH2)mOR6b -(CH2)mOR6b, -O(CH2)mN(R6b)2 and -(CH2)mN(OR6b)2, wherein the
subscript m is an integer of from 1 to 3, each R6a is independently selected from H, hydroxy,
C1-6 alkyl, C1-6 alkoxy, amino, C1-6 alkylamino and di- C1-6 alkylamino, and each R6b is a
member independently selected from the group consisting of H, C1-4 alkyl and C1-4 alkanoyl,
and optionally, two R6b groups attached to nitrogen are combined with the nitrogen atom to
form an azetidine, pyrrolidine or piperidine ring.
[0013] The present invention further provides pharmaceutically acceptable salts of the
above compounds, as well as pharmaceutical compositions containing those compounds.
[0014] In other aspects, the present invention provides methods of treating thrombosis
and thrombosis related conditions or disorders.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0016] The term "alkyl", by itself or as part of another substituent, means, unless
otherwise stated, a straight or branched chain hydrocarbon radical, having the number of
carbon atoms designated (i.e. C1-8 means one to eight carbons). Examples of alkyl groups
include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-
hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers to an unsaturated alkyl group
is one having one or more double bonds. Similarly, the term "alkynyl" refers to an
unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl
groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-
(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and
isomers. The term "cycloalkyl" refers to hydrocarbon rings having the indicated number of
ring atoms (e.g., C3-6cycloalkyl) and being fully saturated or having no more than one double
bond between ring vertices. When "cycloalkyl" is used in combination with "alkyl", as in
C3-5 cycloalkyl-alkyl, the cycloalkyl portion is meant to have from three to five carbon atoms,
while the alkyl portion is an alkylene moiety having from one to three carbon atoms (e.g.,
-CH2-, -CH2CH2- or -CH2CH2CH2-).

[0017] The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in
their conventional sense, and refer to those alkyl groups attached to the remainder of the
molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. For brevity,
the term C1-6alkylamino is meant to include straight chain, branched or cyclic alkyl groups or
combinations thereof, such as methyl, ethyl, 2-methylpropyl, cyclobutyl and
cyclopropylmethyl.
[0018] The terms "halo" or "halogen," by themselves or as part of another substituent,
mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally,
terms such as "haloalkyl," are meant to include monohaloallcyl and polyhaloalkyl. For
example, the term "C1-4 haloalkyl" is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-
chlorobutyl, 3-bromopropyl, and the like.
[0019] The term "aryl" means, unless otherwise stated, a polyunsaturated, typically
aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings)
which are fused together or linked covalently. Exemplary aryl groups are phenyl, naphthyl,
biphenyl and the like. The term "heteroaryl" refers to aryl groups (or rings) that contain from
one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are
optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group
can be attached to the remainder of the molecule through a heteroatom. Non-limiting
examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-
pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-
isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,-
purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-
quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above
noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents
described below.
[0020] As used herein, the term "heteroatom" is meant to include oxygen (O),
nitrogen (N), sulfur (S) and silicon (Si).
[0021] The term "pharmaceutically acceptable salts" is meant to include salts of the
active compounds which are prepared with relatively nontoxic acids or bases, depending on
the particular substituents found on the compounds described herein. When compounds of
the present invention contain relatively acidic functionalities, base addition salts can be

obtained by contacting the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically
acceptable base addition salts include sodium, potassium, calcium, ammonium, organic
amino, or magnesium salt, or a similar salt. When compounds of the present invention
contain relatively basic functionalities, acid addition salts can be obtained by contacting the
neutral form of such compounds with a sufficient amount of the desired acid, either neat or in
a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include
those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric,
sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the
salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric,
malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-
tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, for example, Berge, S.M., et al, "Pharmaceutical Salts", Journal of
Pharmaceutical Science, 1977, 66,1-19). Certain specific compounds of the present
invention contain both basic and acidic functionalities that allow the compounds to be
converted into either base or acid addition salts.
[0022] The neutral forms of the compounds may be regenerated by contacting the salt
with a base or acid and isolating the parent compound in the conventional manner. The
parent form of the compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the
parent form of the compound for the purposes of the present invention.
[0023] In addition to salt forms, the present invention provides compounds which are
in a prodrug form. Prodrugs of the compounds described herein are those compounds that
readily undergo chemical changes under physiological conditions to provide the compounds
of the present invention. Additionally, prodrugs can be converted to the compounds of the
present invention by chemical or biochemical methods in an ex vivo environment. For
example, prodrugs can be slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
[0024] Certain compounds of the present invention can exist in unsolvated forms as
well as solvated forms, including hydrated forms. In general, the solvated forms are

equivalent to unsolvated forms and are intended to be encompassed within the scope of the
present invention. Certain compounds of the present invention may exist in multiple
crystalline or amorphous forms. In general, all physical forms are equivalent for the uses
contemplated by the present invention and are intended to be within the scope of the present
invention.
[0025] Certain compounds of the present invention possess asymmetric carbon atoms
(optical centers) or double bonds; the racemates, diastereomers, geometric isomers and
individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the
scope of the present invention.
[0026] The compounds of the present invention may also contain unnatural
proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
For example, the compounds may be radiolabeled with radioactive isotopes, such as for
example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the
compounds of the present invention, whether radioactive or not, are intended to be
encompassed within the scope of the present invention.
General
Description of the Embodiments
Compounds
[0027] In view of the above, the present invention provides, in one aspect,
compounds that are specifically substituted isoquinolinones. The compounds are represented
by the formula:

[0028] Turning first to the symbols R1 through R4, the symbol R1 represents C1-6
alkyl, C1-6 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl or benzyl. For the terms C3-5
cycloalkyl-alkyl and (as used below) C3-5 cycloalkyl-alkoxy, the alkyl or alkoxy portions
respectively are meant to have from one to three carbon atoms, exclusive of the carbon atoms

used TIJI the cycloalkyl portion. For example, C3.5 cycloalkyl-alkyl is meant to include
cyclopropylmethyl, cyclopentylmethyl, 3-cyclobutylpropyl, 2-cylcopropylethyl, and the like.
Similarly, C3.5 cycloalkyl-alkoxy is meant to include cyclopropylmethoxy,
cyclopentylmethoxy, 3-cyclobutylpropyloxy, 2-cylcopropylethoxy, and the like. Preferably,
R1 is C1-6 alkyl, C3-5 cycloalkyl, or C3-5 cycloalkyl-alkyl. More preferably, Rl is CM alkyl,
C3.5 cycloalkyl, or C3-5 cycloalkyl-alkyl. Still more preferably, R1 is CM alkyl, particularly
CH3 or CH2CH3 with CH3 being the most preferred.
[0029] The symbol R2 represents H, Cx.6 alkyl or C1-6 haloalkyl. Preferably, R2 is H
or Ct_6 alkyl; more preferably H or CM alkyl. Still more preferably, R2 is H or CH3, with H
being the most preferred.
[003O] The symbol R3 represents H, Ci.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_5
cycloalkyl, C3.5 cycloalkyl-alkyl, CM haloalkyl, C« hydroxyalkyl, cyano or -C(0)R3a,
wherein R3a is selected from H, hydroxy, Cue alkyl, CM alkoxy, amino, CM alkylamino and
di- Ci^ alkylamino. Preferably, R3 is H, CM alkyl, C2-4 alkenyl, C2-4 alkynyl, C3.5 cycloalkyl,
C3.5 cycloalkyl-alkyl, CM haloalkyl, cyano or -C(0)R3a. More preferably, R3 is H, CM alkyl,
C2.4 alkenyl, Q2-4 alkynyl, C3-j cycloalkyl, or C3.5 cycloalkyl-alkyl.
[0031] The symbol R4 represents H or Ci.6 alkyl. Preferably, R4 is H or CM alkyl.
More preferably, R4 is H or CH3.
[0032] Turning next to the substituents on the thiophene ring, R5 represents H,
halogen, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CM alkoxy, cyano or -C(0)R5a,
wherein R5a represents CM alkoxy, amino, CM alkylamino and di- CM alkylamino.
Preferably, R5 is H, halogen, CM alkyl, C2-4 alkenyl, C2-4 alkynyl, CM haloalkyl, CM alkoxy,
cyano or -C(0)R5a. More preferably, R5 is halogen, CM alkyl, CM haloalkyl, CM alkoxy,
cyano, -C= CH or -C(0)NH2- Still more preferably, R5 is halogen or CM alkyl. Most
preferably, R5 is chloro, and is attached to the 5-position of the thienyl ring.
[0033] The symbol Ar represents an aromatic ring selected from benzene, pyridine
and pyrimidine, each of which is optionally substituted with from 1-2 R6 substituents,
wherein each R6 is independently selected from halogen, cyano, hydroxy, CM alkyl, C2-6
alkenyl, C2-6 alkynyl, CM alkoxy, CM haloalkyl, CM haloalkoxy, C3.5 cycloalkyl, C3.5
cycloalkyl-alkyl, C3.5 cycloalkyl-alkoxy, amino, CM alkylamino, di-Q-6 alkylamino,
-C(0)R6a, -0(CH2)mOR6b, -(CH2)mOR6b, -0(CH2)mN(R6b)2 and -(CH2)mN(R6b)2, wherein the
subscript m is an integer of from 1 to 3, each R6a is independently selected from H, hydroxy,

Ci-6,alkyl, Ci_6 alkoxy, amino, Q.6 alkylamino and di- Ci_6 alkylamino, and each R6b is
independently selected from H, CM alkyl and CM alkanoyl, and optionally, two R6b groups
attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine or
piperidine ring. Each of the aromatic rings (optionally substituted) is a separate and preferred
embodiment of the present invention.
[O034] The dotted line in Formula I represents an optional double bond. In most
embodiments, the double bond is present, and preferred. In some embodiments, however, the
double bond is not present, the remaining valences being filled with hydrogen atoms. As a
result, the dotted line is meant to represent both of the following:

[O035] A number of particularly preferred embodiments are provided as formulae la,
lb and Ic.
IO036] In a first group of preferred embodiments, the compounds of the present
invention have the formula:

wherein each of R1, R2, R3, R4, R5, and R6 have the meanings provided above, and the
subscript n is an integer of from 0 to 2, indicating the absence (n is 0) or presence (n is 1 or 2)
of substituents that are independently selected from the groups provided above for R6.
Further preferred are those embodiments in which R6, when present, occupy positions on the
benzene ring that are adjacent to the carbon atom bearing the urea-sulfonyl
(-NHC(0)NHS(0)2-) component. Additionally, preferred components provided above with
respect to the general formula I are also preferred for compounds of formula la.
[O037] In one group of preferred embodiments of formula la, n is an integer of from 0
to 2; R1 is CM alkyl, C3-5 cycloalkyl, or C3.5 cycloalkyl-alkyl; R2 is H; R3 is H, CM alkyl, C2A

aikeijyl, CM alkynyl, C3.5 cycloalkyl, C3.5 cycloalkyl-alkyl, CiA haloalkyl, cyano or
-C(0)R.3a; R4 is H or CM alkyl; R5 is halogen, CM alkyl, ClA alkoxy, CM haloalkyl, -CN,
-Cs CH or -CONH2; and R6, when present is selected from the group consisting of CM alkyl,
CM alkoxy, C3.5 cycloalkyl-alkoxy, -0(CH2)mOR6b and -0(CH2)mN(R6b)2 wherein the
subscript m is 1 or 2 and each R6b is independently selected from the group consisting of H,
CM alkyl and CM alkanoyl. Still further preferred are those embodiments in which R1 is CM
alkyl; R4 is H or CH3; R5 is halogen or CM alkyl; and each R6 when present is selected from
CM alkyl, -0(CH2)I„OR6b and -0(CH2)mN(R6b)2. Even further preferred are those
embodiments in which R1 is methyl; R5 is chloro, and is attached at the 5-position of the
thienyl ring; and each R6 when present is selected from CH3, -OCH2CH2OH,
-OCH2CH2OCH3, -OCH2OCH3, -OCH2CH2OC(0)CH3 and -0(CH2)2N(CH3)2. In separate,
but preferred groups of embodiments, the subscript n is 0, or 1, or 2.
[0038] In a second group of preferred embodiments, the compounds of the present
invention have the formula:

wherein each of R1, R2, R3, R4, R5, and R6 have the meanings provided above, and the
subscript n is an integer of from 0 to 2, indicating the absence (n is 0) or presence (n is 1 or 2)
of substituents that are independently selected from the groups provided above for R .
Further preferred are those embodiments in which R6, when present as a single substituent,
occupies the 3-position on the pyridine ring (i.e., that position adjacent to the carbon atom
bearing the urea-sulfonyl (-NHC(0)NHS(0)2-) component). Additionally, preferred
components provided above with respect to the general formula I are also preferred for
compounds of formula lb.
[0039] In one group of preferred embodiments of formula lb, n is an integer of from 0
to 2; R1 is CM alkyl, C3-5 cycloalkyl, or C3-5 cycloalkyl-alkyl; R2 is H; R3 is H, CM alkyl, CM
alkenyl, CM alkynyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, CM haloalkyl, cyano or
-C(0)R3a; R4 is H or CM alkyl; R5 is halogen, CM alkyl, CM alkoxy, CM haloalkyl, -CN,
-C= CH or -CONH2; and R6, when present is selected from the group consisting of CM alkyl,

Ci^jalkoxy, C3.5 cycloalkyl-alkoxy, -0(CH2)mOR6b and -0(CH2)mN(R6b)2 wherein the
subscript m is 1 or 2 and each R^ is independently selected from the group consisting of H,
Ci A alkyl and CM alkanoyl. Still further preferred are those embodiments in which R1 is CM
alkyl; R4 is H or CH3; R5 is halogen or CM alkyl; and each R6 when present is selected from
CM alkyl, -0(CH2)mOR6b and -0(CH2)mN(R6b)2. Even further preferred are those
embodiments in which Rl is methyl; R3 is H, CM alkyl, C2-4 alkenyL C2^t alkynyl, C3.5
cycloalkyl or C3-5 cycloalkyl-alkyl; R4 is H or CH3; R5 is chloro and is attached at the 5-
position of the thienyl ring; and R6, when present is selected from CM alkyl, -0(CH2)mOR6b
and -0(CH2)mN(R6b)2 wherein the subscript m is 1 or 2 and each R6b is independently
selected from H, CM alkyl and CM alkanoyl.
[0040] In still other embodiments, the compounds of the invention have the formula
Ic:

wherein each of R1, R2, R3, R4, R5, and R6 have the meanings provided above, and the
subscript n is an integer of from 0 to 2, indicating the absence (n is 0) or presence (n is 1 or 2)
of substituents that are independently selected from the groups provided above for R .
Preferred components provided above with respect to the general formula I are also preferred
for compounds of formula Ic.
[0041] In one group of preferred embodiments of formula Ic, n is an integer of from 0
to 2; R1 is CM alkyl, C3_5 cycloalkyl, or C3-5 cycloalkyl-alkyl; R2 is H; R3 is H, CM alkyl, C2-4
alkenyl, C2_4 alkynyl, C3.5 cycloalkyl, C3.5 cycloalkyl-alkyl, CM haloalkyl, cyano or
-C(0)R3a; R4 is H or CM alkyl; R5 is halogen, CM alkyl, CM alkoxy, CM haloalkyl, -CN,
-C= CH or -CONH2; and R6, when present is selected from the group consisting of CM alkyl,
CM alkoxy, C3.5 cycloalkyl-alkoxy, -0(CH2)mOR6b and -0(CH2)raN(R6b)2 wherein the
subscript m is 1 or 2 and each R6b is independently selected from the group consisting of H,
CM alkyl and CM alkanoyl. Still further preferred are those embodiments in which R1 is CM
alkyl; R4 is H or CH3; R5 is halogen or CM alkyl; and each R6 when present is selected from
CM alkyl, -0(CH2)mOR6b and -0(CH2)mN(R6b)2. Even further preferred are those

embodiments in which R1 is methyl; R3 is H, CH alkyl, C2-4 alkenyl, C2-4 alkynyl, C3.5
cycloalkyl or C3.5 cycloalkyl-alkyl; R4 is H or CH3; R5 is chloro and is attached at the 5-
position of the thienyl ring; and R6, when present is selected from C14 alkyl, -0(CH2)mOR6b
and -0(CH2)mN(R6b)2 wherein the subscript m is 1 or 2 and each R6b is independently
selected from H, C1.4 alkyl and C1-4 alkanoyl.
[0042] Among the most preferred embodiments of the invention are the compounds
provided below, as well as in the Examples.




v Schemes for the Preparation of Compounds of Formula I

[0O43] Scheme A describes a method of preparing compounds of Formula I wherein
R4=H, R1, R2, R3, R5 is described hereinbefore, Ar is substituted aryl and heteroaryl.


[0044] A compound of Formula I can be prepared by reacting malonic acid and
benzaldehyde 1 in pyridine to provide cinnamic acid 2, which can be converted to an acryloyl
azide by first treating with ethyl chloroformate then sodium azide. Curtius rearrangement
and cyclization of acryloyl azide, in the presence of a catalyst such as iodine in an inert
solvent such, as 1, 2-dichlorobenzene provides isoquinolone 3. The substituted isoquinolone
4 can be prepared by treating the amide functionality of isquinolone 3 with a halogen
substituted aromatic or heteroaromatic compound, wherein the halogen is a leaving group,
preferably ohloro or fluoro, in the presence of a base such as potassium carbonate or cesium
carbonate. Preferred solvents for this transformation are inert solvents such as DMF, DMSO,
and lower alcohols. The methyl group can then be removed by treatment of BBr3 in
dichloromethane, or alternatively lithium iodide in an inert solvent such as DMSO or DMF.
The C-N coupling reaction of the aryltriflate 5 with carbamic acid tert-butyl ester, or primary
or secondary amines can be carried out according to methods described in Buchwald et al.,
Org. Lett. 2O00,2, 1101-1104. The products from coupling reaction of the aryltriflate 5 with
carbamic acid tert-butyl ester can be alkylated under basic condition. The nitro group of
compound 6 can be reduced by procedures known to one skilled in the art to yield a free
amino group. For example, one suitable method of reduction involves hydrogenation, with a
suitable catalyst (e.g., 10% palladium on carbon) in an appropriate solvent, typically an
alcohol. The formation of the sulfonylurea linkage can be accomplished by treating the
reduced product aniline 7 with a pre-mixed solution of 5-chlorothiophene-2-sulfonamide,
N,N'-disuccinimidyl carbonate and tetramethylguanidine in dichloromethane, followed by
treatment with TFA in dichloromethane at room temperature to afford the sulfonylurea 8.


[0045] A compound of Formula I with varying Ar groups can be prepared by first
synthesizing the common intermediate 11 in 6 steps (see Scheme B). Compound 3 from
Scheme A can be demethylated by treatment with boron trfbromide in dichloromethane,
followed by selective triflation with phenyltrifluoromethylsulfonimide to give the triflate 9.
Protection of the lactam nitrogen, with SEM-C1 and C-N coupling using carbamic acid tert-
butyl ester can be carried out according to Buchwald et al., Org. Lett. 2000,2,1101-1104, to
give bis-protected intermediate 10. Standard methylating conditions and removal of the SEM
group with TBAF provides the key intermediate 11. A variety of halo-substituted
nitroaromatic compounds can be coupled with 11 using Method A or B conditions, followed
by reduction using catalytic hydrogenation or tin(II) dichloride dihydrate to give 12 (see,
Examples 46 and 47 below). Also, a variety of halo-substituted anilines can be coupled to 10
using Method C conditions as outlined below to give 12 (see, Example 48). The formation of
sulfonylurea linkage can be accomplished by treating the product aniline 12 with the ethyl
carbamate of 5-chloro-thiophene-2-sulfonamide in refluxing toluene, followed by treatment
with TFA in dichloromethane at room temperature to afford the sulfonylurea 13.


[0046] Scheme C describes a method of preparing a compounds of Formula I wherein
R4=H, R-Me, R2=H, R5= CI, R3 is described hereinbefore. Ar is a substituted or
unsubstituted aryl or heteroaryl group.
[0047] As seen in Scheme C, compounds of Formula I can be prepared by starting
with deprotection of the t-Boc group of compound 14 which can be readily obtained from
Scheme B, followed by halogenation to provide compound 15. Conversion of 15 to
compound 16 can be accomplished using Stille or Suzuki coupling conditions to provide
compound 16 with appropriately substituted R3 group. The formation of a sulfonylurea
linkage can be accomplished by treating the reduced product aniline 7 with a pre-mixed
solution of 5-chlorothiophene-2-sulfonamide, N,N'-disuccinimidyl carbonate and
tetramethylgoianidine in dichloromethane, followed by treatment with TFA in
dichloromethane at room temperature to afford the sulfonylurea 17.
Compositions
[0048] In another aspect of the invention, pharmaceutical compositions are provided
in which compounds of formulae I, la, lb, or Ic, alone or in combination, are combined with
a pharmaceutically acceptable carrier. Preferred compounds for use in the compositions of
the present invention are those compounds identified above as specific or preferred
embodiments.
[0049] The pharmaceutical compositions of the invention may be in the form of
solutions or suspensions. In the management of thrombotic disorders the compounds or

pharmaceutical compositions of the invention may also be in such forms as, for example,
tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or
suspensions or injectable administration, and the like, or incorporated into shaped articles.
[0050] Typical adjuvants which may be incorporated into tablets, capsules and the
like include, but are not limited to, binders such as acacia, corn starch or gelatin, and
excipients such as microcrystalline cellulose, disintegrating agents like corn starch or alginic
acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or
flavoring agents. When a dosage form is a capsule, in addition to the above materials it may
also contain liquid carriers such as water, saline, or a fatty oil. Other materials of various
types may be used as coatings or as modifiers of the physical form of the dosage unit. Sterile
compositions for injection can be formulated according to conventional pharmaceutical
practice. For example, dissolution or suspension of the active compound in a vehicle such as
an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired.
Buffers, preservatives, antioxidants and the like can be incorporated according to accepted
pharmaceutical practice.
[0051] Additionally, dosage formulations of compounds of formulae I, la, lb, or Ic,
or pharmaceutical compositions containing a compound of the invention, to be used for
therapeutic administration must be sterile. Sterility can be readily accomplished by filtration
through sterile membranes such as 0.2 micron membranes, or by other conventional methods.
Formulations typically will be stored in a solid form, preferably in a lyophilized form. While
the preferred, route of administration is orally, the dosage formulations of compounds of
formulae I, la, lb, or Ic, or pharmaceutical compositions of the invention may also be
administered by injection, intravenously (bolus and/or infusion), subcutaneously,
intramuscularly, colonically, rectally, nasally, transdermally or intraperitoneally. A variety of
dosage forms may be employed as well including, but not limited to, suppositories, implanted
pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as
ointments, drops and dermal patches. The compounds of formulae I, la, lb, or Ic, and
pharmaceutical compositions of the invention may also be incorporated into shapes and
articles such as implants which may employ inert materials such biodegradable polymers or
synthetic silicones as, for example, SILASTIC, silicone rubber or other polymers
commercially available. The compounds and pharmaceutical compositions of the invention
may also be provided in the form of liposome delivery systems, such as small unilamellar
vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed

frorr^a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines, used
methods well known to one of skill in the art.
Methods of Treatment/Administration
[0052] In yet another aspect, the present invention provides methods for preventing or
treating thrombosis in a mammal by administering to the mammal a therapeutically effective
amount of a compound of formulae I, la, lb, or Ic, alone or as part of a pharmaceutical
composition of the invention as described above. Compounds of formulae I, la, lb, or Ic,
and pharmaceutical compositions of the invention containing a compound of formulae I, la,
lb, or Ic, of the invention are suitable for use alone or as part of a multi-component treatment
regimen for the prevention or treatment of cardiovascular diseases, particularly those related
to thrombosis. For example, a compound or pharmaceutical composition of the invention
may be used as a drug or therapeutic agent for any thrombosis, particularly a platelet-
dependent thrombotic indication, including, but not limited to, acute myocardial infarction,
unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular
disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated
intravascular coagulation and thrombotic cytopenic purpura, thrombotic and restenotic
complications following invasive procedures, e.g., angioplasty, carotid endarterectomy, post
CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and
insertion of endovascular devices and protheses.
[00531 Compounds and pharmaceutical compositions of the invention may also be
used as part of a multi-component treatment regimen in combination with other therapeutic or
diagnostic agents in the prevention or treatment of thrombosis in a mammal. In certain
preferred embodiments, compounds or pharmaceutical compositions of the invention may be
coadministered along with other compounds typically prescribed for these conditions
according to generally accepted medical practice such as anticoagulant agents, thrombolytic
agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen
activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. Still other
agents that can be administered with the compounds of the present invention include
antiplatelet compounds, fibrinolytics, anti-inflammatory compounds, cholesterol-lowering
agents, blood-pressure-lowering agents and serotonin blockers. Suitable antiplatelet
compounds include GPIIB-IIIa antagonists, aspirin, phosphodiesterase HI inhibitors and
thromboxane A2 receptor antagonists. Suitable anticoagulants include thrombin inhibitors,

couaiadin (Warfarin), heparin and Lovenox®. Suitable anti-inflammatory compounds include
non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors and rheumatoid arthritis
agents. Coadministrations of these agents with the compounds of the invention may also
allow for application of reduced doses of the thrombolytic agents and therefore minimize
potential hemorrhagic sidereffects. Compounds and pharmaceutical compositions of the
invention may also act in a synergistic fashion to prevent reocclusion following a successful
thrombolytic therapy and/or reduce the time to reperfusion.
[0054] In related methods, the compounds of the invention are useful for the
prevention of a secondary ischemic event. In these methods, compounds of the invention or
their pharmaceutical compositions are administered to a patient who has suffered a primary
ischemic event in an amount sufficient to prevent or reduce the hkely occurrence of a
secondary event Generally, the primary and/or secondary ischemic event is selected from
myocardial infraction, stable or unstable angina, acute reocclusion after percutaneous
transluminal coronary angioplasty, restenosis, thrombotic stroke, transient ischemic attack,
reversible ischemic neurological deficit and intermittent claudication.
[0055] The compounds and pharmaceutical compositions of the invention may be
utilized in vivo, ordinarily in mammals such as primates, (e.g., humans), sheep, horses, cattle,
pigs, dogs, cats, rats and mice, or in vitro. The biological properties, as defined above, of a
compound or a pharmaceutical composition of the invention can be readily characterized by
methods that are well known in the art such as, for example, by in vivo studies to evaluate
antithrombotic efficacy, and effects on hemostasis and hematological parameters.
[0056] Subjects (typically mammalian) in need of treatment using the compounds or
pharmaceutical compositions of the invention may be administered dosages that will provide
optimal efficacy. The dose and method of administration will vary from subject to subject
and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet,
concurrent medication, overall clinical condition, the particular compound of formulae I, la,
lb, or Ic employed, the specific use for which the compound or pharmaceutical composition
is employed, and other factors which those skilled in the medical arts will recognize.
[0057] Therapeutically effective dosages may be determined by either in vitro or in
vivo methods. For each particular compound or pharmaceutical composition of the invention,
individual determinations may be made to determine the optimal dosage required. The range
of therapeutically effective dosages will be influenced by the route of administration, the

therapeutic objectives and the condition of the patient For injection by hypodermic needle, it
may be assumed the dosage is delivered into the bodily fluids. For other routes of
administration, the absorption efficiency must be individually determined for each compound
by methods well known in pharmacology. Accordingly, it may be necessary for the therapist
to titer the dosage and modify the route of adrninistration as required to obtain the optimal
therapeutic effect.
[0058] The determination of effective dosage levels, that is, the dosage levels
necessary to achieve the desired result, i.e., platelet ADP receptor inhibition, will be readily
determined by one skilled in the art. Typically, applications of a compound or
pharmaceutical composition of the invention are commenced at lower dosage levels, with
dosage levels being increased until the desired effect is achieved. The compounds and
compositions of the invention may be administered orally in an effective amount within the
dosage range of about 0.01 to 1000 mg/kg in a regimen of single or several divided daily
doses. If a pharmaceutically acceptable carrier is used in a pharmaceutical composition of
the invention, typically, about 5 to 500 mg of a compound of formulae I, la, lb, or Ic, is
compounded with a pharmaceutically acceptable carrier as called for by accepted
pharmaceutical practice including, but not limited to, a physiologically acceptable vehicle,
carrier, excipient, binder, preservative, stabilizer, dye, flavor, etc. The amount of active
ingredient in these compositions is such that a suitable dosage in the range indicated is
obtained.
[0059] The following preparations and examples are given to enable those skilled in
the art to more clearly understand and to practice the present invention. They should not be
considered as limiting the scope of the invention, but merely as being illustrative and
representative thereof.
EXAMPLES
[0060] The starting materials and reagents used in preparing these compounds
generally are either available from commercial suppliers, such as Aldrich Chemical Co., or
are prepared by methods known to those skilled in the art following procedures set forth in
references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New
York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science
Publishers, 1989, Volumes 1-5 and Supplemental; and Organic Reactions, Wiley & Sons:

New^York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely
illustrative of some methods by which the compounds of the present invention can be
synthesized, and various modifications to these synthetic reaction schemes can be made and
will be suggested to one skilled in the art having referred to the disclosure contained in this
Application.
[0061] The starting materials and the intermediates of the synthetic reaction schemes
can be isolated and purified if desired using conventional techniques, including but not
limited to, filtration, distillation, crystallization, chromatography, and the like. Such
materials can be characterized using conventional means, including physical constants and
spectral data.
[0062] Unless specified to the contrary, the reactions described herein preferably are
conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range
of from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and
most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 °C.
EXAMPLE 1
3-(4-Fluoro-3-methoxyphenvl)-acrylicacid

[0063] To a solution of 4-fluoro-3-methoxybenzaldehyde (32 g, 0.2 mol) in pyridine
(100 mL) was added malonic acid (43 g, 0.4 mol) and piperidine (3 mL, 0.03 mol). The
reaction solution was stirred at 85°C for 13 hr. Upon cooling, the resulting suspension was
added to cold water (500 mL) and acidified with cone. HC1 (80 mL). The white solid was
filtered off, washed with water and dried to yield 36 g (92%) of 3-(4-fluoro-3-
methoxyphenyl)-acrylic acid. RP-HPLC: 3.71 min. 1H-NMR (DMSO-d6) 5 (ppm) 3.85 (s,
3), 6.53 (d, 1, J=16), 7.20 (m, 2), 7.50 (m, 1), 7.52 (d, 1, J=16).

± EXAMPLE 2
3-(4-Fluoro-3-methoxyphenyl)-acrvlovlazide

[0064] To a chilled solution (ice/acetone) of 3-(4-fluoro-3-methoxyphenyl)-acrylic
acid (37 g, 0.194 mmol) in dry THF (280 mL) and triethylamine (352 mL) was added ethyl
chloroformate (22.5 mL) in THF (50 mL) dropwise over 20 minutes. The resulting
suspension was allowed to warm to 23°C for lh, re-cooled, and a solution of NaN3 (18.7 g) in
water (80 mL) was added. The reaction was stirred at 23°C for 1-2 hr. Workup involved
addition of dichloromethane (250 mL) followed by incremental slow addition of IN HC1.
The aqueous layer was further extracted 2 times with dichloromethane. The organic layers
were combined, washed with IN HC1 and brine, dried over MgS04, and concentrated in
vacuo to afford 39.8 g (95%) of the acyl azide. RP-HPLC: 5.31 min.
EXAMPLE 3
7-Fluoro-6-methoxy-2H-isoquinolin-l-one

[0065] A solution of the acyl azide (39 g, see Example 2) in 1,2-dichlorobenzene (300
mL) was heated to 140°C for approximately lh until gas formation subsides. Catalytic iodine
was added and the temperature was increased to 180°C for 1.5h. The reaction mixture was
allowed to cool to ambient temperature with stirring; the precipitate which formed was
collected by filtration, washed with benzene and dried under vacumn to afford 22.6 g (67%)
of 7-fluoro-6-methoxy-2H-isoquinolin-l-one as a tan solid. RP-HPLC: 2.58 min; ES-MS
(M+H)+= 194.1; 1H-NMR (DMSO-d6) 5 (ppm): 3.8 (3H, s), 6.48 (l,d), 7.11 (t, 1), 7.33 (d,
l);6.77(d,l).

_>, EXAMPLE 4
7-Fluoro-6-methoxv-2-(4-nitrophenvl)-2H-isoquinoliii-1 -one:

[0066] To a solution of 1 l.Og of 7-Fluoro-6-methoxy-2H-isoquinolin-l-one (57
mmol) in DMF (108 mL) was added potassium carbonate (11.8 g), followed by 10.6g of 1-
fluoro-4-nitrobenzene (75 mmol). The reaction mixture was stirred at 120°C for 6 hr then
poured onto ice water. The slurry was extracted with ether to remove excess pFPhNOa. The
precipitate was collected by filtration, washed with ether and dried in vacuo to give 12.1 g
(68%) of the product asa yellow solid. RP-HPLC: 4.79 min; ES-MS (M+H)+ = 315.0; 1H-
NMR (DMSO-d6) 5 (ppm): 4.0 (3H, s), 6.76 (l,d), 7.48 (d, 1), 7.53 (d, 1), 7.83 (d,2), 7.92 (d,
1), 8.38 (d, 2).
EXAMPLE 5
7-Fluoro-6-hydrox v-2-( 4-nitro-phenyl)-2H-isoquinolin-1 -one

[0067] To a chilled suspension of 7-Fluoro-6-methoxy-2-(4-nitrophenyl)-2H-
isoquinolin-1-one (3.14 g, 10 mmol) in dichloromethane (50 mL) was added neat boron
tribromide (8 mL, 85 mmol) via syringe. The brown suspension was stirred at room
temperature for 24 hr. The solvent was decanted, washed with cold DCM, leaving a black
residue, which was triturated on ice with methanol (80 mL). The solid was collected by
filtration, then washed with water and dried to give 2.66 g (89%) of 7-Fluoro-6-hydroxy-2-
(4-nitro-phenyl)-2H-isoqumolin-l-one. RP-HPLC: 3.93 min; ES-MS (M+H)+= 301.0; 1H-
NMR (DMSO-d6) 5 (ppm): 6.66 (d,l), 7.16 (d, 1), 7.43 (d, 1); 7.76 (d, 2), 7.84 (d, 1), 8.33
(d,2), 11.1 (brs, 1).

^ EXAMPLE 6
Trifluoro-methanesulfonic acid 7-fluoro-2-
(4-nitro-phenylV 1 -oxo-1,2-dihydro-isoquinorin-6-yl ester

[0068] To a suspension of 7-Fluoro-6-hydroxy-2-(4-nitro-phenyl)-2H-isoquinolin-l-
one (1.15 g, 3.8 mmol) in dry pyridine (25 mL) and dichloromethane (20 mL) was added neat
trifluoromethanesulfonic anhydride (0.8 mL, 4.76 mmol) drop wise over 5 min. The resulting
solution was stirred at room temp for 2 hr. The reaction mixture was diluted with ethyl
acetate (200 mL), washed with IN HC1 (60 mL), water (50 mL) and brine (50 mL), dried
over sodium sulfate, filtered, concentrated in vacuo and dried to give 1.37 g (83%) of pure
trifluoromethanesulfonic acid 7-fluoro-2-(4-nitro-phenyl)-1 -oxo-1,2-dihydro-isoquinolin-6-yl
ester. RP-HPLC: 6.20 min; ES-MS (M+H)+ = 433.0; 1H-NMR (DMSO-d6) 5(ppm): 6.88
(d, 1), 7.64 (d, 1), 7.80 (d, 2), 8.24 (m, 2,; 8.37 (d, 2).
EXAMPLE 7
[7-Fluoro-2-(4-nitro-phenyl)-l -oxo-1,2-dihydro-
isoquin.olin-6-vl]-carbamic acid tert-butyl ester

[0069] In a dry flask was combined trifluoromethanesulfonic acid 7-fluoro-2-(4-nitro-
phenyl)-l-oxo-l,2-dihydro-isoquinolin-6-yl ester (0.86 g, 2 mmol), t-butyl carbamate (0.33 g,
2.8 mmol), dry powdered cesium carbonate (1.1 g, 3.4 mmol), 9,9-dimethyl-4,5-
bis(diphenylphosphino)xanthene (Xantphos, 0.14 g, 0.24 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3, 38 nig, 0.08 mmol). Under Ar
atmosphere, dry THF (17 mL) was added to the flask, and the mixture was stirred at 75°C for
25 hr. The reaction was concentrated and purified on silica gel using EtOAc/hexane as eluent
to give 0.64 g (80%) of pure [7-Fluoro-2-(4-rritro-phenyl)-l-oxo-l,2-dihydro-isoquinolin-6-

yl]-G*rbamic acid tert-butyl ester as a white solid. RP-HPLC: 5.98 min; ES-MS (M+H)+ =
400.0; 1H-NMR (DMSO-d*) 5 (ppm): 1.47 (s, 9)5 6.77 (d, 1), 7.46 (d, 1), 7.78 (d, 2), 7.87 (d,
1), 8.17 (d, 1), 8.33 (d, 2), 9.54 (s, 1).
EXAMPLE 8
f 7-Fluoro-2-(4-nitro-phenyl)-l -oxo-1,2-dihydro-
isoquinolin-6-vl]-methyl-carbamic acid tert-butyl ester

[0070] To a solution of [7-Fluoro-2-(4-nitro-phenyl)-l-oxo-1,2-dihydro-isoquinolin-
6-yl]-carbamic acid tert-butyl ester (0.36 g, 0.9 mmol) in dry DMF (9 mL) was added cesium
carbonate (1.04 g, 3.19 mmol) followed by neat methyl iodide (0.064 mL, 1.03 mmol). The
mixture was stirred at room temperature for 3.5 hr, extracted into ethyl acetate (150 mL),
washed with water (2 x 50 mL) and brine (50 mL), dried over sodium sulfate, filtered,
concentrated in vacuo and dried to give 0.34 g (93%) of pure [7-Fluoro-2-(4-nitro-phenyl)-l-
oxo-l,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester. RP-HPLC: 5.89
min; ES-MS (M+H)+ = 414.0; 1H-NMR (DMSO-d6) 5 (ppm): 1.33 (s, 9), 3.20 (s, 3), 6.75
(d, 1), 7.52 (d, 1), 7.80 (d, 2), 7.83 (d, 1), 7.93 (d, 1), 8.35 (d, 2).
EXAMPLE 9
[2-(4-Amino-phenvl)-7-fluoro-l -oxo-L2-dihydro-
isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester

[0071] To a suspension of [7-Fluoro-2-(4-nitro-phenyl)-l-oxo-l,2-dihydro-
isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (0.33 g, 0.79 mmol) in ethyl acetate (6
mL) and ethanol (2 mL) under Ar was added 10% Pd/C (0.13 g, 0.12 mmol Pd). The mixture

was^iydrogenated under 1 atm H2 for 2 hr, filtered through Celite and concentrated to give
0.28 g (92%) of [2-(4-Amino-phenyl)-7-fluoro-l-oxo-l,2-dihydro-isoquinolin-6-yl]-methyl-
carbamic acid tert-butyl ester. RP-HPLC: 3.83 min; ES-MS (M+H)+ = 384.0; 1H-NMR
(DMSO-de) 8 (ppm): 1.32 (s, 9), 3.17 (s, 3), 5.31 (br s, 2), 6.60 (m, 3), 7.00 (d, 2), 7.32 (d,
2),7.75(d,l),7.86(d,l).
EXAMPLE 10
5-chloro-N-[({4-[7-fluoro-6-(methvlamino>-l -oxoisoquinolin-2(l H)-
yl]phenyl)amiiio)carbonvl]thiophene-2-sulfonamide

[0072] To a suspension of 5 -chlorothiophene-2-sulfonamide (0.17 g, 0.84 mmol) and
N,N'-disuccinimidyl carbonate (DSC, 0.23 g, 0.91 mmol) in dichloromethane (5 mL) was
added tetramethylguanidine (TMG, 0.19 mL). The resulting solution was stirred at room
temperature for 15 hr. The reaction was concentrated and a solution of [2-(4-Amino-phenyl)-
7-fluoro-l-oxo-l, 2-dihydro-isoquirxolin-6-yl]-methyl-carbamic acid tert-butyl ester (0.27 g,
0.7 mmol) in acetonitrile (5 mL) was added. The resulting solution was stirred at 70°C for 9
hr. The reaction was diluted with dichloromethane, washed with 0.5 N HC1, dried over
sodium sulfate and concentrated to give 0.48 g of crude sulfonylurea.
[0073] To a chilled solution of the crude product in dichloromethane (6 mL) and
triethylsilane (2 mL) was added neat trifiuoroacetic acid (6 mL). After stirring at room temp
for 1 hr, the reaction was concentrated, azeotroped with heptane and dried under high vac to
give 0.65 g of crude 5-chloro-N-[[[4-(7-chloro-6-methylamino-l-oxo-2(lH)-
isoquinolinyl)phenyl]amino] carborxyl]-2-thiophenesulfonamide. This crude material was
triturated with acetonitrile (5 mL), chilled and filtered to give 0.22 g (63%) of pure 5-chloro-
N-[({4-[7-fluoro-6-(memylamino)-l-oxoisoquinolin-2(lH)-
yl]phenyl}amino)carbonyl]thiopheae-2-sulfonamide as a white solid. RP-HPLC: 5.18 min;

ES-^IS (M+H)+ = 507.0; 1H-NMR (DMSO-de) 5 (ppm): 2.79 (s, 3), 6.50 (d, 1), 6.53 (br s,
1), 6.70 (d, 1), 7.24 (m, 2), 7.30 (d, 2), 7.46 (d, 2), 7.64 (m, 2).
EXAMPLE 11
2-(4-Amino-phenylV6-cvclopropvlamipo-7-fluoro-2H-isoquinolin-l-one

[0074] An analogous C-N coupling procedure to that described in Example 7 was
performed on trifluoro-methanesulfonic acid 7-fluoro-2-(4-nitro-phenyl)-l-oxo-l,2-dihydro-
isoquinolin-6-yl ester (Example 6) using cyclopropylamine as the nucleophile. Reduction of
die nitro group was effected using the procedure outlined in Example 9. ES-MS (M+H)+ =
310.
EXAMPLE 12
(5-Chloro-thiophene-2-sulfonylVcarbamic acid ethyl ester

[0075] To a solution of 5-Chloro-thiophene-2-sulfonic acid amide (4.0 g, 20.2 mmol)
in dry THF (200 mL) was added cesium carbonate (9.9 g, 30.3 mmol) and ethyl
chloroformate (2.9 mL, 30.3 mmol). The mixture was stirred at room temperature for 48 h.
The product was taken up in H2O (150 mL) and washed with EtOAc (100 mL). The aqueous
layer was acidified to pH=3 with IN HC1 (90 mL) and the product extracted with EtOAc (100
mL). The organic layer was washed with brine (100 mL), dried over Na2SC>4 and
concentrated to give a dense clear oil which solidified upon standing to give 4.41 g (81 %) of
5-Chloro-tbiophene-2-sulfonyl)-carbamic acid ethyl ester. RP-HPLC: 4.45 min. 1H-NMR
(CDCI3) 5 (ppm): 7.63 (d, J=4,1H), 7.44 (bs, 1H), 6.95 (d, J=4,1H), 4.20 (q, J=7,2H), 1.27
(t,J=7,3H).


[0076] A mixture of 2-(4-Amino-phenyl)-6-cyclopropylamino-7-fluoro-2H-
isoquinolin-1-one (Example 11) (23 mg, 0.073 mmol) and (5-Chloro-thiophene-2-sulfonyl)-
carbamic acid ethyl ester (Example 12) (28 mg, 0.10 mmol, 1.35 eq) in dry toluene (1.5 mL)
was heated at 110°C for 2hr. Upon cooling, the reaction was concentrated in vacuo and the
crude residue was purified by HPLC (C-18) to give 17 mg (46%) of pure 5-chloro-N-[({4-[6-
(cyclopropylamino)-7-fluoro-l -oxoisoquinolin-2(l H)-yl]phenyl} amino)carbonyl]thiophene-
2-sulfonamide. ES-MS (M+H)+= 533, 535 (CI).

[0077] An analogous C-N coupling procedure to that described in Example 7 was
performed on trifluoro-methanesulfonic acid 7-fluoro-2-(4-nitro-phenyl)-l-oxo-l,2-dihydro-
isoquinolin-6-yl ester (Example 6) using formamide as the nucleophile. Reduction of the
nitro group was effected using the procedure outlined in Example 9. Coupling to form the
sulfonyl urea was achieved using the method described in Example 13 to give 5-chloro-N-
[({4-[7-fluoro^-(formylamino)-l-oxoisoquinolin-2(lH)-
yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+= 521, 523 (CI).


[0078] An analogous C-N coupling procedure to that described in Example 7 was
performed on trifluoro-methanesulfonic acid 7-fmoro-2-(4-rritro-phenyl)-l-oxo-l,2-dihydro-
isoquinolin-6-yl ester (Example 6) using acetamide as the nucleophile. Reduction of the nitro
group was effected using the procedure outlined in Example 9. Coupling to form the sulfonyl
urea was achieved using the method described in Example 13 to give N-(2-{4-[({[(5-
chloromien-2-yl)sulfonyl]amino}carbonyl)ainino]phenyl}-7-fluoro-l-oxo-l,2-
dihydroisoquinolin-6-yl)acetamide. ES-MS (M+H)+ = 535, 537 (CI).

[0079] An analogous C-N coupling procedure to that described in Example 7 was
performed on Trifluoro-methanesulfonic acid 7-fiuoro-2-(4-nitro-phenyl)-l-oxo-l,2-dihydro-
isoquinolin-6-yl ester( Example 6) using N-methylformamide as the nucleophile, followed by
alkylation and reduction of the nitro group using the procedure outlined in Examples 8 and 9.
Coupling to form the sulfonyl urea was achieved using the method described in Example 13
to give 5-cUoro-N-[({4-[7-fluoro-6-[formyl(methyl)amino]-l-oxoisoquinolin-2(lH)-
yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ = 535, 537 (CI).


[0080] An analogous C-N coupling procedure to that described in Example 7 was
performed on trifluoro-methanesulfonic acid 7-fluoro-2-(4-rntro-phenyl)-l-oxo-l,2-dihydro-
isoquinolin-6-yl ester (Example 6) using N-methylacetamide as the nucleophile, followed by
alkylation and reduction of the nitro group using the procedure outlined in Examples 8 and 9.
Coupling to form the sulfonyl urea was achieved using the method described in Example 13
to give N-(2-{4-[({[(5-chlorotWen-2-yl)sulfonyl]arnino}carbonyl) amino]phenyl}-7-fluoro-l-
oxo-1,2-dihydroisoquinolin-6-yl)-N-methylacetamide. ES-MS (M+H)+ = 549,551 (CI).

[0081] An analogous C-N coupling procedure to that described in Example 7 was
performed on trifluoro-methanesulfonic acid 7-fluoro-2-(4-nitro-phenyl)-l-oxo-l,2-dihydro-
isoquinolin-6-yl ester (Example 6) using morpholine as the nucleophile. Reduction of the
nitro group was effected using the procedure outlined in Example 9. Coupling to form the
sulfonyl urea was achieved using the method described in Example 13 to give 5-chloro-N-
({[4-(7-fluoro-6-morpholin-4-yl-l-oxoisoquinolin-2(lH)-
yl)phenyl]arrimo}carbonyl)thiophene-2-sulfonamide. ES-MS (M+H)+ = 563, 565 (CI).


{0082] An analogous alkylation procedure to that described in Example 8 was
performed on [7-fluoro-2-(4-nitro-phenyl)-l-oxo-l,2-dmydro-isoquinolin-6-yl]-carbamic acid
tert-butyl ester (Example 7) using ethyl iodide as the alkylating agent. Reduction of the nitro
group and coupling to form the stilfonyl urea was achieved using the method described in
Exs. 9 and 10, resp. to give 5-cMoro-N-[({4-[6-(emylammo)-7-fluoro-l-oxoisoquinolin-
2(lH)-yl]phenyl}arnino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ = 521, 523
(CI).

[0083J An analogous alkylation procedure to that described in Example 8 was
performed on [7-fluoro-2-(4-dtro-phenyl)-l-oxo-l,2-dihydro-isoquinolin-6-yl]-carbamic acid
tert-butyl ester (Example 7) using l-bromo-2-fluoroethane as the alkylating agent. Reduction
of the nitro group and coupling to form the sulfonyl urea was achieved using the method
described in Exs. 9 and 10, resp. to give 5-cMoro-N4({^[7-fluoro-6-[(2-fluoroethyl)amino]-
l-oxoisoqumolm-2(lH>yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS
(M+H)+ = 539, 541 (CI).


[0084] An analogous alkylation procedure to that described in Example 8 was
performed on [7-fluoro-2-(4-rdtro-phenyl)-l-oxo-l,2-dihyd^o4soqumoliQ-6-yl]-carbamic acid
tert-butyl ester (Example 7) using 2,2,2-trifluoroethyl-p-toluenesulfonate as the alkylating
agent with additional heating at 95°C. Reduction of the nitro group and coupling to form the
sulfonyl urea was achieved using the method described in Exs. 9 and 10, respectively, to give
5-chloro-N-[({4-[7-fluoro-1 -oxo-6-[(2,2,2-Mfluoroemyl)amino]
isoquinolin-2(lH)-yI]phenyl}aiiiino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ =
575, 577 (CI).

[0085] An analogous alkylation procedure to that described in Example 8 was
performed on [7-fluoro-2-(4-nitro-phenyl)-l-oxo-l,2-dihydro4soquinolm-6-yl]-carbamic acid
tert-butyl ester (Example 7) using proparyl bromide as the alkylating agent. Reduction of the
nitro group and coupling to form the sulfonyl urea was achieved using the method described
in Exs. 9 and 10, resp. to give 5-chloro-N-[({4-[7-fiuoro-l-oxo-6-(prop-2-
ynylammo)isoqumolm-2(lH)-yl]phenyl}anmio)carbonyl]thiophene-2-sulfonamide. ES-MS
(M+H)+ = 531, 533 (CI).


[00861 An analogous alkylation procedure to that described in Example 8 was
performed on [7-fluoro-2-(4-nitro-phenyl)-l-oxo-l,2-dihydro-isoquinolm-6-yl]-carbamic acid
tert-butyl ester (Example 7) using 4-chlorobenzylbromide as the alkylating agent. Reduction
of the nitro group and coupling to form the sulfonyl urea was achieved using the method
described in Exs. 9 and 10, resp. to give 5-chloro-N-[({4-[6-[(4-chlorobenzyl)amino]-7-
fluoro-1 -oxoisoquinolin-2( 1 H)-yl]phenyl} amino)carbonyl]
thiophene-2-sulfonamide. ES-MS(M+H)+= 617,619(201).

[0087] The alkylated intermediate synthesized in Example 23 was treated with TFA
and methylated with methyl iodide and cesium carbonate. Reduction of the nitro group and
coupling to form the sulfonyl urea was achieved using the method described in Example 9
and 10, to give 5-chloro-N-[({4-[6-[(4-chlorobenzyl)(methyl)amino]-7-fiuoro-l-
oxoisoquinolin-2(lH)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)
= 631,633(201).


[0088] Reduction of [7-fluoro-2-(4-nitro-phenyl)-l-oxo-l,2-dihydro-isoquinolin-6-
yl]-carbamic acid tert-butyl ester (Example 7) was effected using the procedure outlined in
Example 9. Coupling to form the sulfonyl urea was achieved using the method described in
Example 10 to give N-({[4-(6-arnino-7-fluoro-l-oxoisoquinolin-2(lH)-
yl)phenyl]ammo}carbonyl)-5-chlorothiopliene-2-sulfonamide. ES-MS (M+H)+ = 493,495
(CI).

[0089] To a suspension of the sulfonyl urea from Example 25 (11 mg, 0.023 mmol) in
glacial acetic acid (0.9 mL) was added formaldehyde (37 wt% in water) (12 uL, 0.16 mmol) .
followed by sodium triacetoxyborohydride (11 mg, 0.052 mmol). The reaction mixture was
stirred at room temperature overnight and concentrated in vacuo. The crude residue was
purified by HPLC to give 5-chloro-N-[({4-[6-(dimethylamino)-7-fluoro-l-oxoisoquinolin-
2(lH)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+= 521,523
(CI).


[0090] An analogous coupling procedure described in Example 10 was performed on
[2-(4-Ammo-phenyl)-7-fluoro-l-oxo-l,2-dmydro-isoquinolin-6-yl]-methyl-carbamicacid
tert-butyl ester (Example 9) using commercially available thiophene-2-sulfonamide to give
N-[( (4-[7-fIuoro-6-(methylamino)-1 -oxoisoquinolin-2(l H)-yl]phenyl} amino)
carbonyl]thiophene-2-sulfonamide. ES-MS(M+H)+= 473.

[0091] An analogous coupling procedure as that described in Example 10 was
performed on [2-(4-Amino-phenyl)-7-fluoro-l -oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-
carbamic acid tert-butyl ester (Example 9) and commercially available 5-bromothiophene-2-
sulfonamide to give 5-bromo-N-[({4-[7-fluoro-6-(memylamino)-l-oxoisoquinolin-2(lH)-
yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+= 551, 553 (Br).


[0092] To a solution of triphosgene (9 mg, 31 umol) in dichloromethane (0.2 mL)
was slowly added a solution of [2-(4-Amino-phenyl)-7-fluoro-l-oxo-l, 2-dihydro-
isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (30 mg, 78 umol) and DIEA (27 uL,
156umol) in dichloromethane (1.0 mL). The mixture was stirred at room temperature for 15
min.. To this solution was then quickly added a solution of 5-methylthiophene-2-
sulfonamide (28 mg, 156 umol) and DIEA (27 JJJL, l56\xmol) in dichloromethane (1.0 mL).
The mixture was then stirred at room temperature for 15 min.. The reaction mixture was then
diluted with dichloromethane, washed with 0.5 N HC1, dried over sodium sulfate and
concentrated to give 62 mg of crude sulfonylurea as a cloudy oil. The crude mixture was
dissolved inTFA, reacted at room temperature for 15 min., and concentrated in vacuo to give
the crude final product as yellow oil which was purified by HPLC to give 17 mg (45%) of N-
({[4-(6-amino-7-fluoro-l-oxoisoquinolin-2(lH)-yl)phenyl]amino}carbonyl)-5-
methylthiophene-2-sulfonamide as a white solid. ES-MS (M+H)+ = 487.1; 1H-NMR
(DMSO-d6) 6 (ppm): 8.84-8.80 (bd, J=4.5 Hz, 1H), 7.66-7.60 (d, J=12.8 Hz, 1H), 7.50-7.44
(d, J=8.8 Hz, 2H), 7.40-7.36 (bs, 1H), 7.25-7.15 (m, 3H), 6.80-6-74 (bs, 1H), 6.74-6.66 (d,
J=8.4 Hz, 1H), 6.56-6.48 (bs, 1H), 6.50-6.46 (d, J=8Hz, 1H), 2.82-2.77 (bd, J=4.5 Hz, 3H).


[0093] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-l-oxo-l,2-
dihydro4soquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-
emylmiophene-2-sulfonanaidetogiveN-({[4-(6-ammo-7-fluoro-l-oxoisoquinolin-2(lH)-
yl)phenyl]ammo}carbonyl)-5-emylthiophene-2-sulfonamide. ES-MS (M+H)+ = 501.1.

[0094] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-
propylthiophene-2-sulfonic acid amide to give N-({[4-(6-amino-7-fluoro-l-oxoisoquinolin-
2(lH)-yl)phenyl]amino}carbonyl)-5-propylthiophene-2-sulfonamide. ES-MS (M+H)+ =
515.1; 1H-NMR (DMSO-d6) 5 (ppm): 9.06-9.00 (s, 1H), 7.66-7.62 (d, J=12.4 Hz, 1H), 7.62-
7.58 (d, J=3.7 Hz, 1H), 7.48-7.42 (m, 2H), 7.32-7.26 (m, 2H), 7.24-7.20 (d, J=7.3 Hz, 1H),
6.96-6-90 (d, J-3.6 Hz, 1H), 6.74-6.66 (d, J=8.4 Hz, 1H), 6.58-6.48 (bs, 1H), 6.50-6.46 (d,
J=7.3 Hz, 1H), 2.84-2.76 (m, 5H), 1.68-1.56 (tq, J=7.3, 7.6 Hz, 2H), 0.94-0.86 (t, J=7.3 Hz,
3H).


[00$5] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Ammo-phenyl)-7-fluoro-l-oxo-l,2-
dmydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-
difluoromethyl-thiophene-2-sulfonic acid amide to giveN-({[4-(6-amino-7-fluoro-l-
oxoisoquinolin-2( 1 H)-yl)phenyl]amino} carbonyl)-5-difluoromethylthiophene-2-sulfonamide.
ES-MS (M+H)+ = 523.1; 1H-NMR (DMSO-d6) 8 (ppm): 8.70-8.64 (s, 1H), 7.66-7.60 (d,
J=12.4 Hz), 7.56-7.48 (m, 2h), 7.38-7.10 (t, J=55.3 Hz, 1H), 7.36-7.32 (m, 1H), 7.28-7.24 (m,
1H), 7.22-7.18 (d, J=7.7 Hz, 1H), 7.12-7.06 (m, 2H), 6.72-6.66 (d, J=8.4 Hz, 1H), 6.52-6.46
(bs, 1H), 6.48-6.44 (d, J=7.3 Hz, 1H), 2.81-2.77 (bd, J-4.7 Hz, 3H).

[0096] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Arriino-phenyl)-7-fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-
cyanothiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-l-oxoisoquinolin-2(lH)-
yl)phenyl]amino}carbonyl)-5-cyanothiophene-2-sulfbnamide. ES-MS (M+H)+ = 498.1.


[0093] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-
metboxythiophene-2-sulfonamide to giveN-({[4-(6-ariiino-7-fluoro-l-oxoisoquinolin-2(lH)-
yl)phenyl]ammo}carbonyl)-5-etb.yltbiopb.ene-2-sulfonarnide. ES-MS (M+H)+ = 503.1; 1H-
NMR (DMSO-d6) 8 (ppm): 9.15-9.00 (s, 1H), 7.68-7.60 (d, J-12.5 Hz, 1H), 7.52-7.50 (d,
J=3.3 Hz, 1H), 7.48-7.44 (d, J=8.8 Hz, 2H), 7.34-7.28 (d, J=8.8 Hz, 2H), 7.25-7.20 (d, J=7.3
Hz, 1H), 6.74-6.68 (d, J=7.7 Hz, 1H), 6.56-6.50 (bs, 1H), 6.52 (d, J=7.7 Hz, 1H), 6.44-6.40
(d, J=3.3 Hz, 1H), 3.94-3.92 (s, 3H), 2.82-2.78 (bd, J-4.4 Hz, 3H).

[0098] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Aimno-phenyl)-7~fiuoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-
ethynylthiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-l-oxoisoquinolin-2(lH)-
yl)phenyl]amino}carbonyl)-5-ethynylthiophene-2-sulfonainide. ES-MS (M+H)+ = 497.1;
1H-NMR (DMSO-de) 8 (ppm): 9.22-9.18 (bs, 1H), 7.70-7.66 (m, 1H), 7.65-7.60 (d, J=12.4
Hz, 1H), 7.48-7.42 (d, J-9.1 Hz, 2H), 7.40-7.36 (m, 1H), 7.32-7.25 (d, J=8.8 Hz, 2H), 7.24-
7.18 (d, J=7.7 Hz, 1H), 6.72-6.66 (d, J=8.4 Hz, 1H), 6.58-6.48 (bs, 1H), 6.50-6.46 (d, J=7.3
Hz, 1H), 4.86-4.84 (s, 1H), 2.82-2.76 (s, 3H).


[0099] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-
carboxanidethiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-l-oxoisoquinolin-
2(lH)-yl)phenyl]ammo}carbonyl)-5-carboxamidethiophene-2-sulfonarnide. ES-MS (M+H)+
= 516.1.

[0100] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-l -oxo-1,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 4-
chlorothiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-l-oxoisoquinolin-2(lH)-
yl)phenyl]amino}carbonyl)-4-chlorothiophene-2-sulfonamide. ES-MS (M+H)+ = 507.0,
509.0 (CI).


[0101] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-pheayl)-7-fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 4-methyl-
thiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-l-oxoisoquinolin-2(lH)-
yl)phenyl]ammo}carbonyl)-4-methylthiophene-2-sulfonamide. ES-MS (M+H)+ = 487.1.

[0102] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fIuoro-l-oxo-l,2-
diTiydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 4-
difluoromethylthiophene-2-sulfonamide to give N-({[4-(6-amino-7-iluoro-l-oxoisoquinolin-
2(lH)-yl)phenyl]ammo}carbonyl)-4-difluoromethyltniophene-2-sulfonamide. ES-MS
(M+H)+ = 523.1; 1H-NMR (DMSO-d6) 5 (ppm): 9.24-9.16 (bs, 1H), 8.34-8.28 (m, 1H), 7.88-
7.84 (m, 1H), 7.66-7.60 (d, J=12.4 Hz, 1H), 7.48-7.42 (d, J=8.8 Hz, 2H), 7.34-7.26 (d, J=8.8
Hz, 2H), 7.25-7.20 (d, J=7.3 Hz, 1H), 7.19-6.91 (t, J=55.3 Hz, 1H), 6.72-6.66 (d, 8.4 Hz, 1H),
6.58-6.48 (bs, 1H), 6.50-6.46 (d, J=7.3 Hz, 1H), 2.82-2.77 (s, 3H).


[0103] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) using 3-chloro-
thiophene-2-sulfonic acid amide as the coupling partner to give N-({[4-(6-amino-7-fluoro-l-
oxoisoquinolm-2(lH)-yl)phenyl]anuno}carbonyl)-3-cbJorothiophene-2-sulfonamide. ES-MS
(M+H)+ = 507.0,509.0 (CI); 1H-NMR (DMSO-d6) 5 (ppm): 8.98-8.91 (bs, 1H), 8.06-7.98
(m, 1H), 7.66-7.60 (d, J=12.8 Hz, 1H), 7.48-7.40 (d, J=8.8 Hz, 2H), 7.30-7.25 (d, J=8.8 Hz,
2H), 7.24-7.20 (m, 1H), 7.24-7.18 (d, J=7.3 Hz, 1H), 6.72-6.66 (d, J=8.4 Hz, 1H), 6.56-6.48
(bs, 1H), 6.50-6.46 (d, J=7.3 Hz, 1H), 2.82-2.75 (s, 3H).

[0104] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 3-methyl-
tWophene-2-sulfonanu^etogiveN-(([4-(6-amino-7-fluoro-l-oxoisoquinolin-2(lH)-
yl)phenyl]amino}carbonyl)-3-methylthiophene-2-sulfonarnide. ES-MS (M+H)+ = 487.1; 1H-
NMR (DMSO-de) 5 (ppm): 8.96-8.92 (bs, 1H), 7.86-7.82 (d, J=5.1 Hz, 1H), 7.66-7.60 (d,

J=l£4 Hz, 1H), 7.46-7.40 (m, 2H), 7.32-7.26 (m, 2H), 7.24-7.20 (d, J=7.3 Hz, 1H), 7.03-7.00
(d, J=5.1 Hz, 1H), 6.72-6.68 (d, J=8.8 Hz, 1H), 6.56-6.48 (bs, 1H), 6.50-6.46 (d, J=7.7 Hz,
1H), 2.82-2.78 (bd, J=4.8 Hz, 3H), 2.45-2.43 (s, 3H).

[0105] An analogous sulfonylurea coupling and de-protection procedure to that
described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and
benzenesulfonamide to give N-({[4-(6-amino-7-fiuoro-l-oxoisoquinolin-2(lH)-
yl)phenyl]amino}carbonyl)-benzenesulfonamide. ES-MS (M+H)+ =
467.1; 1H-NMP (AMEO-56) 5 (ppm): 9.13-9.06 (bs, 1H), 7.98-7.9>2 (d, J=8.4 Hz, 2H), 7.70-
7.56 (m, 4H), 7.44-7.37 (d, J=8.8Hz, 2H), 7.39-7.24 (d, J=8.8Hz, 2H), 7.21-7.18 (d, J=7.3
Hz, 1H), 6.74-6.66 (d, J=8.4 Hz, 1H), 6.56-6.48 (bs, 1H), 6.49-6.46 (d, J=7.7 Hz, 1H), 2.82-
2.76 (bd, J=4.4 Hz, 3H).
EXAMPLE 43
Trifluoromethanesulfonic acid 7-fluoro-l-oxo-l,2-dihydro-isoquinolm-6-vl ester

[0106] To a chilled suspension of 7-Fluoro-6-methoxy-2H-isoquinolin-l-one (from
Example 3) (9.65 g, 50 mmol) in dichloromethane (200 mL) was added neat boron tribromide
(21 mL, 220 mmol) via syringe. The yellow suspension was stirred at room temperature for
17 hr. The reaction was slowly poured into methanol (300 mL) on an ice bath. The resulting
solution was concentrated in vacuo, washed and concentrated several times with methanol

and,dichloromethane, and dried to give 13 g of crude phenol. 1H-NMR (DMSO-d6) 5
(ppm): 6.38 (d, 1), 7.04 (m, 2), 7.73 (d, 1), 11.05 (s, 1).
[0107] To a suspension of 10.7 g of crude phenol in pyridine (160 mL) was added
DMAP (7.6 g, 62.3 mmol) followed by phenyltrifluoromethylsulfonimide (17.4 g, 48.6
mmol) portionwise over approx. 5 min. The reaction mixture was stirred at room temperature
for 1.5 hr, extracted into ethyl acetate (600 mL), washed with water (3 x 250 mL) and brine
(250 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and dried
to give 24 g crude product, which was triturated with dichloromethane/hexane (2:1) to give
11.6 g (90% yield for 2 steps) of rrifluoromethane-sulfonic acid 7-fluoro-l-oxo-l,2-dihydro-
isoquinolin-6-yl ester. 1H-NMR (DMSO-d6) 5 (ppm): 6.63-6.65 (s, 1), 7.26-7.29 (t, 1), 8.11-
8.16 (m, 2), 11.61 (brs, 1).
EXAMPLE 44
f 7-Fluoro-1 -oxo-2-(2-trimethvlsilanyl-ethox ymethvl)-
l,2-dihydro-isoquinolin-6-yl]-carbamic acid tert-butvl ester

[0108] To a solution of trifluoromethane-sulfonic acid 7-fTuoro-l-oxo-l,2-dihydro-
isoquinolin-6-yl ester (10.5 g, 33.8 mmol) in THF (155 mL) at 0°C was added neat 2-
(trimethylsilyl)-ethoxymethyl chloride (SEM-C1,15 mL, 85 mmol) dropwise over 5 min,
followed by neat DBU (19 mL, 127 mmol). The reaction slurry was stirred at room
temperature for 2hr, diluted with ethyl acetate (600 mL), washed with 0.25N HC1 (200 mL),
water (200 mL) and brine (250 mL), dried over NaaSO,}, filtered, concentrated and dried to
give crude product. Silica gel chromatography using 5-20% ethyl acetate/hexane as eluent
gave 9.2 g (62%) of pure SEM-protected triflate. 1H-NMR (DMSO-d6) 5 (ppm): 0.085 (s,
9), 0.81-0.85 (d, 2), 3.53-3.57 (t, 2), 5.32 (s, 2), 6.72-6.74 (d, 1), 7.56-7.58 (d, 1), 8.12-8.14
(d, 1), 8.20-8.23 (d, 1).
[0109] In a dry flask was combined the triflate (9.2 g, 21 mmol), t-butyl carbamate
(3.42 g, 29.2 mmol), dry powdered cesium carbonate (11.3 g, 34.7 mmol), 9,9-dimethyl-4,5-
bis(diphenylphosphino)xanthene (Xantphos, 1.45 g, 2.5 mmol), and

tris(^ibenzylideneacetone)dipaUadium(0) (Pd2dba3, 0.38 g, 0.83 mmol Pd). Under Ar
atmosphere, dry THF (140 mL) was added to the flask, and the mixture was stirred at 70°C
for 3 hr. Upon cooling, the reaction was diluted with hexane (80 mL), filtered and
concentrated to give 9.0 g crude product, which was purified by column chromatography
(silica, 10-25% EtOAc/hexane) to give 6.1 g (72%) of pure [7-Fluoro-l-oxo-2-(2-trimethyl-
sUanyl-emoxymemyl)-l,2-dmydro-isoqumolin-6-yl]-carbamic acid tert-butyl ester. ES-MS
(M+H)+ = 409; 1H-NMR (DMSO-d6) 6 (ppm): -0.10 (s, 9), 0.80-0.84 (t, 2), 1.46 (s, 9), 3.51-
3.55 (t, 2), 5.27 (s, 2), 6.58-6.60 (d, 1), 7.36-7.38 (d, 1), 7.82-7.85 (d, 1), 8.05-8.07 (d, 1),
9.45 (s,NH).
EXAMPLE 45
(7-Fluoro-l-oxo-1,2-dihvdro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester

[0110] To a solution of [7-Fluoro-l-oxo-2-(2-trirnethyl-silanyl-ethoxymethyl)-l,2-
dihydro-isoquinolin-6-yl]-carbamic acid tert-butyl ester (5.95 g, 14.6 mmol) in dry
dimethylformamide (50 mL) was added powdered cesium carbonate (12 g, 36.8 mmol)
followed by neat methyl iodide (0.95 mL, 15.2 mmol). After 1 hr at room temperature the
reaction was diluted with ethyl acetate (400 mL), washed with water (2 x 100 mL) and brine
(100 mL), dried overNa2SC>4, filtered, concentrated and dried to give crude methylated
product. This crude material was dissolved in 1M tetrabutylammonium fluoride (85 mL in
THF) and stirred at 65°C for 2 hr. The reaction mixture was extracted into ethyl acetate (400
mL), washed with dilute HC1 (100 mL), water (100 mL) and brine (100 mL), and dried to
give a crude product, which was purified by column chromatography (silica, 40-70%
EtOAc/dichloromethane) to give 3.34 g (78%) of pure (7-Fluoro-l-oxo-l,2-dihydro-
isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester. ES-MS (M+H)+ = 293.1; 1H-NMR
(DMSO-d6) 5 (ppm): 1.32 (s, 9), 3.17 (s, 3), 6.50-6.52 (d, 1), 7.13-7.16 (t, 1), 7.70-7.72 (d,
l),7.81-7.84(d,l), 11.35 (brs,l).


Method A: Using substituted 4-fluoronitrobenzenes.
[0111] To a solution of (7-Fluoro-l-oxo-l,2-dihydro-isoquinolin-6-yl)-nxethyl-
carbamic acid tert-butyl ester (Example 45) (70mg, 0.24 mmol) and 3-chloro-4-
fluoronitrobenzene (55 nig, 0.31 mmol, 1.3 eq) in dry dimethylformamide (2 mL) was added
powdered cesium carbonate (0.2 g, 0.6 mmol, 2.5 eq). The mixture was stirred vigorously at
65-70°C for 5 hr, then chilled on an ice bath. Addition of water precipitated out the desired
product which upon filtration and drying under high vacuum gave 95 mg (89%) of pure nitro-
aryl product. 1H-NMR (DMSO-d6) 6 (ppm): 1.34 (s, 9), 3.21 (s, 3), 6.76-6.78 ( 7.39 (d, 1), 7.84-7.85 (d, 1), 7.91-7.93 (d, 2), 8.34-8.36 (dd, 1), 8.54-8.55 (d, 1).
[0112] This nitro intermediate (89 mg, 0.2 mmol) was reduced by reaction with tin
(II) dichloride dihydrate (134 mg, 0.6 mmol, 3 eq) in ethanol (3 mL) at 70°C for 2hr. Upon
cooling, the reaction was diluted with ethyl acetate (20 mL), treated with Celite and 5%
sodium bicarbonate (10 mL) to precipitate the tin (II) oxide. The Celite/Sn02 was filtered
off, and the organic layer washed with 5% NaHCC>3 (10 mL) and brine (10 mL), dried over
Na2SC>4, cone, in vacuo to gave 83 mg (100%) of the desired aniline [2-(4-Amino-2-chloro-
phenyl)-7-fluoro-l -oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester.
ES-MS (M+H)+= 418, 420 (CI).

Method B: Using substituted 4-halo-nitrobenzenes or 2-halo-5-nitropyridines.
[0113] In a dry flask was combined (7-Fluoro-l-oxo-1,2-dihydro-isoquinolin-6-yl)-
methyl-carbamic acid tert-butyl ester (Example 45) (58 mg, 0.2 mmol), 2-bromo-5-

nitrepyridine (61 mg, 0.3 mmol, 1.5 eq), dry powdered cesium carbonate (113 mg, 0.35
mmol, 1.73 eq), 9,9-dimemyl-4,5-bis(diphenylphosphmo)-xanthene (Xantphos, 15 mg, 0.026
mrnol), and tris(dibenzylideneacetone)dipalladium(0) (Pdadba3,4.5 mg, 0.01 mmol Pd).
Under Ar atmosphere, dry THF (2 mL) was added to the flask, and the mixture was stirred at
80°C for 2 hr. Upon cooling, the reaction was concentrated and the crude residue was
purified by column chromatography (silica 2-15% EtOAc/dichloromethane) to give 68 mg
(83%) ofpurenitro-pyridyl product. lH-NMR(DMSO-d6) 5 (ppm): 1.35 (s, 9), 3.21 (s, 3),
6.81-6.83 (d, 1), 7.84-7.85 (d, 1), 7.88-7.90 (d, 1), 7.99-8.01 (d, 1), 8.24-8.26 (d, 1), 8.76-8.79
(dd, 1), 9.39-9.40 (d, 1).
[0114] This nitro intermediate (67 mg, 0.16 mmol) was reduced under catalytic
hydrogenation conditions using 1 atm LL, 10% Pd/C (26 mg, 0.024 mmol Pd) in ethanol (2
mL) for 3hr to give 60 mg (97%) of [2-(5-Amino-pyridin-2-yl)-7-fluoro-l-oxo-l,2-dihydro-
isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester. ES-MS (M+H)+ =385.

Method C: Using substituted 4-haloanilines or 5-halo-2-aminopyridines and.
pyrimidines
[0115] In a dry flask was combined (7-Fluoro-l-oxo-l,2-dihydro-isoquinolin-6-yl)-
methyl-carbamic acid tert-butyl ester (Example 45, compound 10, Scheme B) (102 mg, 0.35
mmol), 2-amino-5-iodopyridine (84 mg, 0.38 mmol, 1.1 eq), copper (I) iodide (7 mg, 0.037
mmol, 0.11 eq), 8-hydroxyquinoline (6 mg, 0.041 mmol, 0.12 eq) and powdered potassium
carbonate (58 mg, 0.42 mmol, 1.2 eq). Under Ar atmosphere, dry dimethylsulfoxide (DMSO,
1.5 mL) was added, and the mixture was stirred at 115°C for 50 hr. The reaction was cooled,
concentrated and purified by chromatography (silica, 2-15% isopropyl
alcohol/dichloromethane) to give 67 mg (50%) of [2-(6-Amino-pyridin-3-yl)-7-fluoro-l-oxo-
l,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester as a grey solid. ES-MS
(M+H)+ = 385. 1H-NMR (DMSO-d6) 5 (ppm): 1.33 (s, 9), 3.19 (s, 3), 6.25 (br m, NH2), 6.53

(m, V), 6.64-6.65 (d, 1), 7.37-7.39 (d, 1), 7.44-7.46 (d, 1), 7.77-7.79 (d, 1), 7.87-7.90 (d, 1),
7.95 (m, 1H).

[0116] An analogous procedure to that outlined in Example 46 (Method A) using 3,4—
difluoronirrobenzene was used to prepare the intermediate aniline. Formation of the sulfonyl
urea was achieved using the method described in Example 13, followed by TFA de-
protection, to give 5-chloro-N-[({3-fluoro-4-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-
2(lH)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ = 525, 527 (CI).

[0117] An analogous procedure to that outlined in Example 46 (Method A) using 3-
chloro-4-fluoromtrobenzene, was used to prepare the intermediate aniline. Formation of the
sulfonyl urea was achieved using the method described in Example 13, followed by TFA de-
protection, to give 5-chloro-N-[({3-chloro-4-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-
2(lH)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+= 541, 543
(2C1).


[0118] An analogous procedure to that outlined in Example 46 (Method A) using 3-
bromo-4-fluoronitrobenzene was used to prepared the intermediate aniline. Formation of the
sulfonyl urea was achieved using the method described in Example 13, followed by TFA de-
protection, to give N-[({3-bromo-4-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-
yl]phenyl}aniino)carbonyl]-5-chlorothiophene-2-sulfonamide. ES-MS (M+H)+ = 585,587,
589 (BrCl).

[0119] An analogous procedure to that outlined in Example 46 (Method A) using 4-
fluoro-3-methylnitrobenzene was used to afford the substituted aniline. Formation of the
sulfonyl urea was achieved using the method described in Example 13, followed by TFA
deprotection, to give 5-chloro-N-[({4-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-
yl]-3-methylphenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ = 520, 522
(CI).


[0120] An analogous procedure to that outlined in Example 46 (Method A) using 4-
fluoro-2-methylnitrobenzene was used to prepare the substituted aniline. Formation of the
sulfonyl urea was achieved using the method described in Example 13, followed by TFA
deprotection, to give 5-cWoro-N-[({4-[7-fluoro-6-(memylarnmo)-l^xoisoquinolin-2(lH)-
yl]-2-methylphenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+Hf=520,522
(CI).

[0121] An analogous procedure to that outlined in Example 47 (Method B) using 2-
bromo-5-nitropyridine was used to prepare the substituted aminopyridine. Formation of the
sulfonyl urea was achieved using the method described in Example 13, followed by TFA
deprotection, to give 5-chloro-N-[({6-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-
yl]pyridin-3-yl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ - 508, 510 (CI).

[0122] An analogous procedure to that outlined in Example 47 (Method B) using 2-
chloro-5-nitro-6-methylpyridine was used to prepare the substituted aminopyridine.
Formation of the sulfonyl urea was achieved using the method described in Example 13,
followed by TFA deprotection, to give 5-chloro-N-[({6-[7-fluoro-6-(methylamino)-l-
oxoisoqumolm-2(lH)-yl]-2-methylpyridin-3-yl}amino)carbonyl]thiophene-2-sulfonamide.
ES-MS (M+H)+ =522, 524 (CI).


[0123] An analogous procedure to that outlined in Example 47 (Method B) using 2-
chloro-4-methyl-5-nitropyridine was used to prepare the substituted aminopyridine.
Formation of the sulfonyl urea was achieved using the method described in Example 13,
followed by TFA deprotection, to give 5-cMoro-N-[({6-[7-fluoro-6-(methylamino)-l-
oxoisoquinolin-2( 1 H)-yl]-4-methylpyridin-3 -yl} amino)carbonyl3thiophene-2-sulfonamide.
ES-MS (M+H)+ = 522, 524 (CI).

[0124] An analogous procedure to that outlined in Example 47 (Method B) using 2-
chloro-3-methyl-5-nitropyridine was used to prepare the substituted aminopyridine.
Formation of the sulfonyl urea was achieved using the method described in Example 13,
followed by TFA deprotection, to give 5-chloro-N-[({6-[7-fluoro-6-(methylamino)-l-
oxoisoqumolm-2(lH)-yl]-5-methylpyridm-3-yl}amino)carbonyl]thiophene-2-sulfonamide.
ES-MS (M+H)+ =522, 524 (CI).


[0125] An analogous procedure to that outlined in Example 48 (Method C) using 2-
fluoro-4-iodoaniline was used to prepare the substituted aniline. Formation of the sulfonyl
urea was achieved using the method described in Example 13, followed by TFA deprotection,
to give 5-chloro-N-[({2-fiuoro-4-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-
yl]phenyl}arnino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ =525, 527 (CI).

[0126] An analogous procedure to that outlined in Example 48 (Method C) using 2-
amino-5-bromopyridine was used to prepare the intermediate aminopyridine. Formation of
the sulfonyl urea was achieved using the method described in Example 13, followed by TFA
deprotection, to give 5-chloro-N-[({5-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-
yl]pyridin-2-yl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+=508, 510 (CI).


[Ol?^] An analogous procedure to that outlined in Example 48 (Method C) using 2-
amino-3-methyl-5-bromopyridine was used to prepare the substituted aniline. Formation of
the sulfonyl urea was achieved using the method described in Example 13, followed by TFA
deprotection, to give 5-cMoro-N-[({5-[7-fluoro-6-(memylamino)-l-oxoisoquinolin-2(lH)-
yl]-3-memylpyridm-2-yl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ =521,
523 (CI).

[0128J An analogous procedure to that outlined in Example 48 (Method C) using 2-
amino-5-iodopyrimidine was used to prepare the intermediate arninopyrimidine. Formation
of the sulfonyl urea was achieved using the method described in Example 13, followed by
TFA deprotection, to give 5-chloro-N-[({5-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-
2(lH)-yl]pyrimidin-2-yl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+= 509,
5II (CI).

[0129] To a solution of 2-fluoro-5-nitrobenzyl alcohol (1 g, 5.84 mmol) in 5 mL
dichloromethane and triethylamine (0.81 ml, 5.84 mmol), was added acetyl chloride (0.415
ml, leq) dropwise. The solution was stirred at room temperature for 12 hours, diluted with
ethyl acetate and extracted with brine. Combine organic layers was dried over sodium
sulfate, concentrated in vacuo to give acetic acid 2-fluoro-5-nitro-benzyl ester.


[0130] Acetic acid 2-fluoro-5-nitro-benzyl ester was coupled to (7-Fluoro-l-oxo-1,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46). Formation of the sulfonyl urea was achieved using the method described in Example 10,
followed by TFA deprotection, to give 5-[({[(5-chlorothien-2-
yl)sulfonyl]amino} carbonyl)ammo]-2-[7-fluoro-6-(methylamino)-l -oxoisoquinolin-2(l H)-
yljbenzyl acetate. ES-MS (M+H)+ = 579, 581 (CI).

[0131] This analog compound was obtained from hydrolysis of the intermediate, Boc
protected compound of Example 62, then followed by TFA deprotection to give 5-chloro-N-
({[4- [7-fluoro-6-(methylamino)-1 -oxoisoquinolin-2( 1 H)-yl]-3 -
(hydroxymemyl)phenyl]amino}carbonyl)thiophene-2-sulfonamide. ES-MS (M+H)+= 537,
539(C1).

[0132] To a solution of 2-fluoro-5-nitrobenzyl alcohol (lg, 5.84mmol) in 25 mL
ether, was added tetrabromomethane (3.87 g, 11.7mmol), followed by triphenylphosphine

(3.3.9 g, 11.7 mmol). The mixture was stirred at room temperature for 2 hours. The reaction
was concentrated and the crude residue purified by column chromatography (silica, 10%
EtOAc/hexane) to give pure 2-bromomethyl-l-fluoro-4-nitro-benzene.
[0133] To a solution of 2-bromomethyl-l-fluoro-4-nitro-benzene (0.2 g, 0.85mmol)
in 5 mL dry THF, was added piperidine (0.11ml, 1 mmol) and DD3A (0.3 ml, 1.7 mmol) at 0
°C. The resulting reaction was stirred at 0 °C to room temperature for 1 hour, then diluted
with EtOAc and washed with brine. Combined organic layer was dried over sodium sulfate,
concentrated in vacuo and the crude residue was purified by column chromatography (10%
EtOAc/hexane) to give pure l-(2-fluoro-5-nitro-ben2yl)piperidinebenzene.

[0134] l-(2-Fluoro-5-nitro-benzyl)piperidinebenzene was coupled to (7-Fluoro-l-
oxo-l,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A
(Example 46) . Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-({[4-[7-fluoro-6-
(memylamino)-l-oxoisoquinolin-2(lH)-yl]-3-(piperidin-l-
ylmethyl)phenyl]amino}carbonyl)thiophene-2-sulfonamide. ES-MS (M+H)+ = 604, 606(C1).

[0135] To a solution of 2-fluoro-5-nitro-benzoic acid (0.269g, 1.45mmol) in 3 mL
ethanol, was added concentrated sulfuric acid (0.5 ml). The solution was refluxed under
argon for 3 hours. The mixture was stirred at room temperature for 2 hours, then diluted with

ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate,
concentrated in vacuo to give pure 2-fluoro-5-nitro-benzoic acid ethyl ester.

[0136] 2-Fluoro-5-nitro-benzoic acid ethyl ester was coupled to (7-Fhioro-l-oxo-1,2-
dihydro-isoquinolin-6-yl)-rnethyl-carbamic acid tert-butyl ester using Method A (Example
46). Formation of the sulfonyl urea was achieved using the method described in Example 10,
followed by TFA deprotection, to give ethyl 5-[({[(5-chlorothien-2-
yl)sulfonyl]arrmio}carbonyl)ammo]-2-[7-fluoro-6-(memylamino)-l-oxoisoquinolin-2(lH)-
yl]benzoate. ES-MS (M+H)+ -579, 581(C1).

[0137] This analog compound was obtained from hydrolysis of ethyl 5-[({[(5-
chlorothien-2-yl)sulfonyl]arnino}carbonyl)amino]-2-[7-fluoro-6-(methylamino)-l-
oxoisoquinolin-2(lH)-yl]benzoate of Example 65 using the procedure described in Example
63. 5-[({[(5-cUorothien-2-yl)sulfonyl]amino}carbonyl)amino]-2-[7-fluoro-6-(methylamino)-
l-oxoisoquinolin-2(lH)-yl]benzoic acid. ES-MS (M+H)+ = 551, 553(C1).


[0138] The substituted aniline was generated by Method A (Example 46) using 2-
fluoro-5-nitro-benzonitril. Formation of the sulfonyl urea was achieved using the method
described in Example 10, followed by TFA deprotection, to give 5-chloro-N-[({3-cyano-4-[7-
fluoro-6-(methylarrimo)-lK)xoisoqumolm-2(lH)-yl]phenyl}ammo)carbonyl]
sulfonamide. ES-MS (M+H)+ =532,534 (CI).

[0139] This analog compound was obtained during the TFA de-protection step in
Example 67. 5-[({[(5-chlorothien-2-yl)sulfonyl]amino}carbonyl)amino]-2-[7-fluoro-6-
(methylamino)-l-oxoisoquinolin-2(lH)-yl]benzamide. ES-MS (M+H)+ = 550,552 (CI).

[0140] To a solution of 2-bromomethyl-l-fluoro-4-nitro-benzene (131 mg, 0.56
mmol), which was generated in Example 64) and dimethylamine hydrochloride (44 mg, 0.54
mmol) in 4 mL dioxane, was added cesium carbonate (546 mg, 1.68 mmol). The mixture was
heated to 70 °C under argon for 12 hours. Work up and RP prep HPLC to give (2-fmoro-5-
nitro-benzyl)-dimethyl-amine.


[0141] (2-Fluoro-5-nitro-benzyl)-dimethyl-amine was coupled to (7-Fluoro-l-oxo-
l,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A
(Example 46). Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-[({3-
[(dimemylammo)memyl]-4-[7-fluoro-6-(memylammo)-l-oxoisoquinolin-2(lH)-
yl]phenyl}amino)carbonyl]tliiophene-2-sulfonamide. ES-MS (M+H)+=564, 566(d).

[0142] To a solution of 3-bromo-4-fluoronitrobenzene (696 mg, 3.16 mmol) and
tributyl(l-ethoxyvinyl)tin (1.07 ml, 3.5 mmol) in 10 mL toluene, was added
tetrakis(triphenylphosphine)palladium(0) (183 mg, 016 mmol). The mixture was purged with
argon for 3 minutes, and then heated to 110 °C under argon for 2 days. The reaction mixture
was cooled to room temperature, 3 mL 1 N HC1 was added and stirred at room temperature
for 40 minutes. Workup followed by column chromatographic purification (silica 10% - 30%
EtOAc/hexane) to give pure l-(2-fluoro-5-nitro-phenyl)-ethanone.

[0143] l-(2-fluoro-5-nitro-phenyl)-ethanone was coupled to (7-Fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46). Formation of the sulfonyl urea was achieved using the method described in Example 10,
followed by TFA deprotection, to give N-[( {3-acetyl-4-[7-fluoro-6-(methylamino)-l -

oxo^soquinolin-2(lH)-yl]phenyl}amino)carbonyl]-5-cMorothiopliene-2-sulfoiiamide. ES-
MS(M+H)+ =549,551 (CI).

[0144] A mixture of bis(benzonitril)dichloropalladmm(II) (53 mg, 0.14 mmol) and
copper (I) iodide (26 mg, 0.14 mmol) in 6 mL dry THF was purged with argon for 3 minutes,
then was added tri(tert-butyl phosphine) (69 ul, 0.28 mmol), TMS acetylene (0.77 ml, 5.5
mmol), 3-bromo-4-fluoronitrobenzene 505 mg, 2.295 mmol), and di-isopropylamine (0.77
ml, 5.5 mmol). The mixture was stirred at room temperature for 5 hours under argon. To the
reaction mixture was added 7 mL 1 M TBAF/THF and the mixture was stirred at room
temperature for 10 minutes. Workup and purification by column chromatography (silica, 5%
- 35% EtOAc/hexane) give 2-ethynyl-l-fluoro-4-nitro-benzene.

[0145] 2-Ethynyl-l-fluoro-4-nitro-benzene was coupled to (7-Fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46). Formation of the sulfonyl urea was achieved using the method described in Example 10,
followed by TFA deprotection, to give 5-chloro-N-[({3-ethynyl-4-[7-fluoro-6-
(memylammo)-l-oxoisoquinolin-2(lH)-yl3phenyl}amino)carbonyl]thiophene-2-sulfonamide.
ES-MS (M+H)+-531, 533(C1).


[0146] To a solution of 2-ethynyl-l-fluoro-4-nitro-benzene (70 mg, 0.42 mmol,
obtained in Example 71) in 3 mL ethanol, 5% Pd/BaS04 (48 mg) was added. The mixture
was hydrogenated at 1 atm for 1.5 hrs. Catalyst was removed by filtering through a celite
pad. The filtrate was concentrated to give pure l-fluoro-4-rritro-2-vinyl-benzene.

[0147] 1 -Fluoro-4-nitro-2-vinyl-benzene was coupled to (7-Fluoro-1 -oxo-1,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46). Formation of the sulfonyl urea was achieved using the method described in Example 10,
followed by TFA deprotection, to give 5-chloro-N-[({4-[7-fluoro-6-(methylamino)-l-
oxoisoquinolm-2(lH)-yl]-3-vinylphenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS
(M+H)+~533,535(C1).

[0148] To a solution of [7-fluoro-2-(4-nitro-2-vinyl-phenyl)-l-oxo-l,2-dihydro-
isoquinohn-6-yl]-methyl-carbamic acid tert-butyl ester (60 mg, 0.137 mmol, the intermediate
material generated in Example 72) in 1.5 mL ethanol and 2.5 mL ethylacetate, 5% PdVC (60
mg) was added and the mixture was hydrogenated at 1 atm for 10 hrs. Catalyst was removed
by filtering through a celite pad. The filtrate was concentrated to give desired aniline.


[0149] Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-[({3-ethyl-4-[7-fluoro-6-
(memylanimo)-l-oxoisoquinolm-2(lH)-yl]phenyl}arm^o)carbonyl]tMophene-2-sulfonarm^e.
ES-MS (M+H)+=535, 537(d).

[0150] This analog compound was obtained from reduction of N-[( {3-acetyl-4-[7-
fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-yl]phenyl}amino)carbonyl]-5-
chlorothiophene-2-sulfonamide of Example 70. To a solution of N-[({3-acetyl-4-[7-fluoro-6-
(memylaniino)-l-oxoisoqumolin-2(lH)-yl]phenyl}amino)carbonyl]-5-chlorothiophene-2-
sulfonamide (18 mg, 0.033 mmol) in 2 mL ethanol, was added sodium borohydride (20 mg,
0.53 mmol). The mixture was stirred at room temperature for 30 minutes. Workup and
purification provided 5-chloro-N-({[4-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-
yl]-3-(l-hydroxyemyl)phenyl]amino}carbonyl)thiophene-2-sulfonarnide as a mixture of
rotamers. ES-MS (M+H)+ =551, 553(C1).


[0151] To a solution of 5-fluoro-2-nitro-phenol (369 mg, 2.35 mmol) in 5 mL THF,
sodium hydride (96 mg, 2.46 mmol) was added at room temperature, followed by methyl
iodide (0.88 ml, 14 mmol). The mixture was stirred at room temperature for 10 hours, and
then cesium carbonate (744mg, 2.35 mmol) was added. The mixture was stirred at room
temperature for additional 4 hours, then diluted with ethyl acetate and washed with brine.
The organic layers were combined and concentrated in vacuo to give a crude residue, which
was purified by column chromatography (silica 5-25% EtOAc/hexane) to give pure 4-fiuoro-
2-methoxy-1 -nitro-benzene.

[0152] 4-Fluoro-2-methoxy-1 -nitro-benzene was coupled to (7-Fluoro-1 -oxo-1,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46). . Formation of the sulfonyl urea was achieved using the method described in Example
10, followed by TFA deprotection, to give 5-chloro-N-[({4-[7-fluoro-6-(methylarnino)-l-
oxoisoquinolin-2(lH)-yl]-2-methoxyphenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-
MS (M+H)+ =537, 539(C1).

[0153] To a solution of 5-fluoro-2-nitro-phenol (234 mg, 1.49 mmol) in 5 mL THF,
sodium hydride (122 mg, 2.9 mmol) was added, followed by chloromethoxy methane (113 ul,
1.49 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 10 hours,
then diluted with ethyl acetate and washed with brine. The organic layers were combined and

concentrated in vacuo to give a crude residue, which was purified by column chromatography
(silica 5-25% EtOAc/hexane) to give 4-fluoro-2-methoxymethoxy-l -nitro-benzene.

[0154] 4-Fluoro-2-methoxymethoxy-1 -nitro-benzene was coupled to (7-Fluoro-1 -
oxo-l,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-buryl ester using Method A
(Example 46). Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-({[4-[7-fluoro-6-
(methylamino)-1 -oxoisoquinolin-2( 1 H)-yl]-2-
(methoxymemoxy)phenyl]amino}carbonyl)thiophene-2-sulfonamide. ES-MS (M+H)+ =567,
569(Q).

[0155] This analog compound was obtained from TFA deprotection step in Example
76. 5-chloro-N-[( {4-[7-fluoro-6-(methylamino)~ 1 -oxoisoquinolin-2(l H)-yl]-2-
hydroxyphenyl}amino)carbonyl]thiophene-2-sulfonamide.ES-MS (M+H)+ = 523, 525(C1).


[015£] 2-Ethynyl-4-fluoro-1 -nitro-benzene was obtained from 2-bromo-4-fluoro-1 -
nitro-benzene using the procedure described in Example 71.
[0157] 4-Fluoro-l-nitro-2-vinyl-benzene was obtained using 2-ethynyl-4-fluoro-l-
nitro-benzene using the procedure described in Example 72.

[0158] 4-Fluoro-l-nitro-2-vinyl-benzene was coupled to (7-Fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46). Formation of the sulfonyl urea was achieved using the method described in Example
10, followed by TFA deprotection, to give 5-cMoro-N-[({4-[7-fluoro-6-(methylamino)-l-
oxoisoquinolin-2(l H)-ylj-2-vinylphenyl} amino)carbonyl]thiophene-2-sulfonamide. ES-MS
(M+H)+ = 533, 535(d).

[0159] A mixture of 5-fluoro-2-nitro-phenol (464 mg, 2.95 mmol), benzyl bromide
(0.37 ml, 3.10 mmol) and cesium carbonate (1.055 g, 3.24 mmol) in MeCN(10 mL) was
stirred room temperature under argon for 48 hours. The reaction mixture was diluted with
ethyl acetate and washed with brine. The organic layers were combined and concentrated in
vacuo to give a crude residue, which was purified by column chromatography (silica 5-25%
EtOAc/hexane) to give 2-benzyloxy-4-fluoro-l -nitro-benzene.


[0160] 2-Benzyloxy-4-fmoro4-nitro-benzene was coupled to (7-Fluoro-l-oxo-l,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46).
[0161] Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give N-[({2-(benzyloxy)-4-[7-fluoro-6-
(memylammo)-l^xoisoqumolm-2(lH)-yl]phenyl}ammo)carbonyl]-5-chlorothiophene-2-
sulfonamide. ES-MS (M+H)+ =613,615(C1).

[0162] [2-(3-Bromo-4-nitro-phenyl)-7-fluoro-l -oxo-1,2-dihydro-isoquinolin-6-yl]-
methyl-carbamic acid tert-butyl ester was generated by Method A (Example 46) using 2-
bromo-4-fluoro-l-nitro-benzene. A mixture of [2-(3-Bromo-4-nitro-phenyl)-7-fluoro-l-oxo-
l,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (21 mg, 0.0427 mmol),
tetrakis(triphenylphosphine)palladium(0) (2.5 mg, 0.002 mmol), copper (I) iodide (2 mg,
0.008mmol), TMS acetylene (10 ul, 0.07 mmol), n-butylamine (1.5 ml) and 1 mL DMF was
purged with argon for 2 minutes. The mixture was then subjected to microwave irradiation
(120°C) for 5 minutes, then diluted with ethyl acetate and washed with brine. The organic
layers were combined and concentrated in vacuo to give a crude residue, which was purified
by column chromatography (silica 5-25% EtOAc/hexane) to give

[2-{p-butylamino-4-nitro-phenyl)-7-fluoro-1 -oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-
earbamic acid tert-butyl ester.

[0163] Reduction of the nitro group, sulfonyl urea formation, followed by TFA
deprotection, provided N-[({2-(butylamino)-4-[7-fluoro-6-(memylamino)-l -oxoisoquinolin-
2(lH)-yl]phenyl}arnino)carbonyl]-5-chlorothiophene-2-sulfonarnide. ES-MS (M+H)+ =578,
580(C1).

[0164] This analog compound was obtained from [7-fluoro-2-(4-nitro-3-vinyl-
phenyl)-l-oxo-l,2-dihydro-isoquinolin-6-yI]-methyl-carbamic acid tert-butyl ester
(intermediate in Example 78) using the reduction procedure described in Example 73.


[0145J Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-[({2-ethyl-4-[7-fluoro-6-
(methylammo)-l-oxoisoqumolm-2(lH)-yl]phenyl}ammo)carbonyl]tlu^phene-2-stdfonamide.
ES-MS (M+H)+ = 535,537(C1).

{0166] Acetic acid 2-(5-mioro-2-nitro-phenoxy)-ethyl ester was obtained starting
with acetic acid 2-bromo-ethyl ester and using the procedure described in Example 79.

[0167J Acetic acid 2-(5-fluoro-2-mtro-phenoxy)-ethyl ester was coupled to (7-Fluoro-
1 -oxo-1,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A
(Example 46). Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 2-{2-[({[(5-chlorothien-2-
yl)sulfonyl]ammo}carbonyl)arnino]-5-[7-fluoro-6-(mefhylamino)-l-oxoisoquinolin-2(lH)-
yl]phenoxy}ethyl acetate. ES-MS (M+H)+=609, 611 (CI).


[0168] This analog compound was obtained from hydrolysis (as described in Example
63) of the intermediate Boc protected compound of Example 82, followed by TFA
deprotection. 5-chloro-N-({[4-[7-fluoro-6-(methylarnino)-l-oxoisoquinolin-2(lH)-yl]-2-(2-
hydroxyethoxy)phenyl]amino}carbonyl)thiophene-2-sulfonamide. ES-MS (M+H)+ = 567,
569(C1).

[0169] 4-Fluoro-2-isopropoxy-l -nitro-benzene was obtained using 5-fluoro-2-nitro-
phenol and isopropanol under Mitsunobu reaction condition. The general procedure is
described as follows: to a solution of 4-fiuoro-2-isopropoxy-l-nitro-benzene (313 mg, 1.99
mmol), triphenylphosphine (783 mg, 2.98 mmol) and ispropanol (161 mg, 2.59 mmol) in 2
mL THF, was added diethyl azodicarboxylate (0.49 ml, 2.99 mmol) dropwise at 0 °C. The
mixture was warmed to room temperature and stirred for 30 minutes, then diluted with ethyl
acetate and washed with brine. The organic layers were combined and concentrated in vacuo
to give a crude residue, which was purified by column chromatography (silica 5-25%
EtOAc/hexane) to give 4-fiuoro-2-isopropoxy-l-nitro-benzene.


[0170] 4-Fluoro-2-isopropoxy-l-nitro-benzene was coupled to (7-Fluoro-l-oxo-1,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46). Formation of the sulfonyl urea was achieved using the method described in Example
10, followed by TFA deprotection, to give 5-chloro-N-[( {4-[7-fluoro-6-(methylamino)-l -
oxoisoqumolm-2(lH)-yl]-2-isopropoxyphenyl}amino)carbonyl]thiophene-2 -sulfonamide.
ES-MS (M+H)+ =565,567(a).

10171] To a solution of 5-fluoro-2-nitro-benzaldehyde (573 mg, 3.39 mmol) in 4 mL
DCM, was added (diemylamino)sulfurtrifluride (0.448 ml, 3.39 mmol) dropwise at 0 °C over
3 minutes. The reaction mixture was stirred at 0 °C for 1 hour, then diluted with
dichloromethane and washed with brine. The organic layers were combined and
concentrated in vacuo to give a crude residue, which was purified by column chromatography
(silica 15-40% EtOAc/hexane) to give 2-difluoromethyl-4-fluoro-l-nitro-benzene.

[0172] 2-Difluoroniethyl-4-fluoro-l-mtro-benzene was coupled to (7-Fluoro-l-oxo-
l,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A
(Example 46). Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to 5-chloro-N-[({2-(difluoromethyl)-4-[7-
fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-yl]phenyl}amino)carbonyl]thiophene-2-
sulfonamide. ES-MS (M+H)+=557, 559(C1).


[0173] 2-Cyclopropylmethoxy-4-fluoro-l -nitro-benzene was obtained from
cyclopropyl methanol using the procedure described in Example 84.

[0174] 2-Cyclopropylmethoxy-4-fluoro-l -nitro-benzene was coupled to (7-Fluoro-l -
oxo-l,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A
(Example 46). Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to 5-chloro-N-[({2-(cyclopropylmethoxy)-4-[7-
fluoro-6-(memylamino)-l-oxoisoquinolin-2(lH)-yl]phenyl}amino)carbonyl]thiophene-2-
sulfonamide. ES-MS (M+H)+ =577, 579(C1).

[0175] The substituted aniline was generated by Method C (Example 48) using 4-
bromo-2-trifluoromethoxy-phenylamine. Formation of the sulfonyl urea was achieved vising
the method described in Example 10, followed by TFA deprotection, to give 5-chloro-N-({[4-
[7-fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-yl]-2-

(Mfluoromethoxy)phenyl]amino}carbonyl)thiophene-2-sulfonainide. ES-MS (M+H)+= 591,
593(a).

[0176] l-(5~Fmoro-2-rritro-phenyl)-ethanone was obtained using 2-bromo-4-fluoro-l-
nitro-benzene with the procedure described in Example 70.

[0177] 1 -(5-fluoro-2-nitro-phenyl)-ethanone was coupled to (7-Fluoro-1 -oxo-1,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46). Formation of the sulfonyl urea was achieved using the method described in Example
10, followed by TFA deprotection, to give N-[({2-acetyl-4-[7-fluoro-6-(methylamino)-l-
oxoisoquinolin-2(lH)-yl]phenyl}amino)carbonyl]-5-chlorothiophene-2-sulfonamide. ES-MS
(M+H)+=549, 551 (CI).

[0178] To a solution of trifluoroethanol in 4 mL dry THF, was added tert-butoxide
(378 mg, 3.37 mmol) at 0 °C. The resulting mixture was added dropwise to the solution of
2,4-difluoro-l-nitro-benzene (536 mg, 3.37 mmol) in 5 mL dry THF at 0°C. The mixture was

stingd at 0°C for 30 minutes, then diluted with ethyl acetate and washed with brine. The
organic layers were combined and concentrated in vacuo to give 4-flnoro-l-mtro-2-(2,2,2-
trifluoro-ethoxy)-benzene.

[0179J 4-Fluoro-l-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene was coupled to (7-Fluoro-
l-oxo-l,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A
(Example 46). Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-({[4-[7-fluoro-6-
(methylamino)-l-oxoisoquinolin-2(lH)-yl]-2-(2,2,2-
trifluoroethoxy)phenyl]amino}carbonyl)miophene-2-sulfonamide. ES-MS (M+H)+ =605,
607(C1).

[0180] 2-Ethoxy-4-fluoro-l-nitro-benzene was obtained as a side product when
prepared Example 89 using 2,2,2-trifluoro-ethanol as described in Example 84.

[0181] 2-Ethoxy-4-fluoro-1 -nitro-benzene was coupled to (7-Fluoro-1 -oxo-1,2-
dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A (Example
46).

[0182] Formation of the sulfohyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-[({2-ethoxy-4-[7-fluoro-6-
(memylammo)-l-oxoisoqumolm-2(lH)-yl]phenyl}ammo)carbonyl]miophene-2-sulfonamide.
ES-MS (M+H)+=551, 553(C1).

[0183] 4-Fl\ioro-2-(2-methoxy-ethoxy)-l-nitro-benzene was obtained from 2-
methoxy-ethanol using the procedure described in Example 89.

[0184] 4-Fluoro-2-(2-methoxy-ethoxy)-1 -nitro-benzene was coupled to (7-Fluoro-1 -
oxo-l,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A
(Example 46). Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-({[4-[7-fluoro-6-
(methylamino)-1 -oxoisoquinolin-2(l H)-yl]-2-(2-
methoxyethoxy)phenyl]amino}carbonyl)thiophene-2-sulfonamide. ES-MS (M+H)+ =581,
583(C1).


[0185] To a solution of 2-isopropyl-phenyIamine (262 mg, 1.94 mmol) and sodium
acetate (159 mg, 1.94 mmol) in 5 mL acetic acid, was added iodide monochloride (409 mg,
2.58 mmol) at room temperature. The mixture was stirred at room temperature for 20
minutes, then diluted with ethyl acetate and washed with saturated sodium bicarbonate. The
organic layers were combined and concentrated in vacuo to give a crude residue, which was
purified by column chromatography (silica 5-25% EtOAc/hexane) to give 4-iodo-2-
isopropyl-phenylamine.

[0186] 4-Iodo-2-isopropyl-phenylamine was coupled to (7-Fluoro-1 -oxo-1,2-dihydro-
isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method C (Example 48).
Formation of the sulfonyl urea was achieved using the method described in Example 10,
followed by TFA deprotection, to give 5-chloro-N-[({4-[7-fluoro-6-(methylamino)-l-
oxoisoquinolin-2(l H)-yl]-2-isopropylphenyl} amino)carbonyl]thiophene-2-sulfonamide. ES-
MS (M+H)+ =549, 551(0).


[0187] [2-(5-Fluoro-2-nitro-phenoxy)-ethyl]-dimeihyl-amine was obtained from 2-
dimethylamino-ethanol using the procedure described in Example 89.

[0188] [2-(5-Fluoro-2-nitro-phenoxy)-ethyl]-dimethyl-amine was coupled to (7-
Fluoro-l-oxo-l,2-dihydro-isoquinolin-6-yl)-rnethyl-carbamic acid tert-butyl ester using
Method A (Example 46). Formation of the sulfonyl urea was achieved using the method
described in Example 10, followed by TFA deprotection, to give 5-chloro-N-[({2-[2-
(dmiemylamino)ethoxy]^-[7-fluoro-6-(methylamino)-l-oxoisoquinolin-2(lH)-
yl]phenyl}arnino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+=594, 596(C1).

[0189] [2-(3 -Cyclopropyl -4-nitro-phenyl)-7-fluoro-1 -oxo-1,2-dihy dro-isoquinolin-6-
yl]-methyl-carbamic acid tert-butyl ester was obtained from [7-fluoro-2-(4-nitro-3-vinyl-
phenyl)-l-oxo-l,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl (intermediate in
Example 78).
[0190] To a solution of [7-fluoro-2-(4-nitro-3-vinyl-phenyl)-l-oxo-l,2-dihydro-
isoquinolin-6-yl]-methyl-carbamic acid tert-butyl (12 mg, 0.027 mmol) in 1 mL ether and 1
mL THF, was added diazomethane solution (generated by adding 40 % potassium hydroxide
aqueous solution to 2-methyl-3-nitro-nitrosoguanidine (40 mg, 0.27 mmol) in 2 mL ether at
-78°C) at 0°C, followed by 10 mg palladium (II) acetate (10 mg, 0.4 mmol). The reaction
mixture was stirred at 0°C for 1 hour, then diluted with ethyl acetate and washed with brine.

The^organic layers were combined and concentrated in vacuo to give a crude residue, which
was purified by column chromatography (silica 25-50% EtOAc/hexane) to give[2-(3-
cyclopropyM-m^C"phenyl)-7-fluoro-l-oxo-l,2-dmydro-isoqumoHn-6-yl]-memyl-carbamic
acid tert-butyl ester.

[0191J Catalytic hydrogenation of [2-(3-cyclopropyl-4-nitro-phenyl)-7-fluoro-l-oxo-
l,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester, formation of the sulfonyl
urea, followed by TFA deprotection, provided 5-chloro-N-[({2-cyclopropyl-4-[7-fluoro-6-
(methylamino)-1 -oxoisoquinolin-2(l H)-yl]phenyl} amino)carbonyl] thiophene-2-sulfonamide.
ES-MS (M+H)+ =547, 549(C1).

[0192] The substituted aniline was generated by Method A (Example 46) using 1-
fluoro-4-nitro-2-trifluoromethyl-benzene. Formation of the sulfonyl urea was achieved using
the method described in Example 10, followed by TFA deprotection, to give 5-chloro-N-({[4-
[7-fluoro-6-(methylarnino)-l-oxoisoquinolin-2(lH)-yl]-3-
(trifluoromethyl)phenyl]amino}carbonyl)thiophene-2-sulfonamide. ES-MS (M+H) = 575,
577 (CI).


[0193] The substituted aniline was generated by Method C (Example 48) coupling 4-
bromo-2,6-dimethyl-phenylamine to (7-Fluoro-1 -oxo-1,2-dihydro-isoquinolin-6-yl)-methyl-
carbamic acid tert-butyl ester. Formation of the sulfonyl urea was achieved using the method
described in Example 10, followed by TFA deprotection, to give 5-chloro-N-[({4-[7-fiuoro-6-
(memylarrmio)-l-oxoisoqumolin-2(lH)-yl]-2,6-dimem^
2-sulfonamide. ES-MS (M+H)+ =535,537(C1).

[0194] 4-Fluoro-1 -nitro-2-trifluoromethyl-benzene was coupled to (7-Fluoro-1 -oxo-
l,2-dihydro-isoquinolin-6-yl)-methyl-carbarnic acid tert-butyl ester using Method A
(Example 46). Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-({[4-[7-fluoro-6-
(methylamino)-l-oxoisoquinolin-2(lH)-yl]-2-
(trifluoromethyl)phenyl]amino}carbonyl)thiophene-2-sulfonamide. ES-MS (M+H)+ =575,
577 (CI).


[0195] To a solution of 5-fluoro-2-nitro-benzoic acid (1 g, 5.4 mmol in 5 mL THF,
was added (trimethylsilyl)diazomethane (2 M in ether, 11 ml, 22 mmol) at 0 °C. The
reaction mixture was warmed to room temperature under argon and stirred for 30 minutes,
then diluted with ethyl acetate and washed with brine. The organic layers were combined and
concentrated in vacuo to give a crude residue, which was purified by column chromatography
(silica 5-30% EtOAc/hexane) to give 5-fiuoro-2-nitro-benzoic acid methyl ester.

[0196] 5-Fluoro-2-nitro-benzoic acid methyl ester was coupled to (7-Fluoro-l-oxo-
1,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method A
(Example 46).
[0197] Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give methyl 2-[({[(5-chlorothien-2-
yl)sulfonyl]amino) carbonyl)amino]-5-[7-fluoro-6-(methylamino)-1 -oxoisoquinolin-2( 1H)-
yljbenzoate. ES-MS (M+H)+=565, 567(C1).


[0198] This analog compound was obtained from hydrolysis (as described in Example
63) of methyl 2-[({[(5-cHorotm^-2-yl)sulfonyl]amino}carbonyl)amino]-5-[7-fluoro-6-
(memylamino)-l-oxoisoquinolin-2(lH)-yl]benzoate obtained in Example 98.2-[({[(5-
chlorothien-2-yl)smfonyl]an^o}carbonyl)ammo]-5-[7-fluoro-6-(memylamino)-l-
oxoisoquinolin-2(lH)-yl]benzoic acid. ES-MS (M+H)+=551,553(C1).

[0199] To a solution of 2-isopropyl-6-methyl-phenylamine (1 ml, 6.4 mmol) in 6.5
mL acetic acid, was added bromine (0.33 ml, 6.4 mmol) dropwise over 10 minutes at room
temperature. The mixture was stirred at room temperature under argon for 20 minutes. A
precipitate was formed and collected by filtration and washed with ether to give pure 4-
bromo-2-isopropyl-6-methyl-phenylamine.

[0200] 4-Bromo-2-isopropyl-6-methyl-phenylamine was coupled to (7-Fluoro-l-oxo-
l,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester using Method C
(Example 48). Formation of the sulfonyl urea was achieved using the method described in
Example 10, followed by TFA deprotection, to give 5-chloro-N-[({4-[7-fluoro-6-
(methylamino)-l-oxoisoquinolin-2(lH)-yl]-2-isopropyl-6-
memylphenyl}arnino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ =563, 565(C1).


[0201] 3-Methyl-2-nitro-benzoic acid methyl ester was obtained from 3-methyl-2-
nitro-benzoic acid using the procedure described in Example 98, then reduced to 2-amino-3-
methyl-benzoic acid methyl ester by hydrogenation as described in Method A (Example 46).
2-Amino-5-bromo-3-methyl-benzoic acid methyl ester was obtained using the procedure in
Example 100.

[0202] 2-Amino-5-bromo-3-methyl-benzoic acid methyl ester was coupled to (7-
Fluoro-l-oxo-l,2-dihydro-isoquinolin-6-yl)-methyl-earbamic acid tert-butyl ester using
Method C (Example 48). Formation of the sulfonyl urea was achieved using the method
described in Example 10, followed by TFA deprotection, to methyl 2-[({[(5-chlorothien-2-
yl)sulfonyl]ammo}carbonyl)ammo]-5-[7-fluoro-6-(methylaniino)-l-oxoisoquinolin-2(lH)-
yl]-3-methylbenzoate. ES-MS (M+H)+ =579, 581 (CI).

[0203] [7-Fluoro-2-(3-methanesulfonyl-4-nitro-phenyl)-l -oxo-1,2-dihydro-
isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester was obtained from [2-(3-bromo-4-

nitr ester in Example 78.
[0204] To a slolution of [2-(3-bromo-4-nitro-phenyl)-7-fluoro-1 -oxo-1,2-dihydro-
isoquinoIin-6-yl]-methyl-carbamic acid tert-butyl ester ( 10 mg, 0.02 mmol) in DMSO 0.5
ml, sodium methanesulfinate (62 mg, 0.06 mmol) was added. The reaction mixture was
subjected to microwave irradiation (temperature 12 °C) for 45 seconds. A precipitate was
formed and collected by filtration to give [7-fluoro-2-(3-methanesulfonyl-4-nitro-phenyl)-l-
oxo-l,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester.

[0205] [7-fluoro-2-(3-methanesulfonyl-4-nitro-phenyl)-l -oxo-1,2-dihydro-
isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester was hydrogenated to provide an
aniline. Formation of the sulfonyl urea was achieved using the method described in Example
10, followed by TFA deprotection, to give 5-chloro-N-({[4-[7-fluoro-6-(memylamino)-l-
oxoisoqumolin-2(lH)-yl]-2-(memylsulfonyl)phenyl]amino}carbonyl)thiophene-2-
sulfonamide. ES-MS (M+H)+ =585, 587(C1).

[0206] The substituted aniline was generated by Method C (Example 48) using 2-
chloro-4-iodo-phenylamine. Formation of the sulfonyl urea was achieved using the method
described in Example 10, followed by TFA deprotection, to give 5-chloro-N-[({2-chloro-4-

[7-finoro-6-(methylanifoo)-1-oxoisoqim^
sulfonamide. ES-MS (M+H)+ =541,543(C1).

[0207] [7-Muoro-2-(4-rritro-phenyl)-l -oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-
carbamic acid tert-butyl ester (l.Og, 24 mmol, from Example 8) was dissolved in 12.5 mL of
TFA and stirred for 0.5h. The solvent was removed in vacuo and re-dissolved in
dichloromethane/heptane and concentrated to give l.Og (97%) of the TFA salt as a yellowish
solid. ES-MS (M+H)+=314.2.

[0208] To a mixture of 7-Fluoro-6-methylamino-2-(4-nitro-phenyl)-2H-isoquinolin-l -
one (100 mg, 0.27 mmol) (Example 104) in DMF (3 mL) was added N-chlorosuccinimide
(76 mg, 0.57 mmol). After 18 hours all starting material was consumed. Tin dichloride
dehydrate 244 mg (0.11 mmol) was added to the reaction mixture, and the reaction was
heated to 80°C for 2hr. Upon cooling the reaction mixture was treated with 1 mL of 10%
sodium carbonate and extracted 3 times with EtOAc. The combined organic layers were
dried over Na2S04 anhydrous and concentrated in vacuo to give a mixture of the 5-C1 and
4,5-dichloro anilines. This mixture was coupled directly with 76 mg (0.28 mmol) of (5-
Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (Example 12) in toluene (0.54 mL)

and refluxed for 4h. The resulting mixture of monochloro and dichloro sulfonylureas were
separated by preparative RP-HPLC to give 9.4 mg (6% yield overall) of 5-chloro-N-[({4-[5-
chloro-7-fiuoro-6-(memylamino)-1 -oxoisoquinolin-2(lH)-
yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+ = 541.3 (2C1)

[0209] The dichloro sulfonylurea was purified from the above reaction in Example
105 to afford 15 mg (10% overall yield) of 5-cMoro-N-[({4-[4,5-dichloro-7-fluoro-6-
(methylamino)-l -oxoisoquinolin-2(l H)-yl]phenyl} amino)carbonyl]thiophene-2-sulfonamide.
ES-MS (M+H)+= 576.2 (3CI).

[0210] 7-Fluoro-6-methylamino-2-(4-nitro-phenyl)-2H-isoquinolin-l-one(800mg,
1.9 mmol, TFA salt from example 104) was partially dissolved in 18 mL of DMF containing
517 mg (2 equiv) of K2CO3. Recrystallized N-bromosuccinimide (433 mg, 2.4 mmol) was
added and the reaction was warmed to 70°C and stirred for 18h. The reaction mixture was
quenched with 25 mL of water and cooled to 0°C. The resulting precipitate was collected by
filtration, washed with water, and dried in vacuo at 23°C to give 600 mg (82%) of an off-
white solid. ES-MS (M+H)+ = 392.3 (Br).


[0211] 5-Bromo-7-fluoro-6-methylamino-2-(4-nitro-phenyl)-2H-isoquinolin-l -one
(400mg, 1.0 mmol, Example 107) was combined with 920 mg (4.0 mmol) of tin dichloride
dehydrate in 5 mL of DMF and heated to 70°C for 2 h. The reaction was then cooled to 40°C
and 1 mL of 10% sodium carbonate was added slowly along with 2 g of celite. The reaction
mixture was then extracted 3 times with EtOAc and the combined organic layers were dried
over sodium sulfate, concentrated in vacuo to afford 338 mg (94%) of a yellowish solid. ES-
MS(M+H)+ = 361.2 (Br).

[0212] The sulfonylurea is prepared via the method described in Example 13. N-[({4-
[5-bromo-7-fluoro-6-(methylamino)-l-oxoisoquinolm-2(lH)-yl]phenyl}amino)
carbonyl]-5-chlorothiophene-2-sulfonamide. ES-MS (M+H)+= 585.5(Cl,Br).


[0213J To a suspension of 2-(4-Amino-phenyl)-5-bromo-7-fluoro-6-methylamino-
2H-isoquinolin-l -one from Example 108 (26 mg, 0.07 mmol) in DME (0.5 mL) was added
tetrakis(triphenylphosphine)palladium (4 mg, 5 mol%). The suspension was degassed and
purged with Ar. K2CO3 (10 mg, 0.07 mmol), water (0.2 mL) and the pyridine complex of
2,4,6-trivinylcyclotriboroxance (9 mg, 0.04 mmol) were then added and the mixture heated to
100 °C. After 30 rnin., the reaction mixture was cooled to room temperature. The product
was then extracted with EtOAc (20 mL), washed with brine (10 mL). The combined organic
layers was dried over sodium sulfate and concentrated in vacuo to give 26 mg of the crude
product, which was used without additional purification. ES-MS (M+H)+ = 310.3.

[0214] Coupling to form the sulfonyl urea was achieved using the method described
in Example 13 using Example 110 as a coupling partner to give 5-chloro-N-[({4-[7-fiuoro-6-
(methylamino)-1 -oxo-5-vinylisoquinolin-2(l H)-yl]phenyl} amkio)carbonyl]thiophene-2-
sulfonamide. ES-MS (M+H)+ =533.0, 535.0 (CI).

[0215J To a solution of 2-(4-Ammo-phenyl)-7-fluoro-6-memylamino-5-vinyl-2H-
isoquinolin-1-one from Example 110 (27 mg, 0.09 mmol) in ethyl acetate (1 mL) and ethanol

(1 irX) under Ar was added 10% Pd/C (19 mg, 0.18 mmol Pd). The mixture was
hydrogenated under 1 atm H2 for 2 hr, filtered through Celite and concentrated to give 26 mg
of the crude product, which was used without additional purification. ES-MS (M+H)+ =
312.3.

[0216] Coupling to form the sulfonyl urea was achieved using the method described
in Example 13 using 2-(4-Ammo-phenyl)-5-emyl-7-fluoro-6-memylamino-2H-isoquinolin-l-
one from previous example as a coupling partner to give 5-chloro-N-[( {4-[5-ethyl-7-fluoro-6-
(memylammo)-l-oxoisoqumolm-2(lH)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide.
ES-MS (M+H)+= 535.0, 537.0 (CI).

[0217] To a suspension of 2-(4-Amino-phenyl)-5-bromo-7-fluoro-6-methylamino-
2H-isoquinolin-l-one from Example 108 (50 mg, 0.14 mmol) in toluene (0.6 mL) was added
tetrakis(triphenylphosphine)palladium (16 mg). The suspension was degassed and purged
with Ar. K3PO4 (103 mg, 0.49 mmol), water (0.2 mL) and cyclopropyl boronic acid (15 mg,
0.18 mmol) were then added and the mixture heated to 100 °C. After reacting overnight, the
mixture was cooled to r.t. The reaction mixture was then extracted with EtOAc (20 mL),
washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo to give 48

mg of the crude product The crude was purified over silica gel to give 12 mg (25%) of the
pure product. ES-MS (M+H)+ = 324.1.

[02181 Coupling to form the sulfonyl urea was achieved using the method described
in Example 13 using to give 5-cWoro-N-[({4-[5-cyclopropyl-7-fluoro-6-(methylarnino)-l-
oxoisoqumolm-2(lH)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonarnide ES-MS (M+H)+ =
547.1, 549.1 (CI).

[0219] 2-(4-Amino-phenyl)-5-bromo-7-fluoro-6-methylamino-2H-isoquinolin-1 -one
from Example 108 (50 mg, 0.14 mmol) and tributylethoxyvinyl tin (102 uL, .28 mmol) were
combined in toluene (0.7 mL) and then the mixture degassed and purged with Ar.
Tetrakis(triphenylphosphine)palladium (16 mg, 10 mol%) was added and the mixture heated
to 100 °C. The mixture was stirred under Ar for 3 h, after which the reaction mixture was
cooled to room temperature. Water (30 mL) was added to the reaction mixture and the
product extracted with EtOAc (30 mL), washed with a 5% ammonia/water solution (30 mL)
and brine (30 mL), dried over sodium sulfate and concentrated in vacuo to give 146 mg of the
crude ethoxyvinyl compound. The crude mixture was then dissolved in THF (10 mL), treated
with 2N HC1 (3 mL) and stirred at room temperature for 1.5 h. The mixture was then

neutralized with NaHC03 and extracted with EtOAc (30 mL). The EtOAc layer was washed
with brine (25 mL), dried over sodium sulfate and concentrated in vacuo to give the crude
ketone, which was purified over silica gel to give the final product. ES-MS (M+H)+ = 326.1.

[0220] Coupling to form the sulfonyl urea was achieved using the method described
in Example 13 to gjveN-[({4-[5-acetyl-7-fluoro~6-(methylamino)-l-oxoisoquinolin-2(lH)-
yl]phenyl}amino)carbonyl]-5-chIorothiophene-2-sulfonamide. ES-MS (M+H)+ = 549.0,
551.0(d).

[0221] A 110 mg (0.28 mmol) portion of 5-Bromo-7-fluoro-6-rnethylamino-2-(4-
nitro-phenyl)-2H-isoquinolin-l-one (Example 107) and 55 mg (2.2 equiv) of CuCN in 1.4
mL of NMP was heated to 200°C for 2h. After cooling to 50°C, 10 mL of 10% aq KCN was
added, and mixture was stirred, filtered, washed with water and dried to give 123 mg (130%)
of7-Fluoro-6-memylann^o-2-(4-nitro-phenyl)-l-oxo-l,2-dihydro--isoquinoline-5-
caxbonitrile. A 50 mg (0.15 mmol) portion of this 5-cyano material was reduced with 36 mg
of Raney Nickel (Aldrich) in 1:1:2 water/AcOH/pyridine containing 58 mg of sodium
hypophosphite. The reaction was then extracted 3 times with ethyl acetate, drying over
Na2S04 (anh.), and concentration in vacuo afforded 10 mg (20%) of the resulting aniline.
This material was then coupled using the method described in Example 13 to give 7.8 mg

(46°/^) of 5-cUoro-N-[({4-[5-cyano-7-fluoro-6-(me%lamino)-l-oxoisoquinolin-2(lH)-
yl]pkenyl}aimno)carbonyl]thiophene-2-sulfoiiaiiiide. ES-MS (M+H)+ = 532.1 (CI).

(0222] [7-Fluoro-l-oxo-2-(2-trimethyl-silanyI-ethoxymethyl)-l,2-dihydro-
isoquinolin-6-yl]-earbarnic acid tert-butyl ester (200mg, 0.5 mmol, Example 44) was
dissolved in 1.5 mL of dry THF and further dried by stirring for lb. in the presence of 3 A
molecular sieves. The reaction mixture was then cooled to -78°C and 1.0 mL of t-BuLi
(1.9M) was added dropwise. After lh, 123 uL (4 equiv) of Mel was added and the reaction
mixture was warmed slowly to 23 °C. After addition of 2 mL of sat. NH4CI and extraction 3
times with ethyl acetate, the combined organic layers were dried over Na2S0.4, concentrated
and purified on silica gel eluting with a 5% to 20% ethyl acetate/hexane gradient to afford 44
mg(20%) of [7-Fluoro-5-methyl-l-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-l,2-dihydro-
isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester. ES-MS (M+H)+ = 437.4.

[0223] [7-Fluoro-5-memyl-l-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-l,2-dihydro-
isoquinolin-6-ylJ-methyl-carbamic acid tert-butyl ester (44 mg, 0.10 mmol, Example 119)
was treated with TFA for lh and concentrated in vacuo. Treatment of this crude material
with 25 mg (0.115 mmol) of p-iodoaniline, 4 mg of Cul, 3 mg 8-hydroxyquinoline and 17 mg
of K2CO3 in 200 u.L of DMSO at 120°C for 18 hrs, after which the reaction was cooled to
room temperature, diluted with ethyl acetate and washed with brine. The combined organic

layers were dried over Na2S04 and concentrated in vacuo to give a crude residue, which was
subjected to coupling with 57 mg of (5-CUoro-thiopheiie-2-sulfonyl)-carbainic acid ethyl
ester as described in Example 13, gave 10 mg of 5-chloro-N-[({4-[7-fluoro-5-methyl-6-
(memylammo)-l-oxoisoqumolm-2(lH)-yl]ph^
after RP-HPLC purification. ES-MS (M+H)+ - 521.1 (CI).

[02241 Step 1:l Preparation of 7-rluoro-6-(methylamino)-3,4-dihydroisoquinolin-
l(2H)-one.

[0225] A mixture of tert-butyl 7-fluoro-l -oxo-l,2-dihydroisoquinolin-6-
yl(methyl)carbamate (Example 45, 700 mg, 2.40 mmol) and Pt02 (470 mg) in MeOH (30
mL) containing concentrated HC1 (8 drops) was hydrogenated under 300 psi in a high
pressure vessel overnight. The reaction mixture was then filtered and the filtrate was
concentrated in vacuo. The residue was treated with TFA (10 mL) and stirred for 1 hr, after
which, the TFA solution was concentrated in vacuo. The residue was purified by RP-HPLC
to give the noted intermediate compound (142 mg). ES-MS (M+H)+ =195.
10226] Step 2: Preparation of 2-(4-ammophenyl)-7-fluoro-6-(memylamino)-3,4-
dihydroisoquinolin-1 (2H)-one.

{0227] A mixture of 7-fluoro-6-(memylamino)-3,4-dihydroisoquinolin-l(2H)-one (70
mg, 0.36 mmol), 4-iodoaniline (119 mg, 0.543 mmol), Cul (27 mg, 0.14 mmol), 1,2-
diaminocyclohexane (44 uL, 0.36 mmol) and K3PO4 (153 mg, 0.722 mmol) in dioxane (1.5

mL) was heated at 110 °C overnight, then diluted with CH3CN (5 mL) and H20 (5 mL) and
filtered. The filtrate was purified by RP-HPLC to give the noted intermediate compound as a
solid (62 mg). ES-MS (M+H)+ = 286.
[0228] Step 3: Preparation of 1 -(5-chlorothiophen-2-ylsulfonyl)-3 -(4-(7-ftuoro-6-
(methylamino)-1 -oxo-3,4-dihydroisoquinolin-2(l H)-yl)phenyl)urea.

[0229] To a solution of 2-(4-aminophenyl)-7-fluoro-6-(methylamino)-3,4-
dihydroisoquinolin-l(2H)-one (62 mg, 0.22 mmol) in HOAc (4 mL) at 100 C, ethyl 5-
chlorothiophen-2-ylsulfonylcarbamate (119 mg, 0.44 mmol) was added. After being stirred
at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue
was purified by RP-HPLC to give the titled compound as a powder (25 mg). ES-MS (M+H)+
-509,511 (CI pattern).
EXAMPLE 122
l-(5-chlorothiophen-2-ylsulfonyl)-3-(4-(5,7-difluoro-6-(methylamino)-l-oxo-3,4-
dihydroisoquinolin-2(lH)-yl)phenyl)urea

[0230] To a solution of 1 -(5-chlorothiophen-2-ylsulfonyl)-3-(4-(7-fluoro-6-
(methyIamino)-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)phenyl)urea (17 mg, 0.033 mmol) in
DMF (2 mL) at room temperature, selectFluor (l-(chloromethyl)-4-fluoro-l,4-
diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), 32 mg, 0.090 mmol) was added. After
being stirred at room temperature for lh, the reaction mixture was concentrated in vacuo.
The residue was purified by RP-HPLC to give the titled compound as a powder (1 mg). ES-
MS (M+H)+ = 527, 529 (CI pattern).

EXAMPLE 123
This example provides an assay for the inhibition of ADP-mediated platelet
aggregation in vitro using platelet-rich plasma (PRP).
[0231] The effect of compounds of the invention on ADP-induced human platelet
aggregation using platelet-rich plasma (PRP) is preferably assessed in a 96-well microtiter
assay. Human venous blood is collected from healthy, drug-free volunteers into 0.38%
sodium citrate (final concentration; e.g., 6 mL of 3.8% per 60 mL of blood). Platelet-rich
plasma (PRP) is prepared by centrifugation at 160 x g for 20 minutes at room temperature.
PRP is collected, and the platelet concentration is determined using a Coulter counter or
liemocytometer (platelet concentration should be 2-4 x 108 platelets per mL).
[0232] Inhibition of ADP-dependent aggregation is preferably determined in 96-well
flat-bottom microtiter plates using a microtiter plate shaker and plate reader similar to the
procedure described by Frantantoni et al., Am. J. Clin. Pathol. 94:613 (1990). All steps are
performed at room temperature. The total reaction volume of 0.2 mL/well includes: PRP (~6
x 107 total platelets in the presence of plasma), serial dilutions of test compounds (buffer for
control wells ) in 0.6% DMSO. After about 5 minutes preincubation at room temperature,
ADP is added to a final concentration of 2 uM which induces submaximal aggregation.
Buffer is added instead of ADP to one set of control wells (ADP- control). The OD of the
samples is then determined at 650 nm using a microtiter plate reader (Softmax, Molecular
Devices, Menlo Park, CA) resulting in the 0 minute reading. The plates are then agitated for
5 min on a microtiter plate shaker and the 5 minute reading is obtained in the plate reader.
Aggregation is calculated from the decrease of OD at 650 nm at t = 5 minutes compared to t
= 0 minutes and is expressed as % of the decrease in the ADP control samples after
correcting for changes in the unaggregated control samples.
Inhibition of l"3H12-MeS-ADP Binding to Platelets
[0233] Having first determined that the compounds according to the invention inhibit
AJDP-dependent platelet aggregation with the above assay, a second assay is used to
determine whether such inhibition is mediated by interaction with platelet ADP receptors.
Utilizing the second assay the potency of inhibition of such compounds with respect to [3H]2-

MeS^ADP binding to whole platelets is determined. [3H]2-MeS-ADP binding experiments
are routinely performed with outdated human platelets collected by standard procedures at
hospital blood banks. Apyrase-washed outdated platelets are prepared as follows (all steps at
room temperature, if not indicated otherwise):
[0234] Outdated platelet suspensions are diluted with 1 volume of CGS and platelets
pelleted by centrifugation at 1900 x g for 45 minutes. Platelet pellets are resuspended at 3-
6xl09 platelets /ml in CGS containing 1 U/ml apyrase (grade V, Sigma, St. Louis, MO) and
incubated for 15 minutes at 37°C. After centrifugation at 730 x g for 20 minutes, pellets are
resuspended inHepes-Tyrode's buffer containing 0.1% BSA (Sigma, St. Louis, MO) at a
concentration of 6.66x108 platelets/ml. Binding experiments are performed after > 45
minutes resting of the platelets.
[0235] Alternatively, binding experiments are performed with fresh human platelets
prepared as described in I.(Inhibition of ADP-Mediated Platelet Aggregation in vitro), except
that platelets are resuspended in Hepes-Tyrode's buffer containing 0.1% BSA (Sigma, St.
Louis, MO) at a concentration of 6.66x10 platelets/ml. Very similar results are obtained
with fresh and outdated platelets.
[0236] A platelet ADP receptor binding assay using the tritiated potent agonist ligand
[3H]2-MeS-ADP (Jantzen, H.M. et al. (1999)Thromb. Hemost. 81:111-117) has been
adapted to the 96-well microtiter format. In an assay volume of 0.2 ml Hepes-Tyrode's
buffer with 0.1% BSA and 0.6% DMSO, 1x10s apyrase-washed platelets are preincubated in
96-well flat bottom microtiter plates for 5 minutes with serial dilutions of test compounds
before addition of InM [3H]2-MeS-ADP ([3H]2-methylthioadenosine-5'-diphosphate,
ammonium salt; specific activity 48-49 Ci/mmole, obtained by custom synthesis from
Amersham Life Science, Inc., Arlington Heights, IL, or NEN Life Science Products, Boston,
MA). Total binding is determined in the absence of test compounds. Samples for nonspecific
binding may contain 10"5 M unlabelled 2-MeS-ADP (RBI, Natick, MA). After incubation for
15 minutes at room temperature, unbound radioligand is separated by rapid filtration and two
washes with cold (4-8°C) Binding Wash Buffer (10 mM Hepes pH 7.4, 138 mM NaCl) using
a 96-well cell harvester (Minidisc 96, Skatron Instruments, Sterling, VA) and 8x12 GF/C
glassfiber filtermats (Printed Filtermat A, for 1450 Microbeta, Wallac Inc., Gaithersburg,
MD). The platelet-bound radioactivity on the filtermats is determined in a scintillation
counter (Microbeta 1450, Wallac Inc., Gaithersburg, MD). Specific binding is determined by

subtraction of non-specific binding from total binding, and specific binding in the presence of
test compounds is expressed as % of specific binding in the absence of test compounds
dilutions.





[0237] It should be understood that the foregoing discussion, embodiments and
examples merely present a detailed description of certain preferred embodiments. It will be
apparent to those of ordinary skill in the art that various modifications and equivalents can be
made without departing from the spirit and scope of the invention. All the patents, journal
articles and other documents discussed or cited above are herein incorporated by reference.

WE CLAIM:
1. A compound having the formula:

or a pharmaceutically acceptable salt thereof such as herein described, wherein the dotted line
represents an optional double bond;
R1 is a member selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-5
cycloalkyl, C3-5 cycloalkyl-alkyl and benzyl;
R2 is a member selected from the group consisting of H, C1-6 alkyl and C1-6 haloalkyl;
R3 is a member selected from the group consisting of H, C1-6 alkyl. C2-6 alkenyl, C2-6
alkynyi, C3-5 cycloalkyl. C3-5 cycloalkyl-alkyl, C1-6 haloalkyl. C1-6 hydroxyalkyl,
cyano and -C(O)R3a, wherein R3a is a member selected from the group consisting
of H, hydroxy. C1-6 alkyl. C1-6 alkoxy, amino, C1-6 alkylamino and di- C1-6
alkylamino;
R4 is a member selected from the group consisting of H and C1-6 alkyl;
R3 is a member selected from the group consisting of H, halogen. C1-6 alkyl. C2-6 alkenyl,
C2-6 alkynyl. C1-6 haloalkyl, C1-6 alkoxy, cyano and -C(O)R3a, wherein R5a is a
member selected from the group consisting of C1-6 alkoxy, amino, C1-6 alkylamino
and di- C1-6 alkylamino; and
Ar is an aromatic ring selected from the group consisting of benzene, pyridine and
pyrimidine, each of which is optionally substituted with from 1-2 R6 substituents,
wherein each R6 is independently selected from the group consisting of halogen,
cyano, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyi. C1-6 alkoxy, C1-6
haloalkyl, C1-6 haloalkoxy, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C3-5
cycloalkyl-alkoxy, amino, C1-6 alkylamino, di-C1-6 alkylamino, -C(O)R6a,
-O(CH2)mOR6b, -(CH2)mOR6b, -O(CH2)mN(R6b)2 and -(CH2)mN(R6b)2,
wherein the subscript m is an integer of from 1 to 3, each R6a is a member
independently selected from the group consisting of H, hydroxy, C1-6 alkyl,
C1-6 alkoxy, amino, C1-6 alkylamino and di- C1-6 alkylamino, and each R6b is
a member independently selected from the group consisting of H, C1-4
alkyl and C1-4 alkanoyl, and optionally, two R6b groups attached to nitrogen

are combined with the nitrogen atom to form an azetidine, pyrrolidine or
piperidine ring.
2. A compound as claimed in claim 1, having the formula:

wherein the subscript n is an integer of from 0 to 2.
3. A compound as claimed in claim 1 , having the formula:

wherein the subscript n is an integer of from 0 to 2.
4. A compound as claimed in claim I, having the formula:

wherein the subscript n is an integer of from 0 to 2.
5. A compound as claimed in claim 2, wherein n is an integer of from 0 to
2; R1 is C1-4 alkyl, C3-5 cycloalkyl, or C3-5 cycloalkyl-alkyl; R2 is H; R3 is H, C1-4 alkyl, C2-4
alkenyl, C2-4 alkynyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C1-4 haloalkyl, cyano or -C(O)R3a;
R4 is H or C1-4 alkyl; R5 is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl. -CN, -C≡ CH or
-CONH2; and R6, when present is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy,
C3-5 cycloalkyl-alkoxy, -O(CH2)mOR6b and -O(CH2)mN(R6b)2 wherein the subscript m is 1 or 2
and each R6b is independently selected from the group consisting of H, C1-4 alkyl and C1-4
alkanoyl.

6. A compound as claimed in claim 5, wherein R1 is C1-4 alkyl; R4 is H or
CH3: R5 is halogen or C1-4 alkyl; and R6 when present is selected from C1-4 alkyl,
-O(CH2)mOR6b and -O(CH2)mN(R6b)2.
7. A compound as claimed in claim 6, wherein R1 is methyl; R5 is chloro.
and is attached at the 5-position of the thienyl ring; and R6 when present is selected from the
group consisting of CH3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2OCH3,
-OCH2CH2OC(O)CH, and -O(CH2)2N(CH3)2.
8. A compound as claimed in claim 7, wherein n is 0.
9. A compound as claimed in claim 7, wherein nis1.
10. A compound as claimed in claim 7 , wherein n is 2.
11. A compound as claimed in claim 3 , wherein n is 0 or 1; R1 is C1-4
alkyl, C3-5 cycloalkyl, or C3-5 cycloalkyl-alkyl; R2 is H; R3 is H, C1-4 alkyl, C2-4 alkenyl, C2-4
alkynyl. C3-5 cycloalkyl, C3-5- cycloalkyl-alkyl, C1-4 haloalkyl. cyano or -C(O)R3a; R4 is H or
C1-4 alkyl; R5 is halogen, C1-4 alkyl. C1-4 alkoxy, C1-4 haloalkyl. -CN, -C≡ CH or -CONH2; and
R6, when present is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C3-5
cycloalkyl-alkoxy, -O(CH2)mOR6b and -0(CH2)mN(R6b)2 wherein the subscript m is 1 or 2 and
each R6b is independently selected from the group consisting of H, C1-4 alkyl and C1-4
alkanoyl.
12. A compound as claimed in claim 11 , wherein R1 is C1-4 alkyl; R4 is H
or CH3; R5 is halogen or C1-4 alkyl; and R6 when present is selected from C1-4 alkyl,
-O(CH:)mOR6b and -O(CH2)mN(R6b)2.
13. A compound as claimed in claim 12 , wherein R1 is methyl: R3 is H, C1-
4 alkyl, C2-4 alkenyl, C2-4 alkynyl. C3-5 cycloalkyl or C3-5 cycloalkyl-alkyl; R4 is H or CH3; R5 is
chloro and is attached at the 5-position of the thienyl ring; and R6, when present is selected
from the group consisting of C1-4 alkyl, -O(CH2)mOR6b and -O(CH2)mN(R6b)2 wherein the
subscript m is 1 or 2 and each R6b is independently selected from the group consisting of H,
C1-4 alkyl and C1-4 alkanoyl.
14. A compound as claimed in claim 4, wherein n is 0 or 1; R1 is C1-4 alkyl,
C3-5 cycloalkyl, or C3-5 cycloalkyl-alkyl; R2 is H; R3 is H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,

C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C1-4 haloalkyl. cyano or -C(O)R3a; R4 is H or C1-4 alkyl;
R5 is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, -CN, -C≡ CH or -CONH2: and R6, when
present is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C3-5 cycloalkyl-alkoxy,
-O(CH2)mOR6b and -O(CH2)mN(R6b)2 wherein the subscript m is 1 or 2 and each R6b is
independently selected from the group consisting of H, C1-4 alkyl and C1-4 alkanoyl.
15. A compound as claimed in claim 14, wherein R1 is C1-4 alkyl: R4 is H
or CH3; R3 is halogen or C1-4 alkyl; and R6 when present is selected from C1-4 alkyl,
-O(CH2)mOR6b and -O(CH2)mN(R6b)2.
16. A compound as claimed in claim 15 , wherein R1 is methyl; R3 is H, C1-
4 alkyl, C2-4 alkenyl, C2-4 alkynyl. C3-5 cycloalkyl or C3-5 cycloalkyl-alkyl; R4 is H or CH3; R5 is
chloro and is attached at the 5-position of the thienyl ring; and R6, when present is selected
from the group consisting of C1-4 alkyl, -O(CH2)mOR6b and -O(CH2)mN(R6b)2 wherein the
subscript m is 1 or 2 and each R6b is independently selected from the group consisting of H,
C1-4 alkyl and C1-4 alkanoyl.
17. A compound as claimed in claim 1 , selected from the group consisting
of:




18. A pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a compound having the formula:

or a pharmaceutically acceptable salt thereof such as herein described, wherein the dotted line
represents an optional double bond;
R1 is a member selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-5
cycloalkyl, C3-5 cycloalkyl-alkyl and benzyl;
R2 is a member selected from the group consisting of H, C1-6 alkyl and C1-6 haloalkyl;
R3 is a member selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C3-6
alkynyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl,
cyano and -C(O)R1a, wherein R3a is a member selected from the group consisting
of H, hydroxy, C1-6 alkyl, C1-6 alkoxy, amino, C1-6 alkylamino and di- C1-6
alkylamino;

R4 is a member selected from the group consisting of H and C1-6 alkyl;
R5 is a member selected from the group consisting of H, halogen, C1-6 alkyl. C2-6 alkenyl,
C1-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, cyano and -C(O)R5a, wherein R5a is a
member selected from the group consisting of C1-6 alkoxy, amino, C1-6 alkylamino
and di- C1-6 alkylamino; and
Ar is an aromatic ring selected from the group consisting of benzene, pyridine and
pyrimidine, each of which is optionally substituted with from 1-2 R6 substituents,
wherein each R6 is independently selected from the group consisting of halogen,
cyano, hydroxy, C1-6 alkyl, C3-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6
haloalkyl, C1-6 haloalkoxy, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C3-5
cycloalkyl-alkoxy, amino, C1-6 alkylamino, di-C1-6 alkylamino, -C(O)R6a,
-O(CH2)mOR6b, -(CH2)mOR6b,-O(CH2)mN(R6b)2 and -(CH2)mN(R5b)2,
wherein the subscript m is an integer of from 1 to 3, each R6a is a member
independently selected from the group consisting of H, hydroxy, C1-6 alkyl.
C1-6 alkoxy, amino, C1-6 alkylamino and di- C1-6 alkylamino, and each R6b is
a member independently selected from the group consisting of H, C1-4
alkyl and C1-4 alkanoyl. and optionally, two R6b groups attached to nitrogen
are combined with the nitrogen atom to form an azetidine, pyrrolidine or
piperidine ring.
19. A pharmaceutical composition as claimed in claim 18 , wherein said
compound has the formula:

wherein n is 0 or 1; R1 is C1-4 alkyl, C3-5 cycloalkyl, or C3-5 cycloalkyl-alkyl; R2 is H; R3 is H,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C1-4 haloalkyl,
cyano and -C(O)R3a; R4 is H or C1-4 alkyl; R5 is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl,
-CN, -C≡ CH or -CONH2; and R6, when present is selected from the group consisting of C1-4
alkyl, C1-4 alkoxy, C3-5 cycloalkyl-alkoxy, -O(CH2)mOR6b and -O(CH2)mN(R6b)2 wherein the

subscript m is 1 or 2 and each R6b is independently selected from the group consisting of H,
C1-4 alkyl and C1-4 alkanoyl.
20. A pharmaceutical composition as claimed in claim 19 , wherein R1 is
methyl; R3 is H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-5 cycloalkyl or C3-5 cycloalkyl-alkyl;
R4 is H or CH3; R3 is chloro and is attached at the 5-position of the thienyl ring; and R6, when
present is selected from the group consisting of C1-4 alkyl. -O(CH2)mOR6b and
-O(CH2)mN(R6b)2 wherein the subscript m is 1 or 2 and each R6b is independently selected
from the group consisting of H, C1-4 alkyl and C1-4 alkanoyl.
21. A pharmaceutical composition as claimed in claim 18 , wherein said
compound is selected from the group consisting of:




22. The composition as claimed in claim 18, wherein said composition is
useful in treating thrombosis in a subject.
23. The composition as claimed in claim 22, wherein said composition is
optionally made in combination with a second therapeutic agent selected from the group
consisting of antiplatelet compounds, anticoagulants, fibrinolytics, anti-inflammatory
compounds, cholesterol-lowering agents, blood pressure-lowering agents and serotonin
blockers.
24. The composition as claimed in claim 23, wherein said second
therapeutic agent is an antiplatelet compound selected from the group consisting of GPIIB-
IIIa antagonists, aspirin, phosphodiesterase III inhibitors and thromboxane A2 receptor
antoagonists.
25. The composition as claimed in claim 23, wherein said second
therapeutic agent is an anticoagulant selected from the group consisting of thrombin
inhibitors, Coumadin, heparin and enoxaparin.

26. The composition as claimed in claim 23, wherein said second
therapeutic agent is an anti-inflammatory compound selected from the group consisting of
non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors and rheumatoid arthritis
agents.
27. The composition as claimed in claim 23, wherein said composition is
prepared to the form of an oral formulation.
28. The composition as claimed in claim 22 , wherein said compound has
the formula:

wherein n is 0 or 1: R1 is C1-4 alkyl, C3-5 cycloalkyl, or C3-5 cycloalkyl-alkyl; R2 is H; R3 is H.
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-5 cycloalkyl, C3-5 cycloalkyl-alkyl, C1-4 haloalkyl.
cyano or -C(O)R3a; R4 is H or C1-4 alkyl; R1 is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl,
-CN, -C≡ CH or -CONH2; and R6, when present is selected from the group consisting of C1-4
alkyl, C1-4 alkoxy. C3-5 cycloalkyl-alkoxy, -O(CH2)mOR6b and -O(CH2)mN(R6b)2 wherein the
subscript m is 1 or 2 and each R6b is independently selected from the group consisting of H,
C1-4 alkyl and C1-4 alkanoyl.
29. The composition as claimed in claim 28, wherein R1 is methyl; R3 is H,
C1-4 alkyl, C1-4 alkenyl, C2-4 alkynyl, C3-5 cycloalkyi or C3-5 cycloalkyl-alkyl; R4 is H or CH3;
R5 is chloro and is attached at the 5-position of the thienyl ring; and R6, when present is
selected from the group consisting of C1-4 alkyl, -O(CH2)mOR6b and -O(CH2)mN(R6b)2 wherein
the subscript m is 1 or 2 and each R6b is independently selected from the group consisting of
H, C1-4 alkyl and C1-4 alkanoyl.
30. The composition as claimed in claim 22 , wherein said compound is
selected from the group consisting of:






The invention discloses a isoquinolinone compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional
double bond, and R1, R2, R3, R4 and R5 are as defined in the specification.
The invention is also for a pharmaceutical composition comprising the said compound useful
for the treatment of thrombosis and thrombosis related conditions or disorders.

Documents:

00829-kolnp-2006-abstract.pdf

00829-kolnp-2006-assignment.pdf

00829-kolnp-2006-claims.pdf

00829-kolnp-2006-correspondence others.pdf

00829-kolnp-2006-description complete.pdf

00829-kolnp-2006-form 1.pdf

00829-kolnp-2006-form 3.pdf

00829-kolnp-2006-form 5.pdf

00829-kolnp-2006-international publication.pdf

00829-kolnp-2006-international search authority.pdf

00829-kolnp-2006-pct form.pdf

00829-kolnp-2006-priority documents.pdf

829-KOLNP-2006-ABSTRACT.pdf

829-KOLNP-2006-AMENDED CLAIMS.pdf

829-kolnp-2006-assignment.pdf

829-KOLNP-2006-CANCELLED PAGES.pdf

829-kolnp-2006-correspondence.pdf

829-KOLNP-2006-DESCRIPTION (COMPLETE).pdf

829-kolnp-2006-examination report.pdf

829-KOLNP-2006-FORM 1.pdf

829-kolnp-2006-form 18.pdf

829-KOLNP-2006-FORM 2.pdf

829-kolnp-2006-form 3-1.1.pdf

829-KOLNP-2006-FORM 3.pdf

829-kolnp-2006-form 5.pdf

829-KOLNP-2006-FORM-27.pdf

829-kolnp-2006-gpa.pdf

829-kolnp-2006-granted-abstract.pdf

829-kolnp-2006-granted-claims.pdf

829-kolnp-2006-granted-form 1.pdf

829-kolnp-2006-granted-form 2.pdf

829-kolnp-2006-granted-specification.pdf

829-kolnp-2006-others-1.1.pdf

829-KOLNP-2006-OTHERS.pdf

829-KOLNP-2006-PETITION UNDER RULE 137.pdf

829-kolnp-2006-reply to examination report-1.1.pdf

829-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf


Patent Number 247498
Indian Patent Application Number 829/KOLNP/2006
PG Journal Number 15/2011
Publication Date 15-Apr-2011
Grant Date 12-Apr-2011
Date of Filing 05-Apr-2006
Name of Patentee PORTOLA PHARMACEUTICALS, INC.
Applicant Address 270 E. GRAND AVENUE SUITE 22, SOUTH SAN FRANCISCO, CA 94080
Inventors:
# Inventor's Name Inventor's Address
1 SCARBOROUGH ROBERT M 22, GREENBRIER COURT, HALF MOON BAY, CA 94019
2 MARLOWE CHARLES K 636 CALIFORNIA WAY, REDWOOD CITY, CA 94062
3 SMYTH MARK S 860 POLLUX DRIVE, FORTER CITY, CA 94404
4 ZHANG XIAOMING 1089 REMSEN COURT, SUNNYVALE, CA 94087
5 KANE-MAGUIRE KIM A 3425 LODGE DRIVE BELMONT, CA 94002
PCT International Classification Number C07D217/24; C07D401/04
PCT International Application Number PCT/US2004/032104
PCT International Filing date 2004-09-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/508,402 2003-10-03 U.S.A.