Title of Invention

INHIBITORS OF VEGF RECEPTOR AND HGF RECEPTOR SIGNALING

Abstract The invention rolates to the inhibition of vascular endthellal growth factor (VEGF) receptor signaling and hepatocyre growth factor (HGF) receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
Full Text WO 2006/010264 PCT/CA2005/001177
INHIBITORS OF VEGF RECEPTOR AND HGF RECEPTOR SIGNALING
BACKGROUND OF THE INVENTION Field of the Invention
[0001] This invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. More particularly, the invention relates to compounds and methods for the inhibition of VEGF receptor signaling and HGF receptor signaling.
Summary of the Related Art
[0002] Angiogenesis is an important component of certain normal physiological processes such as embryogenesis and wound healing, but aberrant angiogenesis contributes to some pathological disorders and in particular to tumor growth.1'2 VEGF-A (vascular endothelial growth factor A) is a key factor promoting neovascularization (angiogenesis) of tumors.3-7 VEGF induces endothelial cell proliferation and migration by signaling through two high affinity receptors, the fins-like tyrosine kinase receptor, Flt-1, and the kinace insert domain-containing receptor, KDR.8,9,10. These signaling responses are critically dependent upon receptor dirnerization and activation of intrinsic receptor tyrosine kinase (RTK) activity. The binding of VEGF as a disulfide-linked homodimer stimulates receptor dimerization and activation of the RTK domain 11.The kinase activity autophosphorylales cytoplasmic receptor tyrosine residues, which then serve as binding sites for molecules involved in the propagation of a signaling cascade. Although multiple pathways are likely to be elucidated for both receptors, KDR signaling is most extensively studied, with a mitogenic response suggested to involve ERK-1 and ERK-2 mitogen-activated protein kinases 12. [0003] Disruption of VEGF receptor signaling is a highly attractive therapeutic target
in cancer, a CLIENT-HOST DIVIDED ARCHITECTURE FOR INPUT-OUTPUT COORDINATION ure endothelium remains relatively quiescent (with the exception ot the temale reproductive system and wound healing). A number of experimental approaches to inhibiting VEGF signaling have been examined, including use of neutralizing antibodies 13,l4,15, receptor antagonists 16, soluble receptors 17, antisense constructs18 and dominant-negative strategies
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[0004] Despite the attractiveness of anti-angiogenic therapy by VEGF inhibition alone, several issues may limit this approach. VEGF expression levels can themselves be elevated by numerous diverse stimuli and perhaps most importantly, the hypoxic state of tumors resulting from VEGFr inhibition, car. leal to the induction of factors that themselves

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promote tumor invasion and metastasis thus, potentially undermining the impact of VEGF inhibitors as cancer therapeutics20
[0005] The HGF (hepatocyte growth factor) and the HGF receptor, c-met, are
implicated in the ability of tumor cells to undermine the activity of VEGF inhibition20.
HGF derived from either stromal fibroblasts surrounding tumor cells or expressed from the
tumor itself has been suggested to play a critical role in tumor angiogenesis, invasion and
metastasis 21,22. For example, invasive growth of certain cancer cells is drastically enhanced
by tumor-stromal interactions involving the HGF/c-Met (HGF receptor) pathway 23,24,25
HGF, which was originally identified as a potent mitogen forhepatocytes26,27 is primarily
secreted from stromal cells, and the secreted HGF can promote motility and invasion of
various cancer cells that express c-Met in a paracrine manner 28,29,30. Binding of HGF to c-
Met leads to receptor phosphorylation and activation of Ras/mitogen-activated protein
kinase (MAPK) signaling pathway, thereby enhancing malignant behaviors of cancer cells
30>31. Moreover, stimulation of the HGF/c-met pathway itself can lead to the induction of
VEGF expression, itself contributing directly to angiogenic activity32'
[0006] Thus, anti-tumor anti-angiogenic strategies or approaches that target both
VEGF/VEGFr signaling and HGF/c-met signaling may circumvent the ability of rumor cells
to overcome VEGF inhibition alone and may represent improved cancer therapeutics.
[0007] Here we describe small molecules that are potent inhibitors of both the VEGF
receptor KDR and the HGF receptor c-met.
BRIEF SUMMARY OF THE INVENTION
[0008] The present invention provides new compounds and methods for treating cell
proliferative diseases. The compounds of the invention are dual function inhibitors, capable
of inhibiting both VEGF and HGF. Accordingly, the invention provides new inhibitors of
VEGF receptor signaling and HGF receptor signaling, including the VEGF receptor KDR
and the HGF receptor c-met.
[000S] In a first aspect, the invention provides compounds of formula A that are
useful as inhibitors of VEGF receptor signaling and HGF receptor signaling.
[0010] In a second aspect, the invention provides compounds of formula B that are
useful as inhibitors of VEGF receptor signaling and HGF receptor signaling.
[0011] In a third aspect, the invention provides compositions comprising a compound
of the present invention that is an inhibitor of VEGF receptor signaling and HGF receptor
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signaling, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
carrier, excipient, or diluent.
[0012] In a fourth aspect, the invention provides a method of simultaneously
inhibiting VEGF receptor signaling and HGF receptor signaling in a cell, comprising
contacting a cell in which inhibition of VEGF receptor signaling and HGF receptor
signaling is desired with a compound of the invention.
[0013] The foregoing merely summarizes certain aspects of the invention and is not
intended to be limiting in nature. These aspects and other aspects and embodiments are
described more fully below.
DETAILED DESCRIPTION OF TIIE PREFERRED EMBODIMENTS [0014] The invention provides compounds and methods for inhibiting the VEGF receptor iCDR and the HGF receptor c-met. The invention also provides compositions and methods for treating cell proliferative diseases and conditions. The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the art. The issued patents, applications, and references that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of inconsistencies, the present disclosure will prevail.
[0015] For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise):
[0016] The terms" inhibitor of VEGF receptor signaling" and "inhibitor of HGF receptor signaling" are used to identify a compound having a structure as defined herein, which is capable of interacting with a HGF receptor and a VEGF receptor and inhibiting the activity of HGF and VEGF. In some preferred embodiments, such reduction of activity is at least about 50%, more preferably at least about 75%, and still more preferably at least about 90%.
[0017] For simplicity, chemical moieties aie defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an "alkyl" moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term "alkylene."
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(Similarly, in circumstances in which a divalent moiety is required and is stated as being "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2,4, or 6 for S, depending on the oxidation state of the S). On occasion a moiety may be defined, for example, as (A)3-B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-. Also, a number of moieties disclosed herein exist in multiple tautomeric forms, all of which are intended to be encompassed by any given tautomeric structure.
10018] The term "hydrocarbyl" refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A "Co" hydrocarbyl is used to refer to a covalent bond. Thus, "Co-Cj-hydrocarbyl" includes a covalent bond, methyl, ethyl, ethenyi, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.
[0019] The term "alkyl" as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkyl groups include, without limitation, methyl, ethyl, propy], isopropyi, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A "Co" alkyl (as in "Cc-C3.alkyl") is a covalent bond (like "C" hydrocarbyl).
[0020] The term "alkenyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkenyl groups include, without limitation, ethenyi, propenyl, butenyi, pentenyl, and hexenyl. [0021] The term "alkynyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl. [0022] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Preferred alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Preferred alkenylene groups include, without limitation,
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ethenylene, propenylene, and butenylene. Preferred alkynylene groups include, without limitation, ethynyiene, propynylene, and butynyiene.
[0023] The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 lo 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
[0024] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, NH, N-alkyl, SO, SO2, SO2NH, orNHSO2. [0025] An "aryl" group is a C6-Cu aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Preferably, the aryl group is a C [0026] A "heterocyclyl" or "heterocyclic" group is a ring structure having from about 3 to about 12 atoms, wherein one or more atoms are selected from the group consisting of N, O, S, SO, and SO2. The heterocyclic group is optionally substituted on carbon at one or more positions. The heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Preferred heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certain preferred embodiments, the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocyles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds where an annular O or S atom is adjacent to another O or S atom.
[0027] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6,10, or 14 rc-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring
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selected from the group consisting of N, 0, and S. The term "heteroaryl" is also meant to encompass rnonocyclic and bicyclic groups. For example, a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyi. A "heteroaralkyl" or "heteroarylalkyl" group comprises a heteroaryl group covalently linked to an alkyl group, either of which is independently optionally substituted or unsubstituted. Preferred heteroalkyl groups comprise a Ci-Ce alkyl group and a heteroaryl group having 5, 6,9, or 10 ring atoms. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms. Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms. [0028] For simplicity, reference to a "Cn-Cm" heterocyclyl or heteroaryl means a heterocyclyl or heteroaryl having from "n" to "m" annular atoms, where "n" and "m" are integers. Thus, for example, a Cs-Cg-heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (Cs) and piperidinyl (Ce); C6-hetoaryl includes, for example, pyridyl and pyrimidyl.
[0029] An "arylene," "heteroarylene," or "heterocyclylene" group is an aryl,
heteroaryl, or heterocyclyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
[0030) Preferred heterocyclyls and heteroaryis include, but are not limited to,
acrid inyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, pyridotriazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-bjtetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyi, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochrotnanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyI, oxazotidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,
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quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroftiranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyI, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-trazolyl, 1,3,4-triazoIyl, and xanthenyl.
[0031] As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl,
heteroaryl, heterocyclic, urea, etc.) is described as "optionally substituted" it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Preferred substituents, which are themselves not further substituted (unless expressly stated otherwise) are:
(a) halo, hydroxy, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino,
(b) C1-C5 alky I or alkenyl or arylalkyl imino, carbamoyi, azido, carboxamido,
mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalky!, C)-Cs alkyl, Ci-Cs
alkenyl, CrCg alkoxy, Ci-Cs alkoxycarbonyl, aryloxycarbonyl, C2-C8 acyl, C2-
Cg acylamino, Ci-C8 alkylthio, arylalkylthio, arylthio, Cj-Cs alkylsulfinyl,
arylalkylsulfinyl, arylsulfmyl, Cj-Cs alkylsulfonyl, arylalkylsulfonyl,
arylsulfonyl, Co-Ce Mallcyl carbamoyi, C2-C15 iV^V-dialkylcarbamoyl, C3-C7
cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or
heterocycle or another aryl ring, C3-C7 heterocycle, C5-C14 heteroaryl, or any of
these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein
each of the foregoing is further optionally substituted with one more moieties
listed in (a), above; and
(c) -(CH2)S-NR3OR31, wherein s is from 0 (in which case the nitrogen is directly
bonded to the moiety that is substituted) to 6, and R30 and R31 are each
independently hydrogen, cyano, oxo, carboxamido, amidino, CpCg
hydroxyalkyl, CrC3 alkylaryl, aryl-C,-C3 alkyl, CrC8 alkyi, Ci-C8 alkenyl, Cr
Cs alkoxy, Ci-Cg aikoxycarbonyi, aryioxycarbonyi, aryl-C]-C3 alkoxycarbonyl,
C2-C8 acyl, Ci-Cg alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl, aryl,
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cycloalky!, heterocyclyl, or heteroaryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; or R3C and R31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents from (a), above.
[0032] Especially preferred substituents on allcyl groups include halogen and hydroxy,
[0033] Especially preferred substituents or ring groups, such as aryl, heteroaryl,
cycloalkyl and heterocyclyl, include halogen, alkoxy and alky].
[0034] A "halohydrocarbyl" is a hydrocarbyl moiety in which from one to all
hydrogens have been replaced with one or more halo.
[0035] The term "halogen" or "halo" as employed herein refers to chlorine, bromine,
fluorine, or iodine. As herein employed, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acvlamino" refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-). The term "carbamcyl" refers to an amide group attached at the carbonyl carbon atom (i.e., NH2-CO-). The nitrogen atom of an acylamino or carbamoyl substituent is additionally substituted. The term "sulfonamido" refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term "amino" is meant to include NH2, alkylamino, arylamino, and cyclic amino groups. The term "ureido" as employed herein refers to a substituted or unsubstituted urea moiety. [0036] The term "radical" as used herein means a chemical moiety comprising one or more unpaired electrons.
[0037] A moiety that is substituted is one in which one or more hydrogens have been
independently replaced with another chemical substituent. As a non-limiting example, substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chIoro-4-f!uoro-phenyl, 2-fluoro-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4-dimethyl-5-ethyi-octyl and 3-cyclopentyl-octyl. Included within this definition are methvlenes (-CH2-) substituted with oxygen to form carbonyl -CO-). [0038] An "unsubstituted" moiety as defined above (e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as defined above that does not have any of the optional substituents for which the definition of the moiety (above) otherwise provides. Thus, for example, while an "aryl" includes phenyl and phenyl substituted with a halo, "unsubstituted aryl" does not include phenyl substituted with a halo.

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[0039] Throughout the specification, preferred embodiments of one or more chemical substituents are identified. Also preferred are combinations of preferred embodiments. For example, paragraph [0048] describes preferred embodiments of X and X1 in the compounds of formula (A) and paragraph [0053] describes preferred embodiments of R1 in the compounds of formula (A). Thus, also contemplated as within the scope of the invention are compounds of formula (A) in which X and X1 are as described in paragraph [0048] and R1 is as described in paragraph [0053]. Furthermore, compounds excluded from any one particular genus of compounds (e.g., through a proviso clause) are intended to be excluded from the scope of the invention entirely, including from other disclosed genera, unless expressly stated to the contrary.
Compounds
[0040J In the first aspect, the invention comprises compounds of formula (A), that are inhibitors of VEGF receptor signaling and HGF receptor signaling:

and pharmaceutically acceptable salts and complexes thereof, wherein T is selected from the group consisting of arylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said arylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 1 to 3 independently selected R20;
each R20 is independently selected from the group consisting of-H, halogen, trihalomethyl, -CN, -NO2j -NH2, -OR17, -OCF3, -NR17R)Ji, -S(0)o-2R!?, -S(O)2NR17R17, -C(O)OR17, -C(O)NRl7R17, -N(R17)SO2Rn, -N(R17)C(O)R17, -N(R17)C(O)OR17, -C(O)R17, -C(O)SRn, C1-C4 alkoxy, d-Q alkylthio, -O(CH2)naryI, -0(CH2)nheteroaryl, -(CH2)0-5(aryl), -(CH2)0-s(heteroaryl), Ci-C6 alkyl, C2-C6 alkenyl, CrC6 alkynyl, -CH2(CH2)o. 4-T2, an optionally substituted CM alkylcarbonyl, CM alkoxy, an amino optionally substituted by CM alkyl optionally substituted by CM alkoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe2, -NHEt and -NEt2, and wherein the aryl, heteroaryl, C|-Q; alkyl, CrQ alkenyl, and C2-Cs alkyny! are optionally substituted;

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W is selected from the group consisting of O, S, NH and NMe;
Z is selected from the group consisting of O, or S and NH;
X and X1 are independently selected from the group consisting of H, CpC6 alkyl, halo, cyano, or nitro, wherein CpC^ alkyl is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C7 cycloalkyl;
R\ R2, R3 and R4 independently represent hydrogen, halo, trihalomethyl, -CN, -NO2, -NH2, -OR'7, -NR17R18, -C(O)OR17, -C(O)R17, C-C4 alkoxy, CrC4 alkylthio, C,~C6 alkyl, C2-C6 alkenyl or C2-Co alkynyl, wherein C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl are optionally substituted;
R17 is selected from the group consisting of H and R18;
R!S is selected from the group consisting of a (Ci-C6)alkyl, an aryl, a aryl(Ci-Q)alkyl, a
heterocyclyl and a heterocyclyl(Ci-C6)alkyi, each of which is optionally substituted, or
R17 and R1S, taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from the group consisting of N, 0, S and P;
R16 is selected from the group consisting of-H, -CN, -(CH2)o-5(aryl), -(CH2)o-s(heteroaryl), C|-Cri alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)(M-T2, an optionally substituted C14 alkylcarbonyl, and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe2, -NHEt and -NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-Ce alkenyl, and C2-C6 allcynyl are optionally substituted;
Q is selected from the group consisting of CH2,0, S, N(H), N(CrC6 alkyl), N-Y-(aryl), -N-
OMe, -NCH2OMe and -N-Bn;
D is selected from the group consisting of C-E and N;
L is N, or CR, wherein R is selected from the group consisting of -H, halo, -CN, C1-C6
alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein C,-C E is selected from the group consisting of E1, E2 and E3, wherein
E! is selected from the group consisting of-H, halogen, nitro, azido, C1-C6 alkyl, C3-C10 cycloalkyl, -C(O)NR42R43, -Y-NR42R43, -NR42C(O)R43, -SO2R42, -SO2NR42R43, -NR37SO2R42, -NR37SO2NR42R43, -C(=N-OR42)R43, -C(=NR42)R43, -NR37C(=NR42)R43,
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-C(=NR42)NR37R43, -NR37C(=NR42)NR37R4\ -C(O)R42, -CO2R42, -C(O)(heterocyclyl), -C(0)(C6-Cio aryl), -C(O)(heteroaryl), -Y-(C6-C!0 aryl), -Y-(heteroaryl), -Y-(5-10 membered heterocyclic), -NR6aR6b, -NR6aSO2R6b, -NR6aC(O)R6b, -OC(O)R'5b, -NR6aC(O)OR6b, -OC(O)NR6aR6b,-OR6a, -SR6a, -S(O)R63, -SO^R63, -SO3R6a, -SO2NR6aR6b, -SO2NR42R43, -COR6a, -CChR6*, -CONR5aR6b, -(Cr C4)fluoroalkyl, -(C]-C4)fluoroalkoxy, -(CZ3Z4)aCN, wherein n is an integer ranging from 0 to 6, and the aforementioned El groups other than -H and halogen are optionally substituted by 1 to 5 independently selected R38, orE1 is selected from a moiety selected from the group consisting of -(CZ3Z4)a-aryl, -(CZ3Z4)a-heterocycle, (C2-C6)alkynyl, -(CZ3ZV(C3-C6)cycloalkyI, -(CZ3Z4)a-(C5-C6)cycloalkenyl, (C2-C6) alkenyl and (Ci-C6)alkyL which is optionally substituted with 1 to 3 independently selected Y2 groups, where a is 0,1, 2, or 3, and wherein when a is 2 or 3, the CZ3Z4 units may be the same or different; wherein
each R38 is.independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, CrC6 alkyl, -(CH.^OCCl-l^iNR^R39, -(CH2)n0(CH2)i0R375 -(CH2)nOR37, -SCO^d-Cs alkyl), -(CH2)n(C5-Cio aryl), -(CH2)n(C5-Cio heteroaryl), -(CH2)n(5-10 membered beterocyclyl); -C(O)(CH2)r(C6-C10 aryl), -(CH2)nO(CH2)j(C6-C,o aryl), -(CH2)nO(CH2)i(5-10 membered heterocyclyl), -C(O)(CH2)n(5-10 membered heterocyclyl), -(CH2)jNR39(CH2)iNR36R39, -(CH2)jNR39CH2C(O)NR36R39, -(CH2)jNR39(CH2)lNR37C(O)R40, -(CH^NR^CCH^OCCH^.OR37, -(CH2)jNR39(CH2)iS(O)j(Ci-C6 alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-C10 aryl), -SO2(CH:)n(5-10 membered heterocyclyl), -(CH2)nNR36R39, -NR37SO2NR36R39, SO2R3€, C2-C6 alkenyl, C3-C10 cycloalkyl and C1-C6 alkylamino, wherein j is an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 0 to 6, the -(CH2);- and -(CH2)n- moieties of the foregoing R38 groups optionally include a carbon-carbon double or triple bond where n is an integer between 2 and 6, and the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R3S groups are optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -(CH2)nNR36R39, Ci-C6 alkyl, C3-Ci0 cycloalkyl, -(CH2)n(C6-C10 aryl), -(CH2)n(5-10 membered
11

WO 2006/010264 PCT/CA2OO5/0O1177
heterocyclyl), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;
each R42 and R43 is independently selected from the group consisting of H, C\~C6 alkyl, C\-C6 heteroalkyl, -Y-(C3-C!0 cycloalkyl), -Y-(C6-C]0 aryl), -Y-(C6-Ci0 heteroaryl), -Y-(5-10 membered heterocyclic), -Y-O-Y'-OR37, -Y'-CO2-R37, and -Y-OR37, wherein the alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or more substituents independently selected from R44, wherein
Y is a bond or is -(C(R37)(H))n,
n is an integer ranging from 1 to 6, and
Y1 is -(C(R37)(H))n, or
R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1 to 5 independently selected R44 substituents, with the proviso that R42 and R43 are not both bonded to the nitrogen directly through an oxygen;
each R44 is independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, -SO2R36, -NR36SO2R39, -NR36SO2NR37R4\ CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, -CrC6 alkylamino, -(CH2)jO(CH2)1NR36R39, -(CH2)nO(CH2)iOR37> -(CH2)nOR37, -SCO^Ci-Cg alkyl), -(CH2)n(C6-C,o aryl), -(CH2)n(5-10 membered heterocyclic), -C(O)(CH2)n(C6-C10 aryl), -(CH2)nO(CH2)j(C6-C10 aryl), -(CH2)nO(CH2)i(5 to 10 membered heterocyclic), -C(O)(CH2)n(5 to 10 membered heterocyclic), -(CH^jNR^CH^NR^R39, -(CH2)jNR39CH2C(O)NR36R39, -(CH2)jNR39(CH2)iNR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)iOR37, -(CH2)jNR39(CH2)iS(O)j(CI-C6 alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-C10 aryl), and -SO2(CH2)n(5 to 10 membered heterocyclic) wherein,] is an integer from 0 to 2, n is an integer from 0 to 6 and i is an integer ranging from 2 to 6, the -(CH2)i-and -(CH2)ni- moieties of the foregoing R44 groups optionally include a carbon-carbon double or triple bond wherein n is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R44 groups are optionally substituted by 1 or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R' 12

WO 2006/010264 PCT7CA2O05/O01177
C3-C10 cycloalkyl, -(CH2)n(C6-Cio aryl), -(CHiM.S to 10 membered heterocyclic), -(CH2)n0(CH2)i0R37 and -(CH2)nOR37, wherein n is an integer from 0 to 6 and i is an integer from 2 to 6; and
each R40 is independently selected from H, d-Cio allcyl, -(CH2)n(C6-C10 aryl), CrCto
cycloalkyl, and -(CH2)n(5-10 membered heterocyclic), wherein n is an integer ranging from 0 to 6;
each R36 and R39 is independently selected from the group consisting of H, -OH, Ci-Cg alkyl, C3-C10 cycloalkyl, -(CH2)n(C6-Cio aryl), -(CH2)n(5-10 membered heterocyclic), -(CH2)nO(CH2),OR37, -(CH2)nCN(CH2)nOR37, -(CH2)nCN(CH2)nR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R36 and R39 groups are optionally substituted by one or more substiuients independently selected from -OH, halo, cyano, nitro, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -CO(O)R40, -OC(O)OR40, -NR37C(O)R41, -C(O)NR37R41, -NR37R41, -CrC6 alkyl, -(CH2),,(C6-Cio aryl), -(CH2)n(5 to 10 membered heterocyclic), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that when R36 and R39 are both attached to the same nitrogen, then R36 and R39 are not both bonded to the nitrogen directly through an oxygen;
each R37 and R4! is independently selected from the group consisting of H, OR36, CpCe
alkyl and C3-C10 cycloalkyl;
each R6a and R6b is independently selected from the group consisting of hydrogen, -(CZ5zV(C3-C6)cycloalkyl, -(CZ5Z6)u-(C5-C6)cycloalkenyl, -(CZ5Z6)u-ary!, -(CZ5zVheteroaryl, -(CZsZ6)u-heterocycle, (C2-Gs)alkenyl, and (CrCV)alkyl, each of which is optionally substituted with 1 to 3 independently selected Y3 groups, where u is 0,1,2, or 3, and wherein when u is 2 or 3, the CZ5Z6 units may be the same or different, or
R6a and R6b taken together with adjacent atoms can form a heterocycle;
each Z3, Z4, Z5 and Z6 is independently selected from the group consisting of H, F and (Cr C6)alkyl, or
each Z3 and Z4, or Z5 and Z6 are selected together to form a carbocycle, or
two Z3 groups on adjacent carbon atoms are selected together to optionally form a carbocycle;
13

WO 2006/010264 PCT/CA2005/001177
each Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, araidino, methylguanidino, azido, -C(O)Z7, -OC(O)NH;>, -OC(O) NHZ7, -OC(O)NZ7Z8, -NHC(O)Z7, -NHC(0)NH2, -NHC(0)NHZ7, -NHC(O)NZ7Z8, -C(O)OH, -C(O)OZ7, -C(O)NH2) -C(O)NHZ7,-C(O)NZ7Z8, -P(O)3H2, -P(O)3(Z7)2, -S(O)3H, -S(O)Z7, -S(O)2Z7, -S(O)3Z7, -Z7, -OZ7, -OH, -NH2, -NHZ7, -NZ7Z8, -C(=NH)NH2,-C(=NOH)NH2) -N-morpholino, (CrC6)alkyl, (C2-C6)alkenyl, (C2-Cs)alkynyl, (C,-C6)haloalkyl, (C2-C6)haloalkenyl, (C2-C6)haloaikynyl, (Ci-C6)haloalkoxy, -(CZ9Z10)rNH2) -(CZ9Zl0)tNHZ3, -(CZ9Z10)rNZ7Z*, -X6(CZ9Z10)r-(C3-C8)cycloalkyl, -X6(CZ9Z10)r-(C5-C8)cycloalkenyl, -X6(CZ9Z10)r-aryl and -X6(CZ9Z'V heterocycle, wherein ris 1,2, 3 or 4; X6 is selected from the group consisting of O, S, NH, -C(O)-, -C(O)NH-, -C(O)O-5 -S(O>, -
S(O)2- and -S(O)3-;
Z7 and Z8 are independently selected from the group consisting of an alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms, an alkynyi of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8 carbon atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14 carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15 carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or Z7 and Z8 together may optionally form a heterocycle;
Z9 and Z10 are independently selected from the group consisting of H, F, a (C]-Ci2)alkyl, a (C two Z9 groups on adjacent carbon atoms are taken together to form a carbocycle; or any two Y2 or Y3 groups attached to adjacent carbon atoms may be taken together to be -
OfCCZ^CZ10)]^ or -Otqz'XZ'0)]^,, or any two Y2 or Y3 groups attached to the same or adjacent carbon atoms may be selected
together to form a carbocycle or heterocycle; and wherein
any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halogen, SO or SO? group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halogen, (Ci-C4)alkyl, (Cj-C^alkoxy and an -N[(C,-C4)alkyl][(CrC4)alkyl]; E2 is -OCH or -OC-tCR^R'VR46;
R45 is independently selected from the group consisting of H, a (Ci-Cb)alkyl and a (C3-Cg)cycloalkyl;
14

WO 2006/010264 PCT/CA2OO5/OO1177
R46 is selected from the group consisting of heterocyclyi, -N(R47)-C(O)-N(R4;)(Rltt), -N(R47)~C(S)-N(R47)(R48), -N(R47)-C(O)-OR4S, -N(R47)-C(O)-(CH2)n-R48, -N(R47)-SO2R47S -(CH2)nNR47R48, -(CH2)nOR4t, -(CH2)nSR49, -(CH2)n3(O)R49, -(CH2)nS(O)2R49, -OC(O)R49, -OC(O)OR49, -C(O)NR47R48, heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-Cfijalkoxy, -NO2, (CrC6)alkyl, -CN, -SO2R50 and -(CH2)nNR50R51, and aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-OOalkoxy, -NO2, (Cj-C6)alkyl, -CN, -SOiR50 and -(CH2)nNR5f)R51;
R47 and R48 are independently selected from the group consisting of H, (Ci-C6)alkyl, (C3-C8)cycloaUcyI, heterocyclyi, -(CH2)nNR5OR51) -(CH^OR50, -(CH2)nC(O)R49, -C(O)2R49, -(CH2)nSR49, -(CH2)nS(O)R"9) -(CH2)nS(O)2R49, -(CH,)^49, -(CH2)nCN, aryl optionally substituted wiih one or more substituents selected from the group consisting of haio, -CF3, (Ci-C6)alkoxy, -NO2, (Ci-C6)alkyl, -CN, -(CH2)nOR495 -(CH2)nheterocyclyl, -(CH2),,heteroaryl, -SO2R50 and -(CH2)nNR50R51, and heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3; (Q-Qalkoxy, -NO2, (C|-C6)alkyl, -CN, -(CH2)nOR49, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2RS0 and -(CH2)nNRi0R5i, or
R47 and R48, together with the atom to which they are attached, form a 3-8 membered ring;
R*9 is selected from the group consisting of (Ci-QOalkyl, (C3-Cs)cycloalkyl,
heterocyclyl(Ci-C6)alkylene, aryl(Ci-C6)alkylene wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (C-QOalkyl, -CN, -SO2R50 and -(CH2)nNR50R51, heteroaryl(Ci-C6)alkylene wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (d-C6)alkoxy, -NO2, (CrC6)alkyl, -CN, -SO2R50 and -(CH2)nNRs0R51, aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (C\-C6)alkoxy, -NQ2, (Ci-C6)allcyl, -CN, -SO2R50 and -(CH2)nNR50R51, and heteroaryl optionahy substituted with one or more substituents selected from the group consisting of halo, -CF3, (C,-C6)alkoxy, -NO2, (C,-C6)alkyl, -CN, -SO2R50 and -(CH2)r,NR50R5!;
R50 and R51 are independently selected from the group consisting cf H, (C)-C6)alkyl, (C3-C«)cycloalkyl and -C(O)R45, or
15

WO 2006/010264 POT/CA2005/001177
R50 and R51, together with the atom to which they are attached, form a 3-8 membered ring;
and
E3 is the group defined by -(Zn)-(Z'V(Z13)mb wherein Zu is heterocyclyl or heterocyclylene;
Z12 is selected from the group consisting of OC(O), OC(S) and C(O); Z!3 is selected from the group consisting of heterocyclyl, aralkyl, N(H)R52, (d-CsJalkyl, -
OR52, halo, S(O)2R56, (CrC3)hydroxyalkyl and (C|-C3)haloalkyl; m isOor 1; ml isOor 1; R52 is selected from the group consisting of H, -(CH2)qS(O)2R54, R55NR53R53, (Ci-C3)alkyl,
-(CH2)qOR53, -C(O)R54 and -C(O)OR53; q is 0,1, 2, 3 or 4; R53 is (Ci-C3)alkyl; R54 is (C,-C3)alkyl or N(H)R53; R53 is (CrC6) alkyl; and
R56 is selected from the group consisting of NH2, (Ci-C3)alkyl and OR52.
[0041] In a preferred embodiment of the compounds according to paragraph [0040], T
is aryl or heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with 1 to 3 independently selected R20.
[0042] In a preferred embodiment of the compounds according to paragraph [0040], T
is selected from the group consisting of arylalkyl, cycloalkyl and heterocyclyl, wherein each of said arylalkyl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R20.
[0043] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0042], R20 is selected from the group consisting of H, halogen, -OR17 and -C(O)OR17.
[0044] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0043], R20 is fluorine or chloride.
[0045] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0044], W is O.
[0046] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0045], Z is S or O,
[0047] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0046], Z is S.
16

WO 2006/010264 PCT/CA20O5/001177
[0048] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0047], X and X1 are independently selected from the group consisting of H and d-
C6alkyl, wherein the CrCgalkyl is optionally substituted.
[0049] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0048], X and X1 are both H.
[0050] In a preferred embodiment of the compounds according to paragraphs [0040]
to f0048], X and X1 taken together with the atom to which they are attached, form a C3-
C7cycloalkyl.
[0051] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0050], Rl, R2, R3 and R4 are independently selected from the group consisting of H,
halogen, trihalomethyl, OR17, -NR17R18 and Ci-C6alkyl.
[0052] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0051], R1, R2 and R4 are independently selected from the group consisting of H, halo and
-OR17.
[0053] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0052], R1 is H or halogen.
[0054] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0053], Rl is halogen.
[0055] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0054], R2, R3 and R4 are each H.
[0056] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0055], R17 is a CrC6alkyl.
[0057] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0056], R16 is H or Ci-C6alkyl.
[0058] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0057], Q is selected from the group consisting of CH2, S, -N-(Ci-C6alkyl), N-Y-(aryl)
and -N-OMe.
[0059] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0058], Q is S.
[0060] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0058], Q is CH2.
[0061] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0058], Q is -N-(Ci-C6alkyl).
17

NVO 2M6/010264 PCT/CA2005/«H)l 177
£0062] In a preferred embodiment of the compounds according to paragraphs [0040}
to [0058], Q is -N-Y-(aryl).
[0063] In a preferred embodiment of the compounds according to paragraphs [0040] to [0058], Q is -N-OMe.
[0064] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0063], D is C-E.
[00661 In a preferred embodiment of the compounds according to paragraphs [0040]
to [0064], D is CH.
[0066] In a preferred embodiment of the compounds according to paragraphs [0040] to [0065], L is C-R.
[0067] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0065], R is H or halogen.
[0068] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0065], L is N.
[0069] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0068], E is selected from the group consisting of E1 and E2.
[0070] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0069], EisE1.
[0071] In a preferred embodiment of the compounds according to paragraphs [0040] to [0070], E is E1, wherein E1 is selected from the group consisting of H, halogen, -C(O)NR42R43, -SO2NR42R43, C(=NR42)NR37R43, -CO2R42, -C(O)(heterocyclyl), -C(O)(heteroaryI), -Y-(C6-Ci0 aryi), -Y-(heteroaryl), -Y-(5 to 10 membered heterocyclic), -SR6a, -S(O)R6a, -SO2R6a, wherein each of said E1 other than H and halogen are optionally substituted with 1 to 5 independently selected R38, or El is (Cl-C6)alkyl, which is optionally substituted with 1 to 3 independently selected Y2 groups. [0072] In a preferred embodiment of the compounds according to paragraphs [0040] to [0071], R38 is selected from the group consisting of halogen, -C(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, Ci-C6alkyl, -C(CH2)jO(CH2)iNR36R39, -(CH2)nOR37, -S(O)j(C,-C6alkyl), -(CH2)n-(5 to 10 membered heterocyclic), -(CH2)O(CH2)i(5 to 10 membered heterocyclic), -(CH2)n(5 to 10 membered heteroaryl), -(CH2)jNR39(CH2)iNR36R39, -(CH2),NR39(CH2)nR36, ~(CH2)nNR36R39: wherein j is an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 1 to 6,, the -(CH2);- and -(CH2)n- moieties of the foregoing R38 groups optionally include a carbon-carbon double or triple bond where n is an integer between 2 and 6, and the alkyl, ary],
18

WO 2006/010264 PCT/OA2005/001177
heteroaryl, and heterocyclic moieties of the foregoing R38 groups are optionally substituted
by one or more substituents independently selected from the group consisting of halo,
cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(0)OR4°, -OC(O)R40, -OC(O)OR40, -
NR36C(O)R39, -C(O)Mt36R39, -(CH2)nNR36R39, C,-C6 alkyl, C3-C,o cycloalkyl, -(CH2)n(C6-
Cio aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37,
wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6.
[0073] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0072], the alkyl, aryl, heteroaryl, and heterocyclic moieties of the foregoing R38 groups
are optionally substituted by one or more subslituents independently selected from the
group consisting of-OH and -C(O)OR40.
[0074] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0073], each R42 and R43 is independently selected from the group consisting of H, -Y-
(C3-C10 cycloalkyl), -Y-(C6-Cto aryl), -Y-(C6-C]0 heteroaryl) and -Y-(5 to 10 membered
heterocyclic), wherein the cycloalkyl, aryl, heteroaryl and heterocyclic moieties of the
foregoing R42 and R43 groups are optionally substituted by 1 or more substituents
independently selected from R44.
[0075] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0073], each R42 and R43 is independently selected from the group consisting of II, Ci-Ce
alkyl, d-Co heteroalkyl, -Y'-CO2-R37 and -Y-OR37.
[0076] In a preferred embodiment of the compounds according to paragraphs
[0040]to [0075], one of R42 and R43 is H.
[0077] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0076], one of R42 and R43 is -(C6-C10 heteroaryl) or -Y-(5 to 10 membered heterocyclic).
[0078] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0077], Y is a bond.
[0079] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0077] Y is -(C(R37)(H))n.
[0080] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0079], R42 and R43 taken together with the nitrogen to which they are attached form a
C5-C9 heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1
to 5 independently selected R44 substituents, with the proviso that R42 and R43 are not both
bonded to the nitrogen directly through an oxygen.
19

WO 2006/(110264 PCT/CA2005/001177
[0081] 111 a preferred embodiment of the compounds according to paragraphs [0040]
to [0080], R44 is independently selected from the group consisting of-C(O)NR36R39, -OR37
and CrC6allcyl.
[0082] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0081], each R'10 is independently selected from the group consisting of H and CJ-CJO
alkyl.
[0083] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0082], each R3° andR39 is independently selected from the group consisting of H, Q-
C6alkyl, -(CH2)n(5 to 10 membered heterocyclic), -(CH2)nOR37 and -C(O)OR40, wherein n is
an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that
when R36 and R39 are both attached to the same nitrogen, then R36 and R39 are not both
bonded to the nitrogen directly through an oxygen.
[0084] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0083], each R37 and R4! is independently selected from the group consisting of H and
Ci-C6alkyl.
[0085] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0084], R6a is selected from the group consisting of-(CZ5Z6)u-aryl, -(CZsZ6)u-heteroaryl
and Ci-Cgalkyl, each of which is optionally substituted with 1 to 3 indepedently selected Y3
groups, wherein u is 0, 1,2 or 3, and wherein when u is 2 or 3, the CZ5Z6 units may be the
same or different.
[0086] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0085], R6a is selected from the group consisting of-(CZ5Z6)u-aryl and -(CZ5Z6)U-
heteroaryl, each of which is optionally substituted with 1 to 3 indepedently selected Y3
groups, wherein u is 0.
[0087] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0086], Y2 is -OH.
[0088] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0086], Y3 is -OH.
[0089] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0069], E2 is -CsC-(CR45R45)n-R451 wherein n is an integer ranging from 1 to 6.
[0090] In a preferred embodiment of the compounds according to paragraph [00S9],
R45 is H.
[0091] In a preferred embodiment of the compounds according to paragraph [0089] to
[0090], R46 is a heterocyclyl.
20

WO 2006/010264 PCT/CA2005/001177
[0092] In a preferred embodiment of the compounds according to paragraph [0040],
the compounds are represented by the formula A-0:

and pharmaceutically acceptable salts and complexes thereof, wherein
Z is O or S;
X and X1 are independently selected from the group consisting of H, Ci-C& alkyl, halo,
cyano and nitro, wherein Cj-Co alkyl is optionally substituted; R!, R2, R3 and R4 are independently selected from the group consisting of hydrogen, halo,
trihalomethyl, -OR17, Q-C6 alkyl, C2-Co alkenyl or C2-C(, alkynyl, wherein Ci-O;
alkyl, C2-C6 alkenyl and C2-C6 alkynyl are optionally substituted; Q is O, S, NH, N(Ci-C6 alkyl), or N-Y-(aryl); DisCRu,orN; L is N, or CR, wherein R is H, halo, -CN, CrC6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl,
wherein Cj-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
and R7 is H, halogen, C,-C6 alkyl, -C(=O)NR9R10, -C(=O)(aryl), -C(=0)(heterocyclyl), -
C(=O)(heteroaryl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -S-aryl, -S-Ci-C6
alkyl, -SO-Ci-C6 alkyl, -SO2-Ci-C6 alkyl, -Y-NR9R10, -SO2NR9R10 or CO2R9,
wherein Ci-Cg alkyl, aryl, heterocycle and heteroaryl are each independently
optionally substituted; R9 and R10 are independently selected from H, C^Ce alkyl, -Y-(cycloalkyl), -Y-(aryl), -Y-
(heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y1-CO2-Rn, and -Y-O-R11,
wherein Ci-Q alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally
substituted, or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Y is a bond or is -(C(Rn)(H))r, wherein t is an integer from 1 to 6;
21

WO 21)06/010264 PCT/CA2005/001177
Rn at each occuiTence is independently H or C1-C6 alkyl, wherein Cj-Cs alkyl is optionally
substituted, each R20 is independently selected from the group consisting of hydrogen, halo,
trihalomethyl, OR17, C1-C0 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein Ci-C6
alkyl, C2-C6 a!kenyl and C2-C6 alkynyl are optionally substituted, and each R17 is an independently selected Ci-Cealkyl, wherein said Ci-C6alkyl is optionally
substituted.
[0093] In a preferred embodiment of the compounds according to paragraph [0092], X and X1 are both hydrogen.
[0094] In a preferred embodiment of the compounds according to paragraphs [0092] to [0093], R1 is hydrogen or halogen.
[0095] In a preferred embodiment of the compounds according to paragraphs [0092]
to [0094], R1 is fluorine.
[0096] In a preferred embodiment of the compounds according to paragraphs [0092]
to [0095], R4 is hydrogen or halogen.
[0097] In a preferred embodiment of the compounds according to paragraphs [0092]
to [0096], R4 is fluorine.
[0098] In a preferred embodiment of the compounds according to paragraphs [0092]
to [0097], R2 is selected from the group consisting of H, haiogen, trihalomethyl and -OR17.
[0099] In a preferred embodiment of the compounds according to paragraphs [0092 j
to [0098], R3, and R2Oare each hydrogen.
[0100] In a preferred embodiment of the compounds according to paragraphs [0092] to [0098], R20 is -OR17.
[0101] In a preferred embodiment of the compounds according to paragraphs [0092] to [0100], Q is S, N(Ci-C6 alkyl), or N-Y-(aryl).
[0102] • In a preferred embodiment of the compounds according to paragraphs [0092] to [0100],QisNH.
[0103] In a preferred embodiment of the compounds according to paragraphs [0092] to [0102],DisCRn.
[0104] In a preferred embodiment of the compounds according to paragraphs [0092] to [0103],LisCHorN.
[0105] In a preferred embodiment of the compounds according to paragraphs [0092] to [0104], R7 is H, halogen, Cj-C6 alkyl, -CONR9R10, -SO2NH2, -SO2NR9R!0, -Y-heterocyclyl, -Y-heteroaryh -S-aryi, -S-C,-C6 alkyl, -SO-Ci-Q alkyl, or -SO2-CrC6 alkyl, wherein Q-Q
22

WO 2006/010264 PCT/CA2005/001177
alky I, is unsubstituted or is substituted with one or two of hydroxy or halogen, and
heterocyclyl, and heteroaryl are unsubstituted or substituted with one or two of alkoxy,
alkyl, or haloalkyl.
[0106] In a preferred embodiment of the compounds according to paragraphs [0092] to
[0105], R7 is -CONR9R10.
[0107] In a preferred embodiment of the compound according to paragraphs [0092] to
[0105],R7isY-heteroaryl.
[0108] In a preferred embodiment of the compounds according to paragraph [0106], R9
and Rt0 are independently H, C,-C6 alkyl, -Y-O-R11, -Y-(heterocycle), -Y'-CQrR11, or -Y-
(aryl), wherein C]-Ce alkyl is unsubstituted or is substituted with one or two of hydroxy or
halogen, and heterocyclyl, and aryl are unsubstituted or are substituted with one or two of
alkoxy, alkyl, or haloalkyl.
[0109] In a preferred embodiment of the compounds according to paragraph [0106], R9
and R10 are taken together with the nitrogen to which they are attached to form a
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring, wherein said
ring is unsubstituted or is substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0110] In a preferred embodiment of the compounds according to paragraphs [0092] to
[0105], R7 is H, halogen, CrC6 alkyl, -SO2NR9R10, -C(=O)(heterocyc!yI), -Y-
(heterocyclyl), or -Y-(heteroaryl), wherein d-Cg alkyl is unsubstituted or is substituted with
one or two of hydroxy or halogen, and heterocyclyl, and heteroaryl are unsubstituted or are
substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0111] In a preferred embodiment of the compounds according to paragraphs [0092] to
[0110], Z is sulfur.
[0112] In a preferred embodiment of the compounds according to paragraph [0040], the
compounds are represented by the formula A-l:

and pharmaceutically acceptable salts and complexes thereof, wherein
23

WO 2(106/010264 PCT/CA2005/IMI1177
R1 is selected from the group consisting of hydrogen, halo, C]-C6 alkyl, C2-C6 alkenyl or
C2-C6 alkynyl, wherein Ci-C0- alkyl, C2-Q alkenyl and C2-C6 alkynyl are optionally
substituted;
X and X1 are independently selected from the group consisting of H and CrC6 alkyl, wherein Q-C6 alkyl is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C7 cycloalkyl;
R7 is H, halogen, CrC6 alkyl, -C(=O)NR9R10, -C(O)(aryl), -C(=0)(heterocyclyl), -
C(=O)(heteroaryl)s -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -SR6a, -S-aryl, -S-(heteroaryl), -S~CrC6 alkyl, -SO-CrC6 alkyl, -SO2-Ci-C6 alkyl, -Y-NR9R10, -SCbNR9R!(), CO2R\ ~CHC-(CR4sR45)n-R46and-C(-NR42)NR37R43, wherein n is an integer ranging from 0 to 6 and wherein CrC6 allcyl, aryl, heterocycle and heteroaryl are each independently optionally substituted with 1 to 5 independently selected R38;
R9 and R10 are independently selected from H, Ci-C alkyl, -Y-(cycloalkyl), -Y-(C,-C6 heteroalkyl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y1-CO2-Rn, Y-C(O)OR37 and -Y-O-R11, wherein said Cj-Ce alkyl,heteroalkyls cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally substituted with one or more independently selected R44, or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44;
each R20 is independently selected from the group consisting of H, halo, -OR17 and -C(O)OR";
Y is a bond or is -(C(R")(H))r, wherein t is an integer from 1 to 6;
Y>is-(C(Rn)(E))V;and
Rl! at each occurrence is independently H or C1-C6 alkyl, wherein C1-C6 alkyl is optionally
substituted.
[01131 In a preferred embodiment of the compounds according to paragraph [0112], R1
is hydrogen or halogen.
[0114] In a preferred embodiment of the compounds according to paragraph [0112] to
[0113],R! is fluorine.
[0115] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0114], R7 is selected from the group consisting of H, -C(=O)MR.9R10, -Y-(aryl), -Y-
(heteroaryl) and -S-Cj-C6 alkyl, wherein said -Y-(aryl), -Y-(heteroaryl) and -S-CrC6 alkyl
are optionally substituted with 1 to 5 independently selected R3S.
24

WO 2006/010264 PCT/CA2005/OOI177
[0116} In a preferred embodiment of the compounds according to paragraphs [0112] to [0115], R7 is -C(=O)NR9R10, optionally substituted with one or more independently selected R44.
[0117] In a preferred embodiment of the compounds according to paragraphs [0112] to [0115], R? is -Y'(aryl), optionally substituted with 1 to 5 independently selected R38. [0118] In a preferred embodiment of the compounds according to paragraphs [0112] to [0115], R1 is -Y-(heteroaryl), optionally substituted with 1 to 5 independently selected R38. [0119] In a preferred embodiment of the compounds according to paragraphs [0112] to [0118], R38 is selected from the group consisting of halogen, -OR37, Ci-Csalkyl, -(CH2)n-(5 to 10 membered heterocyclyl), -(CH2)jNR39(CH2)nR36, -(CH2)JNR39(CH2)iNR36R39, -(CH2)n-hcteroaryJ, -C(O)NR36R39, -(CH2)nO(CH2),(5to 10 membered heterocyclyl) and -(CHZ^OCCHj^NR^R39, wherein n is an integer ranging from 0 to 6, j is an integer ranging from 0 to 2 , j is an integer ranging from 1 to 6 and wherein the alkyl, heteroaryl and heterocyclyl moieties of the foregoing R38 groups are optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -(CH2)nNR36R39, Ci-C6 alkyl, C3-Ci0 cycloalkyl, ~(CH2)n(C6-Cio aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6.. [0120] In a preferred embodiment of the compounds according to paragraphs [0112] to [0119], R38 is selected from the group consisting of-OR37, Ci-C6alkyl, -(CH2)n(5 to 10 membered heterocyclyl) and -(CH2)nO(CH2)j(5 to 10 membered heterocyclyl). [0121] In a preferred embodiment of the compounds according to paragraphs [0112] to [0120], R9 and R10 are independently selected from the group consisting of H, C\-C6 alkyl, -C,-C6 heteroalky!, -Y-(aryl), -Y-(heterocycIyl), -Y-(heteroaryl), -Y-O-R" and Y-C(O)OR37, wherein a C1-C6 alkyl, Cj-Co heteroalkyl, aryl, heterocyclcyl and heteroaiyl are each optionally substituted with 1 or more independently selected R44. [0122] In a preferred embodiment of the compounds according to paragraphs [0112] to [0121 ], R44 is selected from the group consisting of Cj-Ca alkyl, -OR37, -C(O)NR36R39 and -C(O)OR45.
[0123] In a preferred embodiment of the compounds according to paragraphs [0112] to [0122], R36 is selected from the grouip consisting of H, Q-C6 alkyl, -(CH2)nOR37 and -(CH2)n(heterocyclyl).
25

WO 2006/010264 PCT/CA2005/001177
[0124] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0123],R39isHorCi-C6alkyl.
[0125] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0124], R37 is H or CrC6 alkyl.
[0126] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0125], R20 is selected from the group consisting of H, halogen, -OR17 and -C(O)OR17.
[0127] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0126], R17 is H or CrC [0128] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0127], R20 is halogen.
[0129] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0128],R20isClorF.
[0130] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0129], R6a is -(CZ^Varyl.
[0131] In a preferred embodiment of the compounds according to paragraph [0112] to
[0114], R7 is selected from the group consisting of H, halogen, Ct-C6 alkyl, -C0NR9R10, -
SO2NH2, -SOJNRV0, -Y-heterocyclyl, -Y-heteroaryl, -S-aryt, -S-C,-C6 alkyl, -SO-CrC6
alkyl, or -SO2-Ci-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or is substituted with one or
two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are
substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0132] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0114], R7 is selected from the group consisting of H, halogen, CrQ alkyl, -SC^NR'R10, -
C(=O)(heterocyclyl), -Y-(heterocyclyl), -Y-(heteroaryl), -S-aryl, -S-C]-C6 alkyl, -SO-Ci-Q
alkyl, or -SO2-Ci-Q alkyl, wherein d-Cs alkyl is unsubstituted or is substituted with one or
two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are
substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0133] In a preferred embodiment of the compounds according to paragraph [0116], R9
and R10 are independently selected from the group consisting of H, CrC& alkyl, C1-C6
heteroalkyl, -Y-O-R11, -Y-(heterocycle), -Y-CO2-R11, -Y-(aryl) and -Y-(heteroaryl),
wherein C1-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or
halogen, and the heterocyclyl, aryl and heteroaryl are unsubstituted or are substituted with
one or two of alkoxy, alkyl, or haloalkyl.
[0134] In a preferred embodiment of the compounds according to paragraph [0116], R9
and R!0 are taken together with the nitrogen to which they are attached to form a
26

WO 2006/010264 PCT/CA2005/001177
27
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with one or two of atkoxy, alkyl, or haloalkyl. [0135] In a preferred embodiment of the compounds according to paragraph [0116], NR9R10 is selected from:


WO 2006/010264 PCT/CA2005/001177
[0136] In a preferred embodiment of the compounds according to paragraph [0118] R7
is unsubstituted heteroaryl.
[0137] In a preferred embodiment of the compounds according to paragraph [0136], R7
is thiazolyl, pyridinyl, pyrimidinyl, and imidazolyl, each of which is preferably
unsubstituted or is substituted with one or two of alkoxy, or alkyl.
[0138] In a preferred embodiment of the compounds according to paragraphs [0131] to
[0132], R7 is C1-C6 alkyl, unsubstituted or substituted with hydroxy.
[0139] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0138], X and X1 are both H.
[0140] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0139], R17 is selected from the group consisting of H and C1-C6 alkyl.
[0141] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0140], R38 is selected from the group consisting of-OR37, C|-C6 alkyl and -(CH2)n(5 to 10
membered heterocylic), wherein n is an integer ranging from 0 to 6.
[0142] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0141], RJ? is selected from the group consisting of H and C1-C6 alkyl.
[0143] In a preferred embodiment of the compounds according to paragraph [0040], the
compounds are represented by the formula A-2:

and pharmaceutical ly acceptable salts and complexes thereof, wherein
R1 is selected from the group consisting of hydrogen, halo, Q-C6 alkyl, C2-C6 alkenyl or
C2-C6 alkynyl, wherein C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl are optionally
substituted;
R4 is selected from the group consisting of H and halogen;
R7 is selected from the group consisting of H, halogen, Ci-Ce alkyl, -C(=O)NR9R10, -
C(=O)(aryl), -C(=O)(heterocyclyl), -C(=O)(heteroaryl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -S-aryl, -S-C,-C6 alkyl, -SO-Ci-C6 alkyl, -SO2-Ci-C6 alkyl, -Y-NR9R10, -SO2NR9R!0 and CO2R9, wherein CrC6 alkyl, aryl, heterocycle and
28

WO 2006/010264 PCT/CA20O5/0O1177
heteroaryl are each independently optionally substituted with 1 to 5 independently
selected R38; R9 and R10 are independently selected from the group consisting of H, Ci-Q alkyl. -Y-
(cycloalkyi), -Y-(aryl). -Y-(heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y1-
COrRU and -Y-O-R1', wherein Ci-C6 alkyl, cycloalkyl, aryl, heterocycle, and
heteroaryl are each optionally substituted with one or more independently selected
R^or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Y is a bond or is -(C(Rn)(H)V> wherein t is an integer from 1 to 6; Y, is-(C(RM)(H)>, and
R" at each occurrence is independently H or Q-Ce alkyl, wherein CrC6 alkyl is optionally substituted.
(0144] In a preferred embodiment of the compounds according to paragraph [0143], Rl is hydrogen or halogen.
[0145] In a preferred embodiment of the compounds according to paragraphs [0143] to 1.0144], RWs fluorine.
[0146] In a preferred embodiment of the compounds according to paragraphs [0143] to [0145], R4 is selected from the group consisting of H and halogen, [0147] In a preferred embodiment of the compounds according to paragraphs [0143] to [0146], R4 is fluorine.
[0148] In a preferred embodiment of the compounds according to paragraphs [0143] to [0147], R7 is selected ftom the group consisting of H, halogen, C1-C6 alkyl, -C(=O)NR9R10, -SO2NH2, -SO2NR9R10, -Y-hetcrocydyl -Y-heteroaryl, -S-aryl, -S-Cl-C6 alkyl, -SO-C1-C6 alkyl and -SO2-C1-C6 alkyl, wherein CI-C6 alkyl, heterocyclyl, heteroaryl and aryl are each optionally substituted with 1 to 5 independently selected R38. [0149] In a preferred embodiment of the compounds according tc paragraphs [0143] to [0147], R7 is selected from the group consisting of H, halogen^ C1-C6 alkyl, -C(=O)NR9R10, -SO2NH2, -SO2NR9R10, -Y-heterocyclyl -Y-heteroaryl, -S-aryl, -S-Cl-C6 alkyl, -SO-C1-C6 alkyl and -SO2-C1-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, haloalkyi or (CH2)jNR39(CI-I2)nO(CH2)iOR37.
29

WO 2006/010264 PCT/CA2005/001177
£0150] In apreferred embodiment of the compounds according to paragraphs [0143] to
[0147], R7 is selected from the group consisting of H, halogen, C1-C6 alkyl, -SO2NR9R10,
-C(=O)(heterocyclyl), -Y-(heterocyclyl), -Y-(heteroaryl), -S-aryl, -S-C1-C6 alkyl, -SO-C1-
C6 allcyl, or -SO2-C1-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or is substituted with
one or two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or
are substituted with one or two of alkoxy, alkyl, haloalkyl or
(CH2)jNR39(CH2)nO(CH2)iOR37.
[0151] In a preferred embodiment of the compounds according to paragraphs [0143] to
[0150], R7 is selected from the group consisting of C1-C6 alkyl, -C(=O)NR9R10, -Y-
(heterocyclyl, -Y-(heteroaryl), -S-C1-C6 alkyl and -SO-C1-C6 alkyl, wherein C1-C6 alky!
is unsubstituted or is substituted with one or two of hydroxy or halogen, and the
heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy,
alkyl, haloalkyl or (CH2)jNR39(CH2)nO(CH2)iOR37.
[0152] In a preferred embodiment of the compounds according to paragraphs [0143] to
[01Sl],R7isCONR9R10.
[0153] In a preferred embodiment of the compounds according to paragraph [0152], R9
and RIO are independently selected from the group consisting of H, C1-C6 alkyl, -Y-O
Rl 1, -Y-(heterocycle), -Y1-CO2-R11 and -Y-(aryl), wherein the alkyl, heterocyclyl and
aryl moieties of the foregoing R9 and R10 groups are optionally substituted with 1 or more
substituents independently selected from R44.
[0154] In a preferred embodiment of the compounds according to paragraphs [0152] to
[0153], R9 and R10 are independently selected from the group consisting of H, C1-C6
alkyl, -Y-O-Rll, -Y-(heterocycle), -Y1-CO2-R11 and -Y-(aryl), wherein C1-C6 alkyl is
unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl,
and aryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, haloalkyl or
(CH2)jNR39(CH2)nO(CH2)iOR37.
[0155] In a preferred embodiment of the compounds according to paragraph [0152], R9
and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyi ring or a heteroaryl ring, wherein said ring is optionally substituted.
[0156] In a preferred embodiment of the compounds according to paragraph [0155], R9
and R10 are taken together with the nitrogen to which they are attached to form a
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring, wherein said
ring is unsubstituted or is substituted with one or two of alkoxy,. alkyl, or haloalkyl.
30

WO 2006/010264 PCT/CA20O5/OO1177
[0157] In a preferred embodiment of the compounds according to paragraph [0152], NR9R10 is selected from the group consisting of:

[0158] In a preferred embodiment of the compounds according to paragraph [0040], the compounds are represented by the formula A-3:

and pharmaceuticslly acceptable salts and complexes thereof, wherein
R7 is selected from the group consisting of H, -Y-(aryl) and -Y-(heteroaryl), wherein -Y-
(aryl) and -Y-(heteroaryl) are optionally substituted with 1 to 5 independently
selected R38; R1 is selected from the group consisting of hydrogen, halo, Q-Q alkyl. C2-C6 alkenyl and
C2-C6 alkynyl, wherein C1-C6 alkyl, Cz-C^ alkenyl and C2-Q alkynyl are optionally
substituted; R12 is selected from the group consisting of H, C\-Ce alkyl, -O(Ci-C wherein C1-C6 alkyl and aryl are optionally substituted; Y is a bond or is -(C(RH)(H))r, wherein t is an integer from 1 to 6; Rn is H or Ci-Ce alkyl, wherein Ci-Ce alkyl is optionally substituted; and each R20 is independently selected from the group consisting of H and halogen. [0159] In a preferred embodiment of the compounds according to paragraph [0158], R1 is hydrogen or halogen.
[0160] In a preferred embodiment of the compounds according to paragraphs [0158] to [0159], R! is fluorine.
[0161] In a preferred embodiment of the compounds according to paragraphs [0158] to [0160], R12 is unsubstituted Cj-C3 alkyl or unsubstituted -Y-phenyl.
31

WO 2006/010264 PCT/CA2U05/001177
[0162] In apreferred embodiment of the compounds according to paragraphs [0158] to
[016i],R20isCl.
[0163] In a preferred embodiment of the compounds according to paragraph [0040], the
compounds are represented by the formula A-4:

and pharmaceutically acceptable salts and complexes thereof, wherein
Z is O or S;
X and X! are independently selected from the group consisting of H, Ci-Cg alkyl, halo,
cyano and nitro, wherein Cj-Ce alkyl is optionally substituted; R1, R2, R3, R4, R1 and R6 are independently selected from the group consisting of hydrogen,
halo, C,-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and NR17R1S, wherein CrC6 alkyl,
Cz-C(, alkenyl and C2-C6 alkynyl are optionally substituted; R17 and R18 are independently Ci-C6alfcyl; Q is O, S, NH, N(Ci-C6 alkyl), or N-Y-(aryl); DisCR",orN; L is N, or CR, wherein R is selected from the group consisting of H, halo, -CN, CrQ alkyl,
C2-G5 alkenyl and C2-C6 alkynyl, wherein Ci-C6 alkyl, C2-C6 alkenyl, and C2-C.6
alkynyl are optionally substituted; and
R13 is heterocyclyl or heteroaryl, wherein heterocyclyi and heteroaryl are optionally substituted with 1 to 5 independently selected R38; Y is a bond or is -(C(Rn)(H))r, wherein t is an integer from 1 to 6; and R!1 at each occurrence is independently H or C\-C$ alkyl, wherein Ci-Cg alkyl is optionally
substituted.
[0164] In a preferred embodiment of the compounds according to paragraph [0163], X and X1 are both hydrogen.
[0165] In a preferred embodiment of the compounds according to paragraphs [0163] to [0i64], R1, R2, R3 and R4 are independently H or halogen.
[0166] In a preferred embodiment of the compounds according to paragraphs [0163] to [0165], R1 is hydrogen or halogen.
32

WO 2006/010264 PCT/CA2O05/O01177
[0167] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0166], R1 is fluorine or chlorine.
[0168] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0167], R4 is hydrogen or halogen.
[0169] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0168], R4 is fluorine or chlorine.
[0170] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0169], R2, R\ R5, and R6 are each hydrogen.
[0171] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0170], Q is selected from the group consisting of S, N(Ci-C6 alky!) and N-Y-(aryl).
[0172] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0171], Q is S.
[0173] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0172],DisCRu.
[0174] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0173], Rl 1 isH.
[0175] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0174],LisCHorN.
[0176] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0175],LisCH.
rfl177l In s» nrpfprrprl pmhnHimpnt nf ihp mmnnimHe arrdrAino tn nnrnoranfic Ffii/v^i-
J3

WO 2006/010264 PCT/CA2005/00117?

and pharmaceutically acceptable salts and complexes thereof, wherein
R7 is selected from the group consisting of H, -C(O)NR42R43, -Y-(aryl), -Y-(heteroaryl), -
C(0)-(C3-Cio cycloalkyl), -C(O)-(heterocyclyl), -C(O)-(C6-Ci0 aryl) and -C(O)-
(heteroaryl), wherein the aforementioned R7 groups other than H are optionally
substituted with 1 to 5 independently selected R38; R4 is selected from the group consisting of H and halogen; and T is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl and
arylalkyl, each of which is optionally substituted with 1 to 3 independently selected R20; [0182] In a preferred embodiment of the compounds according to paragraph [0181], R7 is selected from the group consisting of H, C(O)NR42R43 and -Y-(heteroaryl), wherein -Y-(heteroaryl) is optionally substituted with ) to 5 independently selected R38; [0183] In a preferred embodiment of the compounds according to paragraphs [0181] to [0182],R7isC(O)NR42R43;
[0184] In a preferred embodiment of the compounds according to paragraphs [0181] to [0183], R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9 heterocyclyl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44 substituents, with the proviso that R42 and R43 are not both bonded to the nitrogen directly through and oxygen.
[0185] In a preferred embodiment of the compounds according to paragraphs [0181 ] to [0184], R4 is halogen.
[0186] In a preferred embodiment of the compounds according to paragraphs [0181] to [0185], R4 is fluorine.
[0187] In a preferred embodiment of the compounds according to paragraph [0040], the compounds are represented by the formula A-6:
34

WO 2006/010264 PCT/C A2005/001177

and pharmaceutically acceptable salts and complexes thereof, wherein
R1 is selected from the group consisting of hydrogen, halo, Ci-Q alkyl, C2-C6 alkenyl or C2-Q; alkynyl, wherein Q-C6 allcyl, C2-C6 alkeny! and C2-C6 alkynyl are optionally substituted;
R7 is selected from the group consisting of H, halogen, Ci~C6 alkyl, -C(O)NR9R10, -
C(=O)(aryl), -C(=O)(heterocyclyl), -C(=O)(heteroaryl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -SR6a, -S-aryl, -S-(heteroaryl), -S-Ci-C6 alkyl, -SO-Ci-C6 alkyl, -SCVCi-Ce alkyl, -Y-NR9R10, -SO2NR9R10, CO2R9, -CHC-(CR45R45)n-R46 and -C(=NR42)NR37R43, wherein n is an integer ranging from 0 to 6 and wherein CpCg alkyl, aryl, heterocycle and heteroaryl are each independently optionally substituted with 1 to 5 independently selected R38;
R9 and R10 are independently selected from the group consisting of H, Cj-C$ alkyl, -Y-(cycloalkyl), -Y-(CrC6heteroalkyl), -Y-(aryl), -Y-{heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y'-CO2-Rn, Y-C(O)OR37 and -Y-O-R11, wherein said C,-C6 alkyl,heteroalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally substituted with one or more independently selected R4\ or
R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44;
each R20 is independently selected from the group consisting of H, halo, -OR17 and -C(O)OR17;
Y is a bond or is -(C(R! l)(H))r, wherein t is an integer from 1 to 6;
YMs-(CCRn)(H)X-;and
R11 at each occurrence is independently H or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted.
[0188] In a preferred embodiment of the compounds according to paragraph [0187], R7
is selected from the group consisting of H, C(O)NR9R10 and -Y-(heteroaryl), wherein -Y-
(heteroaryi) is optionally substituted with 1 to 5 independently selected R38;
35

WO 2006/010264 PCT/CA2005/OO1177
[0189] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0188],R7isC(O)NR9R10;
[0190] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0189], R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring, wherein said ring is optionally substituted with 1 to 5 independently
selected R44 substituents.
[0191] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0190], R' is -Y-(heteroaryl), wherein said -Y-(heteroaryl) is optionally substituted with 1 to
5 independently selected R38.
[0192] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0191], R7 is -Y-(heteroaryl), wherein said -Y-(heteroaryl) is optionally substituted with one
Ci-Cc alkyi.
[0193] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0192], R! is halogen.
[0194] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0193], R'is fluorine.
[0195] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0194], R!7 is selected from the group consisting of H and Ci-Ce alkyi.
[0196] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0195], R38 is selected from the group consisting of-OR37, C-C6 alky! and -{CH2)n(5 to 10
membered heterocylic), wherein n is an integer ranging from 0 to 6.
[0197] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0196], Rj7 is selected from the group consisting of H and Ci-Ct alkyi.
[0198] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0197], each R20 is independently selected from the group consisting of H, halogen and -O-
(Ci-C6)alkyl.
[0199] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0198], two R20 are H and the third R20 is selected from the group consisting of H, halogen
and-O-(Ci-C6 alkyi).
[0200] In a second aspect, the invention comprises compounds of formula (B), which
are inhibitors of VEGF receptor signaling and fIGF receptor signaling:
36

WO 2006/010264 PCT/CA2OO5/001177

and pharmaceutically acceptable salts and complexes thereof, wherein T is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 1 to 3 R20;
each R20 is independently selected from the group consisting of-H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR17, -OCF3, -NRl7R18, -S(0)o.2R!7, -S(O)2NR17R17, -C(O)OR17, -C(O)NRI7R17, -N(R17)SO2R17, -N{R17)C(O)R17, -N(R17)C(O)OR17, -C(O)R17, -C(O)SR17, C,-C4 alkoxy, CrC4 alkylthio, -O(CH2)naryl, -O(CH2)nheteroaryl, -(CH2)o-5(aryl), -(CH2)0.5(heteroaryl), CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkyny], ~CH2(CH2)o-4-T2, an optionally substituted CM alkylcarbonyl, C14 alkoxy, an amino optionally substituted by C1-4 alkyl optionally substituted by CM alkoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe?, -NHEt and -NEt2, and wherein the aryl, heteroaryl, C\-Ce alkyl, C2-Cs alkenyl, and C2-Ce alkynyl are optionally substituted; W is selected from the group consisting of O, S and NH; Z is selected from the group consisting of O, or S and NH; X and X1 are independently selected from the group consisting of H, CrC6 alkyl, halo,
cyano, or nitro, wherein Ct-C6 alkyl is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C7 cycloalkyl; R1, R2, RJ and R4 are independently selected from the group consisting of hydrogen, halo, trihalomethyl, -CN, -NO2, -NH2, -ORr/, -NR17R18, -C(O)OR17, -C(O)Ri7, C1-C4 alkoxy, C1-C4 alkylthio, Q-Q alkyl, C2-Ce alkenyl or C2-C6 alkynyl, wherein Q-Cg alkyl, C2-C6 alkenyl and C2-C6 alkynyl are optionally substituted; R17 is selected from the group consisting of H and R18;
R1S is selected from the group consisting of a Ci-Cg alkyl, an aryl, an aryl(CrC6 alkyl), a heterocyclyl and a heterocyclyl(Ci-C6 alkyl), each of which is optionally substituted, or
37

WO 2006/010264 PCT/CA2OO5/OO1177
R17 and R's, taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heleroatom selected from the group consisting of N, 0, S and P; R16 is selected from the group consisting of-H, -CN, -(CH2)o-5(aryl), -(CH2)o.s(heteroaryi), C,-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)0-4-T2, an optionally substituted Cu alkylcarbonyl, and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMez, -NHEt and -NEt2j and wherein the aryl, heteroaryl, Ci-Ce alkyl, Cj-Cg alkenyl, and C2-C6 alkynyl are optionally substituted;
D is selected from the group consisting of CH2, O, S, NH, N-(CrCo alkyl), or N-Y-(aryl), -N-OMe, -NCH2OMe and -N-Bn; Q is selected from the group consisting of C-E and N; L is N, or CR, wherein R is selected from the group consisting of-H, halo, -CN, Ci-Cg
alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein Ci-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted; and E is selected from the group consisting of E1, E2 and E3; wherein E1 is selected from the group consisting of-H, halogen, nitro, azido, C]-Cg alkyl, C3-C10 cycloalkyl, -C(O)NR42R43, -Y-NR42R43, -NR42C(=O)R43, -SO2R42, -SO2NR42R43, -NR37SO2R42, -NR37SO2NR42R43, -C(=N-OR42)R43, -C(=NR42)R43, -NR37C(=NR42)R43, ~C(=NR42)NR37R43, -NR37C(=NR42)NR37R43, -C(O)R42, -CO2R42, -C(O)(heterocyclyl), -C(O)(C6-C,0 aryl), -C(O)(heteroaryl), -Y-(C6-Ci0 aryl), -Y-(heteroaiyl), -Y-(5-10 membered heterocyclic), -NR5aR6b, -NR6aSO2R6b5 -NR6aC(O)Rdb, -OC(O)R6b, -NR6aC(O)OR6b, -OC(O)NR6aR6b,-OR6a, -SR6a, -S(O)R6\ -SO2R6a, -SO3R6a, -SO2NR6aR6b, -SO2NR42R43, -COR6a, -CO2R6a, -CONR6aR6b, -(Cr C4)fluoroalkyl, -(Ci-C4)fiuoroalkoxy, -(CZ3Z4)-,CN, wherein n is an integer ranging from 0 to 6, and the aforementioned E1 groups other than -H and halogen are optionally substituted by 1 to 5 independently selected R38, or E1 is selected from a moiety selected from the group consisting of -(CZ3Z4)a-aryl, -(CZ3Z4)a-heterocycle, (C2-C 38

WO 2006/010264 PCT/CA2005/001177
each R38 is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, CrC6 alkyl, -(CH2)JO(CH2),NR36R39, -(CH2)nO(CH2)iOR371 -(CH2)nOR37, -SCO^d-Ce alkyl), -(CH2)n(C6-C10 aryl), -(Cn2UC5-C]0 heteroaryl), -(CH2)n(5-10 membered heterocyclyl); -C(O)(CH2)a(C6-C10 aryl), -(CH^OCCII^Q-C,,, atyl), -(CH2),,O(CH2)i(5-10 membered heterocyclyl), -C(O)(CH2)n(5-10 membered heterocyclyl), -(CH2)jNR39(CH2),NR36R39, -(CH2)jNR39CH2C(O)NR36R395 -(CH2)JNR39(CH2)iNR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)iOR37) -(CH2)jNR39(CH2),S(O)j(C,-C6 alkyl), -(CH^NR^CH^R36, -SO2(CH2)n(C6-CI0 aryl), -SO2(CH2)n(5-10 membered heterocyclyl), -(CH2)nNR36R3S, -NR37SO2NR3(iR39, SO2R36, C2-C6 alkenyl, C3-C10 cycloalkyl and C;-C6 alkylamino, wherein j is an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 0 to 6, the -(CH2),- and -(CH2)n- moieties of the foregoing R38 groups optionally include a carbon-carbon double or triple bond where n is an integer between 2 and 6, and the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R3S groups are optionally substituted by one or more substituents independently selected from halo, cyano, nitro, trifluorornethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R405 -OC(0)OR4°, -NR3(5C(O)R3?, -C(O)NR36R39, -{CH2)nNR36R39, CrC6 alkyl, C3-C10 cycloalkyl, -(CH2)n(C6-Cio aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)jOR37, and -(CH2)nOR37, wherein n is an integer langing from 0 to 6 and i is an integer ranging from 2 to 6;
each R42 and R43 is independently selected from the group consisting of H, Cj-Q alkyl, Q-C6 heteroalkyl, -Y-(C3-C!0 cycloalkyl), -Y-(C5-Ci0 aryl), -Y-(C6-Ci0 heteroaryl), -Y-(5-10 membered heterocyclic), -Y-O-Y'-OR37, -Y'-CO2-R37, and -Y-OR37, wherein the alkyl. heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or more substituents independently selected from R44, wherein
Y is a bond or is -(C(R37)(H))n,
n is an integer ranging from 1 to 6, and
Y1is-(C(R37)(H))n,or
R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1
39

WO 2006/010264 PCT/CA2005/001177
to 5 R44 substituents, with the proviso that R42 and R43 are not both bonded to the nitrogen directly through an oxygen;
each R44 is independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -OC(O)R40, -0C(O)0R40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SCbNR36R39, -SO2R36, -NR36SO2R39, -NR36SO2NR37R41, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, -C,-C6 alkylaraino, -(CH2)jO(CH2)iNR36R39, -CCH2)nO(CH2)iOR37, -(CH2)nOR37, -S(O)j(C,-C6 alkyl), -(CH2)n(C6-C10 aryl), -(CH2)n(5-10 membered heterocyclic), -C(0)(CH2)n(C6-C,o aryl), -{CH2)nO(CH2)j(C6.C,0 aryl), -(CH2)nO(CH2)i(5 to 10 membered heterocyciic), -C(O)(CH2)n(5 to 10 membered heterocyclic), ~(CH2)jNR39(CH2),NR36R39, -(CH2)jNR39CH2C(O)NR36R39, -(CH2)jNR39(CH2),NR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)iOR37, -(CH2)jNR39(CH2)iS(O)j(C1-C6 alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-C10 aryl), and -SO2(CH2)n(5 to 10 membered heterocyclic) wherein, j is an integer from 0 to 2, n is an integer from 0 to 6 and i is an integer ranging from 2 to 6, the -(CH2)i-and -(CH2)ni- moieties of the foregoing R44 groups optionally include a carbon-carbon double or triple bond wherein n is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R44 groups are optionally substituted by 1 or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(0)OR4°, -OC(O)R4Q, -OC(O)OR40,-
40

WO 2006/010264 PCT/CA2005/001177
CO(O)R40, -OC(O)OR40, -NR37C(O)R41, -C(O)NR37R41, -NR37R4t, -C,-C6 alkyl, -(CH2)n(C6-Cio aryl), -(CH2)n(5 to 10 membered heterocyclic), -(CH2)r.O(CH2)iOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that when R36 and R39 are both attached to the same nitrogen, then Rj6 and R39 are not both bonded to the nitrogen directly through an oxygen;
each R37 and R4! is independently selected from the group consisting of H, OR36, CrC6
alkyl and C3-CIQ cycloalkyl;
each Roa and Rob is independently selected from the group consisting of hydrogen, -(CZ'ZV(C3-C6)cycIoalkyl, -(CZsZ6)u-(C5-C6)cycloa!keny!, -(CZ5Z6)u-aryl, -(CZ^u-heterocycle, (C2-C6)alkenyl, and (Ci-Ce)alkyl, which is optionally substituted with 1 to 3 independently selected Y3 groups, where u is 0,1, 2, or 3. and wherein when u is 2 or 3, the CZSZ° units may be the same or different, or
R03 and R6b taken together with adjacent atoms can form a heterocycle;
each Z3, Z4, Z5 and if is independently selected from the group consisting of H, F and (C|-C6)alkyl, or
each Z3 and Z4, or Z5 and Z6 are selected together to form a carbocycle, or
two 'V groups on adjacent carbon atoms are selected together to optionally form a carbocycle;
each Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, azido, -C(O)Z7, -0C(0)NH2, -OC(O) NHZ7, -OC(O)NZ7Z8, -NHC(O)Z7, -NHC(O)NH2, -NHC(0)NHZ7, -NHC(O)NZ7Z8, -C(O)OH, -C(O)OZ7, -C(O)NH2: -C(O)NHZ7,-C(O)NZ7Z!i! -P(O)3H2, -P(O)3(Z7)2, -S(O)2fi -S{O)Z7, -S(O)2Z75 -S(O)jZ7, -Z7, -OZ7, -OH, -NH2: -NHZ7r ¦• MZ7Z8: -C(-Nl-i)NH25-C(-NOH)NH2, -N-morphoiino, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C2-C6)haioalkenyl, (C2-C6)haioalkynyl,"(C1-C6)haloalkoxy, -(CZ9Z10)rNH2, -(CZ9Z10)rNHZ3, -(CZ9Z10)rNZ7Z3, -X6(CZ9Z10)r(C3-Cs)cycloalkyl, -X6(CZ9Z10)r(C5-C8)cycloalkenyl, -X6(CZ9Z!0)r-aryl and -X6(CZ9ZJ0)r heterocycle, wherein
r is 1,2. 3 or 4;
X6 is selected from the group consisting of O, S, NH, -C(O)-, -C(O)NH-, -C(O)O-, -S(O)-, -S(O)2- and -S(O)3-;
Z7 and 7} are independently selected from the group consisting of an alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms, an alkynyl of 2 to 12 carbon atoms, a
41

WO 2006/010264 PCT/CA2005/001177
cycloalkyl of 3 to 8 carbon atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14 carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15 carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or
Z7 and Z8 together may optionally form a heterocycle;
Z9 and Z!o are independently selected from the group consisting of H, F, a (CrC[2)alkyl, a (C6-Ci4)aryl, a (C5-Ci4)heteroaryl, a (C7-Cis)aralkyl and a (C5-Ci4)heteroaralkyl, or
Z9 and Z10 are taken together form a carbocycle, or
two Z9 groups on adjacent carbon atoms are taken together to form a carbocycle; or
any two Y2 or Y3 groups attached to adjacent carbon atoms may be taken together to be -O[C(Z9)(Z10)]rO or -O[C(Z9XZI0)]rH, or
any two Y2 or Y3 groups attached to the same or adjacent carbon atoms may be selected together to form a carbocycle or heterocycle; and wherein
any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halogen, SO or SO2 group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halogen, (CrC4)alkyl> (CrC4)alkoxy and an -N[(Ci-C4)alkyl][(C,-C4)alkyl];
E2 is -C=CH or -OC-(CR4SR45)n~R46;
R45 is independently selected from the group consisting of H, a (Ci-C6)alkyl and a (C3-C8)cycloalkyl;
R46 is selected from the group consisting of heterocyclyl, -N(R47)-C(O)-N(R47)(R48), -N(R47)-C(S)-N(R47)(R48), -N(R47)-C(O)-0R48, -N(R47)-C(O)-(CH2)n-R48, -N(R47)-SO2R47, -(CH2)nNR47R48, -(CH2)nOR4S, -(CH2)nSR49, -(CH2)nS(O)R49, -(CH2)nS(O)2R49, -OC(O)R49, -OC(O)OR49, -C(O)NR47R48, heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (CrC6)alkoxy, -NO2, (CrC6)alkyl, -CN, -SO2R50 and -(CH2)nNR50R51, and aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (CrC6)alkyl, -CN, ~SO2R50 and -(CH2)nNR5OR51;
R47 and R48 are independently selected from the group consisting of H, (Ci-Q)alkyl, (C3-C8)cycloalkyl( heterocyclyl, -(CH2)nNR5ORsl, - 42

WO 2006/010264 PCT7CA20O5/O0J177
optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (CrC6)alkoxy, -NO2, (C,-Chalky], -CN, -(CH2)nOR49, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2RS0 and -(CH2)nNR50R51, or
R47 and R48, together with the atom to which they are attached, form a 3-8 membered ring;
R49 is selected from the group consisting of (C|-C6)alkyl, (Ca-C^cycloalkyl,
heterocyclyJ(Ci-C6)alkylene, aryl(CrC6)alkylene wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2l (Ci-C6)alkyl, -CN, -SO2R50 and -(CH2)nNR50R51, heteroaryl(Ci-Co)alkylene wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (Ci-Cs)alkyl, CN, -SO3RS0 and -(CH2)nNR50R5\ aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)a!koxy, -NO2, (C;-C6ialky!, -CN, -SOzR* and -(CH2)nNR50R51, and heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (Ci-C6)alkyL -CN, -SO2RS0 and -(CH2)nNR50R51;
R5u and R51 are- independently selected from the group consisting of H, (Ci-C^alkyl, (CV C»)cycloa!kyl and -C(O)R45, or
R'^° and R*1, together with the atom tc which they are attached, form a 3-8 membered ring; and
E3 is the group defined by -(Zu)-(Zl2)m-(Zn)mh wherein
Z1! is heterocyclyl or heterocyclylene;
Z12 is selected from the group consisting of OC(O), OC(S) and C(O):
Z13 is selected from the group consisting of heterocyclyl, aralkyl, N(H)R52, (Ci-C3)alk>'i, -OR52, halo, S(O)2R56, (Ci-C3)hydroxyalkyl and (Ci-C3)haloalkyl;
rn isOor 3,
ml is 0 or 1;
R52 is selected from the group consisting of H, -(CH2)qS(O)2R54, R55NR5:iR53, (CrC3)alkyl, -(CHaJqOR53, -C(O)R54 and -C(O)OR53;
qisO, 1,2,3 or 4;
R53 is (C,-C3)alkyl;
R54 is (Ci-C3)alkyl or N(H)R53;
R55 is (C,-C6) alkyl; and
R56 is selected from the group consisting of NH2, (Ci-C3)alkyl and OR52.
43

WO 2006/1)10264 PCT/CA2O05/001177
[0201] In a preferred embodiment of the compounds according to paragraph [0200], the compounds are represented by the formula B-0:

and pharmaceutically acceptable salts and complexes thereof, wherein
Z is O or S;
X and X'are independently selected from the group consisting of H, Ci-C$ alkyl, halo,
cyano, or nitro, wherein C|-C6 alkyl is optionally substituted; R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen,
halo. Ci-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, wherein Ci-C5 alkyl, C2-C6
alkenyl and C2-C6 alkynyl are optionally substituted; Q is O, S, NH, N(C|-C6 alkyl), or N-Y-(aryl); L is N, or CR, wherein R is halo, -CN, Q-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl,
wherein Ci-Ce alkyl, C2-C& alkenyl, and C2-C6 allcynyl are optionally substituted;
and R7 is selected from the group consisting of H, halogen, Ci-Q alkyl, -C(=O)NR9R10, -
C(=O)(aryl), -C(=0)(heterocyclyl), -C(=O)(heteroaryt), -Y-(aryl), -Y-(heterocyclyl),
-Y-(heteroaryl), -Y-NR9R10, -SO2NR9R10 and CO2R9, wherein CrC6 alkyl, aryl,
heterocyclyl and heteroaryl are each optionally substituted; R9 and R10 are independently selected from the group consisting of H, C1-C6 alkyl, -Y-
(cycloalkyl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y1-
CO2-R11, and -Y-O-R11, wherein C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and
heteroaryl are each optionally substituted, or Ry and Ri0 are taken together with the nitrogen to which they are attached to form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Rs is selected from the group consisting of H, halo and C\-C& alkyl, wherein C1-C6 alkyl is
optionally substituted:
Y is a bond or is -(C(R1!)(H))r, wherein t is an integer from 1 to 6; Y1 is -(C(Rn)(H))t-, and
44

WO 2006/010264 PCT/CA20U5/001177
Rl! at each occurrence is independently H or Ci-C6 alkyl, wherein C1-C6 alkyl is optionally
substituted.
[0202] In a preferred embodiment of the compounds according to paragraph [0201], X and X1 are both hydrogen.
[0203] In a preferred embodiment of the compounds according to paragraphs [0201] to [0202], R1 is hydrogen or halogen.
[0204] In a preferred embodiment of the compounds according to paragraphs [0201] to [0203], R1 is fluorine.
[0205] In a preferred embodiment of the compounds according to paragraphs [0201] to [0204], R4 is hydrogen or halogen.
[0206] In a preferred embodiment of the compounds according to paragraphs [0201] to [0205] R4 is fluorine.
[0207] In a preferred embodiment of the compounds according to paragraphs [0201] to [0206], R2, R3, R5, and R6 are each hydrogen.
[0208] In a preferred embodiment of the compounds according to paragraphs [0201] to [0207], Q is S, N(CrC6 alkyl), or N-Y-(aryl).
[0209] In a preferred embodiment of the compounds according to paragraphs [0201] to [0208], L is CH or N.
[0210] In a preferred embodiment of the compounds according to paragraphs [0201] to [0209], R8 is selected from the group consisting of H, halo and C1-C6 alkyl, wherein Q-Ce alkyl is optionally substituted with OH orNR'V5, where Ri4 and R15 are independently H or C|-C6 alkyl, or R14 and R15 are taken together with the nitrogen to which they are attached to form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted.
[0211] In a preferred embodiment of the compounds according to paragraphs [0201] to [0210]. R7 is selected from the group consisting of H, halogen, CrC6 alkyl, -CONR9R!0, -SO2NH2, -SO2NR9Ri0, -Y-heterocycle -Y-heteroaryl, -S-aryl, -S-CrC6 alkyl, -SO-CrC6 alkyl and -SO2-C1-C6 alkyl, wherein Ci-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocycle, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0212] In a preferred embodiment of the compounds according to paragraphs [0201] to [0211],R7is-CONR9R!0.
[0213] In a preferred embodiment of the compounds according to paragraph [0212], R9 and R10 are independently selected from the group consisting of H, Q-Cb alkyl, -Y-O-R11, -
45

WO 2006/010264 PCT/CA2005/001177
Y-(heterocycle), -Y!*CO2-Rn and -Y-(aryl), wherein Ci-C6 alkyl is unsubstituted or is
substituted with one or two of hydroxy or halogen, and the heterocycle, and aryl are
unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0214] In a preferred embodiment of the compounds according to paragraph [0212], R9
and R10 are taken together with the nitrogen to which they are attached to form a
pyrrolidinyl, piperidinyl, piperazinyi, morpholinyl, or thiomorpholinyl ring, wherein said
ring is unsubstituted or is substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0215] In a preferred embodiment of the compounds according to paragraphs [0201 ] to
[0209], R7 is selected from the group consisting of H, halogen, CrC6 alkyl, -SO2NR9R!0, -
C(=O)(heterocyclyl), -Y-(heterocyciyl), -Y-(heteroaryl), -S-aryl, -S-C,-C6 alkyl, -SO-Cf-C6
alkyl and -SO2-C|-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or is substituted with one
or two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are
substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0216] In a preferred embodiment of the compounds according to paragraphs [0201] to
[0215],Zissuifur.
[0217] In a preferred embodiment of the compounds according to paragraph [0200], the
compounds are represented by the formula B-l:

and pharmaceutically acceptable salts and complexes thereof, wherein
R1 is selected from the group consisting of hydrogen, halo, CrC6 alkyl, C2-C6 alkenyl and C2-C6 aikynyl, wherein Ci-C6 alkyl, C2-C6 alkenyl and C2-C(> aikynyi are optionally substituted;
R7 is selected from the group consisting of H, halogen, C\-Ce alkyl, -C(=0)NR9R!o, -
C(=O)(aryl), -C(=0)(heterocyclyl), -C(=O)(heteroaryl), -Y-(aryl), -Y-(heterocyclyi), -Y-(heteroaryl), -Y-NR9R10, -SO2NR9R10 and CO2R9, wherein CrC6 alkyl, aryl, heterocycle and heteroaryl are each independently optionally substituted;
R9 and R10 are independently selected from the group consisting of H, C]-C6 alkyl, -Y- ¦ (cycloalkyl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -Y-O-Y!-O-Ru, -Y1-
46

WO 2006/(110264 PCT/CA2005/001177
CO2-Rn, and -Y-O-R11, wherein Ci-C6 alkyl, cycloalkyl, aryl, heterocycle, and
heteroaryl are each optionally substituted, or R9 and R10 taken together with the nitrogen to which they are attached form a Cs-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Y is a bond or is -(C(R")(H))t-! wherein t is an integer from 1 to 6; Yiis-CCrtH)),-; Ru at each occurrence is independently H or C1-C6 alkyl, wherein CpC6 alkyl is optionally
substituted; and R12 is selected from the group consisting of H, Ci-Cg alkyl and -Y-(aryl), wherein C\-C$
alkyl and aryl are optionally substituted.
[0218J In a preferred embodiment of the compounds according to paragraph [0217], R1 is hydrogen or halogen.
J0219] In a preferred embodiment of the compounds according to paragraphs [0217] to [0218], R1 is fluorine.
[0220] In a preferred embodiment of the compounds according to paragraphs [0217] to [0219], R12 is unsubslituted C1-C3 alkyl or unsubstituted benzyl.
[0221] In a preferred embodiment of the compounds according to paragraphs [0217] to [0220], R7 is -C(O)NR9R10.
[0222] In a preferred embodiment of the compounds according to paragraphs [0217] to [0220] R7 is selected from the group consisting of

wherein the members of said group are optionally substituted by 1 to 3 independently selected R3g.
47

WO 2006/010264 PCT/CA2005/001177
[0223] In a preferred embodiment of the compounds according to paragraphs [0217] to [0220J R7 is selected from the group consisting of

wherein the members of said group are optionally substituted with 1 to 3 independently
selected R38.
[0224] In the third aspect, the invention provides a composition comprising a compound
according to any one of paragraphs [0040] - [0223] or as depicted in any of the tables and
examples herein together with a pharmaceutically acceptable excipient.
[0225] The fourth aspect of the invention provides a method of inhibiting VEGF
receptor signaling and HGF receptor signaling, the method comprising contacting the
receptor with a compound according to any one of paragraphs [0040] - [0223] or as depicted
in any of the tables herein, or with a composition according to paragraph [0224]. Inhibition
of VEGF and HGF activity can be in a cell or a multicellular organism. If in a multicellular
organism, the method according to this aspect of the invention comprises administering to
the organism a compound according to any one of paragraphs [0040] - [0223] or as depicted
in any of the tables herein, or a composition according to paragraph [0224]. Preferably the
organism is a mammal, more preferably a human.
[0226] The data presented herein demonstrate the inhibitor}' effects of the VEGF and
HGF inhibitors of the invention. These data lead one to reasonably expect that the
compounds of the invention are useful not only for inhibition of VEGF receptor signaling
and HGF receptor signaling, but also as therapeutic agents for the treatment of proliferative
diseases, including cancer and tumor growth.
[0227] Preferred compounds according to the invention include those described in the
examples below. Compounds were named using Chemdraw Ultra version 6.0.2 or version
48

WO 2006/010264 PCT/CA2005/00I177
8.0.3, which are available through Cambridgesoft.com, 100 Cambridge Park Drive, Cambridge, MA 02140, Namepro version 5.09, which is available from ACD labs, 90 Adelaide Street West, Toronto, Ontario, M5H, 3V9. Canada, or were derived therefrom.
Synthetic Schemes and Experimental Procedures
[0228] The compounds of the invention can be prepared according to the reaction schemes or the examples illustrated below utilizing methods known to one of ordinary skill in the art. These schemes serve to exemplify some procedures that can be used to make the compounds of the invention. One skilled in the art will recognize that other general synthetic procedures may be used. The compounds of the invention can be prepared from starting components that are commercially available. Any kind of substitutions can be made to the starting components to obtain the compounds of the invention according to procedures that are well known to those skilled in the art. I. Synthesis (general schemes)
[0229] Thieno[3,2-b]pyridine based compounds of formula A-Q may be prepared according to the procedures illustrated in the scheme A. Thus, thieno[3,2-b]pyridine-7-ol (I) upon treatment with POCI3 is converted to the chloride II. Treatment of this material with a strong base such as rc-BuLi followed by an addition of carbon dioxide affords the carboxylate HI which is used without purification in the next step, providing the acyi chloride IV (presumably as a hydrochloride salt) upon its reaction with oxalyl chloride. The acyl chloride IV is used for the next step without further purification as well: upon its reaction with different primary and secondary amines the compound IV is converted to a variety of primary and secondary amides V which can further be derivatized via a substitution of the chlorine atom in the pyridine ring.
[0230] Thus, V reacting with substituted 4-nitrophenols in a high boiling point solvent, such as diphenyl ether in the presence of a base such as potassium carbonate, produced the nitro derivatives VI which then are reduced to the amines VII upon treatment with a mixture NiCk/NaBKt (or other conventional reagents). The amines VII also may be used for the next step without further purification, and upon treatment with 2-phenylacetyl isothiocyanates afford phenylacetylthioureas VIII bearing the amido-substituents such as the ones shown in the scheme A.
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WO 2006/010264 PCT/CA2005/001177

[0231] Substituenrs X and Y (up to three, same or different in each of the indicated benzene rings)are independently selected from halo, Ci-Q alkyl, Q-C6 alkoxy, cyano, nitro, hydroxy, amino, Ci-Q aikylamino
[0232] Tliienof3,2-d]pyrimidine based compounds of formula A-0 may be prepared according to the procedures illustrated in the scheme B. Thus, thieno[3,2-d]pyrimidins-7-ol (IX) upon treatment with POCI3 is converted to the chloride X. Treatment of this material with a strong base such as lithium tetramethylpiperidide (LiTMP) generated in situ followed by an addition of carbon dioxide affords the carboxylate XI which is used without purification in the next step, providing the acyl chloride XII (presumably as a hydrochloride salt) upon its reaction with oxalyl chloride. The acyl chloride XII reacting with different primary and secondary amines is converted to a variety of primary and secondary amides XIII which can further be derivatized via a substitution of the chlorine atom in the pyrimidine ring.
50

WO 2006/010264 PCT/CA2005/001177
51
[0233] Thus, XIII reacting with substituted 4-nitrophenois in a high boiling point solvent, such as diphenyl ether in the presence of a base such as potassium carbonate, produce the nitro derivatives XIV which are then reduced to the amines XV upon treatment with a mixture NiCyNaBH* (or other conventional reagents). The amines XV upon treatment with 2-phenylacetyI isothiocyanates afford the phenylacetylthioureas XVI bearing the amido-substituents such as the ones shown in the scheme B.


WO 2(106/010264 PCT/CA2005/OO1177
reactions) produces heteroaryl-substituted thienopyridines XVIII which can further be derivatized via a substitution of the chlorine atom in the pyridine ring.

[0236] Substituents X and Y (up to three, same or different in each of the indicated benzene rings) are independently selected from halo, C1-C6 alkyl, CrCs alkoxy, cyano, nitro, hydroxy, amino, Cj-Cg alkylamino
[0237] Thus, XVIII reacting with substituted 4-nitrophenols in a high boiling point solvent, such as diphenyl ether in the presence of a base such as potassium carbonate, produced the nitro derivatives XIX which are then reduced to the amines XX upon treatment with a mixture NiCk/NaBHj (or other conventional reagents). The amines XX could be used for the next step without further purification, and upon treatment with 2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXI bearing the heteroaryl substituents such as the ones shown in the scheme C. Heteroaryls shown in the scheme B, in turn may bear additional substituents exemplified (but not limited to) alky Is, amines, alkylamino, aminoaikyls, alkoxyalkyls, hydroxyalkyls, alkylsulfonylalkyls, etc.- known in the art as solubilizing functionalities.
52

WO 2006/0102(4 PCT/CA2005/001177

[0238] Sub.stitucnts X and Y (up to three, same or different in each of the indicated benzene rings)are independently selected from haio, Q-Ce alkyl, Cj-Q alkoxy, cyano, nitro. hydroxy, amino, C|-C6 alkylamino
[0239] Pyrrolo[2,3-d]pyrimidine based compounds of formula B-0 may be prepared according to the procedures illustrated in the scheme D. Treatment of the 4-chloro-7i?-pyrro!o[2,3-d]pyrimidine (XXII) with an alkyl halide in the presence of a base such as sodium hydride affoids the alkylated chlorides XXIII, which reacting with substituted 4-nitrophenols in a high boiling point solvent, such as diphenyl ether in the presence of a base such as cesium carbonate, produced the nitro derivatives XXIV reduced to the amines XXV upon hydrogenation (or treatment with conventional reducing agents). The amines XXV reacting with 2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXVI bearing the alkyl substituents such as the ones shown in the scheme D.
5J

WO 2006/010264 PCT/CA2005/0O1177

[0240] Substituents X and Y (up to three, same or different in each of the indicated benzene rings) are independently selected from halo, Q-Cealkyl, Ci-Cealkoxy, cyano, nitro, hydroxy, amino, Ci-Coaikylamino
[0241] Thieno[3,2-b]pyridine based phenylacetylureas of formula A-0 bearing aryl substituents may be prepared according to the procedures illustrated in the scheme E. Thus vhloride II upon lithiation and subsequent bromination is converted to the bromide XXVII that reacting with substituted 4-nitrophenols produces more elaborated compound XXVIII. This material can be used for Suzuki type (and like) reactions with a variety of aryl boronic acids (or boronates), in particular with the ones functionalized with basic groups, thus providing compounds XXIX. Reduction of XXIX with a mixture NiCb/NaBJLt (or other conventional reagents) affords amines XXX. The latter upon treatment with 2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXXI bearing aryl substituents such as the ones shown in the scheme E.
Scheme F
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WO 2006/010264 PCT/CA20O5/001177

[0242] Substituents X and Y (up to three, same or different in each of the indicated benzene rings) are independently selected from halo, Ci-C^aHcyl, Ci-Cgalkoxy, cyano, nitro, hydroxy, amino, Ci-Cgalkyfamino
[0243] Bromides XXVIII also can be used for Suzuki type (and like) reactions with a variety of hydroxy phenyl boronic acids (boronates), to form phenolic compounds XXXII. These phenols reacting with different alcohols (Mitsunobu reaction), in particular functional ized with basic groups, provide compounds XXXIII. Reduction of XXXIII with a mixture NiCk/NaBHU (or other conventional reagents) affords amines XXXIV which upon treatment with 2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXXV bearing the aryl substituents such as the ones shown in the scheme F. II. Specific examples
Scheme 1
55

WO 2006/010264 PCT/CA2005/001177

Example 1
l-(4-(2-(Dimethylcarbamoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (8a) Step 1: 7-Chlorothieno[3,2-i]pyridine (2)
[0244] A stirred suspension of thieno[3,2-bJpyridin-7-oi (1, 5.0 g, 33.1 mmol) in POC13 (15 mL) was heated to 105°C in an oil bath for 4 hrs. The resultant solution was cooled to room temperature and the POCI3 was removed under reduced pressure. The residue was cooled in an ice/water bath and cold water was added. The water was made basic with concentrated NH4OH solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate and concentrated to produce an oil which was purified by column chromatography (eluent EtOAc-hexane, 1:4) to afford the title compound as a brown solid (4.5 g, 72% yield). 'H NMR (400 MHz, CDC13) 8 (ppm): 8.60 (d, J= 4.9 Hz, 1H), 7.80 (d, /= 5.5 Hz, 1H), 7.60 (d, J= 5.5 Hz, 1H), 7.30 (d, J= 4.9 Hz, 1H). Steps 2-4: 7-Chloro-N,Ar-diniethylthieno[3,2-&]pyridine-2-carboxamide (5) [0245] To a stirred solution of 2 (3.0 g, 17.8 mmol) in dry THF (60 mL) at -78°C was added n-BuLi (7.8 mL, 19.6 mmol, 2.5 M solution in hexanes) and the resultant suspension was stirred for 15 minutes. Solid carbon dioxide (excess) was added and the mixture was allowed to warm to room temperature over a period of 1 hour. The solvent was removed under reduced pressure and the resultant lithium carboxylate 3 was used without further purification (3.88 g, quantitative).
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WO 2006/010264 PCT/CA2005/001177
[0246] To a stirred suspension of 3 (3.5 g, 15.9 mmol) in dry DCM (50 mL) was added (COC1)2 (3,96 g, 31.2 mmol) and dry DMF (i drop). The reaction mixture was heated to reflux for 2 hrs. The solvents were evaporated to produce 4 (presumably as an HC1 salt) which was used directly in the next step.
[0247] Acyl chloride 4 (2.42 g, 10.5 mmol) was suspended in dry DCM (105 mL) at 0°C and Me2NH (15.7 mL, 2M solution in THF, 31.4 mmol) was added and the reaction mixture was siirred overnight. The solvent was removed and the residue was dissolved in EtOAc and washed with water. The organic phase was collected and dried over anhydrous sodium suifate then filtered and concentrated under reduced pressure to produce a residue, which was purified by column chromatography (eluent EtOAc-hexane, 9:1) to afford 5 as a yellow solid (1.65 g5 45% yield). 'HNMR (400 MHz. CDC13) 8 (ppm): 8.62 (d, J- 4.8 Hz, IH), 7.76 (s, 1H), 7.37 (d, /= 4.8 Hz, IH), 3.35-3.25 (m, 3.11), 3.25-3.20 (m, 3H). Step 5: 7-(2-Fluoro-4-nitrophenoxy)-AW-dimethylthieno[3,2-6]pyridine-2-carboxamitle(6) [0246] A mixture of 5 (1.65 g, 6.85 mmol), potassium carbonate (5.68 g, 41.1 mmol) and 2-fluoro-4-nitrophenol (1.65 g, 10.3 mmol) were heated to 170°C in diphenyl ether (20 mL) for 5 hrs. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was collected, dried over anhydrous sodium suifate and the solvents were removed under reduced pressure. The residue was purified by column chromatography (eluents EtOAc-hexane 9:1, then MeOH-EtOAc 1:4) to afford 6 as a yellow solid (1.02 g, 41% yield). "HNMR (400 MHz, DMSO-d6) 5 (ppm): 8.64 (dr /= 5.3 Hz, IH), 8.46 (dd, J= 2.8 and 10.3 Hz, IH), 8.20 (ddd, J= 1.3 and 2.6 and 9.0 Hz, IH), 7.98 (s, IH), 7.73 (dd, J= 8.3 Hz, IH), 6.99 (dd, /= 0.9 and 4.8 Hz, IH), 3.25-3.30 (m, 3H), 3.02-3.11 (m,3H).
Steps 6-7: l-(4-(2-(Dimethylcarbamoyi)thieno[3,2-Z>]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (8a)
£0249J To a solution of 6 (190 mg, 0. 55 mmol) in MeOH (10 mL) at 0°C was added NiCl2 x 6H2O (241 mg, J .02 ramo!) and NaBHi (81.4 mg, 2.2 mmol). The reaction mixture was stirred for 1 hr, concentrated to dryness and the resultant solid was dissolved in 1 M HC1. The aqueous solution was then made basic with concentrated NHfOH solution and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium suifate and filtered. The solvent was evaporated under reduced pressure and the resultant solid was triturated with diethyl ether to afford 7 as a white solid that was used immediately in the next step.
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WO 2006/010264 PCT/CA20O5/001177
[0250] To a suspension of 7 (465.8 mg, 1.41 mmol) in THF (20 mL) was added benzyl isothiocyanate (374 mg, 2.12 mmol) and the reaction mixture was stirred for 1 hr, concentrated under reduced pressure and the resultant residue was purified by column chromatography (eluent EtOAc-MeOH 19:1) to afford a yellow solid which was triturated with Et2O to afford 8a as an off-white solid (534 mg, 75% yield). 'H NMR (400 MHz, DMSO-d6) 5 (ppm): 12.47 (s, 1H), 11.78 (s, 1H), 8.57 (d, J= 4.2 Hz, 1H), 8.05-7.95 (m, 1H), 7.93 (s, 1H), 7.52 (s, 2H), 7.33 (d, J= 3.9 Hz, 1H), 7.28-7.23 (m, 1H), 6.72 (d, J= 5.3 Hz, 1H), 3.83 (s, 2H), 3.26 (s broad, 3H), 3.05 (s broad, 3H). Examples 2-11:
58
[0251] Examples 2-11 (compounds 8b-k) were prepared using the same procedures as described for the compound 8a, example 1 (scheme 1). Characterization of 8b-k is provided in table 1.


5
WO 2006/010264 PCT/CA2005/001177


WO 2006/010264 PCT/CA2OO5/001177

Example 12
l-(4-(2-(Thiazol-2-yl)thieno[3,2-6jpyridin-7-yJoxy)-3-fluorophsnyl)-3-(2-
pbeny)aostyl)thiourea (13a)
Step 1: 7-Chloro-2-(triroethylstannyl)thieno[3,2-£]pyridine
[0252] To a solution of 2 (1.0 g, 5.9 mmol) in dry THF (60 mL) at -78°C was added n-
BuLi (2.36 mL, 5-9 mmol, 2.5 M solution in hexanes) and the resultant brown precipitate
was stirred for iO min. Trimethytin chloride (1.18 g. 5.9 mmoi) in dry THf (10 mL) was
added slowly and the mixture was allowed to stir at -78°C for 2 hrs, quenched with
methanol at -78°C and the solvents were removed under reduced pressure. The residue was
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WO 2006/010264 PCT/CA2005/001177
dissolved in EtOAc and washed with water; the organic phase was collected, dried over
anhydrous sodium sulfate and filtered. The EtOAc was evaporated under reduced pressure
and the resultant oil was purified by column chromatography (eluent EtOAc-hexane 1:4) to
afford 9 (1.2 g, 63% yield) as a brown solid. 'H NMR (400 MHz, CDC13) 8 ppm: 8.21 (d, J
= 5.1 Hz, 1H), 7.36 (s, 1H), 6.91 (m, 1H), 0.16 (s, 9H).
Step 2: 7-Chloro-2-(thiazol-2-yl)thieno[3,2-6]pyridine (10)
[0253] To a solution of 9 (175 mg, 0.53 mmol) and 2-bromothiazole (94 mg, 0.58
mmol) in dry toluene(6 mL) was added Pd(PPh3)4 (62 mg, 0.053 mmol) and the reaction
mixture was refluxed overnight, cooled to room temperature and the solvents were removed under reduced pressure. The resultant solid was triturated with hexane/Et2O and then purified by column chromatography (eluent EtOAc-hexane 1:1) to give 10 as a white solid
(75 mg, 56% yield). 1H NMR (400 MHz, DMSO-d6) 5 ppm: 8.65 (d, J = 5.1 Hz), 8.2 (s, 1H), 7.97 (s,2H), 7.61 (d,J= 5.1 Hz).
3:7-(2-Fluoro-4-nitrophenoxy)-2-(thiazol-2-yl)thieno[3,2-b]pyridine (11) [0254] To a suspension of 10 (194 mg, 0.77 mmol) in Ph2O (10 mL) was added 2-fluoro-4-nitrophenol (240 mg, 1.53 mmol) and potassium carbonate (425 mg, 3.08 mmol) and the reaction mixture was heated at 180°C for 4 hrs. The reaction mixture was cooled to room temperature and diluted with EtOAc. The resultant solution was washed with water and the organic layer was collected, dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure; the residue was dissolved in DCM, and purified by column chromatography (eluent EtOAc-hexane 4:1) to afford 11 (190 mg, 66 % yield) as a yellow solid. !H NMR (400 MHz, DMSO~d6) 6 ppm: 8.61 (d, J= 5.5 Hz, 1H), 8.46 (dd, J= 2.74 and 10.37 Hz), 8.24 (s, 1H), 8.20-8.10 (m, 1 H), 7.95 (s, 2H), 7.73 (t, J= 8 Hz, 1H), 6.98 (d, J= 5.3 Hz, 1H).
Steps 4-5. l-(4-(2-(Thiazol-2-yl)thieno[3,2-b]pyridin-7-yioxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (13a)
[0255] To a suspension of 11 (190 mg, 0. 55 mmol) in MeOH (10 mL) at 0°C was added NiCl2.6H2O (241 mg, 1.02 mmol) and NaBH4 (81.4 mg, 2.2 mmol). The reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in 1 M HCl. The aqueous solution was then made basic with concentrated ammonium hydroxide solution whereupon 12 precipitated as a grey solid, which was collected by filtration and used crude in the next step.
[0256] To a suspension of the amine 12 (152 mg, 0.44 mmol) in THF (10 mL) was added benzyl isothiocyanate (118 mg, 0.66 mmol) and the reaction mixture was stirred for 1
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WO 2006/010264 PCT/CA2005/001177
hr, concentrated under reduced pressure and purified by column chromatography (eluents EtOAc-hexane 3:1, then EtOAc) to afford a yellow solid. Trituration of this material with Et2O/hexane gave 13a (100 mg, 43 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm: 12.48 (s, 1H), 11.81 (s, 1H), 8.55 (d, J = 5.5 Hz, 1H), 8.19 (s, 1H), 8.00 (d, J = 13.3 Hz, 1H), 7.95 (d, J = 3.1 Hz, 1H), 7.94 (d, J- 3.1 Hz, 1H), 7.53 (m, 2H), 7.33 (m, 3 H), 7.25 (m, 2H), 6.72 (d, J = 5.5 Hz, 1H), 3.82 (s, 2H). Example 13
62
[0257] Examples 13-19 (compounds 13b-h) were prepared using the same procedures as described for the compound 13a (example 12, scheme 2). Characterization of compounds 13b-h (examples 13-19) is provided in table 2.


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Example 20
l-(4-(2-(l-HydroxyelhyI)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-
phenylacetyl)thiourea (18a)
Step 1. 7-Chlorothieno[3,2-b]pyridine-2-carbaldehyde(14)
[0258] To a solution of 2 (200 mg, 1.18 mmol) in dry THF (10 mL) at -78°C was added
n-BuLi (0.57 mL, 1.42 mmol, 2.5 M solution in hexanes) and the resultant suspension was
stirred for 20 min. Dry DMF (0.5 mL, excess) was added and the reaction mixture was
stirred for an additional 2 hrs. The reaction mixture was quenched with methanol at -7S°C
and water was added. The mixture was extracted with EtOAc and the organic extracts were
combined, dried over anhydrous sodium sulfate and filtered. The solvent was removed
under reduced pressure and the resultant yellow solid was triturated with hexane to afford
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14 (250 mg, 100 % yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) ? ppm: 10.2 (s, 1H), 8.78 (d, J= 5.1 Hz, 1H), 8.61 (s, IH), 7.78 (d, J= 5.1 Hz, 1 H). Steps 2-3. l-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yI)ethanol (16) [0259] To a solution of 14 (200 mg, 1 mmol) in dry THF (5 mL) at -78°C was added methylmagnesium bromide (0.51 mL, I mmol, 2 M solution in dibutyl ether) and the reaction mixture was stilted at -78°C for 1 hr. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over anhydrous sodium sulfate and evaporated. The resultant solid was washed with hexane to give 15 as a white solid (177 mg, 83% yield), which was used crude in the next step.
[0260] To a suspension of 15 (170 mg, 0.79 mmol) in Ph2O (10 mL) was added 2-fluoro-4-nitrophenol (250 mg, 1.58 mmol) and potassium carbonate (436 mg, 3.16 mmol) and the reaction mixture was heated at 180°C for 4 hrs, cooled to room temperature and diluted with EtOAc. The solution was washed with water and the organic layer was collected, dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure. The residue was dissolved in DCM, and purified by column chromatography (eluent EtOAc-hexane, 4:1) to afford 16 (125 mg, 47 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ? ppm: 8.52 (dd, J= 0.8 and 5.5 Hz, IH), 8.44 (dd, J= 2.5 and 10.2 Hz, 1H), 8.15 (d, J= 10.2 Hz, 1H), 7.63 (t, J= 8.2 Hz, 1H), 7.41 (s, 1H), 6.86 (d, J= 5.3 Hz, 1H), 5.96 (dd, J= 0.4 Hz and 4.9 Hz), 5.09 (m, 1H), 1.49 (d, J== 6.5 Hz, 3H).
Steps 4-5. l-(4-(2-(l-Hydroxyethyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (18a)
[0261] To a suspension of 16 (129 mg, 0.39 mmol) in MeOH (5 mL) at 0°C was added NiCl2.6H2O (183 mg, 0.77 mmol) and sodium borohydride (57 mg, 1.5 mmol). The reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in 1 M HCl. The aqueous solution was then made basic with concentrated ammonium hydroxide solution, extracted with EtOAc and the organic extract was dried over anhydrous sodium sulfate then filtered. The solvent was removed under reduced pressure to give 17 (110 mg, 94% yield) as brown oil, which was used immediately in the next step.
[0262] To an emulsion of 17(110 mg, 0.36 mmol) in THF (10 mL) was added 2-phenylacetyl isothiocyanate (76 mg, 0.43 mmol) and the reaction mixture was stirred for 1 hr, concentrated and the residue was purified by column chromatography (eluents EtOAc-hexane 3:1, then EtOAc) to afford a yellow solid which upon trituration with diethyl
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ether/hexane gave 18a as an off-white solid (90 mg, 52 % yield). 1H NMR (400 MHz, DMSO-d6) 8 ppm: 12.47 (s, 1H), 11.81 (s, 1H), 8.43 (d, J= 5.5 Hz, 1H), 8.2 (s, 1H), 7.9 (d, J= 12.3 Hz, 1H), 7.51-7.44 (m, 2H), 7.30 (d, J= 0.9 Hz, 1H), 7.33 - 7.31 (m, 3H), 7.30-7.24 (m, 1H), 6.57 (d, J= 5.3 Hz, 1H), 5.91 (d, J= 4.9 Hz, 1H), 5.09 (m, 1H), 3.9 (s, 2H), 1.49 (d,J= 6.3 Hz, 3H).

l-(4-(2-(l-Hydroxy-2-methylpropyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (18b)
[0263] Title compound was prepared using the same procedures as described for the compound 18a (example 20, scheme 3). 1H NMR (400 MHz, DMSO-d6) ? ppm: 12.46 (s, 1H), 11.80 (s, 1H), 8.43 (d, J = 5.9 Hz, 1H), 7.98 (d, J= 2.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.35 (s; 1H). 7.32 (m, 3H), 7.28 (m, 1H), 6.55 (d, J= 5.5 Hz, 1H), 5.91 (d, J= 4.7 Hz, 1H), 4.70 (t, J= 5.1 Hz, 1H), 3.8 (s, 2H), 1.95 (m, 1H), 0.9 (dd, 7= 0.7 and 10.2 Hz, 6H).
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Example 22
l-(4-(6-(2-Morpholincethylcarbamoyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (26a) Step 1: 4-Chlorothieno[3,2-d]pyrimidine (20)
[0264] To a stirred solution of (COC1)2 (7.33 mL, 84.11 mmol) in anhydrous (CH2Cl)2 (20 mL) at 0°C under nitrogen was added DMF (4.47 mL, 57.18 mmol). After 20 min a solution of thieno[3,2-d]pyrimidin-4(3H)-one (19) (4 g, 26.28 mmol) in anhydrous (CH2Cl)2 (5 mL) was added drop wise to the reaction mixture which was stirred for 20 min at 0°C, wanned to room temperature over another 20 min, heated at 80°C for 1.5 hours, and cooled to room temperature. Finally, the reaction mixture was poured into water and extracted with DCM. The extract was washed sequentially with water, brine, dried over Na2SO4, filtered and evaporated to afford the title compound 20 (4.36 g, 97% yield) as a
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yellow solid. 1H NMR (400 MHz, DMSO-d6) ?(ppm): 9.02 (s, 1H), 8.59 (d, J = 5.2 Hz,
lH),7.75(d,J = 5.2Hz, 1H).
Step 2:4-Chlorothieno[3,2-d]pyrimidine-6-carbonyl chloride (22)
[0265] To a stirred solution of 2,2,6,6-tetramethylpiperidine (4.45 mL, 26.37 mmol) in
anhydrous THF(50 mL) at 0°C under nitrogen was added n-BuLi (10.55 mL, 26.37 mmol,
2.5 M in hexanes). The reaction mixture was stirred for 30 min, then a solution of 20 (3 g,
17.58 mmol) in anhydrous THF (10 mL) was added drop wise at -78°C over 30 min
followed by dry ice (10 g). The resultant suspension was warmed to the room temperature
over 2 hours and filtered to afford the lithium carboxylate 21 as a yellow solid (4.5 g),
which was used for the next step without further purification.
[0266] To a stirred solution of (COCl)2 (2.95 mL, 33.82 mmol) in anhydrous DCM (30
mL) at 0°C under nitrogen was added DMF (0.5 mL, 6.45 mmol). The reaction mixture was
stirred for 20 min and treated with a solution of the carboxylate 21 (3.71 g, 16.89 mmol) in
anhydrous DCM (5 mL) (drop wise addition at 0°C), stirred for additional 10 min and
heated at 60°C for 3 hours, cooled to room temperature and concentrated under reduced
pressure to afford the title compound 22 (3.90 g, 99% yield) as a yellow solid. 1H NMR
(400 MHz, DMSO-d6) ?(ppm): 9.02 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 5.2 Hz,
1H).
Step 3:4-Chloro-N(2-morpholinoethyl)thieno[3,2-d]pyrimidine-6-carboxamide (23)
[0267] To a stirred solution of 22 (500 mg, 2.15 mmol) in anhydrous DCM (20 mL) at
0°C under nitrogen was added 4-(2-aminoethyl)-morpholine (307 mg, 2.36 mmol). The
reaction mixture was allowed to warm to the room temperature over 3 hours and was stirred
for additional 14 hours, treated with saturated aqueous solution of NHCO3 and extracted
with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The
residues was purified by flash chromatography on silica gel (eluents MeOH- DCM, 5:95,
then 1:9) to afford the title compound 23 (458 mg, 65% yield) as a white solid. 1H NMR
(400 MHz, CDCl3) S(ppm): 9.13 (t, J = 5.6 Hz, 1H), 9.08 (s, 1H), 8.32 (s, 1H), 3.60-3.54
(m, 4H), 3.44 (q, J = 6.8 Hz, 2H), 2.54-2.48 (m, 2H), 2.46-2.40 (m, 4H).
Step 4:4-(2-Fluoro-4-nitrophenoxy)-N-(2-morpholinoethyl)thieno[3,2-rf|pyrimidine-6-
carboxamide (24)
[0268] To a stirred solution of compound 23 (458 mg, 1.40 mmol) in Ph2O (6 mL) was
added 2-fluoro-4-nitrophenol (242 mg, 1.54 mmol). The reaction mixture was heated at
120°C for 2.5 hours, treated with K2CO3 (80 mg, 0.56 mmol) and heated at the same
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temperature for additional 18 hours. After cooling, the reaction mixture was purified by flash chromatography on a silica gel column (eluents EtOAc-hexane 5:95, 1:1, then MeOH-DCM, 5:95 and 1:9), to afford the title compound 24 (570 mg, 91% yield) as a yellow solid. 1H NMR (400 MHz, CDC13) S(ppm): 9.09 (t, J = 5.6 Hz, 1H), 8.77 (s, 1H), S.41 (dd, J = 2.4 and 10.4 Hz, 1H), 8.30 (s, 1H), 8.22 (dd, J = 2.4 and 8.8 Hz, 1H), 7.88 (t, J = 8.8 Hz, 1H), 3.60-3.52 (m, 4H), 3.45 (q, J = 6.8 Hz, 2H), 2.50 (q, J = 6.8 Hz, 2H), 2.46-2.40 (m, 4H). Step 5: 4-(4-Amino-2-fIuorophenoxy)-A'-(2-mo!pholinoethyl)thieno[3,2-d]pyrimidine-6-carboxamide (25)
[0269] To a stirred solution of 24 (1.30 g, 2.72 mrnol) in anhydrous MeOH (15 mL) at room temperature under nitrogen were added NiCl2 x 6H2O (605 mg, 2.54 mmol) and NaBH4 (192 mg, 5.08 mmol), respectively. The reaction mixture was stirred for 50 min, concentrated, cooled to 0°C, treated with HC1 (10 mL, 1M) followed by addition of NH4OH (29%) (pH 9-10), and finally extracted with AcOEt. The organic extract was successively washed with water and brine, dried over Na2SO4, filtered, and concentrated to afford the title compound 25 (450 mg, 85% yield) as a yellow solid. 1H NMR (400 MHz, CDCI3) &Xppm): 9.04 (t, J = 5.6 Hz, 1H), 8.73 (s, 1H), 8.23 (s, 1H), 7.07 (t, J = 8.8 Hz, 1H), 6.48 (dd, J = 2.4 and 13.2 Hz, 1H), 6.40 (dd, J = 2.4 and 8.8 Hz, 1H), 5.47 (s, 2H), 3.62-3.52 (m, 4H), 3.44 (q. J = 6.8 Hz, 2H), 2.56-2.48 (m, 2H), 2.46-2,40 (m, 4H). Step 6: l-(4-(6-(2-Mori>holinoethylcarbamoy!)thieno[3,2-c?JpyriiTiidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(26a)
[0270] To a stirred solution of 25 (450 mg, 1.07 mmol) in anhydrous THF (10 mL) under nitrogen was slowly added benzyl isothiocyanate (0.5 mL). The reaction mixture was stirred for ] 8 hours and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (eluent MeOH-DCM, 5:95—^10:90) followed by reversed phase chromatography purification (column Phenomene X, C18, eluent H2O-MeOH, 50:50-^5:95,10 mL/min) to afford the title compound 26a (104 mg, 16% yield) as a white solid. !H NMR (400 MHz,. DMSOrfe) 5((ppm): 12.43(s, 1H), 11 -80(s, 1H), 9.07(t, J = 5.6 Hz, 1H), 8.76(s, 1H), 8.28(s, 1H), 7.93(dd, J = 2.4 and 12.0 Hz, 1H), 7.54(t, J = 8.8 Hz, 1H), 7.48(dd, J = 1.2 and 8.8 Hz, 1H), 7.39-7.30(m, 4H), 7.30-7.20(m: 1H), 3.82(s, 2H), 3.60-3.54(m, 4H), 3.45(q, J - 6.4 Hz, 2H), 2.50(m, 2H), 2.48-2.40(m, 4H). Examples 23-27
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[0271] Examples 23-27 (compounds 26b-e) were prepared using the same procedures as described for the compound 26a, example 22 (scheme 4). Characterization of compounds 26b-e (examples 23-27) is provided in table 3.


WO 2006/010264 PCT/CA2005/001177

Example 28
l-(4-(5-Methyl-.5F-pyrrolo[3,2-rfjpyrimidiii-4-yioxy)-3-fluorophenyl)-3-(2-
pbenylacetyi)fhiourea (31a)
Step I: 4-Chloro-5-methyl-J//-pyrrolo[3,2-^]pyrifflidine (28)
[0272] To a stirred solution of 4-chloro-5#-pyrrolo[3,2-t/]pyrirnidine (27) (J. Org.
Chen,., 2001, 66, 17, 5723-5730) (643 mg, 4.15 mmol) in DMF (41 mL) was added NaH
(60% in mineral oil, 330 rng, 8.3 rnmol) in one portion at 0°C and the mixture was stirred
for 1 h followed by addition of methyl iodide (0.28 mL, 4.5 mmol). The reaction mixture
was allowed to warm up to the room temperature, stirred for an additional hour and
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quenched with AcOH (1 mL) to form a suspension which was stirred for 10 min and concentrated under reduced pressure to give a solid. This material was dissolved in AcOEt, the solution was washed with cold saturated NaUCO? solution and water, dried over Na2SO4, and concentrated to produce the title compound 28 as a pale yellow solid (640 mg, 93% yield). lHNMR (400 MHz, CD3OD) 8(ppm): 8.51 (s, IK), 7.75 (d, J = 3.3 Hz, 1H), 6.62 (d, J = 3.3 Hz, 2H), 4.15 (s, 1H). LRMS (M+l) 168.1 (100%), 170.1 (34%). Step 2:4-(2-Fluoro-4-nitrophenoxy)-5-methyl-5//-pyrrolo[3,2-rfjpyrimidine (29) [0273) A suspension of 4-chloro-5-methyl-5#-pyrrolo[3,2-GfJpyrimidine (28) (300 mg, 1.79 mmol), 4-nitro-2-fluorophenol (422 mg, 2.69 mmol) and cesium carbonate (1.2 g, 3.58 mmol) in diphenyl ether (18 mL) was stirred overnight at 140°C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was triturated with EtiO, filtered, and dried to afford the title compound 29 as a grey solid (258 mg, 49% yield). LRMS (M+l) 289.1 (100%).
Step 3:4-(5-Methyl-J//-pyrrolo[3,2-c/]pyrimidin-4-yloxy)-3-fluorobenzenamine (30) [0274] To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methyl-5i/-pyrrolol'3,2-£/J pyrimidine (29) (253.6 mg, 0.879 mmol) in AcOH (3 mL) at 90°C was added iron powder (245 mg, 4.4 mmol). The mixture was stirred vigorously for 10 min and filtered. The filtrate was concentrated under reduced pressure to produce a solid, which was dissolved in DCM. The resultant solution was washed with cold NaHCCb solution and water, dried over Na2SO4 and concentrated to provide a residue which was purified by column chromatography (eluent MeOH-CHaCk 1:20) to afford the title compound 30 as a brown solid (120.6 mg, 53% yield). LRMS (M+l) 240.1 (100%). Step 4: 1 -(4-(5-Methyl-5i?-pyrrolo[3,2-c/]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (31a)
[027S] To a solution of 4-(5-methyl-5//-pyrrolo[3,2- 72

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Example 29
l-(4-(5-Ethyl-5//-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-
phenylacetyl)thiourea (31b)
[0276] Title compound 31b was obtained according to the scheme 5 using procedures
similar to the ones described for example 28 but using ethyl iodide (instead of methyl
iodide) in the step 1. Characterization of 31b is provided in table 4.
Example 30
l-(4-(5-Benzyl-5//-pynolo[3,2-d]pyrimidin-4-yIoxy)-3-fluorophenyl)-3-(2-
phenylacetyl)thiourea (31c)
[0277] Title compound 31c was obtained according to the scheme 5 using procedures
similar to the ones described for the example 28 but using benzyl bromide (instead of
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methyl iodide) in the step 1. Characterization of 31c is provided in table 4.


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Example 31
l acetyl)thiourea (36a)
[C278] Title compound 36a (scheme 6) was obtained according to the procedures
similar to the ones described for the example 28 (scheme 5) but using as a starting material
4-chloro-7if-pyrfolo[2,3-rf)pyrimidine 32 (instead of chloride 27). Characterization of 36a
is provided in table 5.
Example 32
l-(4-(7-Ethyl-7ff-pyrrolo[2,3- acetyl)thiourea (36b)
[0279] Title compound 36b was obtained according to the scheme 6 using the
procedures similar to the ones described for the example 31 but using ethyl iodide (instead
of methyl iodide) in the step 1. Characterization of 36b is provided in table 5.
Example 33
l-(4-(7-Benzyl-7if-pynolo[2>3-f/lpyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenyl
acetyi)thiourea (36c)
[0230] Title compound 36c was obtained according to the scheme 6 using the
procedures similar to the ones described for the example 31 but using benzyl bromide
(instead of methyl iodide) in the step 1. Characterization of 36c is provided in table 5.
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Example 34
7-(2-F!uoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N-diisobutylthieno[3,2-
bjpyridine-2-carboxamide (81)
Step 1: Methyl 7-chlorothieno[3,2-£]pyridine-2-carboxylate (37)
[0281] To a stirred solution of 2 (7.0 g, 41.3 mmol) in anhydrous THF (100 mL) at -
78°C under a nitrogen atmosphere was added n-BuLi (24.7 mL, 2.5 M in hexanes, 61.8
mmol). After 1 hour, methyl chloroformate (9.6 ml, 124 mmol) was added and the reaction
mixture was stirred for an extra hour at the same temperature, quenched with excess
methanoi and allowed to warm to room temperature. The solvent was then evaporated and
the residue was purified by flash chromatography using hexane - AcOEt (70:30) as an
eluent. The product from the column was re-crystallized from ethyl acetate to afford title
compound 37 (4.3g, 46% yield) as a white solid. 'H NMR (400 MHz, DMSO-afe) 8(ppm):
8.75 (dd, J = 0.8 and 4.8 Hz, 1H), 8.26 (d, J= 0.8 Hz, 1H), 7.74 (dd, J- 0.8 and 5.2 Hz, 1H),
3.93 (s, 3H).
Step 2: Methyl 7-(2-fluoro-4-nitrophenoxy)thieno[3,2-fc]pyridine-2-carboxylate (38)
[0282] A mixture of 37 (4.0 g, 17.6 mmol), 2-fluoro-4-nitrophenol (5.5 g. 35.0 mmol)
and K2CO3 (12.1 g, 87.5 mmol) in Ph2O was heated at 180°C for 5 hours. The mixture was
cooled to room temperature, diluted with EtOAc and washed with water. The organic phase
was collected, dried over anhydrous sodium sulfate and the solvents were removed under
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reduced pressure. The residue was purified by flash chromatography using hexanc - AcOEt (70:30) as an eluent. The product from the column was re-crystallized from a mixture of ethyl acetate-hexanes to afford 38 (3.6 g, 59% yield) as a white solid. *H NMR (400 MHz, DMSO-4s) §(ppm): 8.69 (d, J - 5.2 Hz, 1H), 8.47 (dd, J = 2.4 and 10.0 Hz, 1H), 8.27 (s, 1H), 8.21 (m, 1H), 7.77 (dd, J = 8.0 and 9.2 Hz, 1H), 7.06 (dd, J = 0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).
Step 3: 7-(2-Fluoro-4-nitrophenoxy)thienof3,2-&jpyridine-2-carboxylic acid (39) [0283] To a stirred solution of 38 (2.5 g, 7.18 mmol) in THF (50 ml) was added KOH (14.3 ml, 1.0 N in H2O, 14.3 mmol). After 4 hours the reaction mixture was concentrated and the resultant residue was dissolved in HiO (50 ml). The aqueous layer was then washed with ethyl acetate and acidified with IN HC1 (pH = 1). The precipitate that formed upon acidification was collected by filtration, washed with water and dried under high vacuum to afford title compound 39 (2.3 g, 96% yield) as a white solid. 'H NMR (400 MHz, DMSO-cfc) 5(ppm): 8.68 (d, J = 5.2 Hz, 1H), 8.47 (dd, J = 2.8 and 10.4 Hz, 1H), 8.20 (m, 1H), 8.17 (s, IH), 7.76 (dd, J = 8.0 and 8.8 Hz, 1H), 7.04 (d, J - 5.2 Hz, 1H). Step 4: 7-(2-Fluoro-4-nifrophenoxy)rhieno[3,2-Z>]pyridine-2-carbonyl chloride (40) [0284] To a solution of 39 (2.0 g, 5.98 mmol) in anhydrous CH;C12 (30 ml) under an atmosphere of nitrogen, was added oxalyl chloride (2.6 ml, 29.8 mmol). After stirring for 2 hours the solvent was evaporated, anhydrous toluene (10 mL) was added and the resultant mixture was evaporated (procedure of addition of toluene followed by evaporation was perfonned twice) to afford title compound 40 (2.2 g, 94% yield) as a white solid. The product was used without further purification and characterization and was assumed to be the mono-HCl salt.
Step 5:7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-iV;iV-diisobutylthieno[3,2-b]pyridine-2-carboxamide (81)
[0285] To a solution of 40 (150 mg, 0.385 mmol) and TEA (107 p.1, 0.771 mmol) in anhydrous CH2CI2 under an atmosphere of nitrogen was added diisobutylamine (67 u-L, 0.385 mmol). After stirring for 1 hour, methanol (2 mL) was added followed by iron powder (150 mg) and HC1 (cone, 0.4 mL). The reaction mixture was stirred for additional 2 hours and then partitioned between ethyl acetate (20 mL) and a mixture of H2O (20 mL) and NH4OH (2 mL). Organic phase was collected, washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was treated with 2-phenylacetyl isothiocyanate (102 mg, 0.58 mmol) in THF (2 mL), the resultant mixture was allowed to stand for 2 hours
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at ambient temperature, quenched with methanol (5.0 mL), loaded onto 5 ml of silica gel and purified by flash chromatography using hexane - AcOEt (70:30) as an eluent, to afford title compound 81 (41 mg, 18%) as a white solid. lH NMR (400 MHz, CD3OD) 5 (ppm): 8.54 (d, J = 5.6 Hz, 1H), 8.08 (dd, J = 2.0 and 12.0 Hz, 1H), 7.69 (s, 1H), 7.38 - 7.49 (m, 2H), 7.28 - 7.35 (m, 5H), 6.77 (dd, J = 1.2 and 5.6 Hz, 1H), 3.77 (s, 2H), 3.46 (bs, 4H), 2.18 (bs, 1H), 2.02 (bs, 1H), 1.02 (bs, 611), 0.87 (bs, 6H). LRMS (M+l):592.7 (calcd), 593.3 (found).


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Example 48
N-(4-(2-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylearbamothioyl)-2-
phenylacetamidc (44)
Step 1. 2-Bromo-7-chlorothieno(3,2-b]pyridiue (41)
[0286] To a stirred solution of the chloride 2 (10.12 g, 5.59 mmol) in dry THF (200 ml)
at -78°C was added n-BuLi (24 ml, 76.7 mmol, 2.5 M solution in hexanes) and the resultant
suspension was stirred for 15 minutes. Bromine (18.9 g, 120 mmol) was added slowly and
the reaction mixture was stirred for additional 30 min, quenched with water and diluted with
EtOAc, The organic phase was collected, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. Purification by column chromatography (9:1
EtOAc/hexane) afforded title compound 41 (10.5 g, 71% yield) as a yellow solid. 'H NMR
(400 MHz, CDC13) 5 (ppm): 8.62 (d, J= 5.09 Hz, 1H), 7.92 (s, 1H), 7.59 (d, J= 5.09 Hz,
!H).
Step 2, 2-Bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (42)
[0287] A mixture of the bromide 41 (5.1 g, 20.5 mmol), potassium carbonate (5.65 g, 4
mrnol) and 2-fluoro~4-nitrophenol (4,82 g, 30.7 mmol) was heated at 190°C in diphenyl
ether (25 ml) for 3 hrs. After cooling to room temperature it was diluted with DCM and
filtered. The filtrate was concentrated under reduced pressure and the residue was purified
by column chroinatography (eluent EtOAc:hexane, 3:1) to afford title compound 42 as a
yellow solid (5.4 g, 71% yield). !H NMR (400 MHz, DMSO-d*) 5 (ppm): 8.55 (d, J= 5.28
Hz, 1H), 8.46 (dd, J= 2.5 and 10.4 Hz, 1H), 8.19 (d, J= 8.8 Hz, III), 7.87 (s, 1H), 7.72 (t, J
= 8.4 Hz), 6.99 (d, J= 5.47 Hz, 1H).
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Steps 3-4. l-(4-(2-Bromothieno[3>2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (44)
[0288] To a solution of the nitro compound 42 (100 mg, 0.27 mmol) in THF (2 ml) and water (0.5 ml) was added SnCl2 x 2H2O (76.99 mg, 1.5 eq, 0.41 mmol) and the reaction mixture was refluxed for 3 nrs, cooled to room temperature, diluted with EtOAc and washed with cone, ammonium hydroxide solution. EtOAc-extract was collected and the aqueous fractions were combined and washed with DCM. DCM extract was combined with the AcOEt-extract, the mixture was dried over sodium sulfate, filtered and evaporated to form the amine 43 (92 mg, 100%), which was used without any further purification. [02891 To a solution of the amine 43 (92 mg, 0.27 mmol) in THF (10 ml) was added benzyl isothiocyanate (72 mg, 1.5 eq, 0.407 mmol). The reaction mixture was stirred for 1 hr at room temperature, concentrated under reduced pressure and the residue was purifed by column chromatograpy (7:3 hexane:EtOAc to 1:1 MeOH:EtOAc) to afford the title compound 44 as a white solid (28 mg, 20% yield). lH NMR (400 MHz, DMSO-d6) 5 (ppm): 12.48 (s, 1H), 11.81 (s, 1H), 8.55 - 8.52 (m, 1H), 8.01 (d, J= 11.9 Hz, 1H), 7.85 (s, 1H), 7.55 - 7.49 (m, 2H), 7.45 - 7.19 (m, 5H), 6.73 (d, J= 5.7 Hz, 1H), 3.82 (s, 2H). MS (m/z): 518.2/ 520.2 (M+H).

Example 49
N-(3-Fluoro-4-(2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide(47a)
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Step 1. 7-(2-Fluoro-4-nitrophenoxy)-2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridine (45) [0290] A mixture of the nitro compound 42 (500 mg, 1.36 mmol), 6-methoxypyridin-3-ylboronic acid (312 mg, 2.04 mmol) and CsF (620 mg, 4.08 mmol) were suspended in DME (12 ml) and NaHCOs (342 mg, 4.08 mmol), dissolved in the minimum amount of water, was added. The mixture was de-aerated by bubbling N2 through the solution for 10 min, heated at 80°C for 3 hrs and concentrated to dryness. The formed residue was dissolved in DCM and washed with water. The DCM was collected, dried over sodium sulfete, filtered and the DCM was removed by evaporation. The resultant solid was triturated with Et2O to afford the title compound 45 (176 mg, 32% yield), which was used without further purification. !H NMR (400 MHz, DMSO-d*) 5 (ppm): 8.71 (m, 1H), 8.56 (m 1H), 8.46 (m, 3H), 8.22 (mv2H), 8.01 (s, 1H), 7-72 (t, J= 8.6 Hz, 1H), 6.99 (d, 7= 5.47Hz, 1H), 6.90 (m, 1H)5 3.97 (s, 3H).
Step 2. JV-(3-F luoro-4-(2-(6-methoxypyridin-3-)'l)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(47a)
[0291J To a solution of 45 (176 mg, 0. 44 mmol) in MeOH (10 ml) and THF (10 ml) at 0°C was added NiCl2 x 6H2O (210 mg, 0.89 mmol) and NaBH4 (65 mg, 1.76 mmol). The reaction mixture was stirred for 1 hr, concentrated to dryness and the resultant solid was dissolved in 1 M HC1. The acidic solution was then made basic with aqueous ammonium hydroxide and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with Et2O to afford the amine 4fi as a white solid which was used immediately in the next step.
[0292] To a suspension of the amine 46 (162 mg, 0.44 mmol) in THF (7 ml) was added 2-phenyIacetyI isothiocyanate (117 mg, 0.66 mmol). The reaction mixture was stirred for 1 ht, concentrated under reduced pressure and the residue was purified by column chroniatography (eluentEtOAc-MeOH, 95:5); a solid was obtained which was triturated with Et2O to afford title compound 47a (80 mg, 33% yield). !H NMR (400 MHz, DMSO-d6) 5 (ppm): U.50 (s, 1H), 11.85 (s, 1H), 8.70 (s, 1H), 8.68 (d, Jfc 6.07 Hz, 1H), 8.28 (m, 1H), 8.10 (s, 2H), 7.59 (s, 2H), 7.34-7.27 (in, 5H), 7.01 (d, J= 8.61 Hz, 1H), 6.93 (d, J= 5.7 Hz, 1H), 3.93 (s, 3H), 3.83 (s, 2H). Examples 50-54
[0293] Examples 50-54 (compounds 47b-f) were prepared similarly to the compound 47a (example 49) according to the scheme 9.
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Example 55
N-(3-Fluoro-4-(2-(4-(methylsuifonyl)phenyl)thieno[3,2-b]pyridin-7-ybxy)
phenylcarbamothioyl)-2-pheny]acetamide (50)
Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(4-(methylsuIfonyI)phenyl)thieno[3,2-b]pyridine
(48)
£0294] To a solution of 42 (461 mg, 1.3 mmol, scheme 8) in DME (4 mL) was added
4,4>5,5-tetraniethyl-2-(4-(methylsulfonyl)phenyl)-l,3,2-dioxaborolane (500 mg, 2.5 mmol),
CsF (391 mg, 3.8 mmol), Pd(PPh3)4 (72 mg, 63 Mmol) and NaHCO3 (315 mg, 3.8 mmol)
pre-dissolved in H2O (1 ml). The reaction mixture was purged with nitrogen and refluxed
for 2 hours. The DME was removed under reduced pressure and the aqueous layer was
extracted with EtOAc. The extract was dried over sodium sulphate, filtered and evaporated
to form a residue which was purified by column chromatography (eluent EtOAc/hexane,
1:1) to afford the title compound 48 (97 mg, 18% yield) as a white solid. 'HNMR (DMSO)
5 (ppm): 8.63 (d, J= 1.2 Hz, 1H), 8.49 (d-d, /= 2.7 Hz, 1H), 8.33 (s, 1H), 8.22-8.19 (m,
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2H), 8.16 (s, 2H), 8.02 (d, J= 8.6 Hz, 2H), 7.75 (t, J= 8.0 Hz, 1H), 7.77-7.58 (m, 2H), 7.58-7.50 (m, 2H), 6.97 (d, 7 = 5.5 Hz, 1H), 3.33 (s, 3H), MS (m/z): 444.8 (M+H). Step 2. 3-Fluoro-4-(2-(4-(methylsulfonyl)phenyI)thieno[3,2-b]pyridin-7-yloxy)benzenamine (49)
[0295] Nitro compound 48 (97 mg, 2 mmol) was dissolved in a mixture of THF (7 mL) and MeOH (15 mL); NiCl2. x 6H2O (130 mg, 0.5 mmol) was added and the solution was cooled to 0°C. To the cooled mixture NaBH? (42 mg, 1.1 mmol) was added portion wise. The reaction was stir.ed for 20 min and quenched with 2 M HC1. The solvents were removed under reduced pressure and the residue was treated with concentrated ammonium hydroxide solution (pH 10) and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (eluent EtOAc) to afford the title compound 49 (46.7 mg, 51% yield) as a white solid. lHNMR (DMSO) 5 (ppm): 8.52 (d, J= 5.5 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J~ 8.4 Hz, 2H), 8.03 (d, J= 8.4 Hz, 2H), 7.63-7.58 (m, 2H), 7.56-7.52 (m, 2H), 7.13 (t, /- 8.6 Hz, 1H), 6.61 (d, ./= 2.2 Hz, 1H), 6.56 (dd, ./= 10 Hz, 1H), 6.46 (dd, J= 5.7 Hz, 1H), 5.57 (s, 2H), 3.29 (s, 3H), MS (m/z): 414.8 (M+H).
Step3.N-(3-Fluoro-4-(2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)-2~phenylacetamide(50)
[0296] To a solution of 49 (46.7 mg, 0.1 mmol) in dry THF (5 mL), 2-phenylacetyl isothiocyanate (40 mg, 0.2 mmol) was added and the reaction was allowed to stir for 30 minutes. The THF was removed under reduced pressure and the resultant product was purified by column chromatography on silica gel, eluent hexane/EtOAc (1:1), to afford the title compound 50 (35.4 mg, 53% yield). 'HNMR (DMSO) 5 (ppm): 12.49 (s, 1H),11.85 (s, 1H), 8.57 (d, J- 5.5 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J= 8.4Hz, 2H), 8.02 (d, J= 8.4 Hz, 2H), 7.63-7.52 (m, 5H), 7.34 (d, J- 4.1 Hz, 2H), 6.71 (d, /= 5.3 Hz, IH), 3.82 (brs, 2H), 3.27 (s, 3H) MS (m/z) 592.0 (M*).
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Example 56
l-(3-Fluoro-4-(2-(4-(morphoIinomethyl)phenyl)thieno[3,2-b]pyridiii-7-yloxy)phenyl)--3-(2-phenylacetyl)thiourea (55)
Step 1. (4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridm-2-yl)phenyl)methanol (51) 10297] To a solution of 42 (1.0 g, 2.71 mmol) in dry DME (20 ml) was added 4-(hydroxymethyl)phenylboronic acid (823 mg, 5.4 mmol), NaHCO3 (682 mg, 8.13 mmol), CsF (820 mg, 5.4 mmol) and water (10 mL) and the reaction mixture was refluxed under nitrogen for 2 hrs. After cooling to room temperature the DME was removed under reduced pressure, the residue was dissolved in EtOAc and the organic solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The resultant solid residue was triturated with Et20 to afford the title compound 51 as a white solid (880 mg, 82% yield). MS (m/z): 397.1 (M+H).
Step 2.2-(4-(Chlorornethyl)phenyl)-7-(2-fluoro-4-nitrophenoxy)thieno[3s2-b]pyridine (52) [0298] The alcohol 51 (880 mg, 2.22 mmol) was suspended in SOC12 (10 mi) and the reaction mixture was refluxed for 1 hour, cooled and carefully poured onto ice/water. A precipitate was formed which was collected by filtration, washed with additional cold water
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and dried under vacuum to afford the title compound 52 (919 mg, 100% yield), which was used without additional purification. MS (m/z): 415.1(100%) (M+H), 417.1 (36%) (M+H). Step 3. 7-(2-Fluoro-4-nitrophenoxy)-2-(4-(morpholinomethyI)phenyl)thieno[3,2-b]pyridine (53)
[0299] To a suspension of 52 (823 mg, 1.82 mmol) in DMF (10 ml) was added morpholine (317 mg, 3.65 mmol) and the reaction mixture was heated for 4 hours at 60°C, the solvent was removed under reduced pressure and the residual solid was triturated with EtOAc and collected by filtration. It was further washed with EtOAc until no color was observed in the filtrate, to form the title compound 53 (800 mg, 94% yield), which was used without additional purification. !HNMR (DMSO) 5 (ppm): 8.57 (d, J= 4.7 Hz, 1H), 8.46 (dd, /« 2.7 and 10.4 Hz, JH), 8.18 (m, 1H), 8.07 (s, 1H), 7.83 (d, J- 12.2 Hz, 1H), 7.71 (t, 7= 8.02 Hz, III), 7.42 (d,./- 8.2 Hz, 1H), 6.91 (d. /= 5.3 Hz, 1H), 3.56 (m, 4H), 3.51 (m, 2H), 3.33 (m, 2H), 2.50 (m, 2H).
Step 4. 1 -(3-?'li!oro-4-(2-(4-(morpholinomethyl)pheny3)thienof3,2-b]pyridiri-7-yioxy)phenyl)-3-(2-phenylasetyl)thiourea(55)
[0300] To a solution of 53 (1.1 g, 2.37 mmol) in MeOH (20 mL) and THF (20 mL) at 0°C was added NiCfe x 6H2O (1.12 g, 4.73 mmol) and NaBIlj(350 mg, 9.48 mmol). The reaction mixture was allowed to stir for 1 hr, solvents were removed under reduced pressure and the resultant solid residue was dissolved in 1 M HC1. This solution was made basic with concentrated aqueous ammonium hydroxide and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the resultant solid was triturated with Et20 to afford the amine 54 as a white solid (1.02 g, 100% yield), which was used in the next step without further purification.
[0301] To a suspension of the amine 54 (1.02 g> 2.34 mmol) in THF (10 mL) was added 2-phenyIacetyl isothiocyanate (622 mg, 3.52 mmol) and the reaction mixture was stirred for 1 hr at room temperature, concentrated under reduced pressure and purified by column chromatograpy (eluent EtOAc:MeOH, 95:5) to afford title compound 55 as a yellow powder (288 mg, 12% yield). )HNMR(400MHz,DMSO-d6)8(ppffi): 12.48 (s, 1H), 11.84 (s, 1H), 8.63 (m, 1H), 8.18 (s, 1H), 8.01 (d, J = 7.8 Hz, 2H), 7.75 (m, 2H), 7.57 (s, 2H), 7.33 (m, 4H), 6.80 (d, > 11.7 Hz, 2H), 3.83 (s, 5H), 3.37 (d, J- 11.7 Hz, 2H), 3.12 (m, 2H). MS (m/z) 613.3 (M+H). Scheme 12
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WO 2006/010264 PCT/CA2005/001177

Example 57
l-(3-Fluoro-4-(2-(3-morpholinoprop-l-ynyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-
phenylacetyl)thiourea (58)
Step 1.7-(2-Fluoro-4-niti-ophenoxy)-2-(3-morpholinoprop-l-ynyl)thieno[3,2-b]pyridine
(56)
[0302] To a solution of bromide 42 (100 mg, 0.27 mmol) in THF (5 mi) was added 4-
(prop-2-ynyl)morpholine (68 mg, 0.54 mmol) [H-W. Tsou, et. al. J. Med. Chem., 2001,44,
2719-2734], triethylamine (68 mg, 0.67mmol), Cul (5 mg, 0.03 mmol) and Pd(PPh3)2Cl2
(5.3 mg, 7.56 fimol). The reaction mixture was degassed with nitrogen and refluxed for 2
hrs, cooled to room temperature and adsorbed onto silica. Purification by column
chromatography (eluent EtOAc) afforded the title compound 56 as a beige solid (88 mg,
79%). MS (m/z): 397.1 (M+H).
Steps 2-3. l-(3-Fluoro-4-(2-(3-morpholinoprop-l-ynyl)thieno[3,2-b]pyridin-7-
yloxy)phenyl)-3-(2-phenylacetyl)thiourea(58)
[0303] To a solution of the nitro compound 56 (300 mg, 0.724 mmol) in THF (10 mL)
and NH4CI (6 mL) was added SnCb x 2H2O (489 mg, 2.17 mmol) and the reaction mixture
was refluxed for 3 hrs. After cooling the mixture was diluted with EtOAc and washed with
concentrated aqueous ammonium hydroxide. EtOAc phase was separated and the aqueous
phase was extracted with DCM. Both EtOAc phase and DCM extract were combined, dried
over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness to afford
the arnine 57 (277 mg, 100% yield), which was used without further purification.
8
WO 2006/010264 PCT7CA200.VO01177
[0304] To a solution of the atnine 57 (270 mg, 0.74 mmol) in THF (10 mL) was added 2-phenylacetyl isothiocyanate (188 mg, 1.06 mmol) and the reaction mixture was stirred for 1 hr, concentrated under reduced pressure and purified by column chromatography (eluent EtOAc) to afford title compound 58 (37 mg, 10% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 (ppm): 12.47 (s, 1H), i 1.82 (s, 1H), 8.55 (d, /« 5.3 Hz, 1H), 8.01 (d, J* 13.2 Hz, 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.33 (m, 4H), 7.28 (m, 1H), 6.72 (d, J= 5.3 Hz, 1H), 3.82 (s, 2H), 3,64 (s, 2H), 3.61 (m, 5H), 2.51 (m, 4H). MS (m/z): 561.3 (M+H).

Example 58
2-((4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3}2-b]pyridin-2-yl)phenyl)methylamino)ethanoI
(63)
Step 1.2-{4-[7-(2-Fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridin-2-yl]-benzylamino}-
ethanol (59)
[0305J To a suspension of the chloride 52 (500 mg, I.I mmoi) in DME (10 mL) was
added ethanolamine (336 mg, 5.5 mmol). The reaction mixture refiuxed for 2 hrs, the
solvent was removed under reduced pressure; the residue was dissolved in EtOAc and
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washed with water. The organic phase was collected, dried over sodium suifete, filtered and evaporated. The remaining solid was triturated with EhO to afford the title compound 59 as a yellow solid (200 mg, 41% yield). [H NMR (DMSO) 5 (ppm): 8.57 (d, J= 5.5 Hz, 1H), 8.47 (dd, J= 2.7 and 10.4 Hz, 1H), 8.21 {m, 1H), 8.17 (s, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.71 (t, 7= 8.6 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 6.91 (d, J= 5.5 Hz, 1H), 4.48 (t, /= 5.5 Hz, 1H), 3.75 (s, 2H), 3.45 (q, /= 5.6 Hz, 2H), 3.33 (m, 1H), 3.15 (d, /= 5.1 Hz, 2H), 2.56 (t, J = 5.7 Hz, 2H).
Step 2. Carbonic acid 2-(/er/-butoxycarbonyl-{4-[7-(2-fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridin-2-yl]-benzyl}-amino)-ethyl ester tert-butyl ester (60)
[0306] To a solution of 59 (200 mg, 0.45 mmol) in DCM (7 mL) at room temperature was added triethylamine (188 mg, 1.82 mmol), DMAP (cat) and Boc20 (355 mg, 1.82 mmol). The reaction mixture was stirred at room temperature overnight, the DCM was removed under reduced pressure and the residue was dissolved in EtOAc, washed sequentially with dilute HC1 solution, saturated NaHCCh and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated and the residue was purified by column chromatography (eluent EtOAc:hexane, 3:7) to afford title compound 60 (200 mg, 69% yield) as a yellow oil. 'H NMR (DMSO) 5 (ppm): 8.58 (d, J- 5.3 Hz, 1H), 8.47 (dd, J = 2.7 and 10.3 Hz, 1H), 8.21 (m, 1H), 8.09 (s, 1H), 7.87 (m, 2H), 7.72 (t, J= 8.4 Hz, IH), 7.33 (d, J= S.2 Hz, 2H), 6.91 (d, J= 5.3 Hz, 3H), 4.44 (s, 2H), 4.07 (t, J= 5.5 Hz, 2H), 3.40 (m,2H), 1.36 (m, 18H).
Steps 3-4. Carbonic acid 2-[re;-/-butoxycarbonyl-(4-{7-[2-fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridin-2-yl}-benzyl)-amino]-ethy! ester tert-butyl ester (62)
[0307] To a solution of 60 (500 mg, 1.1 mmol) in MeOH (10 mL) at 0°C was added NiCl2 x 6H2O (148 mg, 0.63 mmol) and NaBHi (46 mg, 1.24 mmol). The reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in 1 MHC1. The acidic solution was then made basic with concentrated ammonium hydroxide solution and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the resultant solid was triturated with EtjO to afford the crude amine 61 as a white solid (190 mg, 100% yield), which was used for the next step without characterization and additional purification.
[0308] To a suspension of the amine 61 (190 g, 0.31 mmol) in THF (7 mL) was added 2-phenyIacetyl isothiocyanate (118 mg, 0.62 mmol) and the reaction mixture was stirred for
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1 hr at room temperature, concentrated under reduced pressure and purified by column chromatography (eJuent EtOAc-MeOH, 6:4) to afford title compound 62 as a yellow powder (190 ing, 77% yield). 'H NMR (400 MHz, DMSO-d6) 8 (ppm): 12.48 (s, 1H), 11.83 (s, 1H), 8.51 (s, 1H), 8.04 (s, 1H), 8.01 (d, J= 11.7 Hz, 1H), 7.86 (d, J= 7.7 Hz, 2H), 7.52 (m, 2H), 7.34 (m, 6H), 7.32 (no, 1H), 6.64 (d, /= 5.5 Hz, 1H), 4.43 (s, 2H), 4.07 (t, J= 5.3 Hz. 2H), 3 81 (s, 2H), 3.44 (m, 2H), 1.37 (m, 18H).
Step 5. l-(3-FIuoro-4-(2-(4-((2-hydroxycthylamino)methy])phenyl)thieno[3,2-b]pyridin-7-y loxy)phenyl)-3 -(2-phenylacetyl)thiourea (63)
[0309] To a solution of 62 in DCM (190 mg, 0.24 mmol) was added TFA (excess) at room temperature and the reaction mixture was stirred for 3 hrs, evaporated under reduced pressure and the residual solid was triturated with Et2O to afford the title compound 63 as the di-TFA salt (100 mg, 51% yield). 'HNMR (400 MHz, DMSO-d6) 5 (ppm): 32.49 (s, 1H), 11.84 (s, 1H), S.89 (s, 1H), 8.53 (d, J= 5.1 Hz, IH), 8.14 (s, 1H), 8.01 (m, IH), 7.62 (dd, J~~ 2.5 and 7.7 Hz, 2H), 7.54 (d, /= 2.7 Hz, 2H), 7.33 (m, 4H), 7.28 (m, 1H), 6.67 (d, Jh 5.5 Hz, 1H), 4.64 (m, 1H), 4.30 (m, 1H), 4.22 (t, /= 5.3 Hz, 2H). 3.82 (s, 2H), 3.63 (t, J = 5.3 Hz, 2H), 2.98 (m, IH). MS (m/z) 587.0 (M+H).

[0310] To a solution of 2-methoxyethanamine (900 mg, 12 mmol) in DME (15 mL) was added 3-bromobenzylbromide (2.5 g, 10 mmol) and the reaction mixutre was stirred at 40°C (scheme 14). After 30 minutes, EtsN (1.01 g, 10 mmol) was added and the reaction was allowed to stir for another 10 minutes, filtered and the filtrate was concentrated to afford bromide 64 as a colorless oil (2.0 g, 80% yield). MS (m/z): 244.1 / 246.1 (M+H). tert-B\xty\ 3-bromobenzyl(2-methoxyethyl)carbamate (65)

WO 2006/010264 PCT/CA2005/O01177



[0311] To a solution of compound 64 (997 mg, 4 mmol) in CH2Cl2 (12 mL), di-tert-butylcarbonate (1.8 g, 8 mmol) was added and the reaction mixture was stirred for 3 hrs (scheme 14). DMAP (cat.) was added to the solution and the reaction mixture was allowed to stir for additional 76 hours. Solvent was removed under reduced pressure and the crude product was purified by column chromatography, eluent EtOAc/hexane (1:10) to afford the title compound 65 (778 mg, 56% yield) as a colorless oil. MS (m/z): 368.1 / 370.1 (M+Na).
Table 8 Aryl bromides 66-70 prepared according to the scheme 14

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94
[0312] To a solution of tert-butyl 2-tert-butyloxycarbonylaminoethyl(methyl)carbamate (600 mg, 2.2 mmol) in dry THF (5 tnL) at 0°C, was added NaH (91 mg, 3.8 mmol) and the reaction was stired for 30 minutes. 3- Bromobenzylbromide was added and the reaction was refluxed for 3 hours, cooled to room temperature and poured into MeOH. Solvents were removed under reduced pressure and the product was partitioned between EtOAc and water. Organic phase was collected and dried over anhydrous sodium sulphate, filtered and evaporated. The crude product was purified by column chromatography on silica gel, eluent EtOAc/hexane (1:5), to afford the title compound 71 (672 mg, 80% yield) as a colourless oil. MS (m/z): 343.0/345.0 (M-Boc).


WO 21)06/010264 PCT/CA20O5/001177
Example 59
N-(3-Fluoro-4-(2-(3-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(76a)
Step 1. tert-Buty] 2-methoxyethyl(3-(pinacolatoborolan-2-yl)benzyl)carbarnate (72) [0313] To a solution of bromide 65 (778 mg, 2.3 mmol), in dry toluene (12 mL), was added the bis(pinacolato)diboron (872 mg, 3.4 mmol), KOAc (677 nig, 6.9 minol) and Pd(PPh3)4 (80 mg, 69 umof). The reaction mixture was purged with nitrogen, rcfluxed for 2 hours and was allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue was partitioned between DCM and water (30mL/30mL). The organic phase was collected and dried over anhydrous sodium sulphate, filtered and evaporated.The remained solid was purified by column chromatography, eluent EtOAc/hexane (1:10) to afford title compound 72 (577 mg, 64% yield) as a colorless oil. *H NMR (DMSO) 8 (ppm): 7.54-7.52 (m, 2H), 7.33-7.31 (m, 2H): 4.39 (s, 2H), 3.40-3.35 (m, 2H), 3.33-3.25 (m, 2H), 3.20 (s, 3H), 1.43-1.32 (m, 9H), 1.28 (s, 12H). Step 2. tert-Butyl 3-(7-(2-fluoro-4-nitrophenoxy)thieno{3,2-b}pyridine-2-yl)benzyl(2-methoxyethyl)carbamate (73)
[0314] To a solution of the bromo-nitro compound 42 (272 mg, 0.7 mmol) in DME (4mL), was added pinacolate 72 (578 mg, 1.5 mmol), CsF (226 mg, 2.2 mmol), Pd(PPh3)4 (43 mg, 37 umol) and NaHCOj (186 mg, 2.2 mmol) pre-dissolved in water (2mL). The reaction mixture was purged with nitrogen, refluxed for 1 hour, cooled to room temperature and the solvent was removed under reduced pressure. The residue was extracted with EtOAc, the extract was dried over anhydrous sodium sulfate filtered and concentrated to produce a brown oil which was purified by chromatography on silica gel, eluent EtOAc, to afford the title compound 73 (347 mg, 85% yield) as a white solid. 'H NMR (DMSO) 8 (ppm): 8.60 (d, J = 5.3 Hz, 1H), 8.47 (d-d, J= 7.6 Hz, 1H), 8.19 (d, 7= 6.5 Hz, 1H), 8.07 (s, 1H), 7.80 (d, J= 7.8 Hz, 1H), 7.73-7.69 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.30 (d, /= 7.4 Hz, 1H), 6.95 (d, /= 5.5 Hz, 1H), 4.48 (s, 2H), 3.21 (s,3H), 2.50 (q, /- 2.2 Hz, 4H), 1.44-1.33 (m, 9H), MS (m/z): 554.0 (M+H).
Step 3. terr-Butyl 3-(7-(4-amino-2-fiuorophenoxy)thieno[3,2-b]pyridin-2-yl)benzyl(2-methoxyethyl)carbamate (74)
[0315] To a solution of 73 (347 mg, 0.6 mmol) in THP (4 mL) and MeOH (2 mL), NiCb (372 mg, 1.6 mmol) was added and the solution was cooled to 0°C. NaBfii (95 mg, 2.5 mmol) was added portion wise. After 20 minutes, the reaction was treated with 2 M HC1 and solvents were removed under reduced pressure. The concentrated mixture was basified
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to pH 10 with ammonium hydroxide solution and the mixture was extracted with EtOAc, the extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography, eluent EtOAc, to afford the title compound 74 (235 mg, 72% yield) as a white solid. 5H NMR (DMSO) 5 (ppm): 8.47 (d, J = 5.6 Hz, 1H), 7.97 (s, 1H), 7.77 (d, J= 7.2 Hz, 1H), 7.70 (s, 1H), 7.48 (t, J= 1.6 Hz, 1H), 6.56-6.51 (m, 2H), 6.44 (dd, J= 6.3 Hz, 1H), 5.54 (s, 2H), 4.84 (s, 2H), 3.43 (s, 2H), 3.23 (s, 3H), 2.50 (q, J= 2.2 Hz, 4H), 1.46-1.35 (m, 9H).
Step 4. tert-Buty] 3- [0316] To a solution of 74 (235 mg, 0.5 mmol) in dry THF (5 mL), 2-phenylacetyl isothiocyanate (159 mg, 0.9 mmol) was added and the reaction was allowed to stir for 30 min. The solvent was removed under reduced pressure and the resulting product was purified by chromatography on silica gel using EtOAc/hexane (1:1) as eluting system to give the desired product (440 mg, 90%) as a white solid. *H NMR (DMSO) 8 (ppm): 8.52 (d, J- 5.3 Hz, 1H), 8.01 (t, J~ 6.5 Hz, 2H), 7.79 (d, J= 7.4 Hz, 1H), 7.70 (s, 1H), 7.53-7.52 (m, 2H), 7.47 (t, J- 7.6 Hz, 1H), 7.34 (d, J- 4.5 Hz, 4H), 7.30-7.24 (m, 2H), 6.67 (d, J= 5.3 Hz, 1H), 4.49 (s, 2H), 3.83 (s, 2H), 3.42 (s, 2H), 3.22 (s, 3H), 2.50 (q, J= 2.2 Hz, 4H), 1.45-1.33 (m, 911).
Step5.Ar-(3-Fluoro-4-(2-(3-((2-methoxyethylainino)methyl)phenyl)thieno[3,2-b]pyridm-7-yloxy)phenylcarbamothioyl)-2-phenylacetarnide (76a)
[0317] To a solution of 75 (440 mg, 0.6 mmol) in DCM (10 mL), TFA (145 pL, 1.9 mmol) was added and the reaction was stirred for 12 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluent MeOH/EtOAc (1:10), to afford the title compound 76a (227 mg, 63% yield) as a light yellow solid. ]H NMR (DMSO) 5 (ppm): 8.54 (d, J= 5.5 Hz, 1H), 8.07 (s, IH), S.02-8.0 (m, 2H), 7.93 (d-t, J= 2.0 Hz, 1H), 7.55-7.53 (m, 4H), 7.34-7.32 (m, 4H), 7.29-7.26 (m, IH), 6.68 (d, J= 5.3 Hz, 1H),4.19 (s, 2H), 3.81 (s, IH), 3.57 (t, J= 4.9 Hz, 2H), 3.33 (s, 2H), 3.29 (s, 3H), 3.08 (t, J = 4.9 Hz, 2H), 2.84 (q, /= 2.2 Hz, 4H). Examples 60-65
[0318] Compounds 76b-g (examples 60-65) were synthesized similarly to the compound 76a (example 59) according to the schemes 14-15, starting from bromides 66-69 and 71. Characterization of 76b-g is provided in Table 8a.
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76b-g: Examples 60-65
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Table 8a Characterization of compounds 76b-g (examples 60-65)


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Example 66
l-(3-Fluoro-4-(2-(4-(((tetrahydrofuran-2-yl)methylamino)methyl)phenyl)thieno[3,2-
b}pyridin-7-yIoxy)phenyl)-3-(2-phenylacetyl)thiourea (81)
Step 1. /er/-Butyl(4-(7-ch)orothieno(3,2-b]pyridin-2-yl)phenyl)methyl((tetrahydrofuran-2-
y]) methyl) carbamate (77)
[0319] To a solution of the trimethyltin compound 9 (1.4 g, 3.06 mmol) (scheme 2) and
bromide 70 (2.25g, 6.11 mmol) (scheme 14, Table 8) in dry toluene (50 ml) was added
Pd(PPfi3)+ (176 mg, 0.153 mmol). The reaction mixture was refluxed overnight, cooled to
room temperature and the solvents were removed under reduced pressure. The resultant
solid was triturated with hexane/ether and then purified by column chromatography, eluents
EtOAc/Hexane 1:9, then EtOAc:hexane 4:6, to afford title compound 77 as a white solid
(1.2 g, 86% yield). MS (m/z): 459.2 / 461.2 (M+H).
Step 2. /er/-Butyl (4-(7-(2-fiuoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-
yl)phenyl)methyl((tetrahydrofuran-2-yl)methyl)carbamate(78)
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[0320] To a solution of 77 (1.0 g, 2.18 mmol) in Ph2O (10 ml) was added 2-fiuoro-4-
nitrophenol (856 mg, 5.45 mmol) and potassium carbonate (904 mg, 6.55 mmol). The
reaction mixture was heated at 180°C for 4 hrs, cooled to room temperature, diluted with
DCM, filtered and concentrated. The residue was purified by column chromatography,
eluent EtOAc:hexane 8:2, to afford title compound 78 (250 mg, 20% yield). MS (m/z):
580.3 (M+H).
Steps 3-4. tert-Butyl (4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thiom-eido)phenoxy)thieno[3,2-
b]pyridin-2-yl)phenyl)methyl((tetrahydro&ran-2-yl)methyl)carbamate(80)
[0321] To a solution of 78 (250 mg, 0.431 mmol) in MeOH (10 mL) at 0°C was added
NiCl2 x 6H2O (205 mg, 0.86 mmol) and NaBH* (64 mg, 1.72 mmol). The reaction mixture
was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in
2 M HC1. This solution was then made basic with concentrated aqueous ammonium
hydroxide and extracted with DCM. The DCM extract was dried over anhydrous sodium
sulfate, filtered and evaporated to form the amine 79 (236 mg, 100% yield), which was used
without characterization and further purification.
[0322] To a solution of the amine 79 (236 mg, 0.43 mmol) in THF (10 mL) was added
2-phenylacetyl isothiocyanate (314 nig, 6.44 mmol). The reaction mixture was stirred for 1
hr, concentrated and the residue was purified by column chromatograpy, eluent - gradient
from EtOAc:hexane 1:1 to EtOAc, to afford title compound 80 (200 mg, 64 % yield) as a
white solid. MS (m/z): 725.5 (M+H).
Step5.1-(3-Fluoro-4-(2-(4-(((tetrahydrofuran-2-yl)methylamino)methyl)phenyl)thieno[3,2-
b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(81)
[0323] To a solution of 80 (200 mg, 0.28 mmol) in toluene (5 mL), TFA (excess) was
added. The reaction mixture was allowed to stir overnight, the solvent was removed under
reduced pressure and the remained solid was triturated with diethyl ether to afford title
compound 81 as the di-TFA salt (130 mg, 57% yield). 'H NMR (DMSO) 5 (ppm): 12.47 (s,
1H), 11.83 (s, 1H), 9.06 (s, 2H), 8.53 (dd, J= 2.0 and 5.5 Hz, 1H), 8.13 (s, 1H), 8.0 (d, J =
12.1 Hz, 1H), 7.97 (d, J= 8.7 Hz, 2H), 7.63 (d, J= 8.2 Hz, 2H), 7.53 (m, 2H), 7.32 (m, 4H),
7.27 (m, 1H), 6.68 (d, J= 5.8 Hz, 1H), 4.23 (m, 1H), 3.82 (s, 2H), 3.78 (m, 1H), 3.71 (m,
1H), 3.11 (m, 1H), 2.95 (m, 1H), 2.0 (m, IH), 1.98 (m, 2H), 1.56 (m, 1H). MS (m/z) 627.3
(M+H).
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Example 67
7-[2-Fluoro-4-(3-phen}'iacctyI-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonicacid methoxy-methyl-amide (85)
Step 1. 7-Chloro-N-methoxy-N-methylthieno[3,2-b]pyridine-2-sulfonamide (82) [0324] To a solution of chloride 2 (scheme 1) (700 mg, 4.14 mmol) in THF (20 ml) was added n-BuLi (2 ml, 4.97 mmol, 2.5 M solution in hexanes) at -78° C and the reaction mixture was stirred for 20 mins. SOa-gas was passed over the surface of the solution for 3 hrs at the same temperature, then for an additional hr at 0°C. The reaction mixture was evaporated. DCM (20 ml) and NCS (605 mg, 4.55 mmol) were added and the reaction mixture was stirred at room temperature for 1.5 hrs, filtered through a celite pad and concentrated to produce a pink solid. The solid was dissolved in acetone (20 ml); MeNH(OMe) hydrochloride (608 mg, 6.21 mmol) and triethylamine (627 mg, 6.21 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The EtOAc solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (eluent EtOAc:hexane,
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1:1) to afford the title compound 82 (485 mg, 40% yield) as a pink solid. MS (m/z) 561.1
(M+H).
Step 2.7-(2-Fluoro-4-nitrophenoxy)-A'-methoxy-N-methylthieno[3,2-b]pyridine-2-
sulfonamide (83)
[0325] A mixture of 82 (400 mg, 1.37 mmol), 2-fluoro-4-nitrophenol (321 mg, 2.05
mmol) and K2CO3 (756 mg, 5.48 mmol) were heated to 190°C in diphenyl ether (55 ml) for
3 hrs. The mixture was cooled to room temperature, diluted with DCM and filtered. The
filtrate was concentrated and purified by column chromatography (eluent EtOAc:hexane,
1:1) to afford title compound 83 (225 mg, 40% yield). MS (m/z) 414.0 (M+H).
Steps 3-4. 7-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-
sulfonic acid methoxy-methyl-amide (85)
[0326] To a solution of the nitro compound 83 (225 mg, 0.54 mmol) in THF (5 ml) and
water (2 ml) was added SnCfe x 2H2O (742 mg, 3.3 mmol). The reaction mixture was
refluxed for 3 hrs, diluted with EtOAc and washed with aqueous ammonium hydroxide. The
washings were combined and extracted with DCM. Both EtOAc- and DCM- phases were
combined, dried over anhydrous sodium sulfate, filtered and evaporated to produce the
amine 84 (168 mg, 81% yield), which was used without characterization and further
purification.
[0327] To a solution of the amine 84 (225 mg, 0.59 mmol) in THF (8 ml) was added
phenyl-acetyl isothiocyanate (208 mg, 1.18 mmol). The reaction mixture was stirred for 1
hr, concentrated under reduced pressure and purified by column chromatography (eluent
EtOAc) to afford 85 (323 mg, 98% yield) as a white solid. 'H NMR (400 MHz, DMSOd6)
5 (ppm): 12.52 (s, 1H), 11.86 (s, 1H), 8.74 (d, J= 5.3 Hz, 1H), 8.33 (s, 1H), 8.07 (d, J= 13.5
Hz, 1H), 7.61 (m, 2H), 7.36 (m, 4H), 7.29 (m, 1H), 3.86 (s, 3H), 3.84 (s, 2H), 2.96 (s, 3H).
MS (m/z): 561.3 (M+H).
Example 68
7-[2-Fiuoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonicacid
amide (86)


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[0328] Title compound 86 was obtained following the procedures described for the compound 85 (example 67, scheme 16) but substituting in the first step O-methyl hydroxylamine for ammonia. 1HNMR(400 MHz, DMSO-d6) ? (ppm): 13.82 (s, 1H), 13.15 (s, IH), 9.98 (m, 1H), 9.4-9.2 (m, 4H), 8.87 (s, 2H), 8.64 (m, 5H), 8.15 (s, 1H), 3.82 (s, 2H). MS (m/z): 517.3 (M+H).

Example 69
l-(4-(2-(l-Ethyl-5-methyl-lH-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-(2-methoxyphenyl)acetyl)thiourea(90)
Step 1. 7-Chloro-2-(l-ethy]-5-methyl-lH-imidazol-4-yl)-thieno[3,2-b]pyridine (87) [0329] To a solution of 2 (1.14 g, 6.76 mmol) in THF (60 ml) was added, at -78°C5 n-BuLi (3.38 ml, 2.5 M soln in hexanes) and the reaction mixture was stirred at the same temperature for 10 min. A solution of ZnCb (16.9 ml, 2.5 ml, 0.5M in THF) was added and the reaction mixture was warmed to room temperature. Then a solution of l-ethyl-4-iodo-5-methyl-lH-imidazole (800 mg, 3.38 mmoi) (Pyne, S.G and Cliff, M.D. Synthesis 1994, 681) and Pd(PPh3)4 (390 mg, 0.34 mmol) in THF (15 ml) were added and the reaction mixture was refluxed for 3 hrs, cooled to room temperature, quenched with cone, ammonium
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hydroxide solution and made neutral with concentrated aqueous HC1. The neutral solution was extracted with EtOAc, the extract was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated and the residue was purified by column chromatography (eluent MeOH:EtOAc, 1:9) to afford the title compound 87 (l.ig, 100% yield) as a brown oil. MS (m/z) 278.0 / 280.0 (M+H).
Step 2. 2-( 1 -Ethyl-5-methyl-1 tf-imidazol-4-yl)-7-(2-fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridine (88)
[0330] A suspension of 87 (650 mg, 2.35 mmol), potassium carbonate (970 mg, 7.04 mmol) and 2-fluoro-4-nitrophenol (738 mg, 4.7 mmol) were heated at 190°C in diphenyl ether (15 ml) for 3 hrs. The mixture was cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated and the residue was purified by column chromatography (eluents EtOAc, then MeOHrEtOAc, 1:9) to afford title compound 88 (600 mg, 64%) as a yellow solid. MS (m/z) 399.0 (M+H).
Steps 3-4. l-(4-(2-(l-Ethyl-5-methyl-lH-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-(2-methoxyphenyl)acetyl)thiourea(90)
[0331] To a solution of 88 (200 mg, 0.5 mmol) in MeOH (8 ml) and THF (2 ml) at 0°C was added NiCl2 x 6H2O (237 mg, 1 mmol) and NaBHU (74 mg, 2 mmol). The reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in 1 M HC1. The acidic solution was then made basic with concentrated aqueous ammonium hydroxide and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was triturated with Et2O to afford the crude amine 89 (184 mg, 100% yield) which was used immediately in the next step [without characterization]. [0332] To a solution of the amine 89 (180 mg, 0.49 mmol) in THF (10 ml) was added (2-methoxy-phenyl)-acetyl isothiocyanate (200 mg, 0.98 mmol). The reaction mixture was stirred for 10 min, concentrated and the residue was purified by column chromatography (eiuents EtOAc, then to MeOH-EtOAc, 1:9), to afford title compound 90 (84 mg, 30% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d,) 5 (ppm) 12.56 (s, 1H), 11.73 (s, 1H), 8.43 (d, y= 5.5 Hz, 1H), 8.04 (d, J= 12.3 Hz, 1H), 7.71 (s, 1H), 7.51 (m, 4H), 7.25 (m, 2H), 6.97 (d, J= 8.2 Hz, 1H), 6.92 (t, J= 7.2Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.92 (t, J= 7.2 Hz, IH), 6.56 (d, J= 5.5 Hz, 1H), 4.0 (q, J = 3.2 Hz, 2H), 3.80 (s, 2H), 3.77 (s, 3H), 2.47 (s, 3H), 1.31 (t, J= 3.2 Hz, 2H). MS (m/z) 576.1 (M+H).
104


Example 70
N-(3-Fluoro-4-(2-(l-(2-methoxyethyl)-lH-imidazol-4-yl)thieno[3,2-b]pyridm-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide (96) Step 1.7-Chloro-2-(l-((2-(trimethylsilyI)ethoxy)methyl)-l/?-imidazoI-4-yl)thieno[3,2-b]pyridine (91)
[0333] To a solution of 2 (9.4 g, 56.0 mmol) in THF (150 ml) at -78°C was added n-BuLi (28 ml, 70.0 mmol, 2.5 M soln in hexanes) and the reaction mixture was stirred at -78°C for 45 mins. A solution of ZnCl2 (140 ml, 70.0 mmol, 0.5M in THF) was added and the reaction mixture was warmed to room temperature. To the warmed mixture a solution of 4-iodo-l-(24rimethyIsi!anyl-ethoxymethyi)-lH-irnidazoie [Carl J. Lovev et al. Tetrahedron Lett.. 2004, 45(28). 5529-5532] (9.0 g, 28.0 mmol) and Pd(PPh3)4 (2.5 g, 2.1 mmol) in THF (50 ml) were added. The reaction mixture was heated to reflux for 3 hrs, cooled to room
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temperature, quenched with aqueous ammonium hydroxide and made neutral with aqueous HC1. The neutral solution was extracted with EtOAc, the organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (eluent MeOH-EtOAc, 1:20) to afford the title compound 91 (7.5 g, 73% yield) as a brown oil. MS (m/z) 366.0/368.0 (M+H).
Step 2. 7-(2-Fluoro-4-nitrophenoxy)-2-(l -((2-(trimethylsilyl)ethoxy)methyl)-l#-imidazol-4-yl)thieno[3,2-b]pyridine (92)
[0334] A suspension of 91 (4.2 g, 11.5 mmol), potassium carbonate (7.95 g, 57.5 mmol) and 2-fluoro-4-nitrophenol (4.97 g, 31.6 mmol) was heated at 190°C in diphenyl ether (15 ml) for 4.5 hrs, cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluents hexane and acetone/hexane, 45:55) to afford title compound 92 (3.4 mg, 61% yield) as a yellow solid MS (m/z) 487.0 (M+H).
Step 3.7-(2-Fluoro-4-nitrophenoxy)-2-(lH-imidazol-4-yl)thieno[3,2-b]pyridine (93) [0335] To a suspension of 92 (3.3 g, 6.8 mmol) in EtOH (8 ml) was added concentrated HC1 (7 ml) and distilled water (4 ml). The mixture was heated at 80-90°C for 2.5 h, cooled to room temperature and concentrated under reduced pressure. The remaining residue was subjected to azeotropic distillation with EtOH followed by neutralization with saturated aqueous NaHCOj. The solid that precipitated was filtered and washed with water, and the filtrate was extracted with EtOAc. The solid and EtOAc extract were combined, evaporated under reduced pressure and the residue was collected and dried to afford the title compound 93 (2.4 g, 100% yield) as a yellow solid. MS (m/z) 357.0 (M+H). Step 4. 7-(2-FIuoro-4-nitrophenoxy)-2-(l-(2-methoxyethyl)-ljF/-imidazol-4-yl)thieno[3,2-b]pyridine (94)
[0336] To a solution of 93 (300 mg, 0.84 mmol) in dry DMF (3 ml) at 0°C was added NaH (40 mg, 60 % dispersion in oil, 1.0 mmol). The mixture was allowed to warm to room temperature over 0.5 h then re-cooled to 0°C. Bromoethylmethyl ether (123 mg, 0.88 mmol) was added and mixture was allowed to warm to room temperature over 20 hours, concentrated and partitioned between EtOAc and water. The EtOAc phase was dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (eluents hexane and acetone/hexane 75:25) to afford the title compound 94 (126 mg, 36% yield) as a pale yellow solid. MS (m/z) 415.1.0 (M+H).
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Step 5. 3-Fluoro-4-(2-(l-(2-methoxyethyl)-l/Wmidazol-4-yl)thieno[3,2-b]pyridin-7-
yloxy)benzenamine (95)
[0337] Following the procedure described above for compound 89 (scheme 17) but
replacing the nitro compound 88 with the nitro compound 94, title compound 95 was
obtained as a beige solid (23 mg, 100% yield). MS (m/z) 385.2 (M+H).
Step6.iV-(3-Fluoro-4-(2-(l-(2-methoxyethyI)-l//-imidazol-4-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetarnide(96)
[0338] Following the procedure described above for the compound 90 (scheme 17) but
replacing the amine 89 with the amine 95 and using 2-(2~methoxyphenyl)acetyl
isothiocyanate instead of 2-phenylacetyl isothiocyanate, title compound 96 was obtained as
a beige solid (6 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) 5 (ppm) 12.57 (1H, s),
11.77 (1H, s), 8.53 (1H, d, J=5.4S Hz), 8.08 (1H, d, J=12.03 Hz), 8.02 (1H, s), 7.91 (1H, s),
7.76 (1H, s), 7.59-7.52 (2H, m), 7.28-7.21 (2H, m), 6.98 (1H, d, J=8.22 Hz), 6.91 (1H, d,
J=7.44 Hz), 6.71 (1H, d, J=5.67 Hz), 4.21 (2H, t, J=4.89 Hz), 3.80 (2H, s), 3.77 (3H, s),
3.65 (2H, t, J=4.89 Hz), 3.26 (3H, s). MS (m/z) 592.1 (M+H).
107


Example 71
(S)-N-(3-Fluoro-4-(2-(4-((3-hydroxypyrrolidin--]-yl)methyl)phenyi)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyI)-2-phenyiacetamide(104)
Step 1. (S)-l-(4-Bromobenzyl)pyrroltdin-3-ol (97)
[0339] Title compound 97 was obtained, according to the scheme 14 by reacting (S)-
pyrrolidm-3-ol with 3-bromobenzylbrotnide, as a white solid (1.3g 63% yield). LRMS
256.1/258.1 (M+l).
Step 2.7-Chloro-2-(tributylstannyl)thieno[3,24]pyridine (98)
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{0340] To a solution of the chloride 2 (18.72 g, 110 mmol) in THF (200 mL) at -78°C n-
BuLi (51 mL, 127 mmol) was added and the reaction mixture was stirred for about 30
minutes. The tributylchlorostannane (25.4 mL, 93 mmol) was added and the mixture was
stirred at -78°C for another 60 minutes, quenched with water [at the same temperature] and
allowed to warm up to room temperature. The warmed mixture was extracted with ElOAc,
the extract was dried over anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by flash chromatography, eluents EtOAc-hexane (15:85),
then EtOAc-hexane (25:75) to afford title compound 98 (30.2 g, 77% yield) as a yellow oil.
LRMS (M+l) 459.1 (100%).
Step 3. (S)-l-(4-(7-Chlorothieno[3,2-b]pyridin-2-yl)benzyl)pyrrolidin-3-ol (99)
[0341] To a solution of 98 (2.44 g, 5.30 mmol) and bromide 97 (1.3g, 5.07 mmol) in dry
toluene (30 mL) was added Pd(PPh3)4 (290 mg, 0.25 mmol). The reaction mixture was
heated to reflux for 1.5 h, cooled to room temperature and the solvent was removed under
reduced pressure. The resultant solid was purified by column chromatography, eluents
EtOAc-Hexane (1:1) then MeOH/EtOAc (20:80), to afford title compound 99 (1.24 g, 71%
yield) as a white solid. MS (m/z): 345.1/347.1 (M+H).
Step 4. (S)-2-(4-((3-(tert-Butyldimethylsilyloxy)pyrrolidin-l-yl)methyl)phenyl)-7-
chlorothieno[3,2-b]pyridine(100)
[0342] To a suspension of 99 (0.5 g, 1.45 mmol) in dry THF (7 ml) at 0°C was added
TBDMSOTf (0.5 ml, 2.2 mmol) and the reaction mixture was stirred for 20 min. Et3N (0.61
ml, 4.4 mmol) was added and mixture was stirred at the same conditions for another hour,
quenched by the addition of water (~2 ml) and concentrated to dryness. The remained solid
was partitioned between EtOAc and water. Organic phase was collected, washed with brine,
dried over anhydrous NajSC^ and concentrated. The residue was purified by column
chromatography, eluents EtOAc/hexane (1:1) then MeOH/EtOAc (5:95) to afford title
compound 100 (637 mg, 96% yield) as a white solid. MS (m/z): 459.2/461.2 (M+H).
Step 5. (S)-2-(4-((3-(tert-Butyldimethylsilyloxy)pyrrolidin-1 -yi)methyl)phenyl)-7-(2-fiuoro-
4-niirophenoxy)thieno[3,2-b]pyridine(101)
[0343] To a solution of 100 (250.0 mg, 0.54 mmol) in Ph2O (4 ml) was added 2-fluoro-
4-nitrophenol (171 mg, 1.1 mmol) and potassium carbonate (304 mg, 2.2 mmol). The the
reaction mixture was heated to 195 °C for 3 hrs, cooled to room temperature, diluted with
DCM, filtered and concentrated. The residue was purified by column chromatography,
eiuents EtOAc, then MeOH/EtOAc (20-80), to afford title compound 101 (94 mg, 30%
yield) as a white solid. MS (m/z): 580.3 (M+H).
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Step 6. (S)-N-(4-(2-(4-((3-(ftr/-Butyldimethylsilyloxy)pyrrolidin-1 -
yl)methyl)phenyl)thieno[3,2-bjpyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-
phenylacetamide (103)
[0344] To a solution of the nitro compound 101 (90 mg, 0.16 mmol) in MeOH (4 ml) at
0°C was added NiCl2 x 6H2O (74 mg, 0.31 mmol) and NaBH4 (23 mg, 0.62 mmol). The
reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid
was dissolved in 2 M HC1. The acidic solution was then made basic with aqueous
ammonium hydroxide solution and extracted with EtOAc. The organic extract was dried
over anhydrous sodium sulfate, filtered and evaporated to form the amine 102 (80 mg, 95%
yiled), which was used without further purification and characterization.
[0345] To a solution of the amine 102 (80 mg, 0.15 ramol) in THF (2 mL) was added 2-
phenylacetyl isothiocyanate (64 mg, 0.36 mmol).The reaction mixture was stirred for 1 hr,
concentrated and the residue was purified by column chromatography, eluents
EtOAc:hexane (1:1), then EtOAc, to afford title compound 103 (34 mg, 30 % yield) as a
white solid. MS (m/z): 727.5 (M+H).
Step 7. (S)-N-(3-fluoro-4-(2-(4-((3-hydroxypyrroIidin-l-yl)methyl)phenyl)thieno[3,2-
b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(104)
[0346] To a solution of 103 (34 mg, 0.047 mmol) in CH3CN/MeOH (0.5 mL/2.0 mL),
concentrated HC1 (8 drops) was added and the reaction was allowed to stir 2 h. The solvents
were removed under reduced pressure and the resultant solid was triturated with diethyl
ether followed by purification by Gilson HPLC preparative system, column Aquasil CIS
(25% MeOH in water to 100% MeOH), to afford title compound 104 (2.5 mg, 9% yield), as
a white solid. 1H NMR (DMSO) 5 (ppm): 11.82 (1H, s), 8.51 (1H, d, J=5.28 Hz), 8.23 (1H,
s), 8.02-7.98 (2H, m), 7.82 (2H, d, J=7.83 Hz), 7.52 (2H, br), 7.41 (2H, d, J=7.83 Hz), 7.33-
7.25 (5H, m), 6.64 (1H, d, J-5.09 Hz), 4.20 (1H, br), 3.83 (2H, s), 3.38 (2H, s), 2.34-2.32
(2H, m), 2.03-1.96 (2H, m), 1.56 (2H, br). MS (m/z) 613.3 (M+H).
Example 72
(S)-l-(4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-
yl)benzyl)pyrrolidine-2-carboxylic acid (106)
110


[0347] Title compound 105 was obtained, according to the scheme 14 by reacting (S)-tert-butyl pyrrolidine-2-carboxylate with 3-bromcbenzy!bromide, as a white solid (1.62g, 94% yield). LRMS 340.1/342.1 (M+l).
(S)-l-(4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyI)pyrrolidine-2-carboxylic acid (106)
[0348] Title compound 106 was obtained following the procedures similar to the ones described above for the synthesis of compound 104 (example 71, scheme 19), replacing bromide 97 with the bromide 105 in the second step, skipping the step 4 (TBS-protection) and using in the last step TFA/DCM mixture for terr-butyl ester de-protection. 'H NMR (400 MHz,DMSO-d6): ?12.47 (1H, s), 11.82 (1H, s), 8.53 (1H, br), 8.13 (1H, s), 8.01 (1H, d, J=12.91 Hz), 7.96 (2H, d, J=7.02 Hz), 7.60 (2H, d, J=7.63 Hz), 7.54 (2H, br), 7.34-7.27 (5H, m), 6.67 (1H, d, J-5.09 Hz), 4.40 (1H, br), 4.23 (1H, br), 3.83 (2H, s), 3.38 (111, s), 2.38 (1H, br), 2.00 (2H, br), 1.85 (1H, br). MS (m/z) 641.3 (M+H). Examples 73-82 (compounds 13i-13r)
[0349] Following the procedures described above for the synthesis of compound 13a (example 12, scheme 2) but substituting trimethyltin chloride in the step 1 for tributyltin chloride and 2-bromothiazole in the step 2 for heteroaryl bromides shown in the Table 9, title compounds 13i-13r were synthesized. Characterization of compounds 13i-13r (examples 73-82) is provided in the Table 10.
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112
Table 9 Heteroaryl bromides used in the synthesis of compounds 13i-13r (examples 73-82)


113
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114

115
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Example 83
N-(4-(2-(lH-Imidazol-2-yl)tliieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-
phenylacetamide (313)
Step 1. l-((2-(TrimethylsilyI)ethoxy)methylM/Wmidazo!e (107)
[0350] To a stirred suspension of NaH (60% dispersion in oil, 0.65 g, 16.2 mmol) at 0°C
was added imidazole (1 g, 14.7 mmol) in THF (14 mL). The mixture was warmed to room
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temperature over 30 min, then re-cooled to 0°C followed by an addition of (2-
(chloromethoxy)ethyl)trimethylsilane (2.73 ml, 15.4 mmol). The combined mixture was
warmed to room temperature over lh, quenched with saturated aqueous ammonium
chloride, concentrated to dryness and partitioned between water and EtOAc. Organic phase
was collected, dried over anhydrous sodium sulfate, filtered and evaporated. The residue
was purified by column chromatography (eluents EtOAc, then MeOH/EtOAc 20:80), to
afford the title compound (2.04 g, 70% yield) as a white solid. MS (m/z) 199.3 (M+H).
Step 2. 2-Bromo-l-((2-(trimethylsilyl)ethoxy)methyI)-lH-imidazoIe (108)
[0351] To a solution of 107 (100 mg, 0.50 mmol) in acetonitrile (1 mL) at room
temperature was added cyanogen bromide (107 mg, 1.0 mmol) and the mixture was allowed
to stir at room temperature for 3 h, concentrated to dryness and partitioned between EtOAc
and water. The organic phase was collected, dried over anhydrous sodium sulfate and
concentrated to diyness. The residue was purified by column chromatography (eluents
EtOAc/hexane 25:75, then EtOAc), to afford the title compound 108 (45 mg, 32% yield) as
a colorless oil. MS (m/z) 277.0/279.0 (M+H).
Step 3. 7-Chloro-2-(l-((2-(trimethyIsilyl)ethoxy)methyl)-lH-imidazol-2-yl)thieno[3,2-
bjpyridine (109)
[0352] Starting from the compound 98 (scheme 19) and following the procedure
described above for the synthesis of compound 10 (example 12, scheme 2) but substituting
2-bromothiazole in the step 2 for the bromide 108, title compound 109 was obtained as a
white solid (22 mg, 41% yield). MS (m/z) 366.1/368.1 (M+H).
Step 4. 7-(2-Fluoro-4-nitrophenoxy)-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lJy-imidazol-
2-yl)thieno[3,2-b)pyridine (110)
[0353] Following the procedure described above for the synthesis of compound 11
(example 12, step 3, scheme 2) but substituting compound 10 for compound 109, title
compound 110 was obtained as a yellow solid (104 mg, 50% yield). MS (m/z) 487.3
(M+H).
Steps 5-6. N-(3-Fluoro-4-(2-(l-((2-(trimethylsilyl)ethoxy)methyl)-l#-imidazol-2-
yl)thieno[3,2-b]pyridin-7-yloxy)phenyIcarbamothioyI)-2-phenylacetamide(112)
[0354] Following the procedure described above for the synthesis of compound 13a
(example 12, steps 4-5, scheme 2) but substituting compound 11 for compound 110 and
using intermediate amine 111 (instead of amine 12), title compound 112 was obtained as a
beige solid (48 mg, 33% yield). MS (m/z) 634.3 (M+H).
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Step7.N-(4-(2-(lH-Iraidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyicarbamothioyl)-2-phenylacetamide (113)
[0355] A solution of 112 (21 mg, 0.033 mmol) in 4N HC1 in dioxane (3.5 mL) was allowed to stir at 55°C for 1 h. The mixture was then cooled and solvent was removed under reduced pressure. The resultant gum was triturated with ether several times to form a solid material that was dried under high vacuum to afford the product 113 as a beige solid (5 mg, 28% yield). lH NMR (400 MHz, DMSO-d6) ? ppm 12.50 (1H, s), 11.84 (1H, s), 8.66 (1H, d, J-5.67 Hz), 8.39 (1H, s), 8.06 (1H, d, J=12.72 Hz), 7.68 (2H, s), 7.59-7.58 (2H, ra), 7.36-7.30 (5H, m), 6.86 (1H, d, J=5.48 Hz), 3.83 (2H, s). MS (m/z) 504.1 (M+H). Scheme 21

Example 84
2-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-l-
methyl-N-(2-morpholinoethyl)-lH-imidazole-5-carboxarnide (117)
Step 1. l-Methyl-N-(2-morpholinoethyl)-lH-imidazole-5-carboxamide (115)
[0356] To a suspension of l-methyl-lH-imidazole-5-carboxylic acid (0.92 g, 7.3 mmol)
[Rapoport, H.; et al.; Synthesis 1988; 767.] in dichloromethane (10 ml), was added oxalyl
chloride (2.6 ml, 29.2 mmol) and the reaction mixture was heated to reflux for 1 h, cooled,
concentrated to dryness to form acid chloride 114 (1.05 g, 100%) which was used without
characterization and further purification.
[0357] To a suspension of the acid chloride 114 (1.05 g, 7.3 mmol) in THF (10 mL) was
added 2-morpholinoethanamine (2.38 g, 18.5 mmol). The mixture was stirred at room
temperature for lh, concentrated to dryness and the residue was purified by column
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chromatography (eluent chloroform/MeOH/ammonium hydroxide, 100:2:0.5), to afford the title compound 115 (551 mg, 32% yield) as a white solid. MS (m/z) 239.1 (M+H). Step 2. 2-Bromo-l-methyl-N-(2-morpholinoethyl)-l/?-imidazoIe-5-carboxamide (116) [0358] To a solution of 115 (550 mg, 2.31 mmol) in acetonitrile (5 mL) was added cyanogen bromide (489 mg, 4.6 mmol). The reaction flask was covered with aluminum foil and the mixture was allowed to stir at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (eluents 100% EtOAc to 30%MeOH/EtOAc), to afford title compound 116 as a beige solid (230 mg (31%). MS (m/z) 317.1/319.1 (M+H).
Step 3.2-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-l-methyl-N-(2-morpholinoethyl)-lH-imidazo]e-5-carboxamide(117) [0359] Following the procedures described above for the synthesis of compound 13a (example 12, scheme 2) but substituting trimethyltin chloride in the step 1 for tributyltin chloride and 2-bromothiazole in the step 2 for the bromide 116, title compound 117 was synthesized. 1HNMR (400 MHz, DMSO-d6) ?pprn 8.55 (1H, d, J=5.28 Hz), 8.47 (1H, br), 8.04 (1H, s), 7.97 (1H, d, J=12.52 Hz), 7.67 (1H, s), 7.49 (2H, br), 7.33-7.32 (4H, m), 7.26 (1H, m), 6.70 (1H, d, J=5.09 Hz), 4.18 (3H, s), 3.84 (2H, s), 3.57 (4H, br), 2.47-2.33 (8H, m). MS (m/z) 674.3 (M+H).
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Examples 85 and 86
Methyl 2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-
1 -methyl-l/f-imidazole-S-carboxylate (123), and
N-(3-Fluoro-4-(2-(5-(hydroxymethyl)-l-methyl-l/f-imidazol-2-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-pheny lacetamide (124)
Step 1. Methyl 2-bromo-l -methyl- lH-imidazole-5-carboxy late (118)
[0360] Following the procedure described above for the compound 116 (scheme 21) but
replacing compound 115 with methyl l-methyl-lH-imidazole-5-carboxylate, title
compound 118 was obtained as a beige solid (373 mg, 49% yield). MS (m/z) 219.1/221.1
(M+H).
Step 2. Methyl 2-(7-chlorothieno[3,2-b]pyridin-2-yl)-l-methyl-lH-imidazole-5-carboxylate
(119)
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[0361] Starting from the compound 98 (scheme 19) and following the procedure
described above for the synthesis of compound 10 (example 12, scheme 2) but substituting
2-bromothiazole in the step 2 for the bromide 118, title compound 119 was obtained as a
white solid (580 mg, 100% yield). MS (m/z) 308.1/310.0 (M+H).
Step 3. Methyl 2-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-l-methyl-l//-
imidazole-5-carboxylate (120)
[0362] Following the procedure described above for the synthesis of compound 11
(example 12, step 3, scheme 2) but substituting compound 10 for compound 119, title
compound 120 was obtained as a yellow solid (254 nig, 31% yield). MS (m/z) 429.1
(M+H).
Step 4. Methyl 2-(7-(4-amirio-2-fiuorophenoxy)thieno[3,2-b]pyridin-2-yl)-l-methyl-lH-
imidazole-5-carboxylate (121) and (2-(7-(4-amino-2-fluorophetioxy)thieno[3,2-b]pyridin-2-
yl)l-methyI-lH-imidazol-5-yl)methanol(122)
[0363] Following the procedure described above for the synthesis of compound 12
(example 12, step 4, scheme 2) but substituting compound 11 for compound 120, title
compounds 121 and 122 were obtained as white solids (39 mg, 21% yield and 56 mg, 32%
yield). MS (m/z) 399.1 (M+H) and MS (m/z) 371.1 (M+H) respectively.
Step 5. Methyl 2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno(3,2-
b]pyridin-2-yl)-1 -methyl- lH-imidazole-5-carboxylate (123)
[0364] Following the procedure described above for the synthesis of compound 13a
(example 12, step 3, scheme 2) but substituting compound 12 for compound 121, title
compound 123 was obtained as a beige solid (35 mg, 63% yield). 1H NMR (400
MHz, DMSO-d6) ? ppm 12.48 (1H, s), 11.82 (1H, s), 8.58 (1H, dd, 5.48, 0.98 Hz), 8.13
(1H, d, J=0.98 Hz), 8.03 (1H, d, J=12.52 Hz), 7.81 (1H, d, J=1.17Hz), 7.55-7,54 (2H, m),
7.36-7.31 (4H, m), 7.27 (1H, m), 6.74 (1H, d, J=5.48 Hz), 4.21 (3H, s), 3.83 (3H, s), 3.83
(2H, s). MS (m/z) 576.2 (M+H).
Step 5a. N-(3-Fluoro-4-(2-(5-(hydroxymethyl)-1 -methyl-lH-imidazol-2-yl)thieno[3,2-
b]pyridin-7-yloxy)phenylcarbamothioyI)-2-phenylacetamide(124)
[0365] Following the procedure described above for the synthesis of compound 13a
(example 12, step 3, scheme 2) but substituting compound 12 for compound 122, title
compound 124 was obtained as a beige solid (32 mg, 39% yield). 1H NMR (400
MHz, DMSO-d6) ? ppm 12.48 (1H, s), 11.82 (1H, s), 8.58 (1H, dd, 5.48, 0.98 Hz), 8.13
(1H, d, J=0.98 Hz), 8.03 (1H, d, J=12.52 Hz), 7.81 (1H, d, J=1.17 Hz), 7.55-7.54 (2H, m),
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7.36-7.31 (4H, m), 7.27 (1H, m), 6.74 (1H, d, J=5.48 Hz), 4.21 (3H, s), 3.83 (3H, s), 3.83 (2H, s). MS (m/z) 576.2 (M+H).
Scheme 23

Example 87
Ar-(4-(2-(iV,iV-Diethyicarbamimidoyl)thieno[3,2-b]pyridin-7-yloxy)-3-
fluorophenylcarbamothioyl)-2-phenylacetamide(130)
Step 1.7-Chlorothieno[3,2-b]pyridine-2-carbaldehyde oxime (125)
[0366] To a solution of aldehyde 14 (scheme 3) in MeOH was added NH2OH x HCl
(227 mg, 3.26 mmol) in water (0.5 mL) and the mixture was stirred at room temperature for
0.5 h. The solvents were removed by under reduced pressure and the residue was partitioned
between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate,
filtered and evaporated to dryness to afford the title compound 125 (458 mg, 85% yield) as
a white solid. MS (m/z) 213.1/215.1 (M+H).
Step 2.7-Chlorothieno[3,2-b]pyridine-2-carbonitrile (126)
[0367] A solution of the oxime 125 (100 mg, 0.47 mmol) in acetic anhydride (2 ml) was
set to reflux for 3 h and then at 90°C for 48h. The acetic anhydride was removed under
reduced pressure and the residue was partitioned between a cold aqueous K2CO3 solution
and EtOAc. The organic phase was dried over anhydrous sodium sulfate, concentrated to
dryness and remained solid was purified by column chromatography, eluents 25%
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EtOAc/hexane (25:75), then 100% EtOAc, to afford the title compound 126 (65 mg, 71%
yield). MS(m/z) 195.1/197.1 (M+H).
Step 3. 7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carbonitrile (127)
[0368] Following the procedure described above for the synthesis of compound 11
(example 12, step 3, scheme 2) but substituting compound 10 for compound 126, title
compound 127 was obtained as a yellow solid (] 14 mg, 60% yield). MS (m/z) 316.0
(M+H).
Step 4. N,N-Diethyl-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboximidamide
(128)
[0369] To a solution of nitrile 127 (116 mg, 0.37 mmol) in MeOH (3 mL) was added
NaOMe (25% in MeOH, 0.09 ml, 0.39 mmol) and the mixture was allowed to stir at room
temperature for 18 h. Subsequently, Et2NHx HC1 (1.01 g, 9.25 mmol) was added and the
mixture was heated to reflux for 12 h., cooled to room temperature and the solvent was
removed under reduced pressure. The residue was partitioned between EtOAc and saturated
aqueous ammonium chloride, the organic phase was dried over anhydrous sodium sulfate,
filtered and concentrated to dryness. The remained solid was purified by column
chromatography (eluents EtOAc then CHCl3/MeOH/NH4OH 44:5:0.5), to afford the title
compound 128 (30 mg, 21% yield) as a white solid. MS (m/z) 389.2 (M+H).
Steps 4-5. N-(4-(2-(N,N-Diethylcarbamimidoyl)thieno[3,2-b]pyridin-7-yloxy)-3-
fluorophenylcarbamothioyl)-2-phenylacetarnide(130)
[0370] Following the procedure described above for the synthesis of compound 13a
(example 12, steps 4-5, scheme 2) but substituting compound 11 for compound 128 and
using intermediate amine 129 (instead of amine 12), title compound 130 was obtained as a
beige solid (5 mg, 13% yield). 1H NMR (DMSO) ? (ppm): 8.58 (1H, d, J-5.48 Hz), 8.29
(1H, s), 8.02 (1H, d, J=11.35 Hz), 7.81 (1H, d, J=2.54 Hz), 7.53 (2H, br), 7.34-7.33 (5H, m),
6.74 (1H, d, J=5.28 Hz), 3.83 (2H, s), 3.40 (4H, q, J=6.91 Hz), 1.16 (6H, t, J=6.95 Hz). MS
(m/z) 536.2 (M+H).
Scheme 24
123

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Example 88
N-(S-Fluoro-4-CmorphoIinomethyl)thieno[3,2-b]pyriclin-7-yloxy)phenylcarbamothioyl)-
2-phenylacetamide (134)
Step 1. 4-((7-Chlorothieno[3,2-b]pyridin-2-yI)methyl)morpholine (131)
[0371] To a solution of aldehyde 14 (scheme 3) (316 mg, 1.6 mmol) and morpholine
(0.15 ml, 1.52 mmol) in MeOH (20 mL) was added acetic acid (0.88 ml, 15 mmol),
followed by sodium cyanoborohydride (105 mg, 1.67 mmol). The resultant mixture was
allowed to stir for 18 h, quenched with saturated aqueous potassium carbonate solution (5
mL), evaporated under reduced pressure and the residue was partitioned between EtOAc
and water. The organic phase was dried over anhydrous sodium sulfate, concentrated to
dryness and the remained solid was purified by column chromatography, elucnts
EtOAc/hexane (30:70), then MeOH/EtOAc (1:99), to afford the title compound 131 (120
mg, 29% yield). MS (m/z) 269.0/271.0 (M+H).
Step 2. 4-((7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)methyl)morpholine (132)
[0372] Following the procedure described above for the synthesis of compound 11
(example 12, step 3, scheme 2) but substituting compound 10 for compound 131, title
compound 132 was obtained as a yellow solid (110 mg, 69% yield). MS (m/z) 390.1
(M+H).
Steps 3-4.N-(3-FIuoro-4-(2-(morpholinomethyl)thieno[3,2-b]pyridin-7-
yloxy)pheny{carbamothioyl)-2-phenylacetamide(134)
[0373] Following the procedure described above for the synthesis of compound 13a
(example 12, steps 4-5, scheme 2) but substituting compound 11 for compound 132 and
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using intermediate amine 133 (instead of amine 12), title compound 134 was obtained as a
white solid (38 mg, 27% yield). 1H NMR (DMSO) ? (ppm): 12.89 (1H, s), 12.24 (1H, s),
8.87 (1H, d, J-4.71 Hz), 8.42 (IH, d, J=12.13 Hz), 7.95-7.88 (3H, m), 7.76-7.68 (5H, m),
7.00 (1H, d, J=5.28 Hz), 4.26-4.25 (4H, m), 4.02 (4H, br), 3.76 (2H, s), 2.90 (2H, s). MS
(m/z) 537.2 (M+H).
Examples 89-92
(S)-tert-Butyl l-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-
b]pyridine-2-carbonyl)pyrrolidine-2-carboxylate (135a),
(R)-/e7'/-But)'I3-((7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-
b]pyridine-2-carboxamido)methyl)pyrrolidine-1 -carboxylate (13 5b),
(R)-iV-(4-(2-(3-(Dimethylamino)pyrrolidine-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3-
fluorophenylcarbamothioyl)-2-phenylacetamide (135c), and
N-(3-Fluoro-4-(2-(piperidine-l-carbonyl)thieno[3,2-b]pyridin-7-
yloxy)phenyfcarbamothioyl)-2-phenylacetamide (135d)
[0374] Compounds 135a-d (examples 89-92) were obtained following the procedures
described above for the synthesis of compound 8a (example 1, scheme 1). Characterization


125
of 135a-d is provided in Table 11.


Example 93
N-(3-Fluoro-4-(2-(piperidine-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-pheny!acetamide hydrochloride (136a) [0375] N-(3-FIuoro-4-(2-(piperidine-l-carbonyl)thieno[3,2-Z>]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenyIacetamide (135d, example 92) (686 mg, 1.25 mmol) was solubilized in THF (2 mL); dichloromethane (4 mL) and 1M hydrogen chloride in ether (1.5 mL, 1.5 mmol) were successfully added. The reaction mixture was stirred forlhour, the solvents were partially evaporated under reduced pressure to form a precipitate, which was collected by filtration, to afford the title compound 136a (380 mg, 65% yield) as a light-yellow solid. Characterization of this material is provided in Table 12. Example 94
N-(3-Fluoro-4-(2-(pyrroIidine-l-carbony!)thieno[3,2-b]pyridin-7-y!oxy)phenylcarbamothioyl)-2-phenylaceiarnide hydrochioride (136b) [0376] Following the procedure described above for the synthesis of compound 136a (example 93) but substituting compound 135d (example 92, table 11) for the compound 8o
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(example 37, table 6), title compound 136b was obtained. Characterization of this material
is provided in Table 12.
Example 95
(S)-l-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-
carbonyl)pyrrolidine-2-carboxylic acid hydrochloride (136c)
[0377] Following the procedure described above for the synthesis of compound 136a
(Example 93) but substituting compound 135d (example 92, table 11) for the compound
135a (Example 89, Table 11), title compound 136c was obtained. Characterization of this
material is provided in Table 12.
Example 96
N-(4-(2-(Azepane-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyI)-
2-phenylacetamide hydrochloride (136d)
[0378] Title compound 136d was obtained following the procedures described above
for the synthesis of compound 136a (example 93, table 12). Characterization of 136d is
127
provided in Table 12.


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Example 97
(S)-7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(pyrrolidin-3-
ylmethyl)thieno[3,2-b]pyridine-2-carboxamidehydrochloride(137a)
[0379] To a solution of 135b (table 11) (16 mg, 0.028 mmol) in CH2C12 (15 mL) was
added TFA (1 mL). The reaction mixture was stirred at room temperature until the reaction
is complete, then the reaction mixture was quenched with saturated aqueous sodium
bicarbonate solution a extracted with DCM. The extract was concentrated, the residue was
dissolved in DCM (15 mL) and hydrogen chloride (0.5M in ether, 46 ?L, 0.046 mmol) was
added. The reaction mixture was stirred for one hour, the solvents were partially evaporated
under reduced pressure to form a precipitate, which was collected by filtration, to afford the
title compound 137a (10 mg, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6)
dppm: 12.48(8, 1H), 11.82(s, IB), 9.49-9.43(m, 1H), 9.24(bs, 1H), 8.74(bs, 1H), 8.62(d, J =
5.6 Hz, 1H), 8.3S(s, 1H), 8.03(d, J = 12.0 Hz, 1H), 7.58-7.5(m, 2H), 7.3-7.30(m, 4H), 7.30-
7.24(m, 1H), 6.79(d, J = 5.6 Hz, 1H), 3.80-3.54(m, 3H), 3.30-3.20(m, 1H), 3.20-3.10(m,
lH),2.12-2.02(m, 1H),2.OO-I.95(m, 2H), 1.74-1.63(m, 1H).
Example 98
7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(2-(methylamino)ethyl)
thieno[3,2-b]pyridine-2-carboxamide hydrochloride (137b)
Steps 1-7. tert-Buty\ 2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-
b]pyridine-2-carboxamido)ethyl(methyl)carbamate(138)
[0380J Following the procedures described above for the synthesis of compound 8a
(Example 1, scheme 1) but replacing dimethyl amine with tert-butyl 2-
aminoethyl(methyl)carbamate, title compound 138 was obtained (13%). LRMS (M+l)
638.2 (100%).
Step 8. 7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(2-(methyIamino)ethyl)
thieno[3,2-b]pyridine-2-carboxamide hydrochloride (137b)
[0381] Following the procedure described above for the synthesis of 137a but replacing
compound 135b with compound 138, title compound 137b was obtained as an HC1 salt in
65% yield. 1H NMR (400 MHz, DMSO-d6) ? ppm: 12.49(s, 1H), 11.83(s, 1H), 9.39(t, J -
5.2Hz, 1H), 8.80(bs, 1H), 8.62(d, J = 5.6 Hz, 1H), 8.39(s, 1H), 8.04(d, J = 11.6 Hz, 1H),
7.97(bs, 1H), 7.58-7.50(m, 2H), 7.37-7.31(m, 4H), 7.31-7.24(m, 1H), 6.80(d, J = 5.6 Hz,
1H), 3.78-3.71(m, 0.5H), 3.61(q, J = 6.0 Hz, 1H), 3.21-3.24(m, 0.5H), 3.18-3.04(m, 2H),
2.60(t,J = 4.8 Hz, 2H).
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Examples 99 and 100
N-(3,5-Dichloro-4-(2-(pyrrolidine-l-carbonyl)thieno[3,2-Z>]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (142) and
7-(2,6-dichloro-4-(3-(2-phenylacetyI)thioureido)phenoxy)-2-(pyrrolidine-l-
carbony!)thieno[3,2-b]pyridin-4-ium chloride (143)
Steps 1-4. (7-Chlorothieno[3,2-Z-b]pyridin-2-yl)(pyrrolidin-l-yl)methanone (139)
[0382] Following the procedures described above for the synthesis of compound 5
(scheme 1, example 1) but replacing dimethyl amine in the step 4 for pyrrolidine, title
compound 139 was obtained. LRMS (M+l) 267.1 (100%).
Step 5. (7-(2,6-Dichloro-4-nitrophenoxy)thieno[3,2-&]pyridin-2-yl)(pyrrolidin-1 -
yl)methanone (140)
[0383] Starting from the compound 139 and following the procedure described
above for the synthesis of compound 6 (scheme 1, example 1) but replacing 2-fluoro-4-
nitrophenol with 2,6-dichloro-4-nitrophenol, title compound 140 was obtained in 69% yield.
LRMS (M+l) 438.0 (100%), 439.1 (20%), 440.1 (70%).
Steps 6-7. ;V-(3,5-Dichloro-4-(2-(pynrolidine-l-carbonyl)thieno[3,2-/b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (142)
[0384] Starting from the nitro compound 140 and following the procedures described
above for the synthesis of 8a (steps 6-7, scheme 1, example 1) title compound 142 was
obtained in 49% yield. LRMS (M+l) 585.3 (100%), 586.2 (34%), 587.3 (72%).
7-(2,6-Dichloro-4-(3-(2-phenyiacetyl)thioureido)phenoxy)-2-(pyrroIidine-l-
carbonyl)thieno[3,2-b]pyridin-4-ium chloride (143)
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[0385] Following the procedure described above for the synthesis of compound 136a (Table 12, Example 93) but replacing compound 135d with compound 142, title compound , 143 was obtained in 42% yield. Characterization of 143 is provided in the Table 13. Examples 101 and 102
N-(3-Chloro-4-(2-(pyrrolidine-l-carbonyI)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide hydrochloride (144) and N-(3-Methyl-4-(2-(pyrrolidine-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide hydrochloride (145) [0386] Compounds 144-145 (examples 101-102) were obtained following the procedures described above for the synthesis of compound 143 (example 100). Characterization of compounds 144-145 is provided in the Table 13. Examples 103 and 104
2-Phenyl-N-(4-(2-(pyrrolidine-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide (146) and
N-(3-(Dimethylamino)-4-(2-(pyrrolidine-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (147)
131
[0387] Compounds 146-147 (Examples 103-104) were obtained following the procedures described above for the synthesis of compound 142 (Example 99). Characterization of compounds 145-147 is provided in the Table 13.



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Example 105
N-(3-Fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyriniidin-4-yloxy)pheny]carbamothioyl)-2-
phenylacetamide (152a)
Step 1.4-Ch!oro-6-(tributylstannyl)thieno[3,2-d]pyrimidine (148)
[0388] Starting from 4-chloro-thieno[3,2-d]pyrimidine (20, scheme 4) and following the
procedure described above for the synthesis of tributyltin compound 98 (scheme 19), title
compound 148 was obtained in 79% yield. LRMS (M+l) 461.1 (100%).
Step 2.4-Chloro-6-(thiazol-2-yl)thieno[3,2-d]pyrimidine (149)
[0389] Starting from the tributyltin compound 148 and following the procedure
described above for the synthesis of compound 10 (scheme 2, example 12), title compound
149 was obtained in 81% yield. LRMS (M+l) 254.0 (100%).
Step 3.4-(2-FIuoro-4-nitrophenoxy)-6-(thiazoi-2-yl)thieno(3,2-d]pyrimidine (150)
[0390] Starting from the bis-aryl compound 149 and following the procedure described
above for the synthesis of compound 11 (scheme 2, example 12) title compound 150 was
obtained in 65% yield. LRMS (M+l) 375.0 (100%).
Steps 4-5. iV-(3-Fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (152a)
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[0391] Starting from the nitro compound 150, following the procedure described above for the synthesis of compound 13a (via the intermediate amine 12, scheme 2, example 12), title compound 152a was obtained [via intermediate 3-fiuoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)benzenamine (151)] in 7% yield. Characterization of 152a is provided in the Table 14. Examples 106-108
N-(3-Fluoro-4-(6-(pyridin-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide (152b),
N-(3-Fluoro-4-(6-(thiophen-2-yI)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide (152c), and
iV-(3-Fluoro-4-(6-(thiophen-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide (152d)
[0392] Compounds 152b-d (Examples 106-108) were synthesized according to the Scheme 27, similarly to the compound 152a (Example 105). Characterization of 152b-d is provided in the Table 14.
Table 14 Characterization of Compounds 152a-d (Examples 105-108)

Cpd Ex R Name Characterization
152a 105 N-(3-FIuoro-4-(6-(thiazol-2-yi)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamot hioyl)-2-phenylacetamide 1H NMR (400 MHz, DMSO-d6)d ppm: 8.75(s, 1H), 8.32(s, 1H), 8.05(d, J = 3.2 Hz, 1H), 8:03(d, J = 3.2Hz, 1H), 7.96-7.88(m, 1H),7.58-7.50(m, 1H), 7.50-7.43(m, 1H), 7.36-7.30(m, 4H), 7.30-7.23(m, 1H), 3.83(s, 2H).
152b 106 o iV-(3-FIuoro-4-(6-(pyridin-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamot hioyl)-2-phenylacetamide 1H NMR (400 MHz, X)MSO-d6) ? ppm: 12.44(s, 1H), 11.80(s, 1H), 8.73(s, 1H), 8.70-8.64(m, 1H), 8.47(5,1H), 8.38(m, J = 8.0 Hz, 1H), 8.00(td, J = 2.0 and 8.0 Hz, 1H), 7.92(dd, J - 2.0 and 12.0 Hz, 1H), 7.55(t, J - 8.8 Hz, 1H), 7.53-7.46(m, 2H), 7.36-7.3l(m, 4H), 7.30-7.24(m, 1H), 3.82(s, 2H).
134


Example 109
N-(3-Fluoro-4-(2-(4-hydroxyphenyl)thieno[3,2-&]pyridin-7-yloxy)phenylcarbamothioyl)-2-
phenylacetamide (155a)
Step 1. 4-(7-(2-Fiuoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (153)
[0393] To a solution of 2-bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (42,
scheme 8) (650 mg, 1.76 mmol) in ethylene glycol dimethyl ether (18 mL) were added 4-
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hydroxyphenylboronic acid (486 mg, 3.52 mmoi), tetrakis-triphenylphosphine palladium(O)
(203 mg, 0.18 mmol), cesium fluoride (802 mg, 5.28 mmol) and a solution of sodium
bicarbonate (444 mg, 5.28 mmol) in water (1 mL). The reaction mixture was purged with
nitrogen, heated at 80°C for 4 hours, quenched with saturated aqueous ammonium chloride
and extracted with EtOAc. The extract was washed with water and brine, dried over
anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue
was purified by trituration with methanol and ether to afford title compound 153 (418 mg,
62% yield) as a yellow solid. LRMS (M+l) 383.1 (100%).
Step 2.4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-%yridin-2-yl)phenol (154)
[0394] Following the procedure described above for the synthesis of the amine 49
(scheme 10, example 55) but substituting nitro compound 48 for the nitro compound 153,
title compound 154 was obtained in 99% yield (crude material, used in the next step without
additional purification). LRMS (M+l) 353.1 (100%).
Step 3. AK3-Fluoro-4-(2-(4-hydroxyphenyI)thieno[3,2-%yridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (155a)
[0395] Following the procedure described above for the synthesis of Compound 50
(Scheme 10, Example 55) but substituting amine 49 for the amine 154, title Compound
155a was obtained in 3% yield. Characterization of 155a is provided in the Table 14a.
Examples 110-118
N-(3-Fluoro-4-(2-(4-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenyIcarbamothioyl)-2-
phenylacetamide (155b),
N-(3-Fluoro-4-(2-(3-methoxyphenyl)thienot3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-
phenylacetamide (155c),
N-(3-Fluoro-4-(2-(3-fluoro-4-methoxyphenyl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (155d),
N-(3-Fluoro-4-(2-(4-morpholinophenyl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (155e),
N-(3-Fluoro-4-(2-phenylthieno[3,2-b]pyridin-7-yIoxy)phenylcarbamothioyl)-2-
phenylacetamide (155f),
N-(3-Fluoro-4-(2-(2-morpholinopyrimidin-5-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (155g),
N-(3-Fluoro-4-(2-(2-(2-morphoIinoethoxy)pyrimidin-5-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (155h),
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N-(3-Fluoro-4-(2-(2-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-
phenylacetatnide (1551), and
N-(3-Fluoro-4-(2-(4-hydroxy-3-methoxyphenyl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide(155j)
[0396] Compounds 155b-j (Exampies 110-118) were prepared similarly to the
Compound 155a (Example 109, Scheme 28). Characterization of 155b-j is provided in the
137
Table 14a.



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Scheme 29

BBr3, CH2CI2 -40°C to r.t.

155i: Example 117

155k: Example 119


MeO
BBr3, CH2CI2 -40°C to r.L
155c : Example 111 1551: Example 120
Example 119
N-(3-FIuoro-4-(2-(2-hydroxyphenyl)thieno[3,2-^]pyridin-7-yloxy)phenylcarbamothioy])-2-
phenylacetamide (155k)
[03971 To a cold (-40°C) solution of the compound 155i (80 mg, 0.15 mmol) in DCM (3
mL) was added tribromoborane (1M in DCM, 0.60 mL, 0.60 mmol). The reaction mixture
was stirred overnight at room temperature. Water and methanol were added and the mixture
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was stirred for additional 20 minutes. Organic phase was separated and the aqueous layer was extracted with EtOAc. Both organic phases were combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (eluent MeOH-DCM, 2:98) then triturated with methanol, to afford the title compound 155k (6 mg, 7%yield), as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) ? ppm: 12.47 (d, 1H, J-0.4 Hz), 11.82 (s, 1H), 10.65 (s, 1H), 8.48 (d, 1H, J=5.5 Hz), 8.07 (s, 1H), 8.01 (d, 1H, J-11.5 Hz), 7.84 (d, 1H, J-7.8 Hz), 7.53-7.49 (m, 2H), 7.38-7.23 (m, 6H), 7.01 (d, 1H, J=8.2 Hz), 6.93 (t, 1H, J=7.4 Hz), 6.58 (d, 1H, J=5.5 Hz), 3.83 (s, 2H). LRMS (M+l) 530.2 (100%). Example 120
N-(3-Fluoro-4-(2-(3-hydroxyphenyl)thieno[3>2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (1551)
[0398] Following the procedure described above for the synthesis of compound 155k (example 119, scheme 29) but substituting methoxy-compound 155i for the methoxy-compound 155c, title compound 1551 was prepared in 62% yield. 1H NMR (400 MHz, DMSO-d6) ? ppm: 12.49(s, 1H), 11.84(s, 1H), 8.68(d, J = 5.6 Hz, 1H)5 8.07(d, J = 12.0 Hz, 1H), 7.99(s, 1H), 7.64-7.56(m, 2H), 7.38-7.24(m, 8H), 6.96-6.88(m, 2H), 3.83(s, 2H).
Scheme 30
NO2


NaBK,. MeOH
156
42

NO-.





158



1) TPA, CH2Cl2 HN N
X2HCI


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Example 121
N-(3-Fluoro-4-(2-(4-(piperazin-l-yl)phenyl)thieno[3,2-/)]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenyIacetarnide di-hydrochloride (159)
Step 1. tert-Butyl 4-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-
yl)phenyl)piperazine-1 -carboxylate (156)
[0399] Starting from the nitro-bromo compound 42, following the procedure described
above for the synthesis of compound 48 (scheme 10. example 55) but substituting 4,4,5,5-
tetramethyl-2-(4-(methyIsulfonyi)phenyl)-l,3,2-dioxaborolanefor4~(4-(tert-
butoxycarbonyl)piperazin-l-yl)phenylboronic acid, title compound 156 was obtained in
70% yield. LRMS (M+1) 550.6X100%)."
Step 2. tert-Butyl 4-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-2-b]pyridin-2-
yl)phenyl)piperazine-l-carboxylate(157)
[0400] Following the procedure described above for the synthesis of amine 49 (scheme
10, example 55) but substituting nitro compound 48 for the nitro compound 156, title
compound 157 was obtained in 99% yield (crude material, used in the next step without
additional purification). LRMS (M+l) 520.2 (100%).
Step 3. tert-Butyl 4-(4-(7-(2-tluoro-4-(3-(2-phenylacetyl)tliioureido)phenoxy)thieno[3,2-
ojpyridine-2-yi)phenyi)piperazine-I-carboxyiate(15S)
[0401] Following the procedure described above for the synthesis of compound 50
(scheme 10, example 55) but substituting amine 49 for the amine 157, title compound 158
was obtained in 41% yield. LRMS (M+l) 697.2 (100%).
Step4. N-(3-Fluoro-4-(2-(4-(piperazin-l-yl)phenyl)thieno[3,2-6]pyridin-7-
yIoxy)phenylcarbamothioyl)-2-phenylacetamide di-hydrochloride (159)
[0402] Following the procedure described above for the synthesis of compound 137a
(scheme 25, example 97) but substituting compound 135b for the compound 158, title
compound 159 was obtained in 21% yield. 1H NMR (400 MHz, DMSO-d6) ? ppm: 12.48(s,
1H), 11.84(s, 1H), 9.26(bss 1H), 8.62(d, J = 5.6 Hz, 1H)3 8.05(d, J = 12.0 Hz, 1H), 7.94(s,
1H), 7.81(d, J = 8.8 Hz, 2H), 7.62-7.55(m, 2H), 7.37-7.3 l(m, 4H), 7.31-7.24(m, 1H),
7.10(d, J = 8.8 Hz, 2H), 6.85(d, J = 5.6 Hz, 1H), 3.83(s, 2H), 3.58-3.5 l(m, 4H), 3.26-
3.18(m, 4H). LRMS (M+l) 597.2 (100%).
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Example 122
iV-(3-Fiuoro-4-(2-(3-(2-morphoilnoethoxy)phenyI)thieno[3,2-f>]pyridin-7-
yloxy}phenylcarbamolhioyI)-2-phenylacetamide (163a)
Step 1. 3-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (160)
[0403] Starting from the nitrobromo compound 42, following the procedure described
above for the synthesis of compound 153 (scheme 28, example 109) but substituting 4-
hydroxyphenylboronic acid for 3-hydroxyphenylboronic acid, title compound 160 was
obtained in 66% yield as a gray solid. LRMS (M-i-1) 383.1 (100%).
Step 2. 4-(2-(3-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-
yl)phenoxy)ethyl)morpholine (161)
[0404] Diethylazodicarboxylate (0.6 mL, 3.84 mmol) was added to the solution of 160
(1.05 g, 2.75 mmol), 2-morpholinoethanol (0.5 mL, 3.84 mmol) and triphenylphosphine
(1.01 g, 3.84 mmol) in tetrahydrofuran (27 mL). The reaction mixture was stirred until its
completion, quenched with saturated aqueous ammonium chloride and extracted with
EtOAc. The organic phase was washed with water and brine, dried over anhydrous
magnesium sulfate, filtred and evaporated under reduced pressure. The residue was purified
by flash chromatography, eluent MeOH-DCM (2:98) to afford title compound 161 (906 mg,
66%yield) as a light-yellow solid. LRMS (M+l) 496.3 (100%).
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Step 3.3-Fluoro-4-(2-(3-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-
yloxy)benzenamine (162)
[0405] Following the procedure described above for the synthesis of amine 49 (scheme
10, example 55) but substituting nitro compound 48 for the nitro compound 161, title
compound 162 was obtained in 91% yield (crude material, used in the next step without
additional purification). LRMS (M-H) 466.2 (100%).
Step 4. N-(3-Fluoro-4-(2-(3-(2-morpholinoethoxy)phenyl)th!eno[3,2-A]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide(163a)
[0406] Following the procedure described above for the synthesis of compound 50
(scheme 10, example 55) but substituting amine 49 for the amine 162, title compound 163a
was obtained in 29% yield. Characterization of 163a is provided in the table 15.[LRMS
(M+l) 643.3 (100%).
Examples 123-127
iV-(3-Fluoro-4-(2-(4-(2-morpholinoethoxy)phenyl)tliieno[3,2-b]pyridin-7-
yloxy)pheny lcarbaraothioyl)-2-phenylacetamide (163b)
N-(3-Fluoro-4-(2-(4-(2-(piperidin-l-yr)ethoxy)phenyl)thieno[3,2-b3pyridin-7-
yIoxy)phenylcarbamothioyl)-2-phenyIacetamide(163c)
N-(3-Fluoro-4-(2-(4-(2-(pyridin-2-yl)ethoxy)phenyI)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyi)-2-phenylacetamide hydrochloride (163d)
N-(3-Fluoro-4-(2-(4-(3-morpholinopropoxy)phenyl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (163e)
fert-Butyl2-(4-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-
2-yl)phenoxy)ethyl(methyl)carbamate (163f)
[0407] Starting from the phenol 153 (scheme 28, example 109) and following the
procedures described above for the synthesis of 163a (Scheme 31, Example 122) title
compounds 163b-f were obtained. Characterization of 163b-f is provided in the Table 15.
Examples 128-129
N-(3-Fluoro-4-(2-(3-methoxy-4-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-pheny lacetamide (163 g)
N-(3-Fluoro-4-(2-(2-(2-morpholinoetlioxy)phenyl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide hydrochloride (163h)
[0408] Following the procedures described above for the synthesis of 163a (Scheme 31,
example 122) but replacing in the first step 3-hydroxyphenylboronic acid with 4-hydroxy-3-
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methoxyphenylboronic acid or 2-hydroxyphenylboronic acid, title compounds 163g-h were obtained. Characterization of 163g-h is provided in the table 15.

163a-h: Example 122-128
144
Table 15 Chatracterization of compounds 163a-h (examples 122-128)


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167a: Example 130
Example 130
N-(3-Fluoro-4-(2-(4-(piperidin4-y!methQxy)phenyl)thieno[3,2-b]pyridui-7-
yloxy)phenyIcarbamothioyl)-2-phenylacetamide (167a)
Step 1. tert-Butyl-4-((4-(7-(2-fluoro-4-nitrophenoxy)thieno (3,2-b]pyridin-2-
yl)phenoxy)methyl)piperidine-l-carboxylate(164)
[0409] Starting from the compound 153 (shown in the scheme 28) and following the
procedure described above for the synthesis of compound 161 (step 2, scheme 31, example
122), title compound 164 was obtained in 69% yield. LRMS (M+l) 579.2 (100%).
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Step 2. tert-Butyl 4-((4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-
yl)phenoxy)methyl)piperidine-1 -carboxylate (165)
[0410] Following the procedure described above for the synthesis of amine 157 (scheme
30, example 121) but substituting nitro compound 156 for the nitro compound 164, title
compound 165 was obtained in 99% yield (crude material, used in the next step without
additional purification). LRMS (M+l) 549.2 (100%).
Step3. tert-Butyl-4-((4-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-
6]pyridin-2-yl)phenoxy)methyl)piperidine-1 -carboxylate (166)
[0411] Following the procedure described above for the synthesis of compound 158
(scheme30, example 121) but substituting amind compound 157 for the amino compound
165, title compound 166 was obtained in 31% yield. LRMS (M+l) 726.2 (100%).
Step 4.N-(3-FIuoro-4-(2-(4-(piperidin-4-ylmethoxy)phenyl)thieno[3,2-/b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamidedi-hydrochloride (167a)
[0412] Following the procedure described above for the synthesis of compound 159
(scheme 30, example 121) but substituting Boc-protected amino compound 158 for the Boc-
protected arnino compound 166, title compound 167a (presumably as a di-hydrochloride
salt) was obtained in 15% yield. Characterization of 167a is provided in the table 16. LRMS
(M+l) 626.2 (100%).
Example 131-132
(S)-N-(3-Fluoro-4-(2-(4-(pyrrolidin-2-yImethoxy)pheny!)thieno[3,2-b]pyridin-7-
yloxy)phenyIcarbamothioyl)-2-phenylacetamide (167b) and
N-(4-(2-(4-(4-Aminobutoxy)phenyl)thieno[3,2-b]pyridin-7-yIoxy)-3-
fluorophenylcarbamothioyl)-2-phenylacetamide(167c)
Following the procedures described above for the synthesis of 167a (scheme 32, example
130) but replacing in the first step tert-butyl 4-(hydroxymethyl)piperidine-l-carboxylate
with (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-l-carboxylate or tert-butyl 4-
hydroxybutylcarbamate, title compounds 167b-c were obtained. Characterization of 167b-c
167a-c: Examples 130-132
147
is provided in the table 16.


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148
Table 16 Characterization of compounds I67a-c (examples 130-132)


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170a: Example 133 Example 133
N-(3-Fluoro-4-(thieno[3,2-i]pyrjdin-7-yIoxy)phenyIcarbamothioyl)-2-phenyIacetamide (170a)
Step 1. 7-(2-Fiuoro-4-nitrophenoxy)thieno[3,2-b]pyriciine (168) [0413] Starting from the chloride 2 (scheme 1) and following the procedure described above for the synthesis of compound 6 (scheme 1, example 1), title compound 168 was obtained in 45% yield. LRMS (M+l) 290.3 (100%). Step. 3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)ben2enamine (169) [0414] Starting from the nitro compound 168 and following the procedure described above for the synthesis of amine 49 (scheme 10, example 55), title compound 169 was obtained in 41% yield. LRMS (M+l) 260.3 (100%). Step 3. N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (170a)
[0415] Starting from the amine 169 and following the procedure described above for the synthesis of compound 50 (scheme 10, example 55), title compound 170a was obtained in 29 % yield). 1H NMR(400MHz, DMSO-d6) ? ppm: 12.46(s, 1H), 11.8l(s, 1H), 8.52(d, J = 5.2 Hz, lH),8.17(d, J = 5.2Hz, 1H), 8.01(dd, J = 2.0 and 11.2 Hz, 1H), 7.60(d, J = 5.2 Hz, 1H), 7.58-7.48(m, 2H), 7.36-7.30(m, 4H), 7.30-7.22(m, 1H), 6.64(d, J= 5.2Hz, 1H), 3.82(s, 2H). LRMS (M+l) 437.5 (100%). Example 134
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N-(2-Chloro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamottiioyl)-2-pheny3acetamide (170b)
[0416] Title compound 170b (example 134) was obtained according to the scheme 33 via a 3-step synthesis starting from the chloride 2 and replacing 2-fluoro-4-nitrophenol fin the step 1] with 3-chloro-4-nitrophenol. 1H NMR (400 MHz, DMSO-d6) ? ppm: 12.36(s, H), 11.88(s, 1H), 8,55(d; J = 5.6 Hz, Iff), 8.1594 J - 5.6 Hz, 1H), 8.08(d, J = 8.8 Hz, 1H), 7.61(d, J = 2.8 Hz, 1H), 7.60(d, J=5.6 Hz, 1H), 7.36-7-30(m; 4H), 732(m, J = 2.8 Hz, 1H), 7.30-7.24(m, 1H), 6.73(d, J= 5.6 Hz, 1H), 3.84(s, 2H).
Scheme 34

Example 135
N-(2-Chloro-4-(thieao[3,2-b]pyrimidin-4-yIoxy)phenyIcarbamothioyl)-2-phenylacetamide
(173)
Step 1.4-(3-Chloro-4-nitrophenoxy)thieno(3,2-b]pyrimidine (171)
[0417] Starting from the chloride 20 (scheme 4) and following the procedure described
above for the synthesis of compound 24 (scheme 4, example 22) remplacing 2-fluoro-4-
nitrophenol with 3-chloro-4-nitrophenol, title compound 171 was obtained in 72% yield.
LRMS (MM) 307.7 (100%).
Step 2.2-Chloro-4-(thieno[3,2-b]pyrimidin-4-yloxy)benzenamine (172)
[0418] Starting from the nitro compound 171 and following the procedure described
above for the synthesis of amine 25 (scheme 4, example 22), title compound 172 was
obtained in 80% yield. LRMS (M+l) 277.7 (100%).
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Step3.N-(2-Chloro-4-(thieno[3,2-b]pyrimidin-4-yIoxy)phenylcarbamothioyl)-2-phenylacetatnide (173)
[0419] Starting from the amine 172 and following the procedure described above for the synthesis of compound 26a (scheme 4, example 22), title compound 173 was obtained in 9% yield. 1H NMR (400 MHz, DMSO-d6) ?ppm: 12.35(s; 1H), 11.89(s, 1H), 8.72(s, 1H), 8.48(d, J = 5.6 Hz, 1H), S.04(d, J = 8.8 Hz, 1H), 7.69(d, J = 2.8 Hz, 1H), 7.68(d, J = 5.6 Hz, 1H), 7.40(dd, J - 2.8 and 8.8 Hz, 1H), 7.36-7.30(m, 4H), 7.30-7.24(m, 1H), 3.84(s, 2H). LRMS (M+l) (100%). Exampie 136
2-Phenyl-N-(2-(tHieno[3,2-b]pyrimldin-4-ylaiiiind)pyrimidin-5-ylcarbaniothioyl]acetamide (174)
[0420] Title compound 174 (example 136) was obtained according to the scheme 34 via a 3-step synthesis starting from the chloride 20 and replacing 3-chloro-4-nitrophenol [in the step 1] with 5-nitropyrimidin-2-amine. 1H NMR (400 MHz, DMSO-d6) ? ppm: 11.85(bs, 2H), 10.91(bs, 1H), 8.71(s, lH),8.64(s, 2H), 8.63-8.61(m, 1H), 8.25(d, J = 5.6 Hz, 1H), 7.45(d, J = 5.6 Hz, 1H), 7.34-7.27(m, 4H), 7.27-7.21(m, 1H), 3.79(s, 2H).
151


Example 137
N-(3-Fluoro-4(2-(l-methyl-lif-imidazoM-yOthieno[3,2-b]pyridin-7-
yioxy)phenyJcaj'bamothioyl)-2-(2-fluorophenyi)acetamid6 (178)
Step 1. 7-Chloro-2-(l-methy{-lJy-imidazol-4-yl)thieno[3,2-i]pyridine (175)
[0421] To a solution of chloride 2 (scheme 1) (2.45 g, 14.4 mmol) in THF (48 mL) at -
78°C was slowly added «-BuLi (2.5M in hexane, 7.2 mL, 18.0 mmol). The reaction mixture
was stirred for one hour [at -78°C] followed by slow addition of ZnCl (0.5M in THF, 36
mL, 18.0 mmol). In a few minutes the reaction mixture was allowed to warm to room
temperature and stirred for one hour.
[0422] A solution of 4-iodo-l-methyl-l#-tmidazole (1.50 g, 7.2 mmol) \Tet. Lett. 2004.
45, 5529] in THF (5 mL) and the tetrakis(triphenylphosphine) palladium (0) (0.83 g, 0.72
mmol) were added to the reaction mixture which was heated to reflux for 1 hour, cooled to
room temperature, diluted with aqueous ammonium hydroxide and, finally neutralized with
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a IN HC1 solution. The acidic solution was extracted with DCM, the extract was washed
with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by flash chromatography (eluents DCM,
then DCM-MeOH, 97:3) to afford title compound 175 (1.45 g, 81% yield) as a yellow solid.
LRMS (M+l) 263.9 (100%), 265.9 (33%).
Step 2. 7-(2-Fluoro-4-nitrophenoxy)-2-(l-methyHH-imidazol-4-yl)thienQ[3,2-fc]pyriduie
(176)
[0423] Starting from the chloride 175 and following the procedure described above for
the synthesis of compound 11 (scheme 2, example 12), title compound 176 was obtained in
47%yield.XRMS"(M+l) 371.0(100%).
Step3.3-Fluoro-4-(2-(l-methyl-lff-imidazol-4-yl)thienot3,2-6]pyridin-7-
yloxy)benzenamine (177)
[0424] Starting from the nitro compound 176 and following the procedure described
above for the synthesis of amine 49 (scheme 10, example 55), title compound 177 was
obtained in 74% yield. LRMS (M+l) 341.0 (100%).
Step4.A/"-(3-Fluoro-4-(2-(l-methyl-lii-imidazol-4-yl)thienot3)2-ft3pyridin-7-
yloxy)phenylcarbamothioyl)-2-(2-fluorophenyl)acetamide(178)
[C425] Starting from the amine 177, following the procedure described above for the
synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyl
isothiocyanate with 2-(2-fluorophenyl)acetyl isothiocyanate, title compound 178 was
obtained in 24% yield. !HNMR (400 MHz, DMSO-d6) 5 ppm: 12.44 (s, 1H), 11.88 (s,
1H), 8.46 (d, 1H, J=5.5 Hz), 8.34 (dd, 1H, J-12.3/2.2 Hz), 7.87 (d, 1H5 M.2 Hz), 7.72 (d,
1H, J=1.2Hz), 7.69 (s, 1H), 7.57-7.49 (ro, 2H), 7.43-7.31 (m, 2H), 7.23-7.15 (m, 2H), 6.59
(d, 1H, J=5.5 Hz), 3.94 (s, 2H), 3.73 (s, 3H). LRMS (M+l) 536.1 (100%).
Example 138
Ar-(3-Fluoro-4-(2-(l-methyl-li?-imJdazol-4-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-(2-methoxy phenyl)acetaraide (179)
[0426] Starting from the amine 177, following the procedure described above for the
synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyl
isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 179 was
obtained in 52% yield. 'HNMR (400 MHz, DMSO-d6) 5 ppm: 12.58 (s, 1H), 11.75 (s,
1H), 8.46 (d, 1H, J=5.5 Hz), 8.72 (dd, IH, J=12.3/2.2 Hz), 7.86 (d, 1H, J=1.2 Hz), 7.72 (d,
1H, J=0.8 Hz), 7.70 (s, 1H), 7.57-7.49 (m, 2H), 7.30-7.23 (m, 2H), 7.00 (d, 1H, J=7.8 Hz),
6.92 (dt, 1H, J=7.3/0.9 Hz), 6.58 (d, 1H3 J=5.1 Hz), 3.82 (s, 2H), 3.79 (s, 3H), 3.72 (s, 3H).
153


Af-(3-Fiuoro-4-(2-(l-(2-(methylatnino)ethyl)-l/Apyrazol-4-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide (184)
Step 1. tert~Butyl 2-(4-(7-chlorothieno[3,2-bJpyridin-2-yl)-l//-pyrazo]-l-
yl)ethyl(methyl)carbamate (180)
[0427] Starting from the chloride 2 and following the procedure described above for the
synthesis of 175 (scheme 35, example 138), but replacing 4-iodo-l-methyl-l.ff-imidazole
with /ert-butyl 2-(4-iodo-li7-pyrazol-l-yl)ethyl(methyl)carbamate, title compound 180 was
obtained in 75% yield. LRMS (M+l) 393.1 (100%).
Step 2. tert-Butyl 2-(4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yI)-li?-pyrazol-
1 -yl)ethyl(methyl)carbamate (181)
£0428] Starting from the chloride 180 and following the procedure described above for
the synthesis of compound 11 (scheme 2, example 12), title compound 181 was obtained in
37% yield. LRMS (M+l) 514.1 (100%).
Step 3. ter/-Butyl 2-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-i/f-
pyrazol-1 -yi)ethyl(methyl)carbamate (182)
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[0429] Starting from the nitro compound 181 and following the procedure described
above for the synthesis of amine 49 (scheme 10, example 55), title compound 182 was
obtained in 22% yield. LRMS (M+l) 484.2 (100%).
Step 4. tort-Butyl 2-(4-(7-(2-fluoro-4-(3-(2- methoxyphenyl)acetyl)thioureido)phenoxy)thieno[352-b]pyridin-2-yl)-li7-pyrazol-l-
yl)ethyl(methyl)carbamate(183)
10430] Starting from the amine 182, following the procedure described above for the
synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyI
isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 183 was
obtained in 90% yield. LRMS (M+l) 691.2 (100%).
Step5.iV'-(3-Fiuoro-4-(2-(l-(2-(methylammo)ethyl)-l//-pyraz:ol-4-yl)thieno[3,2-b]pyridin-
7-yloxy)phenylcaibamothioyl)-2-(2-methoxyphenyl)acetamide(184)
[0431J Starting from the compound 183 and following the procedure described above
for the synthesis of compound 159 (scheme 30, step 4, example 121), title compound 184
was obtained in 66% yield. !H NMR (400 MHz, DMSO-dg) § ppm: 8.45(d, J = 5.6 Hz,
1H), 833(s, 1H), 8.00(s, IH), 7.85-7.75(ra, 1H), 7.69(s, 1H), 7.39(t, J = 8.4 Hz, 1H), 7.35-
7.28(m, 1H), 7.28-7.22(m, 1H), 7.22(d, J = 7.6 Hz, IH), 6.97(d, J = 8.4 Hz, 1H), 6.89(t, J =
7.6 Hz, IH), 6.57(d> J = 5.6 Hz, IH), 4.19(t, J = 6.4 Hz, 2H), 3.82(s, 2H), 3.77(s, 3H),
2.88(t, J = 6.4 Hz, 2H), 2.28(s, 3H).
Example 140
]\[-(3-Fluoro-4-(2-(l-(2-morpho{inoethyI)-lJ5r-imidazol-4-yI)thieno[3,2-b]pyridin-7-
yloxy)phenykarbamothioyl)-2-(2-methoxyphenyl)acetamide (185)

[0432] Title compound 185 (example 140) was obtained following the procedures described above for compound 183 [according to the scheme 36] via a 4-step synthesis starting from chloride 2 and replacing fe7-/-butyl 2-(4-iodo-lH-pyrazol-l-yl)ethyl(methyl)carbamate [in the step 1] with 4-(2~(4-iodo-liif-imidazol-l-yl)ethyl)morphoiine [Tet, Lett. 2004,45, 5529]. JHNMR (400 MHz, DMSO-d6) 5 ppm: 12.56(s, 1H), 11.75(s, IH), 8.55(d, J = 5.6Hz, IH), 8.50-8.20(m, lH),7.93(d, J- 1.2Hz,
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1H), 7.78(s, 1H), 7.60-7.55(ra, 2H), 7.35(d, J- 1.2 Hz, 1H), 7.32-7.25(m, 1H), 7.23(dd, J-1.6 and 7.2 Hz, 1H), 7.00(d, J = 7.6 Hz, 1H), 6.92(td, J = 0.8 and 7.6 Hz, 1H), 6.69(d, J = 5.6 Hz, 1H), 4.35(t, J = 6.0 Hz, 2H), 3.81(s, 2H), 3.78(s, 3H), 3.48(t, J = 4.4 Hz, 4H), 2.59(t, J = 6.0 Hz; 2H), 2.35(1, J = 4.4 Hz, 4H).
Scheme 37

Example 141
JV-(3-Fluoro-4-(6-( 1 -hydroxy-2-methylpropy l)thieno[3,2-djpy rimidin-4-
yIoxy)phenylcarbamothioyl)-2-phenyiacetamide(190)
Step 1.4-Chloro-thieno[3,2-d]pyrimidine-6-carbaldehyde (186)
[0433] Starting from 4-chloro-thieno[3,2-d]pyrimidine (20, scheme 4) and following
procedure described above for the synthesis of aldehyde 14 (scheme 3, step 1, example 20),
title compound 186 was obtained in 84% yield. LRMS (M+l) 199.0 (100%).
Steps 2-3. l-[4-(2-Fluoro-4-nitro-phenox7)-thieno[3,2-dJpyrimidin-6-yi]-ethanoi (188)
[0434] Starting from the aldehyde 186 and following procedures described above for the
synthesis of nitro compound 16 (scheme 3, steps 2-3, example 20), title compound 188 was
obtained [via the intermediate alcohol 187], in 25% yield. LRMS (M+l) 336.0 (100%).
Steps 3-4. iV-(3-Fluoro-4-(6-(l-hydroxy-2-methy3propyI)thieno[3,2-d3pyrimidin-4-
yloxy)phenyicarbamothioyl)-2-phenylacetamide(190)
[0435] Starting from the nitro compound 188 and following procedures described above
for the synthesis of compound 18a (scheme 3, steps 4-5, example 20), title compound 190
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was obtained [via the intermediate amino alcohol 189], in 24% yield. *H NMR (400 MHz,
DMSO-d6) 5 ppm: 12.42(s, 1H), 11.80(s, 1H), 8.64(s, IE), 7.90(dd, J - 2.0 and 12.0 Hz,
1H), 7.52(t, J » 8.4 Hz, 1H), 7.48(d, J = 0.8 Hz, 1H), 7.46(dd, J = 2.0 and 8.4 Hz, IE), 7.36-
7.31(m, 4H), 7.31-7.24(m, 1H), 6.15(d, 4.8 Hz, 1H), 4.82(td, J = 0.8 and 5.2 Hz: 1H),
3.82(s, 2H), 2.10-1.98(m, 1H), 0.93(d, J = 6.8 Hz.. 3H), 0.90(d, J- 6.8 Hz, 3H).
Examples! 42-14S
iV-(3-Fluoro-4-(6-(pyrrolidin.e-l-carbonyl)thieno[3,2-d]pyrimidin-4-
yloxy)phenytcarbarnothioyl)-2-phenylacetamide(26f)
jV-(4_(2-(Az6tidine-l-carbonyl)thieno[3,2-b]Dyridine-7-yloxy)-3-
fluoFophetiylcaFbamotliioyl)-2-phenyiacetamide hydrochioride (26gX ~'
l-(4-(6-(iV-EthyI-ALmethylcarbarnoyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-
(2-phenyIacetyl)thiourea (26h)
Ar/Ar-Diethyl-4-{2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-d]pyrimidine-
6-carboxamide (26i)
(R)-Ar-(3-Fluoro-4'(6-(2-(hydroxymethyl)pyrrolidine-l-carbonyl)thieno[3,2-d]pyrimidin-4-
yloxy)phenylcarbamothioyI)-2-phenylacetamide(26j)
(S)-^r-(4-(6"(3-(/cT^Butyid^iletllylsilyloxy)py^roliuirJe-l-carbonyl)thieno[3,2-d]pyrimidin-
4-yloxy)-3-fluorophenyicarbamothioyl)-2-phenylacetamide(26k)
tert-Butyl l-(4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-d]pyrimidine-
6-carbonyl)pyrrolidin-3~yicarbarnate(261)
J0436J Compounds 26f-J (examples 142-148) were obtained by following the
procedures described above for the compound 26a (example 22, scheme 4).
Characterization of 26F-1 is provided in the table 17.
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Table 17 Characterization of compounds 26f-J (examples 142-148)

158


Example 149
A^(4-(6-(3-Aminopyrrolidine-l-carbonyl)thieno[3,2-d'jpyriniidJn-4-yIoxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamidehydrochIoride(191) [0437] Following the procedure described above for the synthesis of compound 159 (scheme 30, example 121) but substituting Boc-protected amino compound 158 for the Boc-protected amino compound 261, title compound 191 was obtained in 40% yield. !H NMR (400 MHz, DMSO-cfe) 5 (ppm): 8.77(s, 1H), 8.12(s, 0.5H), 8.06(s, 0.5H), 7.92(dd, J = 2.4 and 12.0 Hz, 1H), 7.54(t, J = 8.4 Hz, 1H), 7.48(dd, J = 2.4 and 8.4 Hz, 1H), 7.36-7.3 l(m,
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WO 2006/010264 PCT/CA2005/001177
4H), 7.30-7.25(01,1H), 4.2-3.80(m, 1H), 3.08(s, 2H), 3.80-3.5O(m, 4H), 2.10-1.98(m, 1H), 1.82-1.64(m, 1H). LRMS (M+l) 550.6 (100%). Scheme 39

Example 150
2-(2,6-Dichlorophenyl)-iV-(3-fluoro-4-(thieno[3J2-b]pyridin-7-
y loxy)pheny lcarbamothioyl)acetamide (192a)
[0438] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl
isothiocyanate with 2-(2,6-dichIorophenyl)acetyl isothiocyanate, title compound 192a was
obtained in 7 % yield. Characterization of 192a is provided in table 18.
Example 151
iV-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(thiophen-2-
yl)acetamide(192b)
[0439] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-pheny!acetyl
isothiocyanate with 2-(thiophen-2-yl)acetyl isothiocyanate, title compound 192b was
obtained in 9 % yield. Characterization of 192b is provided in table 18.
Example 152
2-(2,6-Difluorophenyl)-A'-(3-fluoro-4-(thieno[3)2-b]pyridin-7-
yloxy)phenylcarbamothioyl)acetamide(192c)
[0440] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl
isothiocyanate with 2-(2,6-difluorophenyl)acetyl isothiocyanate, title compound 192c was
obtained in 23 % yield. Characterization of 192c is provided in table 18.
Example 153
A?-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyI)-l-
phenylcyclopropanecarboxamide (192d)
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WO 2006/010264 PCT/CA2005/001177
[0441] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl
isothiocyanate with 1-phenylcyclopropanecarbonyl isothiocyanate, title compound 192d
was obtained in 41 % yield. Characterization of 192d is provided in table 18.
Example 154
JV^-{3-FJuoro-4-(thieno[352-b]pyridin-7-yloxy)phenylcarbamothioy0-2-phenylpropanarnide
(192e)
[0442] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenyiacetyl
isothiocyanate with 3-methyl-2-phenylbutanoyl isothiocyanate, title compound 192e was
obtained in 49 % yield. Characterization of 192e is provided in table 18.
Example 155
Ar-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-3-phenylpropanamide
(192f)
[0443] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl
isothiocyanate with 3-phenylpropanoyl isothiocyanate, title compound 192f was obtained in
59 % yield. Characterization of 192f is provided in tabie 18.

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162


Example 156
2-(2,6-DichIorophen3'l)-7V-(3-f3uoro-4-(2-(pyrrolidine-l-carbonyl)thieno[3,2-&jpyridin-7-
yloxy)phenylcarbamothioyl)acetamide(195a)
Step 1. (7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-^3pyridin-2~yl)(pyrroiidin-1 -yl)raethanone
(193)
[0444] Starting fi'ora (7-chlorotbieBo[3J2-6]pyridin-2-yI)(pyrrolidin-2-yi)methanone
(139, scheme 26) and following the procedure described above for the synthesis of
compound 6 (scheme 1, example 1), title compound 193 was obtained in (93% yield).
LRMS (M+l) 387.4 (100%).
Step 2. (7-(4-Amino-2-fluorophenoxy)thienof3,2-6]pyridin-2-yl)(pyrrolidin-l-yl)methanone
(194)
J0445J Starting from the nitro compound 193 and following the procedures described
above for the synthesis of amine 7, (scheme 1, examplel) title compound 194 was obtained
in 92% yield. LRMS (M+l) 357.4 (100%).
Step 3. 2-(2,6-Dichlorophenyl)-/v-(3-fluoro-4-(2-(pyrrolidine-1 -carbonyl)thieno[3,2-
&]pyridin-7-yloxy)phenyIcarbarnothioyI)acetamide(195a)
[0446] Starting from the amine 194 and following the procedure described above for the
synthesis of compounds 50 (scheme 10), 170a (scheme 33) or 192a-f (scheme 39), title
compound 195a was obtained in 70% yield. Characterization of 195a is provided in table
19.
Examples 157-181 (compounds 195b-q)
163

WO 2006/010264 PCT/CA2005/001177
164
[0447] Compounds 195b-q (examples 157-181) were obtained starting from the amine 194, following the procedure described above for the synthesis of compound 195a and replacing 2-(2,6-difluorophenyl)acetyl isothiocyanate with an appropriately substituted homologue. Characterization of 195b-q is provided in the table 19.



165


166


167


^xampleT82
i\T-(3-FIuoro-4-(2-(pyrrolidine-l -carbonyl)thieno[3,2-fa]pyridin-7-
yloxy)phenylcarbamothioyl)-2-(2-hydroxyphenyl)acetamide hydrochloride (196a)
[0448] Starting from the compound 195o and following the procedure described above
for the synthesis of compound 155k (scheme 29, example 119), title compound 196a was
obtained in 62% yield. Characterization of 196a is provided in table 20.
Example 183
2-(2,5-Dihydroxyphenyi)-jV-(3-fiuoro-4-(2-(pyrrolidine-l-carbonyi)thieno[3J2-b]pyriuin-7-
yioxy)phenylearbamothioyi)acetaniids hydrochloride (196b)
[0449] Starting from the compound 195p and following the procedure described above
for the synthesis of 196a, title compound 196b was obtained in 83% yield. Characterization
of 196b is provided in table 20.
Example 184
2-(3,4-Dihydroxyphenyl)-i^-(3-fluoro-4-(2-(pyrrolidine-l-carbonyl)thieno[3>2-b]pyridin-7-
yloxy)pheny lcarbamothioy l)acetamide (196c)
[0450] Starting from the compound 195q and following the procedure described above
for the synthesis of 196a, title compound 196c was obtained in 25% yield. Characterization
of 196c is provided in table 20.
168


169


Example 185
A^(4-(2-(4-Hydroxyphenyl)thieno[3,2-6]pyridin-7-yloxy)phenylcarbamothioyI)-2-
phenylacetamide (200)
Step 1.2-Bromo-7-(4-mtrophenoxy)thieno[3.2~b]pyridine (197)
[0451] Starting from the compound 41 (scheme 8) and following the procedure
described above for the synthesis of compound 42 (scheme 8) but replacing 2-fluoro-4-
nitrophenol for 4-nitrophenol, title compound 197 was obtained in 48% yield. LRMS (M+l)
350.9 (100%). 352.9 (100%).
Step 2.4-(7-(4-Nitrophenoxy)thieno[3,2-Z>]pyridin-2-yl)phenol (198)
[0452} Starting from the compound 197 and following the procedure described above
for the synthesis of compound 153 (scheme 28), title compound 198 was obtained in 81%
yield. LRMS (M+l) 365.0 (100%).
Step 3.4-(7-(4-Aminophenoxy)mieno[3>%yridin-2-yl)phenol (199)
[0453J Starting from the compound 198 and following the procedure described above
for the synthesis of compound 154 (scheme 28), title compound 199 was obtained in 83%
yield. LRMS (M+l) 335.0 (100%).
170

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Step4.jV-(4-(2-(4-Hydroxyphenyl)thieno[3,2-6]pyridin-7-yloxy)phenyIcarbamothioyl)-2-phenylacetamide (200)
[0454] Starting from the compound 199 and following the procedure described above for the compound 155a (scheme 28, example 109), title compound 200 was obtained in 3% yield. 'HNMR(400 MHz, DMSO-d6) 8 ppm: 12.38 (s, 1H), 11.74 (s, 1H), 9.94 (s, 1H), 8.46 (d, 1H, JM5.3 Hz), 7.81 (s, 1H), 7.72 (d, 2H, J=9.0 Hz.), 7.69 (dd, 2H, J=6.7/l-8 Hz), 7.34-7.27 (m5 7H), 6.86 (dd, 2H, J=6.7/1.8 Hz), 6.61 (d, 1H, J=5.5 Hz), 3.82 (s, 2H). LRMS (M+l) 512.1 (100%).

Example 186
A44 yloxy)phenylcarbamothioyl)-2-phenylacetamide(203)
Step 1.4-(2-(4-(7-(4-Nitrophenoxy)thieno[3,2-6]pyridin-2-yl)phenoxy)ethyl)morpholine
(201)
[0455] Starting from the compound 198 (scheme 42) and following the procedure
described above for the compound 161 (scheme 31), title compound 201 was obtained in
69% yield. LRMS (M+l) 478.1 (100%).
Step 2.4-(2-(4-(2-Moipholinoethoxy)phenyl)thieno[3,2-6]pyridin-7-yloxy)b6nzenamine
(202)
[0456] Starting from the compound 201 and following the procedure described
above for the compound 162 (scheme 31), title compound 202 was obtained in 69% yield.
LRMS (M+l) 448.2 (100%).
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Step 3. iV-(4-(2-(4-(2-Morpholinoethoxy)phenyl)thieno[3,2-fi]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenyIacetamide(203)
[0457] Starting from the compound 202 and following the procedure described above for the compound 163a (scheme 31), title compound 203 was obtained in 30% yield. [H NMR (400 MHz, DMSO-d6) 8 ppm: 12.38 (s, 3H), 11.73 (s, 1H), 8.47 (d, 1H, J=5.5 Hz), 7.90 (s, 1H), 7.79 (s, 2H, J=9.0), 7.36 (d, 2H, J=9.0 Hz), 7.43-7.27 (m, 7H), 7.05 (d, 2H, J=9.0 Hz), 6.63 (d, 1H, J=5.3 Hz), 4.15 (t, 2H, J=5.6 Hz), 3.82 (s, 2H), 3.58 (t, 4H, J=4.6 Hz), 2.71 (t, 2H, J=5.7 Hz), 2.51-2.46 (m, 4H). LRMS (M+l) 625.2 (100%).

Example 187
A^(3-fluoro-4-(6-(pyrrolidine-l-carbonyl)thieno[2,3-(3(]pyrimidin-4-
yIoxy)phenylcarbamothioyl)-2-phenylacetamide (211)
Step 1.4-Chlorothieno[2,3-t/Jpyrimidine (205)
[0458] Starting from thieno[2,3-c0pyriraidin-4(3H)-one (204) [J. Med. Chem., 1999,42,
26, 5437-5447, Bull. Soc. Chim. Fr., 1975, 587-591] and following the procedure described
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WO 2006/010264 PCT/CA2005/00I177
above for the synthesis of compound 20 (scheme 4, example 22), title compound 205 was
obtained in 93% yield. LRMS (M+l) 169.1 (100%), 171.1 (32%).
Steps 2-4. (4-Chlorothieno[2,3-i/]pyrimidin-6-yl)(pyrrolidin-l-yl)methanone (208)
£0459] Starting from the compound 205 and following the procedures described above
for the synthesis of amide 5 (scheme 1, steps 2-4, example 1), title compound 208 was
obtained [via intermediates 206 and 207], in 76% yield as dark-brown oi! (crude material,
was used for the next step without additional purification). LRMS (M+l) 26S.2 (10094).
Step 5. (4-(2-Fluoro-4~nitrophenoxy)thieno[2,3-i/Jpyrimidm-6-yl)(pyrrolidin-1 -
yl)methanone (209)
[0460] Starting from the compound 208 and following the procedures described above
for the synthesis of nitio compound 6 (scheme I, step 5, example 1), title compound 209
was obtained in 24% yield. LRMS (M+l) 389.1 (100%).
Step 6. (4-(4-Ainino-2-fluorophenoxy)thieno[2,3-c/ipyrimidin-6-yl)(pyrrolidin-l-
yl)methauone (210)
[0461] Starting from the compound 209 and following the procedures described above
for the synthesis of amine 7 (scheme 1, step 6, example 1), crude title compound 210 was
obtained. It was purified by flash chromatography, eluents DCM followed by E>CM-MeOH~
Et3N (97.75:2:0.25), to afford title compound 210 in 54% yield as a yellow solid. LRMS
(M+l) 359.1 (100%).
Step7.iV-(3-Fluoro-4-(6-(pyrrolidine-l-carbonyl)thieno[2,3-d]pyrimidin-4-
yloxy)phenylcarbamothioy])-2-phenylacetamide(2U)
[0462] Starting from the compound 210 and following the procedures described above
for the synthesis of compound 8a (scheme 1, step 7, example 1), crude title compound 211
was obtained. It was purified by flash chromatography, eluents DCM and DCM-MeOH-
Et3N (97.75:2:0.25) followed by trituration with a mixture of MeOH-EtOAc, to afford title
compound 211 in 17% yield as a yellow solid. lH NMR (400 MHz, DMSO-d6) 5(ppm):
12.43 (s, 1H), 11.80 (s, 1H), 8.70 (s, 1H), 8.06 (s, 1H), 7.93 (d, 1H, J=l 1.7/2.3 Hz), 7.53-
7.47 (m, 2H), 7.34-7.26 (m, 5H)3 3.90 (t, 2H, J=6.7 Hz), 3.83 (s, 2H), 3.55 (t, 2H, J=6.7 Hz),
1.99-1.85 (m, 4H). LRMS (M+l) 536.2 (100%).
Scheme 45
173


Example 188
2-PhcnykV-(4-(thieno[3J2-b]pyridin-7-yloxy)phenylcarbamothioyI)acetamide (170c)
Step I. 7-(4-Nitrophenoxy)thieno[3,2-b]pyric(ine(212)
[0463] Staring from the chloride 2, following the procedure described above for the
synthesis of compound 6 (scheme 1, example 1) but substituting 2-fluoro-4-nitrophenol for
4-nitrophenol, tide compound 212 was obtained in 89% yield. MS (m/z) 273.0 (M+H).
Step 2.4-(Thieno[3,2-b]pyridin-7-yioxy)benzenamine (213)
[0464J Staring from the nitro compound 212, following the procedure described above
for the synthesis of amine 49 (scheme 10, example 55), title compound 213 was obtained in
90% yield. MS (m/z) 243.1 (M+H).
Step 3.2-Phenyl-Ar-(4-(thieno[3,2-b]pyridin-7-yloxj0pheny!carbamothioyI)acetamide
(170c)
[0465] Staring from the amine 213, following the procedure described above for the
synthesis of compound 50 (scheme 10, example 55), title compound 170c was obtained in
34% yield. 'HNMR (400 MHz,DMSO-d6) 5 ppm 12.35 (1H, s), 11.69 (1H, s), 8.47 (1H, d,
J=5.28 Hz), 8.10 (1H, d, J=5.2S Hz), 7.70 (1H, s), 7.68 (1H, s), 7.54 (1H, d, J=5.28 Hz),
7.30-7.22 (7H, m), 6.61 (1H, d, J-5.28 Hz), 3.78 (2H, s). MS (m/z) 420.0 (M+H).
174

WO 2006/010264 PCT/CA2005/001177
Example 189
2-Phenyl-iV-(4-(thieno[3,2-b]pyridin-7-yloxy)-2-(trifluoromethyl)phenylcarbamothioyl)acetamide(l70d)
[0466] Title compound 170d was obtained according to the scheme 45 via a three-step synthesis starting from the chloride 2 and replacing 4-nitrophenol [in the first step] with 4-nitro-3»(trifluoromethyi)phenol. ]H NMR (400 MHz, DMSO-d6) 5 (ppm): 12.29 (s, IH), 11.99 (s, 1H), 8.56 (d, J= 5.3 Hz, IH), 8.17 (d, J= 5.3 Hz, IH), 7.84 (d, /= 8.6 Hz, 1H), 7.74 (d, J = 2.7 Hz, 1H), 7.63 (m, 2H), 7.34 (m, 4H), 7.26 (m, 2H), 6.75 (d, ./= 5.3 Hz, 1H), 3.85 (s, 1H). MS (m/z): 488.3 (M+H). Example 190
2-Phenyl-iV-(4-(thieno[3,2-b]pyridin-7-y{amino)phenylcarbamothioyl)acetamide(170e) 10467] Title compound 170e was obtained according to the scheme 45 via a three-step synthesis starting from the chloride 2 and replacing 4-nitrophenol [in the first step] with. 4-nitrobenzenamine. *H NMR (400 MHz, DMSO-d6) 6 (ppm) 12.39 (s, 1H)511.72 (s, 1H), 8.97 (s, 1H), 8.35 (d, J= 5.1 Hz, 1H), 8.03 (d, ./= 5.5 Hz, 1H), 7.64 (d, 7= 8.4 Hz, 2H), 7.49 (d, J= 5.3 Hz, IH), 7.38 (m, 4H), 7.32 (d, J= 8.4 Hz, 3H), 6.94 (d, J- 5.5 Hz, 1H), 3.87 (s, 1H). MS (m/z): 419.2 (M+H). Example 191
2-Phenyl-Af-(4-(tIiieno[3,2-b]pyridin-7-ylthio)phenylcarbamothioyl)acetamide(170f) [0468] Title compound 170f was obtained according to the scheme 45 via a three-step synthesis starting from the chloride 2 and replacing 4-nitrophenol [in the first step] with 4-nitrobenzenethiol. 'H NMR (400 MHz,DMS0-4) 6 ppm 12.65 (IH, s), 11.91 (IH, s), 8.62 (IH, d, J=4.70 Hz), 8.28 (IH, d, J=5.28 Hz), 8.01-7.90 (2H, m), 7.79-7.68 (5H, m), 7.23 (IH, m), 3.95 (2H, m). MS (m/z) 436.0 (M+H) Example 192
iV-(2-Methoxy-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (170g)
[0469] Title compound 170g was obtained according to the scheme 45 via a three-step synthesis starting from the chloride 2 and replacing 4-nitrophenol [in the first step] with 3-methoxy-4-nitrophenol [Hodgson, C, J. Chem. Soc, 1929, 2778). !HNMR (DMSO) 5 (ppm): 12.70 (IH, a), 11.71 (IH, s), 8.63 (IH, d, J-8.80 Hz), 8.51 (IH, d, J-5.28 Hz), 8.14 (IH, d, J=5.48 Hz), 7.50 (IH, dd, J-5.48, 0.78 Hz), 7.36-7.25 (5H, m), 7.13 (IH, d, J=2.54
175


Example 193
N-(2-Methoxy-4-(2-(l-inethy]-l/^imidazol-2-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide(2l7)
Step 1. 7-Chloro-2-(l-methyl-l^r-imidazoI-2-yi)thieno[3,2-b]pyridine (214)
[0470] Starting from tributyltin compound 98 (scheme 19) and following the procedure
described above for the synthesis of compound 10 (scheme 2, step 2, example 12) but
replacing 2-bromothiazole with 2-bromo-l-methyl-l.fMmidazole, title compound 214 was
obtained in 95% yield. MS (m/z) 250.1 (100%), 252.1 (37%), (M+H).
Step 2.7-(3-Methoxy-4-nitrophenoxy)-2-(l-methyl-l//-imidazol-2-yl)thieno[3,2-b}pyridine
(215)
[0471] Starting from compound 214, following the procedure described above for the
synthesis of compound 11 (scheme 2, step 3, example 12) but replacing 2-fluoro-4-
nitrophenol with 3~methoxy-4-nitrophenol [Hodgson, C, J. Chem. Soc, 1929,2778], title
compound 215 was obtained in 9% yield. MS (m/z) 383.1 (M+H).
176

WO 2006/010264 PCT/CA2005/00? 177
Step3.2-Methoxy-4-(2-(l-methyl-lH-imidazol-2-yl)thieno[3,2-b]pyridin-7-
yloxy)benzenamine (216)
[0472] Starting from compound 215 and following the procedure described above for
the synthesis of compound 12 (scheme 2, step 4, example 12), title compound 216 was
obtained in 100% yield. MS (m/z) 353.1 (M+H).
Step4.iV-(2-Methoxy-4-(2-(l-methyl-li?-imidazol-2-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetarmde(217)
[0473] Starting from compound 216 and following the procedure described above for
the synthesis of compound 13a (scheme 2, step 5, example 12), title compound 217 was
obtained in 48% yield; !HNMRr(40G MHz,DMSO-d6) 5 pprnT12.07 (lHrs);n;59 (lH;s),
8.45 (1H, d, J=5.48 Hz), 7.91 (1H, d, J-8,80 Hz), 7.85 (1H, s), 7.41 (1H, s), 7.24-6.98 (8H,
m), 6.66 (IH, d, J-5.67 Hz), 3.99 (3H, s), 3.78 (3H, s), 3.59 (2H, s). MS (m/z) 530.2
(M+H).

Example 194
2-Cyclohexy]-7V-(3-fIuoro-4-(2-(l-methyl-lF-imidazol-2-yl)thieno[3,2-b]pyridm-7-
yloxy)phenylcarbamothioyl)acetamide(220a)
Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(l-methyl-li?-imidazol-2-yl)thieno[3,2-bJpyridine
(218)
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WO 2006/010264 PCT/CA2005/001177
[0474] Starting from compound 214 (scheme 46) and following the procedure described
above for the synthesis of compound 11 (scheme 2, step 3, example 12), title compound 218
was obtained in 45% yield. MS (m/z) 371.1 (M+H).
Step 2.3-Fluoro-4-(2-(l -methyl-l#-imidazol-2-yl)thieno[3,2-b]pyridin-7-
yloxy)benzenamine (219)
[0475] Starting from compound 218 and following the procedure described above for
the synthesis of compound 12 (scheme 2, step 4, example 12), title compound 219 was
obtained in 86% yield. MS (m/z) 341.1 (M+H).
Step 3:2-Cyclohexyl-AL(3-fiuoro-4-(2-(3 -methyl-l#-imidazol-2-yl)thieno|:3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)acetamide(220a)
[0476] To a suspension of 219 (50 mg, 0.145 mmol) in THF (1.5 mL) was added 2-
cyclohexylacetyi isothiocyanate (40 mg, 0,22 mmol) [P. A. S. Smith and R. O. Kan. J. Org.
Chew., 1964,2261] and the reaction mixture was stirred for 3 hours transferred onto a flash
chromatography column and eluted with EtOAc-MeOH mixture (19:1), to afford title
compound 220a (27.5 mg, 31% yield) as a light yellow solid. Characterization of 220a is
provided in the table 21.
Example 195
2-Cyciopentyl-A*H3-fluoro^ yioxy)phenylcarbamothioyl)acetamide(220b)
[0477] Title compound 220b was obtained similarly to the compound 220a from the
amine 219 and 2-cyclopentylacetyl isothiocyanate [~P. A. S. Smith and R. Q. Kan. J. Org.
Chem., 1964.2261] in 47% yield. Characterization of 220b is provided in the table 21.
Example 196
A^-(3-Fluoro-4-(2-(l-methyH//-imidazol-2-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-(2-oxopyrrolidin-l-yl)acetamide(220c)
[0478] Title compound 220c was obtained similarly to the compound 220a from the
amine 219 and 2-(2-oxopyrrolidin-l-yl)acetyl isothiocyanate [prepared according to the
reference P. A. S. Smith and R. O. Kan. J, Ors. Chem.. 1964. 2261] in 18% yield.
Characterization of 220c is provided in the table 21.
Example 197
Ar-(3-Fluoro-4-(2-(l-methy3-l/f-imidazol-2-yl)thieno[3,2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(220d)
[0479] Title compound 220d was obtained similarly to the compound 220a from the
amine 219 and 2-(tetrahydro-2//-pyran-4-yl)acetyi isothiocyanate [prepared according to
178

WO 2006/0) 0264 PCT/CA2005/M)1177
the reference P. A. S. Smith and R. O. Kan. 1 Ore. Chem., 1964. 2261] in 15% yield. Characterization of 220d is provided in the table 21. Example 198
Ar-(3-Fluoro-4-(2-(l-methyl-li^-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(220e)
[0480] Title compound 220f was obtained similarly to the compound 220a from the amine 219 and acetyl isothiocyanate in 28% yield. Characterization of 220f is provided in the table 21. Example 199
(R)-Methyl 4 [0481] To a suspension of 219 (60 mg, 0.186 mmol) in THF (1.9 ml) was added (R)-2-(2,2-dimethyl-5-oxo-l,3-dioxolan-4-yl)acetyl isothiocyanate (60 mg, 0,28 mmol) PP. A. S. Smith and R. O. Kan. J. Org. Chem., 1964, 2261f. The reaction mixture was stirred for 3 hours, concentrated, purified by flash chromatography, eluent EtOAc-MeOH (19:1), to produce a solid material (29.5 mg) which was dissolved in ivieOH, treated with HC1 (IN in EtoO, 0.1 mL) and the mixture was stirred for 10 min at room temperature. The solution was concentrated, and the residue was purified by preparative HPLC (Aquasil CIS column, gradient: 30% MeOH to 95% MeOH in water, 45 min), to afford title compound 220f (15 mg, 13% yield) as a white solid. Characterization of 220f is provided in the table 21.

Table 21 Characterization of compounds 220a-f (examples 194-199)

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WO 2006/010264 PCT/CA2005/001177

Example 200
iV-((3-Fluoro-4-(2-(l-raethyl-li?-imidazol-2-yl)thieno[3,2-Z']pyridin-7-
yloxy)phenyl)(roethyi)carbamothioyl)-2-phenylacetamide(223)
Stepl:iV-(3-Fluoro-4-(2-(l-methy]-li/-in]Jdazol-2-yl)thieno[3>2-b]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide (13d) and iV-(3-fluoro-4-(2-(l-methyl-li/-
iniida2ol-2-yl)thJeno[3,2-b]pyridin-7-yloxy)phenyl)-2-phenylacetamide(221)
[0482] To a suspension of 219 (400 mg, 2.18 mmol) in THF (12 mL) was added 2- 2-
phenylacetyl isothiocyanate (312 mg, 1.76 mmol) [P. A....S. Smith and R. O. Kan. J. Org.
Chem., 1964. 22611 the reaction mixture was stirred for 3 hours, transferred onto a flash
chromatography column and eluted with EtOAc/MeOH mixture (98:2), to afford title
compounds 13d (example 15, 254 mg, 42% yield) and 221 (96 mg, 17% yield).
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WO 2006/010264 PCT/CA2005/001177
[0433] Characterization of 13d (example 15) is provided in the table 2. Compound 221 is characterized by its mass-spectrum: MS (m/z): 459.1 (M+l). Step 2.3-Fluoro-iV-methyl-4-(2-(l-metliyl-liJ-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (222)
[0484] To a solution of 221 (274.8 mg, 0.6 mmol) in DMF (6 mL) NaH (60% in mineral oil, 36 mg; 0.9 mmol) was added in one portion at 0 °C and the reaction mixture was stirred for 1 h, followed by addition of Mel (0.037 mL, 0,6 mmol). The reaction mixture was allowed to warm up to room temperature, stirred overnight, diluted with EtOAc, washed with water, dried over anhydrous Na2S(X| and concentrated under reduced pressure. TheTresiduewas treatedwith 6N HC1 (3lnL), and heated atriOO°C for 3 h, cooled to room temperature and partitioned between water and DCM. Aqueous phase was collected, basifled with IN NaOH to pH 11 and extracted with EtOAc. The extract was dried over anhydrous Na2SC>4 and concentrated. The residue was purified by flash chromatography (eluent EtOAc/MeOH, 9:1) to afford title compound 222 (102 mg, 46% yiled) as a syrup. MS (m/z): 355.1 (M+l).
Step3:iV-((3-Fiuoro-4-(2-.(l-methyi-l//-imidazol-2-yl)thieno[3:>2-b]pyridin-7-yloxy)phenyI)(methyl)carbamothioyl)-2-pheny!acetamide(223) [0485] To a suspension of the 222 (102 mg, 2.88 mmoi) in THF (3 ml) was added 2-phenylacetyl isothiocyanate (51 mg, 0.288 mmol). The reaction mixture was stirred for 1 hr, transferred onto a chromatography column and eluted with a mixture EtOAc/MeOH (19:1) to afford title compound 223 (30 mg, 20% yield) as a white solid. !HNMR: (DMSO-d6) 5 (ppm): 10.88 (s, 1H), 8.51 (d, J=5.3Hz, 1H), 7.91 (s, 1H), 7.41-7.18 (m, 6H), 7.04 (m, 4H), 6.5 (d, ;N5.3Hz, 1H), 4.0 (s, 3H), 3.6 (s, 2H), 3.43 (s, 3H). MS (m/z): 532.3 (M+l).
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Example 201
Ar-(4-(2-(l-Methyl-lif-imidazoi-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyicarbamothioyI)-2-
phenylacetamide (227)
Step 1: 7-Chloro-2-(l-raethyl-lH-imidazol-4-yI)thieno[3,2-b]pyridine (224)
[0486] Starling from the compound 98 (scheme 19), following the procedure described
above for the synthesis of compound 10 (scheme 2, step 2, example 12) but replacing 2-
bromothiazole with 4-bromo-l -methyl- lZJ-imidazole, title compound 224 was obtained in
29% yield. MS (ra/z): 250.1 (100%), 252.1 (37%) (M+l).
Step 2: 2-(l-Methyl-l//-imida2ol-4-yl)-7-(4-nitrophenox50thieno[3,2-6]pyridine (225)
[0487] A mixture of 224 (950mg, 3.81 mmol), 4-nitrophenol (795 mg, 5.72 mmol),
K2CO3 (1.05 g, 7.62 mmol) and Ph2O (5 mL) was stirred at 190°C for 2 h in a sealed tube,
cooled and treated with additional amount of 4-nitrophenol (795 mg, 5.72 mmol). The
mixture was stirred for another hour at the same conditions, cooled to room temperature and
diluted with DCM. The DCM solution was extracted with 2N HC1; the aqueous phase was
collected, basified with concentrated ammonium hydroxide solution (pH~l 1) and extracted
with EtOAc. The extract was dried over anhydrous NajjSC^ and concentrated under reduced
pressure to afford 225 (860 mg, 64% yield) as an orange solid. MS (m/z): 353.1(M+1).
Step 3: 4-(2-(l-Methyl-l/f-imidazol-4-yl)thieno[3s2-b]pyridin-7-yloxy)benzenainine (226)
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[0488] To a solution of 225 (860 mg, 2.44 mmol) and NiCl2 x 6H2O (1.16 nig, 4.88 mmol) in MeOH/THF (49/81 mL) NaBftt (278 mg5 7.32 mmol) was carefully added. The reaction mixture was stirred for 10 min, concentrated under reduced pressure and the residue was suspended in 10% HC1. The suspension was basified with concentrated NH4OH solution (pH ~11) and extracted with EtOAc.
[0489] The extract was dried over anhydrous Na2SC>4 and concentrated under reduced pressure to produce a solid material. The aqueous phase (a suspension) was filtered; the precipitate was collected, washed with MeOH and dried under reduced pressure. [0490] Both precipitate and the solid obtained from the organic phase, were combined to afford title compound 226 (947.4 mg, crude) as a brown solid that was used in the next step without further purification. MS (m/z): 323.1 (M+l). Step4:A'-(4-(2-(l-MethyI-l//-imidazol-4-yl)thieno|;3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (227)
[0491] To a suspension of the 226 (385 mg, -0.99 mmol) in THF (10 mL) was added 2-phenylacetyl isothiocyanate (263 mg, 1.49 mmol). The reaction mixture was stirred for 1 hr, transferred onto a chromatography coiumn and eluted with EtOAc/MeOH (9:1) producing a solid material which was re-crystallized from MeCN to afford tide compound 227 (74.3 mg, 15% yield) as a white solid. !HNMR: (DMSO-de) d(ppm): 12.39 (s, 1H), 11.73 (s, 1H), 8.43 (d, J-5.3Hz, 1H), 7.84 (s, 1H), 7.72 (m, 3H), 7.66 (s, 1H), 7.34-7.27 (m, 7H), 6.69 (d, J=5.3Hz, 1H), 3.S2 (s, 2H), 3.72 (s, 3H). MS (m/z): 500.1 (M+l).

Example 202
jV-(4-(2-(l-MethyI-lH-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (228)
[0492] Title compound 228 was obtained starting from the compound 214 (scheme 46) and following the procedures described above for the synthesis of compound 227 (scheme 49, example 201). lE NMR (DMSO-d6) 5 (ppm): 12.42 (s, 1H), 11.77 (s, 1H), 8.74 (m, 1H), 8.37 (m, 1H), 7.87-7.78 (m, 1H), 7.70 (m, 1H), 7.42-7.20 (m, 7H), 6.90 (m, 1H), 4.05 (d, J=lHz, 3H), 3.83 (s, 2H). MS (m/z): 500.3.
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Example 203
l-(4-(2-(Methylthio)thieno[332-b]pyridin-7-yloxy)-3-fluoroph6nyl)-3-(2-
phenylacetyl)thiourea (232a)
Step 1: 7-Chloro-2-(methylthio)thieno[3,2-b]pyridine (229)
[0433J To a solution of 2 (200 mg, 1,18 mmol) in dry THF (11ml) at -78"C was added
«-BuLi (0.57 mL, 2.5M solution on hexane, 1,41 mmol) and the resultant brown precipitate
was stirred for 10 minutes. Methyl disulfide (0,16ml, l,77mmol) was added slowly, the
mixture was stirred at -78 °C for 3 hours and partitioned between DCM and water. Organic
phase was separated, dried over anhydrous Na2SC>4, filtered and concentrated under reduced
pressure to afford title compound 229 (0,240g, 94% yield, crude) as a yellow solid. MS
(m/z): 216.1 (100%), 218.1 (39%) (M+l).
Step 2: 7-(2-Fluoro-4-nitrophenoxy)-2-(methylthio)thienoj;3,2-b]pyridine (230)
[0494] To a suspension of 229 (100 mg, 0,463 mmol) in diphenyl ether (4 mL), was
added 2-fluoro-4-nitrophenol (109 mg, 0,695 mmol) and sodium carbonate (147 mg, 1,39
mmol). The reaction mixture was heated atr 200°C overnight, cooled to room temperature,
loaded onto a flash chromatography column and eluted with EtOAc/hexane (1:1) to afford
title compound 230 (0,135 mg, 86% yield) as a yellow solid. MS (m/z): 337,0 (M+l).
Step 3:4-(2-(Methylthio)tliieno[3,2-b]pyridin-7-yioxy)-3-fluorobenzenamine (231)
[0495] To as solution of 230 (84 mg, 0,250 mmol) in acetic acid (5 mL) at lOO'C, was
added iron powder (0,069g, l,249mmol). The reaction mixture was allowed to stir for 5
minutes, filtered through a celite pad and concentrated under reduced pressure. The residue
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was purified by column chromatography, eluent DCM/MeOH (50:1), to afford title
compound 231 (61 mg, 80% yield) as yellow oil. MS (m/z): 307.1 (M+l).
Step4:l-(4-(2-(Methylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-
phenylacetyl)thiourea (232a)
[0496] To a suspension of 231 (61 mg) in THF (2 ml) was added 2-phenylacetyI
isothiocyanate (42 mg. 0.199 mmol). The reaction mixture was stirred for 3 hours.
concentrated under reduced pressure and the residue was purified by column
chromatography, eluent EtOAc/hexane (35:65), to produce yellow oil. Purification of this
material by preparative HPLC (column C-18 Aquasil, gradient: 60% MeOH to 95% MeOH)
afforded title compound232a (25 mg, 26% yield) as acream solid7Characterization of
232a is provided in the table 22.
Example 204
l-(4-(2-(Butylthio)thieno[3,2-^3pyridin-7-yloxy)-3-fiuorophenyl)-3-(2-
phenylacetyl)thiourea (232b)
[0497] Starting from the compound 2, following procedures described above for the
synthesis of compound 232a (example 203, scheme 50) but replacing methyl disulfide with
w-butyl disulfide in the step 1, title compound 232b was synthesized. Characterization of
232b is provided in the table 22.
Example 205
l-(4-(2-(Benzylthio)thieno[3,2-fc]pyridm-7-ylo\7)-3-fluorophenyl)-3-(2-
phenylacetyl)thiourea (232c)
[0498] Starting from the compound 2, following procedures described above for the
synthesis of compound 232a (example 203, scheme 50) but replacing methyl disulfide with
benzyl disulfide in the step 1, title compound 232c was synthesized. Characterization of
232c is provided in the table 22.
Example 206
l-(4-(2-(pyridin-2-yltliio)thieno[3,2-6]pyridin-7-yioxy)-3-fluorophenyl)-3-(2-
phenylacetyj)thiourea (232d)
[0499] Starting from the compound 2, following procedures described above for the
synthesis of compound 232a (example 203, scheme 50) but replacing methyl disuifide with
2-pyridyl disulfide in the step 1, title compound 232d was synthesized. Characterization of
232d is provided in the table 22.
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Example 207
l-(4-(2-(MethylsuIfinyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-
phenylacetyl)thiourea (207)
Step 1: 7-{2-Fluoro-4-nitrophenoxy)-2-(methyisulfinyI)thieno[3>2-b]pyridine (233)
[0500] To a solution of 230 (400 mg, 1.189mmol, scheme 50) in DCM (12 mL) at 0°C
was added m-CPBA (77%, 272 mg, 1.189mmol). The reaction mixture was stirred at 0°C
for 30 minutes, water was added and the phases were separated. The organic phase was
collected, washed with a 1% sodium hydroxide solution, dried over anhydrous NaaSO* and
concentrated under reduced pressure. The residue was purified by column chromatograpny,
eluent DCM/MeOH (20:1), to afford title compound 233 (414 mg, 90% yield, crude), which
was used in the next step without further purification. MS (m/z): 353.0 (M+l).
Step 2:4-(2-(Methylsulfinyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (234)
[0501] To as solution of 233 (400 mg, 1.135mmol) in acetic acid (10 mL) at 100°C, was
added iron powder (317 mg, 5.675mmoi), The reaction mixture was stirred for 5 minutes,
filtered through a celite pad and concentrated under reduced pressure. The residue was
purified by column chromatography, eluent EtOAc/hexane (4:1), to afford title compound
234 (0.285g, 69% yield) as a yellow solid. MS (m/z): 323.0 (M+l).
Step 3: l-(4-(2-(Methylsulfinyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyI)-3-(2-
phenylacetyl)thiourea (235)
[0502] To a suspension of 234 (280 mg, 0. 868mmol) in THF (8mL) was added 2-
phenyl acetyl isothiocyanate (185 mg, 1.04 mmol). The reaction mixture was stirred for 3
hours, concentrated; the solid residue washed with EtaO and dried, to afford title compound
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235 (229 mg, 53% yileld) as a white-rose solid. 'HNMR: (DMSO-d6) 5 (ppm):12.41(s,lH), 11.75(s,lH), 8.54(d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.96(d, J=13.5Hz, 1H), 7.48(d, J=5.0Hz, 2H), 7.30-7.26(m, 2H), 7.26-7.18(m, 3H), 6.69(d, J=5.5Hz,lH), 3.25(s, 2H), 2.98(s, 3H). MS (m/z): 500.1 (M+l).

Example 208
l-(4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-y]oxy)-3-fluorophenyl)-3-(2-phenylaceiyi)thiourea (238)
Step 1: 7-(2-Fluoro-4-nitrophenoxy)-2-(methylsulfonyl)thieno[3,2-b]pyridine (236) £0503] To a solution of 233 (50 mg, 0.142mmol) in DCM (2mL), was added mCPBA (77%, 33 mg, 0.142 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour, water was added and the phases were separated. The organic layer was collected, washed with a 1% sodium hydroxide solution, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to afford title compound 236 (46 mg, 88% yield, crude) as a yellow solid which was used in the next step without additional purification. MS (m/z): 369.0 (M+l). Step 2:4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-yloxy)-3-iluorobenzenamine (237) [0504] To a solution of 236 (45 mg, 0.122 mmol) in acetic acid (4 mL) at 100"C, was added iron powder (34 mg, 0.611 mmol). The reaction mixture was stirred for 5 minutes, filtered through a celite pad and concentrated under reduced pressure to afford title compound 237 (20 mg, 48% yield, crude) as a yellow oil that was used in the next step without further purification. MS (m/z): 339.0 (M+l).
Step 3. l-(4-(2-(MethylsuIfonyl)thieno[3,2-b]pyridin-7-yloxy>-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (238)
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[0505] To a suspension of 237 (20 mg, 0.059mmol) in THF (10 mL) was added 2-phenylacetyl isothiocyanate (26 mg, 0.146 minol). The reaction mixture was stirred for 2 hours, concentrated under reduced pressure and the residue was purified by column chromatography, eluent EtOAc/MeOH (19:1), to afford a solid material that was dissolved in a minimum MeOH and precipitated with hexane to afford title compound 238 (9.6 mg, 3 i%) as a white solid. 'HNMR: (DMSO-d6) 5 (ppm):12.48(s;lH), 11.81(s,lH), S.69(d,J=5.5 Hz, 1H), 8.36(s,lH), 8.03(d, J=12.13Hz, 1H)5 7,55(5,211), 7.36-7.30(m, 2H), 7.30-7.24(m, 3H), 6.86(d,J=5.5Hz,lH), 3.83(s,2H), 3.54(s,3H). MS (m/z): 516.2.

Example 209
AT-(3*Fluoro-4-(2-(furan-2-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (242)
Stepl:(7-Chlorothieno[3,2-b]pyridin-2-yl)(taan-2-yl)methanone(239) [0506] To a solution of 2 (100 mg, 0.589 tnmol) in THF (6mL) at -78°C, was added n-BuLi (2.5 M in hexane, 0.259 mL, 8,84 mmol) and the reaction mixture was stirred 15 minutes. 2-Furoyl chloride (0.087 mL, 0.884 mmol) was added drop wise; the mixture was stirred for additional 2 hours and partitioned between DCM and water. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound 239 (35 mg, 23% yield, crude) as a yellow solid, that was used in the next step without additional purification. MS (m/z): 264.0 (100%), 266.0 (40%) (M+l). Step 2: (7-(2-Fluoro-4-nitrobenzyl)thieno[3,2-b]pyridin-2-yl)(fiiran-2-yl)methanone (240) [0507] To a suspension of 239 (35 mg, 0.133mmol) in Ph2O (2 mL) was added 2-fluoro-4-nitrophenol (42 mg, 0.265 mmol) and K2CO3 (73 mg, 0.530 mmol). The reaction
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mixture was heated at 180°C in a sealed flask for 60 hrs, cooled down to room temperature, loaded onto a flash chromatography column and eluted with EtOAc/hexane mixture (1:1), to afford title compound 240 (20 mg 39% yield) as a yellow solid. MS (m/z): 385.1 (M+l), Step 3: (7-(4-Amino-2-fluoroben2yl)thieno[3,2-b3pyridin-2-yl)(furan-2-yl)methanone (241) [0508] To as solution of 240 (20 mg, 0.052 rnmol) in acetic acid (2 mL) at 100°C, was added iron powder (15 mgs 0.260 mmol). The reaction mixture was stirred for 3 minutes, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent EtOAc/hexane (3:7) to afford title compound 241 (3.3 mg, 18% yield) as a yellow solid. MS (m/z): 355.1 (M+l). Step4:jV-(3:Fluoro-4-(2-(fliran-2-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(242)
[0509] To a solution of 241 (3.3 mg, 0.0093mmol) in THF (1 mL) was added 2-phenylacetyl isothiocyanate (2 mg, 0.011 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and purified by column chromatography, eluent EtOAc/hexane (20:80), followed by precipitation from a mixture acetone/hexane. Thus, title compound 242 was obtained (2.2 mg, 44% yield) as a yellow solid. 1HNMR: 1HNMR: (DMSO-d6) 5 (ppm):12.49(s, 1H), 11.82(s, 1H), 8.67(d, J=5.5 Hz, IH), 8.63(s, !H), 8.22(s, IH), 8.03(d, J=13.1 Hz, 1H), 7.79(d, J=3.7 Hz, IH), 7.60-7.55(m, 2H), 7.55-7.25(m,5H), 6.89-6.87(m, IE), 6.83(d, J=5.5Hz, IH), 3.82(s, 2H). MS (m/z): 532.1 (M+l).

Example 210
^-(S-Fluoro^^S-^ethoxymerliylJ-Siy-pyrroloP^-dJpyrimidin^-
yloxy)phenylcarbarnothioyl)-2-phenylacetaraide(246)
Step 1.4-(2-Fluoro-4-nitrophenoxy)-5if-pyrroio[3,2-d]pyrimiduie (243)
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[0510] To a suspension of 27 (0,400g, 2,60ramol) rG.B. Evans. R.H. Furneaux, et.al J. Ore. Chem.. 2001, 66,17, 5723-57301 in diphenylether (25ml) was added 2-fluoro-4-nitrophenol (614 mg, 3.90mmol) and HC1 (2N in Et2O) (0.19 ml, 3.90mmol). The reaction mixture was heated at 120°C for 4 hours, cooled to room temperature and concentrated under reduced pressure, to afford title compound 243 (610 mg, 86% yield) as a black solid. MS (m/z): 274.1 (M+l).
Step 2: 4-(2-Fluoro-4-nitrophenoxy)-5-(methoxyrnethyI)-5//-p3Trolo[3,2-d]pyrimidine (244)
[05113 To a suspension of 243 (150 mg, 0.547 mmol in DMF (6 mL) was added NaH (66 mg, 1.64 mmol). and the reaction mixture was stirred at 0°C for 1 hour. Chloromethyl methyl ester (132 mg, 1.641 mmol) was added drop wise and the mixture was stirred at room temperature over night. MeOH (2 mL) was added and the mixture was stirred for an additional hour and partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford title compound 244 (86 mg, 49% yield, crude) as an orange solid. MS (m/z): 319.1 (M+l). Step 3:3-Fluoro-4-(5-(methoxymethyl)-5i7-pyrroio[3,2-djpyrimidin-4-yloxy)benzenamine (245)
[0512J To as solution of 244 (85 mg, 0.267 raraol) in acetic acid (S mL) at lOO'C, was added iron powder (75 mg, 1.34 mmol). The reaction mixture was stirred for 5 minutes, filtered through Celite® pad and concentrated to dryness; the residue was purified by flash chromatography, eluent DCM/MeOH (30:1) to afford title compound 245 (18 mg, 23% yield) as an orange solid. MS (m/z): 289.1 (M+l). Step4:JV-(3-Fluoro-4-(5-(methoxymethyI)-5i?-pyrrolo[3,2-d]pyriniidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(246)
[0513] To a suspension of 245 (18 mg, 0.062 mmol) in THF (1 mL) was added 2-phenylacetyl isothiocyanate (12 mg, 0.069 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by flash chromatography, eluent hexane/EtOAc (3:2) followed by recrystallization (MeCN/water), and preparative HPLC (Aquasil C-1S, gradiend: 60% MeOH to 95% MeOH in water), to afford title compound 246 (9.2 mg, 33% yield) as a white solid. [HNMR: (CD3OD) 5 (ppm): 8.35(s, 1H), 8.03 (d, J=12.4Hz, 1H), 7.96(d, J=3.13Hz, 1H), 7.44-7.26(m, 6H), 6.69 (d, J=3.13Hz,lH), 5.29 (quintuplet, J=6.65Hz, 1H), 3.75(s, 2H), 3.60 (d, J=10.96Hz, 3H), 1.63(d, J=6.65Hz, 6H). MS (m/z): 464.16 (M+l).
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Example 211
7V'-(3--Fluoro-4-(5-isopropyl-5//-pyrrolo[3,2- Step 1:4-(5i?-PyiTolo[3,2-]pyrimidin-4-yioxy)-3-fluorobenzenair.ine (247) [0514J A solution of 243 (263 mg, 0.966 rnraol, scheme 54) in MeOH (1 OmL) and PdCk (1.8 mg, 0.01 mmol) was stirred in the atmosphere of hydrogen for 60 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water was added to the residue and the aqueous solution was extracted with DCM. The extract was dried over anhydrous NaaSCU and concentrated under reduced pressure, to afford title compound 247 (170 mg, 72% yield, crude) as a gray solid. MS (m/z): 243.08 (M+l).
Step 2:3-Fluoro-4-(5-isopropyI-5Jff-pyrrolo[3?2-d]pyrimidin-4-yIoxy)benzenamine (248) [0515] To a suspension of 247 (80 mg.. 0.327mmol) in THF (4 mL), was added PPh3 (258 mg, 0.983 mmol), DEAD (0.155ml, 0.983mmol) and isopropanol (0.075ml, 0.983 mmoi), and the reaction mixture was allowed to stir for 48 hours. 3N HCI solution (1.0 mL) was added and the mixture was extracted with DCM. Aqueous phase was collected, neutralized with NaOH 10% (pH ~11) and extracted with DCM. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified twice by column chromatography: eluents EtOAc/hexane (3:7) and MeOH/DCM (1:20), to afford title compound 248 (19 mg, 31% yield) as yellow solid. MS (m/z): 287.1 (M+l).
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Step 3; iY-(3-Fluoro-4-(5-isopropyl-5-ff-pyrrolo[3,2-d]pyrimidin-4-yioxy)phenylcarbamothioyl)-2-phenylacetamide(249)
[0516] To a suspension of 248 (10 mg, 0.035mmol) in THF (1 mL) was added 2-phenylacetyl isothiocyanate (0.007 mL, 0.038mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by flash chromatography, eluent EtOAc/hexane (1:1) and preparative HPLC (C-18 Aquasyl column, gradient: 60% to 95% MeOH in water, 45 min), to afford title compound 249 (4 mg, 26% yield) as a white solid. 'HNMR: (CD3OD) 5 (ppm): 8.35(s, 1H), 8.03 (d, J=12.4Hz, 1H), 7.96(d, J=3.13Hz, 1H), 7.44-7.26(m, 6H), 6.69 (d, J=3.13Hz,lH), 5.29 (quintuplet, J=6.65Hz, 1H), 3.75(s, 2H), 3.60 (d, J=10.96Hz, 3H), 1.63(d, }=66SRz, 6H). MS~(m7z): 464.2 (M+l).

Example 212
JV-(4-(5jEf-Pyrroio[3,2-d]pyrimidin-4-yloxy)-3-fmorophenyIcarbamothioyl)-2-(2,6-dichlorophenyl)acetamide (250)
Step 1: Ar-(4-(5/f-pyrrolo[3,2-d]pyrimidin-4-y Ioxy)~3-fluorophenylcarbamothioyl)-2-(2,6-dichlorophenyl)acetamide (250)
[0517] To a solution of 247 (200 mg, 0.819 mmol, scheme 55) in THF (8.2 mL) 2-(2,6-dichlorophenyl)acetyl isothiocyanate (302 mg, 1.33 mmol) was added. The mixture was stirred for 1 h at room temperature, transferred onto a flash chromatography column and eluted with EtOAc/hexane (1:1). The solid material obtained was triturated with diethyl ether, filtered and dried under reduced pressure, to afford title compound 250 (200 mg, 0.408, 50% yield) as a light brown solid. JHNMR: (DMSO-d6) 5 (ppm) 12.69 (s, 1H), 12.26 (s, 1H), 12.04 (s, IH), 7.94 (m, 2H), 7.53 (m, 4H), 7.39 (m, 1H), 6.72 (m, 1H), 4.22 (s, 2H). MS (m/z): 490.1 (100%, 492.1 (77%) (M+l).
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Example 213
A^3-Fiuoro-4-(6-phenyl-5Jf/'-pyrrolo[3J2-d]pyriinidin-4-yIoxy)phenyicarbamothIoyI)-2-
phenylacetamide (255a)
Step 1:4-Chloro-6-(phenylethynyl)pyrimidin-5-amine (251)
[0518] Ethynylbenzene (0,092 mL, 0.92 tnmol) was added to a solution of 4,6-
dichIoropyrimidin-5-amine (100 rag, 0.61 mmol), Pd(PPh3)4(140mg, 0.12 mmol), Cul (116
mg, 0.61 mmol) and DBPEA (0.5 mL, 3.05 mmol) in DME (6.1 mL). The reaction mixture
was stirred in the dark over night at room temperature, diluted with DCM, washed
sequentially with dilute aqueous citric acid and water, dried over anhydrous NajSC^ and
concentrated under reduce pressure. The residue was purified by flash chromatography,
eluent EtOAc/hexane (1:3), to afford title compound 251 (30.8 mg, 22% yield) as a yellow
solid. MS (m/z): 230.1 (100.0%), 232.1 (33%) (M+l).
Step 2:4-Chloro-6-phenyl-5iir-pyrrolo[3;,2-cf|pyrbnidine (252)
[0519] To a solution of 251 (30.8 mg, 0.134 mmol) in NMP (1.4 mL) a suspension of
KH in mineral oil (35%, 31 mL, 0.26S mmol) was added in one portion. The mixture was
stirred at room temperature overnight and partitioned between EtOAc and water. The
organic phase was collected, dried over anhydrous Na2SC>4 and concentrated. The residue
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was purified by flash chromatography, eluent EtOAc/hexane (1:2) to afford title compound affording 252 (22.7 mg, 74% yield). MS (m/z): 230.1 (100%) 232.1 (33%) (M+l). Step 3:4-(2-Fluoro-4-nitrophenoxy)-6-phenyl-5J?-pyrrolo[3,2-rf/pyrimidine (253) [0520] A mixture of 252 (47.9mg, 0.21 mmol), 4-nitrophenol (50 mg, 0.32 mmol), K2CO3 (58 mg, 0.42 mmol) and Ph2O (4 mL) was stirred at 190°C overnight in a sealed tube. The mixture was cooled down, more 4-nitrophenol (50 mg, 0.32 mmol) was added and the mixture was stirred at 190 °C for additional 8 h. It was cooled again, transferred onto a chromatography column and eluted sequentially with EtOAc/hexane (1:10) and EtOAc/hexane (1:3), to afford title compound 253 (71.4 mg, 97% yield) as a white foam. MS (m/z): 351.1 (M+T)7
Step 4:3-Fluoro-4-(6-phenyl-5i?-pyrrolo[3:,2-f/]pyrimidin-4-yloxy)benzenaitune (254) [0521] To a solution of 253 (71.4 mg, 0,21 mmol) in acetic acid (2.1 mL) at 100°C, was added iron powder (59 mg, 1.05 mmol). The reaction mixture was stired for 5 minutes, filtered through a Celite® pad and concentrated under reduced pressure. The residue was purified by column chromatography, eluent EtOAc/hexane (2:1), to afford title compound 254 (27.9 mg, 40% yield). MS (m/z): 321.1 (M+l). Step 5: Ar-(3-Fluoro-4-(6-phenyl-5A'-pyrrolo[3,2-rfipyrimidin-4-yloxy)phenyIcarbamothioyi)-2-pheriylacetaiuide(255a)
[0522] To a suspension of the 254 (26.8 mg, 0.84 mmol) in THF (1.6 ml) was added 2-phenylacetyl isothiocyanate (23 mg, 0.13 mmol). The mixture was stirred for 1 hr transferred onto a chromatography column and eluted sequentially with EtOAc/MeOH (9:1) and EtOAc/hexane (1:1), to afford title compound 255a (30 mg, 72% yield) as a white solid. 1HNMR: (DMSO-d6) 5 (ppm):12.65 (s, 1H), 12.43 (s, 1H), 11.79 (s, 1H), 8.31 (s, 1H), 8.06 (d, J=7.6Hz, 2H), 7.91 (m, 1H), 7.52 (m, 4H), 7.43 (m, 1H), 7.34, (m, 4H), 7.27 (m, 1H), 7.18 (m, 1H), 3.83 (s, 2H). MS (m/z): 498.2 (M+l). Example 214
Ar-(3-Fluoro-4-(6-(pyridin-2-yl)-5AT-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbarnothioyl)-2-phenylacetamide (25 5b)

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WO 2006/010264 PCT/CA2005/O01177
[0523] Following the procedures described above for the synthesis of compound 255a (example 213, scheme 57) but replacing ethynylbenzene in the step 1 with 2-ethynylpyridine, title compound 255b was obtained. !H NMR (DMSO-d6) 5 (ppm): 12.85 (br, 1H), 12.65 (br, 1H), 11.75 (br, 1H), 8.71 (m, 1H), 8.33 (s, 1H), 8.21 (d, J=8Hz, 1H), 7.96 (m, 1H), 7.89 (m, 1H), 7.52-7.42 (m, 3H), 7.34-7.32 (m, 5H), 7.28 (m, 1H), 3.83 (s, 2H). MS (m/z): 499.2 (M+l).

Example 215
iV-(4-(2-(4-Methyl-lii?-pyrazoi-l-yl)thieno[3,2-i]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (258a)
Step 1:2-(4-Methyl-lJff-pyrazol-l-yl)-7-(4-nitrophenoxy)thieno[3)2-^>]pyridine (256) [0524] A mixture of 197 (300 mg, 0.86 mmol, scheme 42), 4-methyl-l#-pyrazole (69 mg, 0.86 mmoi), Cul (16.4 mg, 0.086 nimoi), trans-N'^-diraethylcyclohexane-l^-diamine (24.4 mg, 0.172 mmol) [J.C. Antilla, A. Klapars, et. al. JACS, 2002,124,11684-1688] and K2CO3 (238 mg, 1.72 mmol) in toluene (1.7 mL) was stirred at room temperature in an atmosphere of nitrogen nitrogen overnight, diluted with EtOAc (100 mL), filtered through a Celite® pad, and concentrated under reduced pressure. The residue was purified by flash chromatography with gradient elution with EtOAc/hexane (1:1) to EtOAc/hexane (2:1) to afford title compound 256 (88.8 mg, 37% yield) as a white solid. MS (m/z): 352.06 (M+l).
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WO 2006/010264 PCT/CA2005/OO1177
Step 2:4-(2-(4-Methyl-l^-pyrazol-l-yl)thieno[3,2-&]pyridin-7-yloxy)benzenaraine (257)
[0525] To a solution of 256 (168.4 mg, 0.478 mmol) and NiCl2 x 6H2O (226 mg, 0.956
mmol) in MeOH/THF (10/10 mL) NaBH, (72 mg, 1.92 mmol) was carefully added. The
reaction mixture was stirred for 10 min, concentrated to dryness and the resultant solid was
suspended in 10% HC1. The aqueous solution was basifiied (pH -11) with concentrated
aqueous NH4OH and extracted with EtOAc. The organic extract was collected, dried, over
anhydrous NajSC^ and concentrated under reduced pressure, to afford title compound 257
(134.6.mg3 87% yield) as a white solid. MS (m/z): 322.09 (M+l).
Step3:Ar-(4-(2-(4-Methyl-ii/-pyrazol-I-yl)thieno[3)2-i]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide(258a)
[0526] To a suspension of the 257 (134.6 mg, 0.418 mmol) in THF (4.2 mL) was added
2-phenylacetyl isothiocyanate (111 mg, 0.627 mmol). The reaction mixture was stirred for 1
hr at room temperature, transferred onto a chromatography column and eluted wit a gradient
of gradient EtOAc/hexane, 1:1 to 2:1, to provide a beige solid which was triturated with
diethyl ether to afford title compound 258a (31 mg, 15% yield) as a white solid.
Characterization of 258a is provided in the table 23.
Example 216
JVK4-(2-(lH-Pyrazol-l-yl)thieno[3,2-fe]pyridin-7-yloxy)phenylcarbarnothioyl)-2-
phenylacetamide (258b)
[0527] Following the procedures described above for the synthesis of compound 258a
(example 235, scheme 58) but replacing 4-methy]-l#-pyrazole in the step 1 with IH~
pyrazole, title compound 258b was obtained. Characterization of 258b is provided in the
table 23.
Example 217
iVr-(4-(2-(3,5-Dimethyl-li?-pyrazol-l-yl)thieno[3,2-6]pyridin-7-
yloxy)pheny lcarbamothioyl)-2 -phenylacetami de (25 8c)
[0528] Following the procedures described above for the synthesis of compound 258a
(example 215, scheme 58) but replacing 4-methyl-lif-pyrazole in the step I with 3,5-
dimethyl-I/f-pyrazoie, title compound 258c was obtained. Characterization of 258c is
provided in the table 23.
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WO 2006/010264 PCT/CA2005/001177
Example 218
A^-(4-(lJH-Pyrrolo[2,3-c]pyridin-7-yIoxy)-3-fluorophenyIcarbamothioyl)-2-phenylacetaraide
(262a)
Step 1. 7-Chloro-lJff-pyrrolo[2,3-c]pyridine (259)
[0529] To a solution of 2-chloro-3-nitropyridine (5g, 31.5mmol)) in THF (200mL) at -
7S°C, was added vinyhnagnesium bromide (100mL51.0M in THF) Tlie reaction mixture
was stirred at -20°C for 8 hours, quenched with NHUCi solution (20%, 150mL), extracted
with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by
flash chromatography, eluent EtOAc/hexane (1:5), to afford the title compound 259 (1.23g,
26% yield) as a white solidTzTzfom^elal. JOrgTCftCTu 2002, 67:2345-2347TT]yIS~
(m/z): 153.1(M+H) (found).
Step 2. 7-(2-Fluoro-4~nitrophenoxy)-liJ-pyrrolo[2,3-c]pyridine (260)
[0530] A mixture of 259 (420mg, 2.76mmol), 2-fluoro-4-nitrophenol (65 lmg,
4.14mmol) and K2CO3(1.14g, 8.28mmo!) in Ph2O (15 inL) was heated at 200°C for 6 hours,
cooled to room temperature and partitioned between EtOAc and water. Organic phase was
collected, dried and concentrated. The residue was purified by flash column
chromatography with gradient elution from hexane to hexane/EtOAc (3:1), to afford the title
compound 260 (333 mg, 44% yield) as a yellowish solid. MS (m/z): 274.1(M+H) (found).
Step 3.4-(li?-PyiTolo[2,3-c]pyridin-7-yIoxy)-3-fluorobenzenamine (261)
[0531] To a solution of 260 (lOOmg, 0.36mmol) in AcOH (4mL) at 90°C, was added
iron powder (102mg, 2.1mmol). The reaction mixture was vigorously stirred for 10 min,
cooled, filtered through a Ceiite pad and concentrated. The residue was purified by flash
column chromatography, eluent EtOAc/hexane (1:1), to afford title compound 261 (87mg,
99% yield) as an off-white solid. MS (m/z): 244.1(M+H) (found).
Step 4. Ar-(4-(lH-Pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-
phenylacetamide (262a)
[0532] A mixture of 261 (44mg, 0.18mmoi) and 2-phenylacetyl isothiocyanate (36 QL,
0.19 mmol) in THF (2 mL) was stirred at room temperature for 2 hours, and concentrated.
The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to
afford the title compound 262a (30mg, 40%) as an off-white solid. 'H NMR (DMSO-d6) 5
(ppm): 12.41(s, 1H), l2.07(s, 1H), 11.77(s, 1H), 7.84(dd, 1H, h= 10.95Hz, J2=2.0Hz),
7.58(t, 1H, Ji=J2==2.7Hz), 7.51(d, 1H, J=5.7Hz), 7.43-7.39(m, 2H), 7.37-7.33(m, 4H), 7.31-
7.26(m, 2H), 6.55(dd, 1H, Jr 1.76Hz, J2=2.9Hz), 3.84(s, 2H), MS (m/z): 421.1(M+H)
(found).
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WO 2006/010264 PCT/CA2005/001177
Example 218
N-(4-(lH-Pyrrolo[2,3-c]pyridin-7-yIoxy)-3-fluorophenyIcarbamothioyl)-2-phenylacetaraide
(262a)
Step 1. 7-Chloro-lH-pyrrolo[2,3-c]pyridine (259)
[0529] To a solution of 2-chloro-3-nitropyridine (5g, 31.5mmol)) in THF (200mL) at -
7S°C, was added vinyhnagnesium bromide (100mL,1.0M in THF) The reaction mixture
was stirred at -20°C for 8 hours, quenched with NH4Cl solution (20%, 150mL), extracted
with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by
flash chromatography, eluent EtOAc/hexane (1:5), to afford the title compound 259 (1.23g,
26% yield) as a white solid[z.zhang ,et al. J Org Chem 2002, 67:2345-2347].MS
(m/z): 153.1(M+H) (found).
Step 2. 7-(2-Fluoro-4~nitrophenoxy)-liJ-pyrrolo[2,3-c]pyridine (260)
[0530] A mixture of 259 (420mg, 2.76mmol), 2-fluoro-4-nitrophenol (65 lmg,
4.14mmol) and K2CO3(1.14g, 8.28mmo!) in Ph2O (15 inL) was heated at 200°C for 6 hours,
cooled to room temperature and partitioned between EtOAc and water. Organic phase was
collected, dried and concentrated. The residue was purified by flash column
chromatography with gradient elution from hexane to hexane/EtOAc (3:1), to afford the title
compound 260 (333 mg, 44% yield) as a yellowish solid. MS (m/z): 274.1(M+H) (found).
Step 3.4-(li?-PyiTolo[2,3-c]pyridin-7-yIoxy)-3-fluorobenzenamine (261)
[0531] To a solution of 260 (l00mg, 0.36mmol) in AcOH (4mL) at 90°C, was added
iron powder (102mg, 2.1mmol). The reaction mixture was vigorously stirred for 10 min,
cooled, filtered through a Ceiite pad and concentrated. The residue was purified by flash
column chromatography, eluent EtOAc/hexane (1:1), to afford title compound 261 (87mg,
99% yield) as an off-white solid. MS (m/z): 244.1(M+H) (found).
Step 4. Ar-(4-(lH-Pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-
phenylacetamide (262a)
[0532] A mixture of 261 (44mg, 0.18mmoi) and 2-phenylacetyl isothiocyanate (36 QL,
0.19 mmol) in THF (2 mL) was stirred at room temperature for 2 hours, and concentrated.
The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to
afford the title compound 262a (30mg, 40%) as an off-white solid. 1H NMR (DMSO-d6) ?
(ppm): 12.41(s, 1H), l2.07(s, 1H), 11.77(s, 1H), 7.84(dd, 1H, J1= 10.95Hz, J2=2.0Hz),
7.58(t, 1H, J1=J2==2.7Hz), 7.51(d, 1H, J=5.7Hz), 7.43-7.39(m, 2H), 7.37-7.33(m, 4H), 7.31-
7.26(m, 2H), 6.55(dd, 1H, Jr 1.76Hz, J2=2.9Hz), 3.84(s, 2H), MS (m/z): 421.1(M+H)
(found).


Example 219
N-(3-FLuoro-4-(l-Methyl-lH-pyrrolo[2,3-c]pyridin-7-yloxy)phenylcarbamothioyl)-2-
phenyiacetamide (262b)
Step 1. 7-Chloro-l-methyl-lH-pyrrolo[2,3-c]pyridine(263)
[0533] To a solution of 259 (250mg, 1.64mmol) in DMF (16mL) at 0°C was added NaH
(197mg, 4.92 mmol, 60% in mineral oil), and the mixture was stirred for 30 min, followed
by addition of Mel (112 DL, 1.80mmol), The reaction mixture was stirred at room
temperature for 2 h before acetic acid (lmL) was added. Solvents were removed under
reduced pressure, the residue was partitioned between water and EtOAc. Organic phase was
collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash
column chromatography, eluent EtOAc/hexane (1:1), to afford the title compound 263
(200mg, 92% yield) as an off-white solid. MS (m/z): 167.1(M+H) (found).
Step 2. 7-(2-Fluoro-4-nitrophenoxy)-l-methyl-lH-pyrrolo[2,3-c]pyridine (264)
[0534] Starting from the compound 263 and following the procedure described above
for the synthesis of nitro compound 260 (scheme 59, step 2, example 218), title compound
264 was obtained in 91% yield as a yellow solid. MS (m/z): 288.1(MH-H) (found).
Step3.-Fluoro-4-(l-methyl-lH-pyrrolo[2,3-c]pyridin-7-yloxy)benzenamine(265)
[0535] Starting from the compound 264 and following the procedure described above
for the synthesis of amine 261 (scheme 59, step 3, example 218), title compound 265 was
obtained in 89% yield as an off-white solid. MS (m/z): 25S.1(M+H) (found).
Step 4. N-(3-Fluoro-4-(l-methyl'liir-pyrrolo[2,3-c]pyridin-7-yloxy)phenylcarbainothioyl)-
2-phenyiacetamide (262b)
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WO 2006/010264 PCT/CA2005/001177
[0536] Starting from the compound 265 and following the procedure described above for the synthesis of compound 262a (scheme 59, step 4, example 218), title compound 262b was obtained in 87% yield as an off-white solid. 1H NMR (DMSO-d6)?? (ppm): 12.40(s, 1H), 11.78(s, 1H), 7.83(dd, 1H, J,= 10.95Hz, J2=1.9Hz), 7.56(d, 1H, 2.7Hz), 7.49(d, IH, J=5.5Hz), 7.43-7.39(m, 2H), 7.37-7.33(m, 4H), 7.31-7.26(m, 2H), 6.52(d,lH, J2=2.9Hz), 4.11(s, 3H), 3.84(s, 2K), MS (m/z): 435.1(M+K) (found). Example 220
N-(4-(l-Benzyl-1H-pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide (262c)
[0537] Starting from the compound 259 and following the procedures described above for the synthesis of compound 262b (scheme 60, step 4, example 219) but using benzyl bromide in step 1 instead of methyl iodide, title compound 262c was obtained. 1HNMR (DMSO-de) ??(ppm): 12.36 (s, 1H), ll-76(s, IH), 7.78(m, IH,), 7.58(t, IH, J1=J2=2.7Hz), 7.50(d, 1H, J=5.7Hz), 7.34(m, 5H), 7.30-7.221(m, 5H), 7.l5(dd, 1H, J1= 8.1Hz, J2=0.4Hz), 7.10(t IH), 6.60(d, IH, J=2.9Hz), 5.68(s, 2H), 3.82(s, 2H). MS (m/z): 511.2(M+H) (found).
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Scheme 61

269b: Example 222
Example 221
N-(4-(lH-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fiuorophenyIcarbaraothioyi)-2-phenyi
acetamide (269a)
Step 1. 7-Chloro-lH-pyn-oIo[3,2-b]pyridine (266)
[0538] To a solution of 2-chloro-3-nitropyridine (2.0g, 12.6mmol) [C. Almansa. et al.,
J. Med. Chem.. 2001.44. 350-3611 in THF (80mL) at -78°C, was added vinylmagnesium
bromide (80mL, 1.0M in THF), and the reaction mixture was stirred at -20°C for 8 hours,
quenched with NH4Cl solution (20%, 100mL), extracted with EtOAc, dried over anhydrous
Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluent
EtOAc/Hexane (1:1)-, to afford the title compound 266 (240mg, 11%) as yellow crystals.
MS (m/z): 153.1(M+H) (found).
Step 2. 7-(2-Fluoro-4-nitrophenoxy)-lH-pyrrolo[3,2-b]pyridine(267)
[0039] A mixture of 266 (180mg, 1.18ramol), 2-fluoro-4-nitrophenoi (558mg,
3.55mmol) and K2CO3(981mg, 7.10mmol) in Ph2O(4mL) was heated at 170°C for 8 hours,
cooled to room temperature and partitioned between EtOAc and water. Organic phase was
collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash
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column chromatography with gradient eiution of hexane, to hexane/EtOAc (1:1), to afford
the title compound 267 (84 mg, 26% yield) as a yellowish solid. MS (m/z): 274.1(M+H)
(found).
Step 3. 4-(lH-Pyrrolo[3,2-6]pvridin-7-yloxy)-3-fluorobenzenamine (268)
[0540] To a solution of 267 (35mg, 0.13mmol) in AcOH (lmL) at 90°C, was added iron
powder (36mg, 0.65mmol). The reaction mixture was stirred vigorously for 10min, cooled,
filtered through a Celite pad and concentrated. The residue was partitioned between DCM
and NaHCO3 saturated solution. Phases were separated; the aqueous phase was neutralized
with AcOH and extracted with DCM. Primary organic phase and the extract were combined
and concentrated to give the title compound 268 (3 lmg, 99%) as an off-white solid. MS
(m/z): 244.1(M+H) (found).
Step 4. N-(4-(lH-Pyrrolo[3,2-6]pyridin-7-yloxy)-3-fluoropheriylcarbamothioyl)-2-phenyl
acetamide (269a)
[0541] A mixture of 268 (20mg, 0.08mmol) and 2-phenylacetyl isothiocyanate (16 DL,
0.08mmol) in THF (1 mL) was stirred at room temperature for 2 hours and concentrated.
The residue was purified by flash column chromatography (eluent EtOAc) followed by
preparative HPLC (column Aqusil C18, gradient elution with 60-95% MeOH in water, 45
min) to afford the title compound 269a (13mg, 40% yield) as an off-white solid. 1H NMR
(CD3OD) ? (ppm): 8.41(s, 1H), 8.16(d. 1H, J= 5.6Hz), 8.02(dd, 1H, h=2.3Bz, J2=12.2Hz),
7.62(d, IH, J=3.3Hz), 7.44(rn, 1H), 7.37-7.33(m,4H) 7.31-7.26(m, IH), 6.65(d, IH,
J=3.1Hz), 6.52(d, IH, J=5.7Hz), 3.76(s, 2H), MS (m/z): 421.1(M+H) (found).
Example 222
N(4-(lH-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(2,6-
dichlorophenyl)acetamide dihydrochloride (269b)
[0542] Starting from the compound 268 and following the procedure described above
for the synthesis of compound 269a (example 221) but replacing 2-phenylacethyl
isothiocyanale with 2-(2,6-dichlorophenyl)acetyl isothiocyanate, a white solid was obtained.
This material was dissolved in MeOH and treated with HC1 (lmL, 1.0M in ether). Solvents
were removed under the reduced pressure and the residue was lyophilized, to afford the title
compound 269b (48% yield) as a yellowish solid. 1H NMR (DMSO-d6)?? (ppm): 13.29(s,
IH), 12.32(s.. IE), 12.05(s, IH), 8.52(d, IH,), 8.14(m, 2H), 7.64(m, 2H), 7.5l(d, IH),
7.37(dd, 1H), 6.86(m, 1H), 6.81(dd, IH), 4.22(s, 2H), MS (m/z): 489.1(M+H) (found).

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Scheme 62

Example 223
N-(4-(6-Bromothieno[3r2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-
phenylacetamide (274)
Step 1. 6-Bromothieno[3,2-b]pyridin-7-ol (270)
[0543] To a solution of thieno[3,2-b]pyridin-7-ol (1,2.55g, 16.87 mmol) in acetic acid.
(50mL) was added bromine(1.7 mL, 32.72 mmol). The mixture was heated at 110°C for 1h,
cooled and the resultant precipitate was separated by filtration, to afford the title compound
270 (4.47g, crude) as a dark brown powder, which was used in next step without further
purification. M/S (m/z): 231.9(M+H) (found).
Step 2.6-Bromo-7-chlorothieno[3,2-b]pyridine (271)
[0544] DMF (0.72mL) was added slowly to a solution of (COC1)2 in DCE at 0°C and
the mixture was stirred for 30 min, followed by addition of 270 (crude from above). The
combined mixture was stirred for 10 min at the same conditions and was heated to reflux for
3h. After cooling the mixture was concentrated and partitioned between DCM and water.
Organic phase was collected and dried over anhydrous Na2SO4, filtered and concentrated.
The residue was purified by flash column chromatography (eluent EtOAc), to afford the
title compound 271 (0.66g, 70% yield based on compound 1) as a yellowish solid. MS
(m/z): 249.0(M+H) (found).
Step 3.6-Bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (272)
[0545] Starting from the compound 271 and following the procedure described above
for the synthesis of compound 260 (scheme 59, example 218, step 2), title compound 272
was obtained in 61% yield as an off-white solid. MS (m/z): 368.9(M+H).
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Step 4. 4-(6-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluoroberizenamine (273)
[0546] Starting from the compound 272 and following the procedure described above
for the synthesis of compound 261 (scheme 59, example 218, step 3), title compound 273
was obtained in 92% yield as a light brown solid. MS (m/z): 340.0(M+H).
Step 5.N-(4-(6-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-
phenylacetamide (274)
[0547] Starting from the compound 273 and following the procedure described above
for the synthesis of compound 262a (scheme 59, example 218, step 4), title compound 274
was obtained in 99% yield as a white solid. 1H NMR (DMSO-d6) ? (ppm):12.44(s, 1H),
11.79(s, 1H), 8.82(5, 1H), S.03(d, 1H), 7.99(dd, 1H), 7.54(d, 1H), 7.41(ddJH),7.32-
7.24(m, 6H), 3.80(s, 2H). MS (m/z):517.0 (M+H) (found).

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Evans et al. J. Ore. Chem., 2001,66.17, 5723-5730 and shown in the scheme 6] was added drop wise maintaining the temperature below -70°C over a period of 15 min. Dried CO2-gas was bubbled through the reaction mixture and stirred at room temperature overnight. The precipitate thus formed was collected by filtration and dried to afford the title compound 275 (78mg, 100% yield) as a yellow solid. MS (m/z): 209.9 (RCOOH, M-H) (found). Step 2.4-chloro-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxaimide (276) [0549] A reaction mixture containing carboxylate 275 (78mg, 0.36mmo), oxalyl chloride (63µL, 0.72mmol), and a drop of DMF in DCM was stirred for 2h. Solvents were removed under reduced pressure and the residue was re-dissolved in DCM (4mL). To this solution Me2NH (360 µl ,0.72mmoI; 2M in THF) in THF was added and the mixture was stirred at room temperature for 4h. The solvent was removed under reduced pressure and the residue was purified by flash column chrornatography (eluent EtOAc) to afford the title compound 276 (50mg, 58% yield) as a yellowish solid. MS (m/z): 239.1(M+H) (found). Step 3.4-(2-Fluoro-4-nitrophenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidme-6-carboxamide (277)
[0550] Starting from the compound 276 and following the procedure described above for the synthesis of compound 260 (scheme 59, example 218, step 2) title compound 277 was obtained in 77% yield as an off-white solid. MS (m/z): 360.1(M+H) (found). Step 4.4-(4-Amino-2-fluorophenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (278)
[0551] Starting from the compound 277 and following the procedure described above for the synthesis of compound 261 (scheme 59, example 218, step 3) title compound 278 was obtained in 72 % yield as an off-white solid. MS (m/z): 330.1(M+H) (found). Step5.4-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N,7-trimethyl-7H-pyrrolo [2,3-d]pyrimidine-6-carboxamide(279)
[0552] Starting from the compound 278 and following the procedure described above for the synthesis of compound 262a (scheme 59, example 218, step 4) title compound 279 was obtained in 98% yield as an off-white solid. 1H NMR (DMSO-d6) ? (ppm): 12.45(s, 1H), 11.81(s, 1H), 8.43(s, 1H), 7.89(m, 1H), 7.46(m, 2H),7.34(m, 4H), 7.28(m, 1H), 6.93(m, 1H), 4.03(s, 3H), 3.82(ss 2H), 3.81(s,3H), 3.14(s, 3H), 3.06(s, 3H). MS (m/z): 507.1(M+H) (found).
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Scheme 64

Example 225
N-(3-Fluoro-4-(6-(methylthio)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide (283)
Step 1. 4-chloro-6-(methylthio)thieno[3,2d]pyrimidine (280)
[05531 To a solution of 20 (shown in the scheme 4) (200mg, 1.18mmol) in THF (11 raL) was added n-BuLi (566 µL, 1.42mmol, 2.5M in THF) very slowly at -78°C and the mixture was stirred for 15 min at the same conditions. A solutions of dimethyl disulfide (160uL, 1.77mmol) and Mel (110 L, 1.77mmol) in THF (1 mL) was added drop wise. The reaction mixture was stirred for 2h at -78°C, quenched with saturated aqueus NH4Cl solution, and extracted with DCM. The extract was dried over anhydrous Na2SO4 and concentrated to afford the title compound 280 (210mg, 82% yield) as a yellowish solid. MS (m/z): 217.0(M+H) (found).
Step 2.4-(2-Fluoro-4-nitrophenoxy)-6-(methylthio)thieno[3,2-d]pyrimidine (281) [0554] A mixture of 280 (210mg, 0,97mmol), 2-fluoro-4-nitrophenol (278mg, 1.77mmol) and K2CO3 (560mg, 3.54mmol) in Ph2O (l0mL) was heated at 130°C 60 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography with a gradient elution (hexane to hexane/EtOAc, 1:1) to afford the title compound 281 (288 mg, $8% yield) as a yellowish solid. MS (m/z): 338.1(M+H) (found). Step 3. 3-Fluoro-4-(6-(methylthio)thieno[3,2-d]pyrimidin-4-yloxy)benzenamine (282) [0555] To a solution of 281 (288mg, 0.94mmol) in AcOH (25mL) at 90°C, was added iron powder (238mg, 4.25mmol), and the reaction mixture was stirred vigorously at 90°C
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for 10 min, cooled, filtered through a Celite pad and concentrated. The residue was purified by flash column chromatography (eluent EtOAc) to afford the title compound 282 (248mg, 95%) as an off-white solid. MS (m/z): 308.1 (M+H) (found). Step 4. N-(3-Fluoro-4-(6-(methylthio)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide (283)
[0556] A mixture of 282 (248mg, 0.80mmol) and 2-phenyiacetyl isothiocyanate (214mg, 1.20mmol) in THF (8 mL) was stirred for 2 hours, and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (3:7), to afford title compound 283 (200mg, 52% yield) as an off-white solid. 1H NMR (DMSO-d6) ? (ppm): 12.42(s, IH), H.80(s, ffl), 8.o3(s, IH),7.85(d;lH)77:54-7:44tm, 3H), 7.35 (m, 4H), 7.30(m, IH), 3.8l(s, 2H), MS (m/z): 485.1 (M+H) (found).
Example 226
iV-(3-Fluoro-4-(6-(methylsuifinyl)thieno[3,2-cfjpyrimidin-4-yloxy)phenylcarbamotruoyl)-2-phenylacetamide (286)
Step 1.4-(2-Fluoro-4-nitrophenoxy)-6-(rnethylsulfinyl)thieno[3,2-fl(jpyrimidine (284) [0557] A mixture of 281 (1.1 g, 3.2mmol) and m-CPBA (77%, 890 mg, 12.8 mmol) in DCM at 0°C was stirred for 2 hours, diluted with DCM, washed with ice water, NaHCO3 solution and water again; dried and concentrated to give the title compound 284 (1.15 g, quantitative) as a yellowish solid. MS (m/z): 354.0(M+H) (found). Step 2.4-(2-Fluoro-4-nttrophenoxy)-6-(methylsulfinyI)thieno[3,2-c(}pyrimidine (285) [0558] Starting from the compound 284 and following the procedure described above for the synthesis of compound 282 (scheme 64, step 3, example 225), title compound 285 was obtained in 34% yield as an off-white solid. MS (m/z): 324.0 (M+H) (found).
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Step 3. iV-(3-Fluoro-4-(6-(methylsulfinyl)thieno[3,2-£(]pyrimidin-4-yloxy)phenyl carbamothioyl)-2-phenylacetamide(286)
10559] Starting from the compound 285 and following the procedure described above for the synthesis of compound 283 (scheme 64, step 4, example 225), title compound 286 was obtained in 36% yield as an off-white solid. !H NMR (DMSO-d6) 5 (ppm): 12.45(s, 1H), 11.83(s, 1H), 8.80(s, 1H), 8.13(s,lH), 7.93(dd, 1H, J,=2.3Hz, J2=10.9Hz), 7.55 (t, 1H, J=8.6Hz), 7.48 (ra, 1H), 7.34-7.3l(m, 4H), 7.28-7.25(m, 1H), 3.8l(s, 2H), 3.08(s, 3H). MS (m/z): 501.0(M+H) (found).

Example 227
Methyl 7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3s2-6]pyridme-2-
carboxylate hydrochloride (288)
Step 1. Methyl 7-(4-amino-2~fluoroplienoxy)thieno[3,2-bjpyridine-2-carboxylate (287)
[0560] Starting from the nitro compound 38 (shown in the scheme 7) and following the
procedure described above for the synthesis of compound 261 (scheme 59, step 3, example
218), title compound 287 was obtained in 86% yield as an off-white solid. MS (m/z):319.0
(M+H) (found).
Step 2. Methyl 7-(2-fluoro-4-(3-(2-phenyiacetyi)thioureido)phenox3')thieno[3,2-^pyridine-
2-carboxylate hydrochloride (288)
[0561] Starting from the amine 287, following the procedure described above for the
synthesis of compound 269b (scheme 561, example 222) and replacing 2-(2,6-
dichlorophenyl)acetyl isothiocyanate with 2-phenylacetyl isothiocyanate, title compound
288 was obtained in 72% yield as a yellowish solid. !H NMR (d-DMSO) 5 (ppm): 12.5 l(s,
1H), 11.84(s, IE), 8.64(dd, 1H, Ji=5.1Hz, J2=0.4Hz), 8.24(s, 1H, J=0.4Hz), 8.02(dd, 1H,
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Ji«1.8Hz, J2=13.4Hz), 7.56-7.54(ra, 2H), 7.36-7.3 l(m, 1H), 7.28-7.25(m, 1H), 6.81 (d, 1H, J = 5.5 Hz), 3.91 (s, 3H), 3.81 (s, 2H). MS (m/z):496.3 (M+H) (found).

Example 228
7-(2-Fluoro-4-(3-(2-phenyIacetyi)thioureido)phenoxy)-7V-(pyrrolidin-3-y3)thieno[3,2-
&]pyridine-2-carboxamide (291)
Step 1. fe7'/-Butyl 3-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridirie-2-carboxaniido)
pyrrolidine-1-carboxylate (289)
[0562J A solution of 40 (shown in the scheme 7, 600 mg, 1.54 tnmol), fcr/-butyl 3-
aminopyrrolidine-l-carboxylate (369 mg, 2.0 mmol) in DCM (15 mL) was stirred overnight
at room temperature. The solvent was removed under reduced pressure and the residue was
purified by flash column chromatography, eluents EtOAc and EtOAc/MeOH (10:1), to
afford the title compound 289 (l60mg, 20%) as an off-white solid. MS (m/z): 503.3 (M+H)
(found).
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Step 2. tert-Butyl 3-(7-(4-amino-2-fluorophenoxy)thieno[3J2-b]pyridine-2-carboxamido)
pyrrolidine-1-carboxylate (290)
[0563] A mixture of 289 (90 mg, 0.18 mmol) and Pd(OH)2 in MeOH (2 mL) was
hydrogenated at 1 atm for lh. The catalyst was filtered off and the filtrate was concentrated
to afford the title compound 290 (60mg, 70% yield) as a yellowish solid. MS (m/z): 473.2
(M+H) (found).
Step 3.7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-A;-(pyrrolidin-3-
yl)thieno[3,2-&]pyridine-2-carboxarnide(291)
[0564] A solution of 290 (40 nig, 0.084 mmol) and 2-phenylacetyl isothiocyanate (22
mg, 0.126 mmol) in THF (2 mL) was stirred for 30min. The solventwas removed under
reduced pressure and the residue was purified by flash column chromatography (eluent
EtOAc), to afford a solid material, which was dissolved in a mixture of TFA/DCM (0.5
mL/0.5 mL) and stirred at room temperature for 2h. Solvents were removed under reduced
pressure and the residue was purified by preparative HPLC (Aqusil Cl 8, gradient eluent,
60-95% MeOH in water, 45 min) to afford the title compound 291 (8mg, 80% yield) as an
off-white solid. '"HNMR (d-DMSO) § (ppm): 9.27(d, 1H), 8.57(d, 1H), 8.37(s, 1H), S.30(s,
1H), 8.01(d, 1H), 7.53(m, 2H)5 7.33-7.3 l(m, 4H), 7.29-7.25(m, 1H), 6.74(d, 1H), 4.46(m,
1H), 3.82(s, 2H), 3.11-3.03(111,2H), 2.18-2.09(m, IS), I.93-U9(m, 2H). MS (m/z):
550.2(M+H) (found).
Example 229
iV-(2-Aminoethyl)-7-(2-Duoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-
6]pyridine-2-carboxamide (294)
Step 1. tert-Butyl 2-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-i]pyridme-2-carboxamido)
ethylcarbamate (292)
[0565] A solution of 40 (shown in the scheme 7,100 mg, 0.26 mmol), N-Boc-N-
methylethylenediamine hydrochloride (50 mg, 0.26 mmol) and Et3N (36 uL, 0.52 mmol) in
DCM (2 mL) was stirred for 4h at room temperature and diluted with EtOAc (lOmL). The
combined mixture was washed with brine and phases were separated. The aqueous phase
was extracted with EtOAc, and the extract was combined with the organic phase, dried over
anhydrous Na2SO4 and concentrated to afford title compound 292 (119 mg, 96%, crude) as
yellowish solid. MS (m/z): 477.1 (M+H) (found).
Step 2. tert-Butyl 2~(7-(4-amino-2-fluorophenoxy)thieno[3,2-bJpyridine-2-carboxamido)
ethylcarbamate (293)
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WO 2006/010264 PCT/CA2005/001177
£0566] To a solution of 292 (SOmg, 0.17mmol) in MeOH/THF (1.7 mL/1.7 inL) at 0°C, was added NiCl2 x 6H2O (85 mg, 0.35 mniol), followed by addition of NaBHU (26 mg, 0.68 ramol), portion wise. The reaction mixture was stirred for 15min, treated with 2N aqueous HC1 (2 mL). filtered; the filtrate was neutralized with aqueous NH4OH to pH 7 and partitioned between EtOAc and water. Organic phase was collected, dried over anhydrous Na2SC>4 and concentrated. The residue (75 mg, quantitative yield, crude) was used directly in next step without further purification. MS (m/z): 447.1(M+H) (found). Step 3. A?-(2-Aminoethyl)-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-£]pyridine-2-carboxamide (294)
[0567] Following the procedure described above for the synthesis of compound 291 (example 228), title compound was obtained in 3% yield as an off-white solid. 'H NMR (d-DMSO) § (ppm): 9.00(d, 1H), 8.50(m, 1H), 8.30(m, 1H)5 8.20(d, 1H), 7.92(d, 1H), 7.44(m, 2H), 7.26-7.25(m, 3H), 721-7.18(rn, 1H), 6.66(d, 1H), 3.75(s, 2H)3 3.30-3.20(m, 6H). MS (m/z): 524.3(M+H).
213
Scheme 68


WO 2006/010264 PCT/CA2OO5/0O1177
Example 230
Ar-(3-Fluoro-4-(2-(3-hydroxyazetidine-l-carbonyl)thieno[3,2-Z)]pyridin-7-
yloxy)phcnylcarbaraothioyl)-2-{2-methoxyphenyl)acetamide (300)
Step 1. tert-Butyl 3-(tert-buty]dimethylsily]oxy)azetidine-l-carboxylate (295)
[0568] A solution of tert-butyl 3-hydroxyazetidine-l-carboxylate (1 g, 5.77 mmol),
TBSC1 (6,35 mtnol, 956 mg) in DCM (11.5 mL), was stirred for 72 hrs at room
temperature. The solvent was removed under reduced pressure, EtOAc was added to the
residue, and the solid material was removed by filtration. The filtrate was concentrated
under reduced pressure and the residue was purified by flash chromatography with gradient
elution wit EtOAc/hexane (9:1) to EtOAc/hexane (1:1), to afford title compound 295 (1.25
g, 75% yield) as a syrup. MS (m/z): 310.1 (M+23).
Step 2: 3-(to-/-ButyIdimethylsiIyloxy)azetidine (296)
[0569] A mixture of 295 (200 mg, 0.696 mol), DCM (1 mL) and TFA (lmL) was stirred
for 1 h at room temperature, concentrated under reduced pressure; NaOH (1M, 15 mL) was
added to the residue and the suspension was extracted with DCM, the extract was dried
(anhydrous Na2SO4) and concentrated, to afford title compound 296 (90.4 mg, 69% yield)
as a syrup. MS (m/z): 188.1 (M+l).
Step 3: (i-(terr-Butyldimethyisiiyloxy)azetidin-1 -yi)(7-chlorothieno[3,2-b]pyridin-2-
yl)methanone (297)
[0570] Starting from the acyl chloride 4 (scheme 1), replacing dimethyl amine with the
amine 296 and following the procedure described for the synthesis of amide 5 (scheme 1 as
well), title compound 297 was obtained in 64% yield as a syrup. MS (m/z): 383.0 (M+l).
Step 4: (7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)(3 -hydroxyazetidin-1 -
yl)methanone (298)
[0571] Starting from the amide 297 and following the procedure described above for the
synthesis of compound 230 (scheme 50, example 203), title compound 298 was obtained in
39% yield as a syrup. MS (m/z): 389.05 (M+l).
Step 5: (7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)(3-hydroxyazetidin-l -
yl)methanone (299)
[0572] Starting from the nitro compound 298 and following the procedure described
above for the synthesis of the amine 231 (scheme 50, example 203), title compound 299
was obtained in 83% yield. MS (m/z): 359.07 (M+l).
Step6:Ar-(3-Fluoro-4-(2-(3-hydroxj/azetidine-l-carbonyl)thieno[3,2-b]pyridin-7-
yioxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(300)
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10573] Starting from the amine 299, following the procedure described above for the synthesis of compound 232a (scheme 50, example 203) but replacing 2-phenylacetyl isothiocyanate with (2-methoxy-phenyl)-acetyl isothiocyanate andtitle compound 300 was obtained in 39% yield as a creamy solid. 'HNMR: (CD3OD) d (ppm): 12.58 (s, 1H), 11.77 (s, 1H), 8.62 (m, 1H), 8.09 (d, J=12.3Hz, 1H), 7.95 (s, 1H), 7.56 (m, 2H), 7.26 (m, 2H), 7.00 (m, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 6.50 (d, J=5.9Hz, 1H), 4.81 (m, 1H), 4.59 (m, 1H), 4.35 (m, 2H), 3.87-3.78 (m, 6H). MS (m/z): 567.0 (M+l).
Scheme 69

isxampie u i
iV-(4-(2-(l-methyl-liir-imidazol-2-yl)thieno[3,2-&]pyridin-7-ylamino)phenyl
carbamothioyi)-2-phenylacetamide(302)
Step 1. Af;-(2-(l-Methyl- l#-imidazol-2-yl)thieno[3>%yridin-7-yl)benzene- 1,4-diamine
(301)
[0574] A mixture of 214 (500mg, 2.0mmol, scheme 46) and benzene- 1,4-diamine
(500mg, 4.62 mmol) in wo-PrOH (15 mL) was refluxed overnight, cooled to room
temperature and filtered. The solid was collected, washed with wo-PrOH/HaO mixture, to
afford the title compound 301 (300mg, 44% yield) as a yellowish solid. MS (m/z):
322.1(M+H) (found).
Step2.Ar-(4-(2-(l-Methyl-l/f-imidazol-2-yl)thieno[352-d]pyridin-7-ylamino)phenyl
carbamothioyl)-2-phenylacetamide(302)
[0575] Starting from the compound 301, following the procedures described above for
the synthesis of compound 269b (scheme 6i, example 222) but replacing 2-(2,6-
dichlorophenyl)acetyl isothiocyanate with 2-phenylacethyl isothiocyanate, title compound
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WO 2006/010264 PCT/CA2O05/O01177
302 was obtained in 12% yield, as a yellow solid. !H NMR (d-DMSO) 5 (ppm): 12.47(s, IH), I1.76(s, 1H), 10,83(s, 1H), 8.41(d, 1H, J=6.9Hz), 7.S4(s, 1H), 7.80(s, 1H), 7.78(s, IH), 7.55(s, IH), 7.46(s, 1H), 7.43(s, IH), 7.32(m, 4H), 7.28-7.20(m; IH), 7.20(s> IH), 6.94(d, IH, J=6.8Hz), 3.98(s, 3H), 3.8 l(s, 2H). MS (m/z): 499.1(M+H) (found).

Example 232
Ar-(3-Fluoro-4-(2-(l-methyl-l//-imidazol-2-yl)thieno[3,2-b]pyridin-7-yIoxy) phenyl carbamothioyl)-2-(2-fluorophenyl)acetamidedi-hydrochloride(303a) [0576J A mixture of aniline 219 (100 mg, 0.29 mrnol, scheme 47) and 2-(2-fluorophenyl)acetyl isothiocyanate (115 mg, 0.58 mmol) in THF (3 mL) was stirred for I hour, loaded directly onto a column containing silica gel and eluted sequentially with EtOAc and EtOAc/MeOH (100:1), to produce a white solid. This material was suspended in MeOH (5 mL) and HC1 (1.0M in ether, 1 mL) was added to form a clear solution that was evaporated to dryness. The residue was washed with ether, suspended in H2O, and lyophilized to afford the title compound (80mg, 45% yield) as a yellowish solid. 'H-NMR (DMSO-d6) 6 (ppm): 12.42(s, IH), 11.88(s, IH), 8.65(d. IH, J= 5.5Hz), 8.20(s, IH), 8,05(d, 1H, J=1.7Hz), 7.74(s, 1H), 7.58~7.55(m, 3H) 7.39-7.32(m, 2H), 7.21-7.16(m, 2H), 6.82(d, IH, J=5.5Hz), 4.02(s, 3H), 3.93(ss 2H), MS (m/z): 536.2(M+H) (found). Example 233
//-(S-Fluoro^KS^l-methyl-lif-imidazol^-yOthienotB^-^pyridin-?-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamidedi-hydrochloride(303b) [0577] Starting from the compound 219, following the procedure described above for the synthesis of 303a (example 232) but replacing 2-(2-fluorophenyl)acetyl isothiocyanate with 2-(2-methoxyphenyl)aceryl isothiocyanate, title compound 303 b was obtained in 44% as an off-white solid. ]H NMR (d-DMSO) 5 (ppm): 12.55 (s, IH), 11.73(s, IH), 8.62(m, IH), 8.09(m, IH), 7.65(s, IH), 7.57(m; IH), 7.43(s, IH), 7.27-7.20(m, IH), 6.98(d, IH,
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J=8.2Hz), 6.90(dt, 1H, Jj-l.OHz, J2=7.4Hz), 6.79(m, 1H), 4.02(s, 3H), 3.81(s, 2H), 3.77(Sj 3H). MS (m/z): 548.3(M+H) (found). Example 234
2
[0578] Starting from the compound 214 (scheme 46) and following the procedures described above for the synthesis of compound 228 (example 202) and 303a (example 232), title compound 234 was obtained in 31% yield as an off-white solid. !H NMR (d-DMSO) 5 (ppm): 12.34(s, IE), 11.81(s, 1H), 8.68(m, 1H,), 8.24(s, 1H), 7.79(m, 3H)5 7.62(s, 1H), 7.40-7.13(m, 6H), 6.86(d, 1H), 4.02(s, 3H), 3.93(s, 2H). MS (m/z): 518.1(M+H) (found).
Examples 235
iV-(3-Fluoro-4-(2-(pyrrolidine-l-carbonyl)thieno[3,2-fe]pyridin-7-yloxy)phenyl.carbamoyl)-
2-phenylacetamide hydrochloride (305a)
[0579] A mixture of 194 (93 mg, 0.26 mmol, scheme 40) and 2-phenylacetyl isocyanate
(83 mg, 0.62 mmoL) fj. Hill, et al. JACS, 62; 1940:15951 was stirred for Ih at room
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WO 2006/010264 PCT/CA2005/001177
temperature, loaded directly onto a flash chromatography column and eluted with EtOAc. A white solid was obtained, which was suspended in MeOH and treated with HC1 (1 mL, 1.0M in Et20) to form a clear solution. The solution was concentrated to form a precipitate which was collected by filtration, to afford the title compound 305a (48 mg, 33% yield) as a white solid. 'H NMR (d-DMSO) 5 (ppm): 11.05(s, 1H), 10.62(s, 1H), 8.57(d, 1H), 8.02(s, 1H), 7.8l(d, 1H)S 7.48-7.43(m, 2H), 7.33-7.25(m, 5H), 6.74(d, 1H), 3.85(t, 2H), 3.78(s, 2H), 3.51(t, 2H), 1.9S-1.86(m, 2H). MS (m/z): 519.2(M+H) (found). Example 236
A-(3-Fluoro-4-(2-(l-methyl-l//-imidazol-2-yl)thieno[3,2-Z>]pyridin-7-yloxy)phenyl carbamoyl)-2-pheny lacetamidedihydfochlofide (3 05 b)
[0580] Starting from the compound 219 (scheme 47) and following the procedure described above for the synthesis of compound 305a, title compound 305b was obtained in 15% yield as a white solid. JH NMR (d-DMSO) 5 (ppm): 11.07(s, 1H), 10.66(s, 1H), S.67(d, 1H, J=5.5Hz), S.27(s, 1H), 7.85-7.80(m, 2H), 7.65(s51H), 7.5 l(t, 1H, J=8.6Hz), 7.46(d, 1H), 7.34-7.28(m, 5H), 6.85(ds 1H, J=5.3Hz), 4.03(s, 3H), 3.74(s, 2H). MS (m/z): 502.2(M+H) (found). Example 237
iV-(3-Fluoro-4-(2-(l-methyi-li?-imidazol-4-yl)thieno[3,2-6]pyridin-7-yloxy)phenyl carbamoyl)-2-phenylacetamide dihydrocbioride (305c)
[0581] Starting from the compound 177 (scheme 35) and following the procedure described above for the synthesis of compound 305a, title compound 305c was obtained in 54% yield as a white solid. 'H NMR (d-DMSO) 5 (ppm): 11.08(s, 1H), 10.67(s, 1H), 8.66 (d, 1H, J-6.2Hz), 8.26(s, 1H), 8.21(s, 1H), 7.93(s, 1H), 7.85(dd, 1H, J,=12.9Hz, J2=2.5Hz), 7.53(t, 1H, J=8.8Hz), 7.65(s, 1H), 7.48-7.45(m, 1H)5 7.35-7.30(m, 4H), 7.28-7.24(m, 1H), 6.94(d31H, J=6.1Hz), 3.79(s, 3H), 3.75(s, 2H). MS (m/z): 502.1(M+H) (found).
218
Scheme 72


WO 2006/010264 PCT/CA2005/001177
Example 238
iV-(3-Fluoro-4-(2-(l-methyI-IH-imidazoI-5-yl)thieno[3,2-Z>]pyridin-7-yloxy)phenyl
carbamoyl)-2-phenylacetamide(307)
3-Fluoro-4-[2-(l-methyl-li?-imidazol-5-y])-thieno[3,2-b]pyridin-7-y]oxy]-ph6nyIamine
(306)
[0582] Starting from the compound 98 (scheme 19) and following the procedures
described above for the synthesis of compound 12 (scheme 2, steps 1-4) but replacing 2-
bromothiazole at the Stille coupling stage with 5-bromo-1 -methyl- li/-imidazole (Table 9),
title compound 306 was obtained. MS (m/z): 341.0M+H) (found).
AK3-PIuoro-4 carbamoyl)-2-phenylacetamide (307)
[0583] A mixture of 306 (99mg, 0.29 mmol) and 2-phenylacefyl isocyanate (97 mg,
0.60 mmoL) fA. J. Hill, et al. JACS. 62; 1940; 1595] was stirred for Ih at room temperature,
loaded directly onto a flash chromatography column and gradient eluted with EtOAc, to
MeOH/EtOAc (10:90) to afford the title compound 307 (42% yield) as a white solid. !H
NMR (d-DMSO) 5 (ppm): 11.1 l(s, 1H), 10.68(s, IH, J=5.5Hz), 8.49(d), 7.85(s, IH),
7.82(dd, IH, J>I2.9Hz, J2=2.4Hz), 7.76(s, iH), 7.43(m, 2H), 7.40(s, IH), 7.32(m, 4H),
7.28(m5 IK), 6.61(d, IH, J=5.5Hz), 3.89(s, 3H), 3.74(s, 2H). MS (m/z):502.4 (M+H)
(found).

Example 239
JV-(4-(2-(l-Ethyl-li?-imidazol-4-yl)thieno[3,2-^]pyridin-7-yloxy)-3-fluorophenyI carbamoyl)-2-phenylacetamide(309a)
4-p-(l-Ethyl-li7-imidazoi-4-yl)-thieno[3,2-b3pyridin-7-yloxy]-3-fluoro-phenylamine(308) [0584] Starting from the compound 9$ (scheme 19) and following the procedures described above for the synthesis of compound 12 (scheme 2, steps 1-4) but replacing 2-
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bromothiazole at the Stille coupling stage with 4-bromo-l -ethyl-lF-imidazole (Table 9), title compound 308 was obtained. MS (m/z): 355.1 (M+H) (found). A^(4-(2-(l-Ethyl-l/ir-iniidazol-4-yl)thieno[3,2-&]pyridin-7-yloxy)-3-fluorophenyl carbamoyl)-2-phenylacetamide(309a)
[0585] A mixture of 308 (300mg, 0.85 mmol) and 2-phenylacetyI isocyanate (164 mg, 1.02 mjnoL) [Arthur J. Hilt, et al. JACS, 62; 1940; 1595] was stirred for lh at room temperature, loaded directly onto a flash chromatography column and gradient eiuted with EtOAc, to MeOH/EtOAc (20:80) to afford the title compound 309a (45% yield) as a white solid. lH NMR (d-DMSO) 6 (ppm): 11.07(s, 1H), 10.63(s, 1H), 8.41 (d, 1H, J=5.5Hz), 7.94(d, 1H, J=1.4Hz), TM{dd, 1H, J1=D.lHzrJ2=Z4Hz),J7;77(driHrJ=i.lHz), 7.65(s, 1H), 7.46-7.39(m, 2H), 7.35-7.19(m, 4H), 7.28-7.24(m, 1H), 6.54(dd, 1H, Ji=5.5Hz, J2=0.SHz), 4.03(q, 2H), 3.73(s, 2H), 1.38(t, 3H). MS (m/z): 516.1(M+H) (found). Example 240
Ar-(4-(2-(l-Ethyl-ltf-imidazol-4-yl)thieno[3J2-b]pyridin-7-yloxy)-3-fluorophenyl carbamoyl)-2-(2-fluorophenyl)acetamide (309b)
[0586] A mixture of 308 (320 mg, 0.90 mmol) and (2~fluoro-phenyl)-acetyl isocyanate (600 mg, 3.35 mmoL) fA. J. Hill, et ai. JACS, 62; 1940; 1595] was stirred for lh at room temperature, loaded directly onto a flash chromatography column and gradient eiuted with EtOAc, to MeOH/EtOAc( 20:80), to afford the title compound 309b in 42% yield as a white solid. 'HNMR(d-DMSO) 5 (ppm): 11.10(s, 1H), 10.58(s, 1H), 8.42(d, 1H, J«5.5Hz), 7.94(d, 1H, J=l.lHz), 7.82-7.77(m, 2H), 7.65(s» 1H), 7.45-7.30(m, 4H), 7.19-7.16(m, 2H), 6.54(dd, 1H, Ji^O.THz, J2=5.4Hz), 4.04(q, 2H), 3.83(s, 2H), 1.38(t 3H). MS (m/z): 534.1 (M+H) (found). Example 241
7V-(4-(2-(l-Ethyl-li/-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl carbamoyl)-2-(2-methoxyphenyI)acetamide (309c)
[0587] A mixture of 308 (370 mg, 1.05 mmol) and (2-methoxy-phenyi)-acetyl isocyanate (240 mg, 1.25 mmoL) [A, J. Hill, et al. JACS, 62; 1940; 15951 was stirred for lh at room temperature, loaded directly onto a flash chromatography column and eiuted with EtOAc, to afford the title compound 309c in 42% yield as a white solid. !H NMR (d-DMSO) 5 (ppm): 10.98(s, 1H), 10.69(s, 1H), 8.41(d, 1H, J=5.3Hz), 7.94(d, 1H, J=4.2Hz), 7.81(dd, 1H, Ji=13.1Hz, J2=2.4Hz), 7.77(d, 1H, J=0.9Hz), 7.65(s, 1H), 7.45-7.40(m, 2H), 7.26-7.19(m, 2H), 6.97(d, 1H, J=8.0Hz), 6.89(dt, 1H, Ji=0.8Hz, J2=8.2Hz), 6.54(d, 1H,
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J=5.5Hz), 4.04(q, 2H), 3.75(s, 3H), 3.70(s, 2H), 1.38(t, 3H). MS (m/z): 546.1(M+H) (found).
Example
1-{4-[2-(l-Ethyl-lH-imidazol-4-yl)-thieno[3,2-b]pyrilin-7-yloxy]-3-fluoro-phenyll}-3-[2-(2-fluoro-phenyI)-acetyI]-thiourea (310a)
[0588] To a suspension of the 308 (385 mg, 0.99 mmol) in THF (10 mL) was added 2-(2-fluorophenyl)acetyl isothiocyanate (263 mg, 1.49 mmol) and the reaction mixture was stirred for l hr, transferred onto a flash chromatography column and eluted with EtOAc/MeOH 19:1, to afford title compound 310a (366.9 mg, 67% yield) as a creamy solid. 1HNMR: (DMSO-d6) d (ppm): 12.42 (s, 1H), 11.87 (s, IH), 8.44 (d, J=5.5Hz, 1H), 8.02 (d, J=l 1.5Hz, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.52 (M, 2H), 7.42 (m, 2H), 7.25 (m, 2H), 7.06 (d, J=5.5Hz, 1H), 4.04 (q, J=7.3Hz, 2H), 3.92 (s, 2H), 7.4 (t, J=7.3Hz, 3H). MS (M/z): 550.0 (M+l). Example 243
l-{4-[2-(l-Ethyl-lH-imidazol-4-yl)-thieno[3,2-bjpyridin-7-yloxy>3-fluoro-phenyi}-3-[2-(2-methoxy-phenyl)-acetyl]-thiourea (310b)
[0589] Starting from the compound 308, following the procedure described above for the synthesis of 310a but replacing 2-(2-fluorophenyl)acetyl isothiocyanate with (2-methoxy-phenyl)-acetyl isothiocyanate, title compound 310b was obtained in 82% yield. 1H NMR (DMSO-d6) d (ppm): 12,57 (s, 1H), 11.76 (s, 1H), 8.45 (d, J=5.5Hz, 1H), 8.07 (m, IH), 7.96 (d, J=lHz, IH), 7.79 (d, J=lHz, 1H), 7.69 (s, 1H), 7.6 (m, 2H), 7.26 (m, 2H), 7.0
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(d, J=7.4Hz, 1H), 6.92 (m, 1H), 6.59 (d, J=5.5Hz, 1H), 4.06 (q, J=7.5Hz, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 1.4 (t, J=7.4Hz, 3H). MS (m/z): 562.0 (M+l). Example 244
N-Ethyl-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-methylthieno[3,2-b]pyridine-2-carboxaraide (311)
[0590] Title compound 311 was obtained by following the procedures described above for the synthesis of compound 8a {scheme 1, example 1) but replacing dimethylamine in the step 4 with N-methylethanamine. 1H NMR (400 MHz, DMSO-d6) (ppm) 12.49 (s, 1H), 11.82 (s, IE), 8.64 (d, J= 5.48 Hz, 1H), 8.03 (d, J= 12.7 Hz, 1H) 7.85 (m, 1H), 7.54 (m, 2H), 7.32 (m, 4H), 7.24 (m, 1H), 6.82 (d, J= 5.3 Hz, 1H), 3.83 (s, 2H), 3.53 (m, 2H), 3.38 (m5 2H)5 3.05 (s, 1H), 1.10 m: 3H). MS (calcd.) 522.1, found 523.2 (M+H). Example 245
N-(4-(2-(4-(Dimethylamino)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenyiacetamide (312)
[0591] Title compound 312 was obtained by following the procedures described above for the synthesis of compound 50 (scheme 10, example 55) but replacing 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-l,3,2-dioxaborolane in the first step with 4-(dimethyiammo)phenylboromc acid. 1H NMR (DMSO): 12.48 (1H, s), 11,83 (1H, s), 8.44 (1H, d, J=5.48 Hz), 7.99 (1H, d, J=12.91 Hz), 7.77 (1H, s), 7.68 (2H, d, J-8.41 Hz), 7.51 (2H, br), 7.33-7.28 (5H, m), 6.77 (2H, d, J=8.22 Hz), 6.56 (1H, d, J=4.89 Hz), 3.81 (2H, s), 2.96 (6H, s). MS: calcd: 556.7, found: 556.9 (M+H). Example 246
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JV-(3-FJuoro-4-(2-{3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (313)
[0592] Title compound 313 was obtained by following the procedures described above for the synthesis of compound 75 (scheme 15)but starting from 4-(3-bromobenzyl)morpholine instead of tert-butyl 3-bromobenzyl(2-methoxyethyl)carbamate (65). 1H NMR (DMSO): 12.49 (1H, s), 11.84 (1H, s), 8.52 (1H, d, J=5.48 Hz), 8.05 (1H, s), 8.01 (1H, 4 J=12.72 Hz), 7.79-7.78 (2H, m), 7.53 (2H, br), 7.46 (1H, t, 3=7.63 Hz), 7.39 (1H, d, J-7.63 Hz), 7.34-7.26 (5H, m), 6.66 (1H, d, J-5.28 Hz), 3.82 (2H, s), 3.57 (4H, br), 3.32 (2H, s), 2.38 (4H, br). MS: calcd; 612.7, found: 613.3 (M+l). Example 247
N-(3-Fluoro-4-(thieno[3>2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetaraide (314)
[0593] Title compound 314 was obtained by following the procedures described above for the synthesis ofcompound 173 (scheme 34, example 135) but replacing 3-chloro-4-nitrophenol in the step 1 with 2-fiuoro-4-nitrophenol. 'HNMR (DMSO-d6) d(ppm): 12.42 (bs, 1H), 11.79 (bs, 1H), 8.71 (s, 1H), 8.51 (d, J - 5.2 Hz, 1H), 7.91 (dd, J - 2.4 and 12.0 Hz, 1H), 7.70 (d, J - 5.2 Hz, 1H), 7.53 (dd, J = 8.4 Hz, 1H), 7.47 (dd, J = 2.4 and 8.4 Hz, 1H), 7.38-7.30 (m, 4H), 7.30-7.27 (m, 1H), 3.82 (s, 2H). LRMS: 438.1(cafc) 439.1 (found). Example 248
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jV-(3-FIuoro-4-(thieno[2.3-d]pyrimiciin-4-yioxy)phenylcarbamothioyi)-2-phenyiacetamide (315)
[0594] Title compound 315 was obtained starting from the compound 205 (scheme 44) and following the procedures described above for the synthesis of compound 314. 'HNMR (DMSO-d6) d(ppm): 12.42 (s, 1H), 11.80 (s, 1H), 8.63 (s, 1H), 8.01 (d, J = 5.6 Hz, 1H), 7.91 (dd, J - 2.0 and 12.0 Hz, 1H), 7.70 (d, J = 5.6 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.46 (dd, J = 2.4 and 8.4 Hz, 1H), 7.36-7.30 (m, 4H), 7.30-7.24 (m, 1H), 3.82 (s, 2H). LRMS: 438.4 (calc) 439.3 (found). Example 249
N-(4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yIoxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide (316)
[0595] Title compound 316 was obtained by following the procedures described above for the synthesis of compound 31a (scheme 5, example 28) but skipping N-methylation step. 1HNMR (DMSO-d6) d(ppm): 12.41(s, 1H), 8.32 (s, 1H), 7.91 (d, J = 10 Hz, 1H), 7.48 (s, 1H), 7.56-7.42 (m, 2H), 7.39-7.32 (m , 4H), 7.30-7.22 (m, 1H), 6.66 (s, 1H)S 3.83 (s, 2H). LRMS: 421.1 (calc) 422.1 (found).
ASSAY EXAMPLES
Assay Example 1
Inhibition of c-met and VEGF Activity [0596] The following protocols were used to assay the compounds of the invention.
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In Vitro Receptor Tyrosine Kinase Assays (c-Met/HGF receptor and VEGF receptor KDR)
[0597] These tests measure the ability of compounds to inhibit the enzymatic activity of recombinant human c-Met/HGF receptor and VEGF receptor enzymatic activity. [0598] A 1.3-kb cDNA corresponding to the intracellular domain of c-Met or c-Met IC (Genbank accession number NP000236-1 amino acid 1078 to 1337) was cloned into the BamHI/XhoI sites of the pBlueBacHis2A vector (Invitrogen) for the production of a histidine-tagged version of that enzyme. This constuct was used to generate recombinant baculovirus using the Bac-N-Blue™ system according to the manucfacturer's instructions "(Invitrogen)
[0599] The c-Met IC protein was expressed in Hi-5 cells (Trichoplnsia Ni) upon infection with recombinant baculovirus construct. Briefly, Hi-5 cells grown in suspension and maintained m serum-free medium (SfflOO II supplemented with gentamycin) at a cell density of about 2 X 106 cells/ml were infected with the abovementioned viruses at a multiplicity of infection (MOI) of 0.2 during 72 hours at 27°C with agitation at 120 rpm on a rotary shaker. Infected cells were harvested by centrifugation at 398g for 15 min. Cell pellets were frozen at -S0°C until purification was performed.
[0600] All steps described in cell extraction and purification were performed at 4°C. Frozen Hi-5 cell pellets infected with the C-Met IC recombinant baculovirus were thawed and gently resuspended in Buffer A (20mM Tris pH 8.0,10% giycerol, lug/ml pepstatin, 2ug/ml Aprotinin and leupeptin, 50µg/ml PMSF, 50µg/mi TLCK and 10µM E64, 0.5mM DTT and lmM Levamisole) using 3 ml of buffer per gram of cells. The suspension was Dounce homogenized after which it was centrifuged at 22500g, 30 min., 4°C. The supernatant (cell extract) was used as starting material for purification of c-Met IC. [0601] The supernatant was loaded onto a QsepharoseFF column (Amersham Biosciences) equilibrated with Buffer B (20mM Tris pH 8.0,10% glycerol) supplemented with 0.05M NaCL Following a ten column volume (CV) wash with equilibration buffer, bound proteins were eluted with a 5 CV salt linear gradient spanning from 0.05 to 1M NaCl in Buffer B. Typically, the conductivity of selected fractions ranked between 6.5 and 37 mS/cm. This Qsepharose eluate had an estimated NaCl concentration of 0.33M and was supplemented with a 5M NaCl solution in order to increase NaCl concentration at 0.5M and also with a 5M Imidazole (pH 8.0) solution to achieve a final imidazole concentration of 15mM. This material was loaded onto a HisTrap affinity column (GE Healthcare) equilibrated with Buffer C (50mM NaPO4 pH 8.0, 0.5M NaCl, 10% glycerol) supplemented
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with 15mM imidazole. After a 10 CV wash with equilibration buffer and an 8 CV wash with buffer C + 40mM imidazole, bound proteins were eluted with an 8 CV linear gradient (15 to 500mM) of imidazole in buffer C. C-Met IC enriched fractions from this chromatography step were pooled based on SDS-PAGE analysis. This pool of enzyme underwent buffer exchange using PD-10 column (GE Healthcare) against buffer D (25mM HEPES pH 7.5, 0.1M NaCL 10% glycerol and 2mM D-mercaptoethanol) Final C-Met IC protein preparations concentrations were about 0.5 mg/ml with purity approximating 80%. Purified c-Met IC protein stocks were supplemented with BSA at 1 mg/ml, aliquoted and frozen at -80°C prior to use in enzymatic assay.
[0602] In the case of VEGF receptor KDR aT.6-leb cDNA corresponding to the catalytic domain of VEGFR2 or KDR (Genbank accession number AF035121 amino acid 806 to 1356) was cloned into the Pst 1 site of the pDEST20 Gateway vector (Invitrogen) for the production of a GST-tagged version of that enzyme. This constuct was used to generate recombinant baculovirus using the Bac-to-Bac™ system according to the manucfacturer's instructions (Invitrogen)
[0603] The GST-VEGFR2806-1356 protein was expressed in Sf9 cells (Spodaptera frugiperda) upon infection with recombinant baculovirus construct. Briefly, Sf5 ceiis grown in suspension and maintained in serum-free medium (Sf900 II supplemented with gentamycin) at a cell density of about 2 X 106 cells/ml were infected with the abovementioned viruses at a multiplicity of infection (MOI) of 0.1 during 72 hours at 27°C with agitation at 120 rpm on a rotary shaker. Infected cells were harvested by centrifitgation at 39Sg for 15 min. Cell pellets were frozen at -80°C until purification was performed. [0604] All steps described in cell extraction and purification were performed at 4°C. Frozen Sf9 cell pellets infected with the GST-VEGFR2806-1356 recombinant baculovirus were thawed and gently resuspended in Buffer A (PBS pH 7.3 supplemented with lµg/ml pepstatin, 2µg/ml Aprotinin and Ieupeptin, 50µg/ml PMSF, 50µg/ml TLCK and 10µM E64 and 0.5mM DTT) using 3 ml of buffer per gram of cells. Suspension was Dounce homogenized and 1% Triton X-100 was added to the homogenate after which it was centrifuged at 22500g, 30 min., 4°C. The supernatant (cell extract) was used as starting material for purification of GST-VEGFR2806-1356-
[0605] The supernatant was loaded onto a GST-agarose column (Sigma) equilibrated with PBS pH 7.3. Following a four column volume (CV) wash with PBS pH 7.3 + 1% Triton X-100 and 4 CV wash with buffer B (50mM Tris pH 8.0,20% glycerol and 100mM NaCl), bound proteins were step eluted with 5 CV of buffer B supplemented with 5mM
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DTT and 15mM glutathion.GST-VEGFR2806-1356 enriched fractions from this chromatography step were pooled based on U.V. trace i.e. fractions with high O.D.280- Final GST-VEGFR2806-1356 protein preparations concentrations were about 9.7 mg/ml with purity-approximating 70%. Purified GST-VEGFR2806-1356 protein stocks were aliquoted and frozen at -80°C prior to use in enzymatic assay.
[0606] Inhibition of c-Met/HGF receptor and VEGFR/KDR. was measured in a DELF1A™ assay (Perkin Elmer). The substrate poly(Glu4,Tyr) was immobilized onto black high-binding polystyrene 96-well plates. The coated plates were washed and stored at 4 °C. During the assay, enzymes were pre-incubated with inhibitor and Mg-ATP on ice in polypropylene 96-well platesTor 4 minutes, and then transferred to the coated plates. The subsequent kinase reaction took place at 30 °C for 10-30 minutes. ATP concentrations in the assay were 10 uM for C-Met (5X the Km) and 0.6 uM for VEGFR/KDR (2X the Km). Enzyme concentration was 25 nM (C-Met) or 5 nM (VEGFR/KDR). After incubation, the kinase reactions were quenched with EDTA and the platen were washed. Phosphorylated product was detected by incubation with Europium-iabeled anti-phosphotyrosine MoAb. After washing the plates, bound MoAb was detected by time-resolved fluorescence in a Gemini SpectraMax reader (Molecular Devices). Compounds were evaluated over a range of concentrations and ICso's (concentration of compounds giving 50% inhibition of enzymacic activity) were determined. C-Met phosphoryiatioR eell-basetl assay
[0607] This test measures the ability of compounds to inhibit HGF stimulated auto-phosphorylation of the c-Met/HGF receptor itself in a whole cell system. [0608] MNNGHOS cell line expressing TPR-MET fusion protein were purchased from ATCC. The TPR-MET is the product of a chromosomal translocation placing the TPR locus on chromosome 1 upstream of the MET gene on chromosome 7 encoding for it's cyioplasmic region catalytic domain. Dimerization of the Mr 65,000 TPR-Met oncoprotein through a leucine zipper motif encoded by the TPR portion leads to constitutive activation of the met kinase. Constitutive autophosphorylation occurs on residues Tyr361/365/366 of TPR-Met. These residues are homologous to Tyrl230/1234/]235 of MET which become phosphorylated upon dimerization of the receptor upon HGF binding. [0609] Inhibitor of c-Met formulated as 30 mM stocks in DMSO. For MNNGHOS treatments, cells, compounds were added to tissue culture media at indicated doses for 3 hours prior to cell lysis. Cells were lysed in ice-cold lysis buffer containing 50 mM HEPES (pH 7.5), 150 mM NaCl, 1.5 mM MgC12,10 % glycerol, 1 %Triton X-100, 1 mM 4-(2-
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Aminoethyl)benzenesulfonyl fluoride hydrochloride, 200 µM sodium orthovanadate, 1 mM sodium fluoride, 10 µg/ml of leupeptin, 10 µg/ml of aprotinin/ml, 1 µg/ml of pepstatin and 50ug/ml Na-p-Tosyl-L-lysine chloromethyl ketone hydrochloride . [0610] Lysate were separated on 5-20% PAGE-SDS and immunoblots were performed using Immobilon P polyvinylidene difluoride membranes (Amersham) according to the manufacturer's instructions for handling. The blots were washed in Tris-buffered saline with 0.1% Tween 20 detergent (TBST). Tyr361/365/366 of TPR-Met were detected with polyclonal rabbit antibodies against tyrosine phosphorylated Met (Biosource International) and secondary antibodies anti-rabbit -horseradish peroxidase (Sigma) by chemiluminescenee assays (Amersham, ECL) were performed according to theT manufacturer's instructions and followed by film exposure. Signal was quantitated by densitometry on Alpha-Imager. IC50 values were defined as the dose required to obtain 50% inhibition of the maximal HGF stimulated phosphorylated c-Met levels.
In Vivo Solid Tamor Disease Model
[0611] This test measures the capacity of compounds to inhibit solid tumor growth. [06121 Tumor xenografts were established in the flank of female athymic CD1 mice (Charles River Inc.). by subcutaneous injection of 1X106U87, A431 or SKLMS cells/mouse. Once established, tumors were then serially passaged s.c. in nude mice hosts. Tumor fragments from these host animals were used in subsequent compound evaluation experiments. For compound evaluation experiments female nude mice weighing approximately 20g were implanted s.c. by surgical implantation with tumor fragments of ~30 mg from donor tumors. When the tumors were approximately 100 mm3 in size (~7-10 days following implantation), the animals were randomized a separated into treatment and control groups. Each group contained 6-S tumor-bearing mice, each of which was ear-tagged and followed individually throughout the experiment
[0613] Mice were weighed and tumor measurements are taken by calipers three times weekly, starting on Day 1. These tumor measurements were converted to tumor volume by the well-known formula (L+W/4)3 4/3#. The experiment was terminated when the control tumors reached a size of approximately 1500 mm3. In this model, the change in mean tumor volume for a compound treated group / the change in mean tumor volume of the control group (non-treated or vehicle treated) x 100 (##T / ##C) was subtracted from 100 to give the percent tumor growth inhibition (%TGI) for each test compound. In addition to tumor volumes, body weight of animals were monitored twice weekly for up to 3 weeks.
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[0614] The activities of a number of compounds according to the invention measured by various assays are displayed in the following table, Table 24. In the table, "a" indicates inhibitory activity at a concentration of less than 50 nanomolar; "b" indicates inhibitory activity at a concentration > 50 but 500 nanomolar; and "e" indicates no activity as measured by that assay.

Table 24
ExampleNo CompoundNo C-Met (enz.) (IC50, µM) VEGF(enz.) (IQo, fiM) C-Met cell-basedY1230-34-35 tpr- met inhibition(IC50, µM)
1 8a b a a
2 8b b a b
3 8c b c b
5 8e b b b
7 8g b c b
9 8i b b c
10 8j b b b
11 8k b d b
12 13a b a a
13 13b b a a
14 13c b b b
15 13d b a a
133 170a b b b
16 13e b a c
18 13g b b b
20 18a b d e
22 26a b b a
23 26b b a b
24 26c b c d
25 26d b b e
26 26e b b e
27 26f b b e
28 31a b d e
29 31b c d e
35 8m b b a
36 8n b d b
37 8o b a a
40 8r b a b
75 13k b a a
142 26f b a a
188 170c c d d
221 269a a d d
229

WO 2006/010264 PCT/CA2005/001177
[0615] In the following table, Table 25, "a" indicates % TGI in the range of 75-100; "b" indicates % TGI in the range of 50-74; "c" indicates % TGI in the range of 25-49, and "d" indicates % TGI in the range of 0-24. Regiment of administration was once daily.
230







WO 2006/010264 PCT/CA2005/001177
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10. Plate K. H., Breier G.? Weich H. A., Mennel H. D., Risau W. Vascular endothelial growth
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12. Wheeler-Jones C, Abu-Ghazaleh R., Cospedal R., Houliston R. A., Martin J., Zacbary I.
Vascular endothelial growth factor stimulates prostacylin production and activation of
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13. Kim K. J., Li B., Winer J., Armanini M., Gillett N., Phillips H. S., Ferrara N. Inhibition of
vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.
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14. Kanai T., Konno H., Tanaka T., Baba M., Matsumoto K., Nakaraura S., Yukita A., Asano
M., Suzuki H., Baba S. Anti-tumour and anti-metastatic effects of human-vascular-endothelial-
growth-factor-neutralizing antibody on human colon and gastric carcinoma xenotransplanted
orthotopically into nude mice. Int. J. Cancer, 77: 933-936,1998.
15. Zhu Z., Rockwell P., Lu D., Kotanides H., Pytowski B., Hicklin D. J., Bohlen P., Witte L,
Inhibition of vascular endothelial growth factor-induced receptor activation with anti-kinase
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16. Siemeister G., Schirner M., Reusch P., Barleon B., Marme D., Martiny-Baron G. An
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17. Lin P., Sankar S.; Shan S., Dewhirst M. W., Polverini P. J., Quinn T. Q., Peters K. G.
Inhibition of tumour growth by targeting tumour endothelium using a soluble vascular
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18. Cheng S-Y., Huang H-J. S., Nagane M., Ji X-D., Wang D., Shih C. C-Y., Arap W., Huang
C-M.., Cavenee W. K. Suppression of glioblastoma angiogenicity and tumorigenicity by
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19. Millauer B., Longhi M- P., Plate K. H., Shawver L. K., Risau W., Ullrich A., Strawn L. M.
Dominant-negative inhibition of Flk-1 suppresses the growth of many tumour types in vivo.
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20. Perjnacchietti-S,Michieli-P^Galluz^
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21. Camps JL, Chang SM, Hsu TC, et al Fibroblast-mediated acceleration of human epithelial
tumor growth in vivo. Proc Natl Acad Sci USA, 87: 75-9,1990.
22. Nakamura T, Matsumoto K, Kiritoshi A, Tano Y Induction of hepatocyte growth factor in
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23. Nishimura K, Kitamura M, Takada S, et al Regulation of invasive potential of human
prostate cancer cell lines by hepatocyte growth factor. Int J Urol, 5: 276-81, 1998.
24. Bae-Jump V, Segreti EM, Vandermolen D, Kaurna S Hepatocyte growth factor (HGF)
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25. Nakamura T, Nawa K, Ichihara A Partial purification and characterization of hepatocyte
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26. Nakamura T, Nishizawa T, Hagiya M, et al Molecular cloning and expression of human
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27. Ebert M, Yokoyama M, Friess H, Buchler MW, Korc M Coexpression of the c-met proto-
oncogene and hepatocyte growth factor in human pancreatic cancer. Cancer Res, 54: 5775-8,
1994.
28. Di Renzo MF, Narsimhan RP, Olivero M, et al Expression of the Met/HGF receptor in
normal and neoplastic human tissues. Oncogene, 6:1997-2003,1991.
29. Di Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR Expression of the
Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res, 55:1129-38,
1995.
30. Delehedde M. Sergeant N, Lyon M, Rudland PS, Fernig DG Hepatocyte growth
factor/scatter factor stimulates migration of rat mammary fibroblasts through both mitogen-
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31. Bardelli A, Basile ML, Audero E, et al Concomitant activation of pathways downstream of
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32. Saucier C, Khoury H, Lai KM, Peschard P, Dankort D, Naujokas MA, Holash J,
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induction by Met/HGF and ErbB2 receptors and for early onset of tumor angiogenesis. Proc
Natl Acad Sci USA. 2004 Feb 24;101(S):2345-50.
237

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WHAT IS CLAIMED IS:
1. A compound of the formula (A), that are inhibitors of VEGF receptor signaling and HGF receptor signaling:

and pharmaceutically acceptable salts and complexes thereof, wherein
T is selected from the group consisting of arylalkyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl, wherein each of said arylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is
optionally substituted with. 1 to 3 independently selected R20;
each R20 is independently selected from the group consisting of -H, halogen, trihalomethyi, -CN, -NO2r -NH2, -OR17, -OCF3, -NR17R18, -S(0)o-2R)7, -S(O)2NRl7R17, -C(O)OR17, -C(O)NR17R17, -N(R17)SO2R17, -N(R17)C(O)R17, -N(R17)C(O)OR17, -C(O)R17, -C(O)SR17, CrC4 alkoxy, C1-C4 alkylthio, -O(CH2)naryl, -O(CH2)nheteroaiyl, -(CH2)0-5(aryl), -(CH2)0.5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)0-4-T2, an optionally substituted C1-4 alkylcarbonyl, C1-4 alkoxy, an amino optionally substituted by C1-4 alkyl optionally substituted by C1-4 alkoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe2, -NHEt and -NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
W is selected from the group consisting of O, S, NH and NMe;
Z is selected from the group consisting of O, or S and NH;
X and X1 are independently selected from the group consisting of H, C1-C6 alkyl, halo, cyano, or nitro, wherein C1-C6 alkyl is optionally substituted, or
X and X' taken together with the atom to which they are attached, form a C3-C7 cycloalkyl;
238

WO 2006/010264 PCT/CA2005/001177
R1, R2, R3 and R4 independently represent hydrogen, halo, trihalomethyl, -CN, -NO2, -NH2, -OR17, -NR17R18, -C(O)OR17, -C(O)R17, C1-C4 alkoxy, C1-C4 alkylthio, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl are optionally substituted;
R17 is selected from the group consisting of H and R18;
R18 is selected from the group consisting of a (C1-C6)alkyl, an aryl, a aryI(C1-C6)alkyl, a
heterocyclyl and a heterocyclyl(C1-C6)alkyl, each of which is optionally substituted, or
R17 and R18, taken together with a common nitrogen to which they are attached, form an
optionally1 substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from the group consisting of N, O, S and P;
Rl6 is selected from the group consisting of-H, -CN, -(CH2)0-5(aryl), -(CH2)o-5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)0-4-T2, an optionally substituted C1-4 alkylcarbonyl and a satoated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMc, -OEt -NH2, -NHMe, -NMe2 -NHEt and -NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
Q is selected from the group consisting of CH2,0, S, N(H), N(C1-C6 alkyl), N-Y-(aryl)s -N-
OMe, -NCH20Me and -N-Bn;
D is selected from the group consisting of C-E and N;
L is N, or CR, wherein R is selected from the group consisting of-H, halo, -CN, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted: and
E is selected from the group consisting of E1, E2 and E3, wherein
E1 is selected from the group consisting of -H, halogen, nitro, azido, C1-C2 alkyl, C3-C10 cycloalkyl, -C(O)NR42R43, -Y-NR42R43; -NR42C(=O)R43, -SO2R42, -SO2NR42R43, -NR37SO2R42, -NR37SO2NR42R43, -C(=N-OR42)R43, -C(=NR42)R43, -NR37C(=NR42)R435 -C(=NR42)NR37R43, -NR37C(=NR42)NR37R43, -C(O)R42, -CO2R42, -C(O)(heterocyclyl), -C(O)(C6-C10 aryl), -C(O)(heteroaryl).. -Y-(C6-C]0 aryl), -Y-(heteroaryl), -Y-(5-l0 membered heterocyclic), -NR6aR6b, -NR6aSO2R6b, -NR6aC(O)R6b, -OC(O)R6b, -NR6aC(O)OR6b -OC(O)NR6aR6b,-OR6a,. -SR6a, -S(O)R6a, -SO2R6a, -SO3R6a, -SO2NR6aR6b,
239

WO 2006/010264 PCT/CA2005/001177
-SO2NR42R43, -COR6a, -CO2R6a, -CONR6aR6b, -(C1-C4)fluoroalkyl, -(C1-C4)fluoroalkoxy, -(CZ3Z4)aCN, wherein n is an integer ranging from 0 to 6, and the aforementioned E1 groups other than -H and halogen are optionally substituted by 1 to 5 independently selected R38, or El is selected from a moiety selected from the group consisting of-(CZ3Z4)a-aryl, -(CZ3Z4)3-heterocycle, (C2-C6)alkynyl, -(CZ3Z4)a-(C3-C6)cycloalkyl, -(CZ3Z4)a-(C5-C6)cycloalkenyl, (C2-C6) alkenyl and (C5-C6)aIkyL which is optionally substituted with 1 to 3 independently selected Y2 groups, where a is 0,1,2, or 3, and wherein when a is 2 or 3, the CZ3Z4 units may be the same or different; wherein each R38 is independently selected from halo, cyano, nitrortrifluoromethoxy,triiluoromethyl, azido, -C(O)R40, -C(0)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, C,-C6 allcyl, -(CH2)jO(CH2)iNR36R39, -(CH2)nO(CH2)iOR37, -(CH2)nOR37, -SCO^C-Ce alkyl), -(CH2)a(C6-C10 aryl), -(CH2)n(C5-Cio heteroaryl), -(CH2)n(5-10 membered heterocyclyl); -C(O)(CH2)n(C6-C]0 aryl), -(CH2)nO(CH2)j(C6-Cio aryl), -(CH2)nO(CH2)i(5-10 membered heterocyclyl), -C(O)(CH2)n(5-10 membered heterocyclyl), -(CH2)jNR39(CH2)iNR36R39.. -(CH2)jNR39CH2C(O)NR36R39s -(CH2)jNR39(CH2)iNR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)jOR37, -(CH^jNR^Ca^iSCO^CCj-Ce alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-CI0 aryl), -SO2(CH2)n(5-I0 membered heterocyclyl), -(CH2)nNR36R39, -NR37SO2NR36R39, SO2R36, C2-C6 alkenyl, C3-C10 cycloalkyl and Q-C6 alkylamino, wherein j is an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 0 to 6, the -(CH2)i- and -(CH2)n~ moieties of the foregoing R38 groups optionally include a carbon-carbon double or triple bond where n is an integer between 2 and 6, and the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing RjS groups are optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -(CH2)nNR36R39; d-C6 alkyl, C3-Cl0 cycloalkyl, -(CH2)n(C6-Cl0 aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)jOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;
240

WO 2006/010264 PCT/CA2005/001177
each R42 and R43 is independently selected from the group consisting of H, d-Q alkyl, Ci-C6 heteroalkyl, -Y-(C3-C10 cycloalkyl), ~Y-(C6-Cio aryl), -Y-(C6-Cio heteroaryl), -Y-(5-10 membered heterocyclic), -Y-O-Y'-OR37, -Yi-CO2-R37, and -Y-OR37, wherein the alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or more substituents independently selected from R44, wherein
Y is a bond or is -(C(R37)(H))n,
n is an integer ranging from 1 to 6. and
R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1 to 5 independently selected R44 substituents, with the proviso that R42 and R43 are not both bonded to the nitrogen directly through an oxj'gen;
each R44 is independently selected from the group consisting of halo, cyano, nitro, trifluoromeUioxy, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR3(iC(O)R3S, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, -SO2R36, -NR36SO2R39, -NR36SO2NR37R4\ d-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C!o cycloalkyl -Ci-C6 alkylamino, -(CH2)jO(CH2)iNR36R39, -(CH2)nO(CH2)iOR37, -(CH2)nOR37, -S(O)j(Ci-Q alkyl), -(CH2)n(C6-Cj0 aryl), -(CH2)n(5-10 membered heterocyclic), -C(O)(CH2)n(C6-C10 aryl), -(CH2)nO(CH2)j(C6-Cio aryl), -(CH2)nO(CH2)i(5 to 10 membered heterocyclic), -C(O)(CH2)n(5 to 10 membered heterocyclic), -(CH^jNR39^^),^^3^39, -(CH2)jNR39CH2C(O)IsfR36R39, -(CH2)fNR39(CH2)iNR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)iOR37, -(CH^NR^CH^SCOJjCCi-Ce alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-C10 aryl), and -SO2(CH2)n(5 to 10 membered heterocyclic) wherein, j is an integer from 0 to 2, n is an integer from 0 to 6 and i is an integer ranging from 2 to 6, the -(CH2)i- and -(CH2)ni-moieties of the foregoing R44 groups optionally include a carbon-carbon double or triple bond wherein n is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R44 groups are optionally substituted by 1 or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40,-NR36C(O)R39, -
241

WO 2006/010264 PCT/CA2005/001177
C(O)NR36R39, -(CH2)nNR36R39, -SO2R36, -SO2NR36R39, Cj-C6 alkyl, C3-C10 cycloalkyl, -(CH2)n(C6-Ci0 aryl), -(CH2)n(5 to 10 membered heterocyclic), -(CH2)nO(CH2)iOR37 and -(CH2)nOR37, wherein n is an integer from 0 to 6 and i is an integer from 2 to 6; and
each R40 is independently selected from H, C1-C10 alkyl, -(CH2)n(C6-Cio aryl), C3-C10
cycloalkyl, and -(CH2)n(5-10 membered heterocyclic), wherein n is an integer ranging from 0 to 6;
each R36 and R39 is independently selected from the group consisting of H, -OH, d-C^ alkyl. C3-C10 cycloalkyl, -(CH2)n(C6-Cio aryl), -(CH2)n(5-10 membered heterocyclic), -(eH2%-0(eH2)i©Rsr-(CHr)n^
wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R36 and R39 groups are optionally substituted by one or more substituents independently selected from -OH, halo, cyano, nitro, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -CO(O)R40, -0C(O)0R4°, -NR37C(O)R4i, -C(O)NR37R41, -NR37R41, -d-Q alkyl, -(CH2)n(C6-C10 aryl), -(CH2)n(5 to 10 membered heterocyclic), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37? wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that when R36 and R39 are both attached to the same nitrogen, then R36 and Rj9 are not both bonded to the nitrogen directly through an oxygen;
each R37 and R41 is independently selected from the group consisting of H, OR36, Ci-Ce alkyl
and C3-C10 cycloalkyl;
each R6a and R6b is independently selected from the group consisting of hydrogen, -(CZ5Z6)U-(C3-C6)cycloalkyl, -(CZ5Z6)u-(C5-C6)cycIoalkenyl, -(CZ5Z6)u-aryl, -(CZ5Z6)u-heteroaryl, -(CZ5Z6)u-heterocycle, (C2-C R6a and R6b taken together with adjacent atoms can form a heterocycle;
each Z3, Z4, Z5 and Z6 is independently selected from the group consisting of H, F and (Cj-Cs)alkyl, or
each Z3 and Z4, or Z5 and Z6 are selected together to form a carbocycle, or
two Z3 groups on adjacent carbon atoms are selected together to optionally form a carbocycle;
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WO 2006/010264 PCT/CA2005/0OI177
eacli Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidirxo, amidino, methylguanidino, azido, -C(O)Z7, -OC(O)NH2, -OC(O) NHZ7, -OC(O)NZ7ZS, -NHC(O)Z7, -NHC(O)NH2, -NHC(O)NHZ7, -NHC(O)NZ7ZS, -C(O)OH, -C(O)OZ7, -C(O)NH2, -C(O)NHZ7,-C(O)NZ7ZS, -P(O)3H2, -P(O)3(Z7)2, -S(O)3H, -S(O)Z7, -S(O)2Z7, -S(O)3Z7, -Z7, -OZ7, -OH, -NH2, -NHZ7, -NZ7Z8., -C(=^NH)NH2J-C(=NOH)>]H2, -N-moipholino, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cj-C6)haloalkyl, (C2-C6)haloalkenyl, (C2-C6)haloalkynyl, (d-C6)haloalkoxy, -(CZ9ZI0)rNH2, -(CZ9ZI0)rNHZ3, -(CZ9Z10)fNZ7Zs, -X6(CZ9ZJ0)r-(C3-
heterocycle, wherein ris 1,2, 3 or 4; X6 is selected from the group consisting of O, S, NH, -0(0)-, -C(0)NH-, -C(O)O-, -S(O)-, -
S(O)2- and -S(O)3-; Z7 and Z8 are independently selected from the group consisting of an alkyl of 1 to 12 carbon
atoms, an alkeny] of 2 to 12 carbon atoms, an aikynyl of 2 to 12 carbon atoms, a
cycioaikyi of 3 to 8 carbon atoms, a cycloalkenyl of 5 to S carbon atoms, an aryl of 6 to
14 carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15 carbon atoms.
and a heteroaralkyl of 5 to 14 ring atoms, or Z7 and Z8 together may optionally form a heterocycle; Z9 and Z10 are independently selected from the group consisting of H, F, a (Ci-Ci2)alkyl, a (€&-
Ct4)aryl, a (Cj-Cj4)heteroaryl, a (C7-C]5)aralkyl and a (Cs-Ci^heteroaralkyl, or Z9 and Z10 are talcen together form a carbocycle, or
two Z9 groups on adjacent carbon atoms are taken together to form a carbocycle; or any two Y2 or Y3 groups attached to adjacent carbon atoms may be taken together to be -
O[C(Z9)(Z10)]rO or-O[C(Z9)(Z10)jH-b or any two Y2 or Y3 groups attached to the same or adjacent carbon atoms may be selected
together to form a carbocycle or heterocycle; and wherein any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH
(methine) group which is not attached to a halogen, SO or SO2 group or to a N, O or S
atom optionally bears on said group a substituent selected from hydroxy, halogen, (Cr
C)alkyl, (CrC4)alkoxy and an -N[(CrC4)alkyl][(CrC4)alkyl];
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WO 2006/010264 PCT/CA2005/001177
E2 is -C=CH or -C=C-(CR45R45)n-R46;
R45 is independently selected from the group consisting of H, a (Cj-C6)alkyl and a (C3-C8)cycloalkyl;
R46 is selected from the group consisting of heterocyclyl, -N(R47)-C(O>N(R47)(R48), -N(R47)-C(S)-N(R47)(R48), -N(R47>C(O)-OR4\ -N(R47)-C(O)-(CH2)n-R48.. -N(R47)-SO2R47, -(CH2)nNR47R48, -(CH2)nOR48, -(CH2)nSR49, -(CH2)nS(O)R49, -(CH2)nS(O)2R49, -OC(O)R49, -OC(0)OR49, -C(O)NR47R48, heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, - (CrCg)alkyK -GN, ~SO2R50-and -(G^^NR^-'rand aryl optionally-substituted^vith-one- - -or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (C1-C6)allcyl, -CN, -SO2R50 and -(CH2)nNR50R51;
R47 and R48 are independently selected from the group consisting of H, (Cj-C^alkyl, (C3-
C8)cycloalkyL heterocyclyl, -(CH2)nNR50R51, -(CH2)nOR50, -(CH2)nC(O)R497 -C(O)2R49, -(CH2)nSR49, -(CH2)nS(O)R49, -(CH2)nS(O)2R49, -(CH2)nR49, -(CH2)nCN, aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (CrC6)alkoxy, -NO2; (CrC6)aIkyl, -CN, -(CH2)nOR4y, -(CH2)nheterocyclyl; -(CH2)nlieteroaryl, -SO2R50 and -(CH2)nNRS0R51, and heteroaiyl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Cj-C6)alkoxy, -NO2, (C,-C6)alkyl, -CN, -(CH2)nOR49, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2R50 and -(CH2)nNR50RM5 or
R47 and R48, together with the atom to which they are attached, form a 3-8 membered ring;
R49 is selected from the group consisting of (Ci-C6)all 244

WO 2006/010264 PCT/CA2005/001177
selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (CrC6)alkyl, -
CN, -SO2R50 and -(CH2)nNR50R5J; R30 and R51 are independently selected from the group consisting of H, (Ci-C6)alkyl, (C3-
C8)cyclcalkyl and -C(O)R45, or
R50 and. R51, together witli the atom to which they are attached, form a 3-8 membered ring; and E3 is ihe group defined by -(Z1;)-(Z12)m-(Z13)mi3 wherein Zn is heterocj'clyl or heterocyclylene;
Zn is selected from the group consisting of OC(O), OC(S) and C(O); Znis_selected-fejm thegroup consisting-ofheterocyclylraralkyl,^(H)R3\(ei-e3)alkyr,-OR52,
halo, S(O)2R50', (CrC3)hydroxyalkyl and (Ci-C3)haloalkyl; rn isOor 1; ml isOor 1; R" is selected from the group consisting of H, '(CH2)!,S(O)2Rsl R55NR53R53, (Ci-C3)alkyl, -
(CH2)qORS3, -C(O)R54 and -C(O)OR53; qisO, 1,2, 3 or 4; R53 is (C)-C3)alkyi; RH is (CrC3)alkyi orN(H)R53; R-sis(Ci-C6)alkyi;and R5t) is selected from die group consisting of NR2, (Ci-C3)alkyl and OR52.
2. The compound according to claim 1, wherein T is aryl or heteroaryl, wherein each of
said aryl and heteroaryl is optionally substituted with 1 to 3 independently selected R20. '•"¦'
3. The compound according to claim 1, wherein T is selected from the group consisting^of
aryiallcyj, cycloalkyl and helerocyclyl, wherein each of said arj'lalk>'l5 cycloalkyl and '¦'"
heterocyclyl is optionally substituted with 1 to 3 independently selected R20.
4. The compound according to claim 1, wherein R20 is selected from the group consisting
of H, halogen, -OR17 and -C(O)OR17.
5. The compound according to claim 1, wherein R20 is fluorine or chloride.
6. The compound according to claim 1, wherein Wis O,
7. The compound according to claim 1, wherein Z is S or O.
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8. The compound according to claim 1, wherein Z is S.
9. The compound according to claim 1, wherein X and X1 are independently selected from
the group consisting of H and Ci-C6alkyl, wherein the CrCialkyl is optionally substituted.
10. The compound according to claim 1, wherein X and X1 are both H.
11. The compound according to claim 1, wherein X and X1 taken together with the atom to
which they are attached, form a Cs-Cycyeloalkyl.
12. The compound according to claim 1, wherein R1, R2, R3 and R4 are independently
selected from the group consisting of H, halogen, trihalomethyl, OR17, -NRI7RIS and Cj-
C6alkyl.
13. The compound according to claim 1, wherein R!3 R2 and R4 are independently selected
from the group consisting of H, halo and -ORL7.
14. The compound according to claim 1, wherein R1 is H or halogen.
15. The compound according to claim 1, wlieisiu R is halogen.
16. The compound according to claim 1, wherein R2, R3 and R4 are each H.
i 7. The compound according to claim I, wherein Rn is a Ci-C,saikyi.
18. The compound according to claim 1, wherein R16 is H or Cj-Cealkyl.
19. The compound according to claim 1, wherein Q is selected from the group consisting of
CH2, S, -N-(Ci-C6alkyl), N-Y-(aryl) and -N-OMe.
20. The compound according to claim 1, wherein Q is S.
21. The compound according to claim 1, wherein Q is CH2.
22. The compound according to claim 1, wherein Q is -N-(CVC6alkyl).
23. The compound according to claim 1, wherein Q is -N-Y-(aryl).
24. The compound according to claim 1, wherein Q is -N-OMe.
25. The compound according to claim 1. wherein D is C-E.
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WO 2006/010264 PCT/CA2005/001177
26. The compound according to claim 1, wherein D is CH.
27. The compound according to claim 1, wherein L is C-R.
28. The compound according to claim 1, wherein R is H or halogen.
29. The compound according to claim 1, wherein L is N.
30. The compound according to claim 1, wherein E is selected from the group consisting of
E^ndE2.
31. The compound according to-claim 1, wherein E-is E -.
32. The compound according to claim 1, wherein E is E1, wherein E1 is selected from the
group consisting of H, halogen, ~C(O)NR42R43, -SO2NR42R43> C(=NR42)NR37R43, -CO2R42, -
C(O)(heterocyclyl), -C(O)(heteroaryl), -Y-(C6-Cio aryl}, -Y-(heteroaryI), -Y-(5 to 10 merabered
heterocyclic), -SR6\ -S(O)R6\ -SOaR08, wherein each of said E1 other than H and halogen are
optionally substituted with 1 to 5 independently selected R3S, or El is (Cl-C6)alkyl, which is
optionally substituted with 1 to 3 independently selected Y2 groups.
33. The compound according to claim 1, wherein R3? is selected from the group consisting
of halogen, -C(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, d-Ceaikyl, -
CXCH2)jO(CH2)iNRJ6R39J -(CH2)nOR37, -SCOKC-Cgalkyl), -(CH2)n-(5 to 10 membered
heterocyclic), -(CH2)O(CH2)i(5 to 10 membered heterocyclic), -(CH2)n(5 to 10 membered
heteroaryl), -(CH2)jNR39(CH2)iNR36R39> -(CH2)jNR3p(CH2)nR36, -(CH2)nNR36R39, wherein j is
an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 1
to 6,., the -(CH2)i- and -(CH2)«- moieties of the foregoing R38 groups optionally include a
carbon-carbon double or triple bond where n is an integer between 2 and 6, and the aikyl, aryl,
heteroaryl, and heterocyclic moieties of the foregoing R38 groups are optionally substituted by
one or more substituents independently selected from the group consisting of halo, cyano, nitro,
trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -
C(O)NR36R39, -(CH2)nNR36R39, Ci-C6 alkyl, C3-CJ0 cycloalkyl -(CH2)n(C6-Ci0 aryl), -
(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37, wherein n is an
integer ranging from 0 to 6 and i is an integer ranging from 2 to 6.
247

4
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34. The compound according to claim 1, wherein the alkyl, aryl, heteroaryl, and
heterocyclic moieties of the foregoing R groups are optionally substituted by one or more
substituents independently selected from the group consisting of-OH and -C(O)OR40.
35. The compound according to claim 1, wherein each R42 and R43 is independently
selected from the group consisting of H, -Y-(C3-Cio cycloalkyl), -Y-(C6-Cio aryl), -Y-(C6-Cio
heteroaryl) and -Y-(5 to 10 membered heterocyclic), wherein the cycloalkyl, aryl, heteroaryl
and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or
more substituents independently selected from R44.
36. The compound according to claim 1, wherein each R42 and R43 is independently
selected from the group consisting of H, CVC6 alkyl, Cj-Cs heteroalkyl, -Y'-CCVR37 and -Y-
OR37.
37. The compound according to claim 1, wherein one of R42 and R43 is H.
38. The compound according to claim 1, wherein one of R42 and R43 is -(Ce-Cio heteroary])
or -Y-(5 to 10 membered heterocyclic).
39. The compound according to claim 1, wherein Y is a bond.
40. The compound according to claim 1, wherein Y is -(C(R37)(H))fl.
41. The compound according to claim 1, wherein R42 and R4B taken together with the
nitrogen to which they are attached form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein
said ring is optionally substituted by 1 to 5 independently selected R44 substituents, with the
proviso that R42 and R43 are not both bonded to the nitrogen directly through an oxygen.
42. The compound according to claim 1, wherein R44 is independently selected from the
group consisting of-C(O)NR36R39, -OR37 and CrC6alkyl.
43. The compound according to claim 1, wherein each R40 is independently selected from
the group consisting of H and C1-C10 alkyl.
44. The compound according to claim 1, wherein each R36 and R39 is independently
selected from the group consisting of H, Ci-C6alkyl, -(CH2)n(5 to 10 membered heterocyclic), -
(CH2)nOR37 and -C(O)OR40, wherein n is an integer ranging from 0 to 6 and i is an integer
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WO 2006/010264 PCT/CA2005/00I177
ranging from 2 to 6, with the proviso that when R36 and R39 are both attached to the same nitrogen, then R36 and R39 are not both bonded to the nitrogen directly through an oxygen.
45. The compound according to claim 1, wherein each R37 and R4i is independently
selected from the group consisting of H and Ci-Qalkyl.
46. The compound according to claim 1, wherein Roa is selected from the group consisting
of -(CZ^Varyl, -(CZ5Z6)u-heteroaryl and CrC($alkyl, each of which is optionally substituted
with 1 to 3 indepedently selected Y3 groups, wherein u is 0,1, 2 or 3, and wherein when u is 2
or 3, the CZ5Z6 units may be the same or different
47. The compound according to claim 1, wherein R6a is selected from the group consisting
of -(CZ5Z6)u-aryl and -(CZ5Z6)u-heteroaryl, each of which is optionally substituted with 1 to 3
indepedently selected Y3 groups, wherein u is 0.
48. The compound according to clakn 1, wherein Y2 is -OH.
49. The compound according to claim 1, wherein Y3 is -OH.
50. The compound according to claim 1, wherein E" is -OC-(CR4SR45)n-R46' wherein n is
an integer ranging from 1 to 6.
51. The compound according to claim 50, wherein R45 is H.
52. The compound according to claim 50, wherein R4b is a heterocyclyl.
53. The compound according to claim 1, represented by the formula A-0:

and pharmaceutically acceptable salts and complexes thereof, wherein Z is O or S;
X and X1 are independently selected from the group consisting of H, Cj-Cg alkyl, halo, cyano and nitro, wherein Q-Cg aikyi is optionally substituted:
249

WO 2006/010264 PCT/CA2005/001177
R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, halo,
trihalomethyl, -OR17, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein CrC6 alkyl,
C2-C6 alkenyl and C2-Ce alkynyl are optionally substituted; Q is O, S, NH, N(CrC6 alkyl), or N-Y-(aryl); DisCRu,orN; L is N, or CR, wherein R is H, halo, -CN, Ci-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein
C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 aikynyl are optionally substituted; and R7 is H, halogen, d-Q alkyl, -C(=O)NR9R10, -C(=O)(aryl), -C(=O)(heterocyclyI), -
C(^)(heteroaryl),-Y^aiyl),-Y-(heterocyclyl),-YH;heteroary}),-S-aryl,-»S-CrQ^llQrl,
-SO-Ci-Ce alkyl, -SO2-Ci-C6 alkyl, -Y-NR9R10, -SO2NR9R]0 or CO2R9, wherein Ci-C6
alkyl, aryl, heterocycle and heteroaryl are each independently optionally substituted; R9 and R10 are independently selected from H, CrC6 alkyl, -Y-(cycloalkyl), -Y-(aryl), -Y-
(heterocyclyl), -Y-(heteroaryl), -Y-O-Y^O-R11, -Y'-COs-R11, and -Y-O-R11, wherein
C1-C6 alkyl, cycloalkyl, aryl, heterocycle, and heteroaryi are each optionally substituted,
or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Y is a bond or is -(C(Rn)(H))r, wherein t is an integer from 1 to 6; Y'is-(C(Rn)(H))r, R11 at each occurrence is independently H or C1-C6 alkyl, wherein Cy-Cc, alkyl is optionally
substituted, each R20 is independently selected from the group consisting of hydrogen, halo, trihalomethyl,
OR17, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein CrC6 alkyl, C2-C6 alkenyl
and C2-C6 alkynyl are optionally substituted, and each R17 is an independently selected CrQalkyl, wherein said Ci-C6alkyl is optionally
substituted.
54. The compound according to claim 53, wherein X and X1 are both hydrogen.
55. The compound according to claim 53, wherein R1 is hydrogen or halogen.
56. The compound according to claim 53, wherein R1 is fluorine.
57. The compound according to claim 53, wherein R4 is hydrogen or halogen.
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WO 2006/010264 PCT/CA2005/001177
58. The compound according to claim 53, wherein R4 is fluorine.
59. The compound according to claim 53, wherein R2 is selected from the group consisting
of H, halogen, trihalomethyl and -OR17.
60. The compound according to claim 53, wherein R3, and R20 are each hydrogen.
6L The compound according to claim 53, wherein R20 is -OR27.

62. The compound according to clam 53, wherein Q is S, N(Ci-C6 alkyl), or N-Y-(aryl).
63. The compound according to claim_53, wherein Q_is_NH.
64. The compound according to claim 53, wherein D is CR!'.
65. The compound according to claim 53, wherein L is CH or N.
66. The compound according to claim 53, wherein R7 is H. halogen,, Cj-Cg alkyl, -
CONR9R10, -SO2Mi2, -SG2NR9R!0, -Y-heterocydyl, -Y-heleroaryl, -S-aryl, -S-Ci-Ce alkyl, -
SG"C)-C6 alkyl, or -SCvQ-Q alky], wherein CrCs alkyl, is unsubstituted or is substituted
with, one or two of hydroxy or halogen, and heterocyclyl, and heteroaryi are unsubstituted or
substituted with one or two of alkoxy, alkyl, or haloalkyl.
67. The compound according to claim 53, wherein R7 is -CONR9R10.
68. The compound according to claim 53, wherein R7 is Y-heteroaryl.
69. The compound according to claim 67, wherein R9 and R10 are independently H, C1-C6
alky), -Y-O-R11, -Y-(heterocycle), -Yl-CO2-RH, or -Y-(aryl), wherein Ci-C6 alkyl is
unsubstituted or is substituted with one or two of hydroxy or halogen, and heterocyclyl, and
aryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
70. The compound according to claim 67, wherein Rs and R10 are taken together with the
nitrogen to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with
one or two of alkoxy, alkyl, or haloalkyl
71. The compound according to claim 53, wherein R7 is H, halogen, Ci-C$ alkyl, -
SO2NR9R10, -C(=O)(heterocyclyl), -Y-(heterocyclyl), or -Y-(heteroaryl), wherein Ci-Ce alkyl is
251

WO 2006/010264 PCT/CA2005/001177
unsubstituted or is substituted with one or two of hydroxy or halogen, and heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyi, or haloalkyl.
72. The compound according to claim 53, wherein Z is sulfur.
73. The compound according to claim 1, represented by the formula A-l:

and pharmaceutically acceptable salts and complexes thereof, wherein
R1 is selected from the group consisting of hydrogen, halo, Ci-Ce alkyi, C2-C6 alkenyl or C2-C6
alkynyl, wherein CrC6 alkyi. C2-C6 alkenyl and Cj-C^ alkynyl are optionally substituted;
X and X1 are independently selected from the group consisting of H and CpQ alkyi, wherein CrC6 alkyi is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C? cycloalkyl;
R7 is H, halogen, C,-C6 alkyi, -C(--=O)NR9R10, -C(=O)(aryl), -C(0)(heterocyclyl), -
C(=O)(heteroaryl), -Y-(aryl), -Y-(heterocyciyi), -Y-(heteroaryi), -SR6a, -S-axyl, -S-(heteroaryl), -S-CrC6 alkyi, -SO-CrC6 alkyi, -SOr-Ci-C* alkyi, -Y-NR9R10, -SO2NR9R!0, CO2R9, -CsC-(CR45R45)n-R46 and -C(=NR42)NR37R43, wherein n is an integer ranging from 0 to 6 and wherein C1-C6 alkyi, aryl, heterocycle and heteroaryl are each independently optionally substituted with 1 to 5 independently selected R38;
R9 and R10 are independently selected from H, CrC6 alkyi, -Y-(cycloalkyl), -Y-(CrC6
heteroalkyl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y'-COi-Ru, Y-C(O)OR37 and -Y-O-R1', wherein, said Ci-C6 alkyl5heteroa!kyL cycloalkyl, aryl, heterocycle, and heteroaryi are each optionally substituted with one or more independently selected R44, or
R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44; each R20 is independently selected from the group consisting of H, halo, -OR17 and -C(O)OR17;
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WO 2006/010264 PCT/CA2005/0O1177
Y is a bond or is -(C(Rn)(H))r, wherein t is an integer from 1 to 6; Yl is -(C(Ru)(H))r, and
74. R1' at each occurrence is independently H or C\-Ca alkyl, wherein Cj-C6 alkyl is
optionally substituted.
75. The compound according to claim 73, wherein R1 is hydrogen or halogen.
76. The compound according to claim 73, wherein R1 is fluorine.
77. The compound according to claim 73, wherein R7 is selected from the group consisting
of H, -C(=O)NR9R10, -Y-(aryl), -Y-(heteroaryl) and -S-CrC6 alkyl, wherein said -Y-(aryl), -Y-
(heteroaryl) and -S-Ci-Ce alkyl axe optionally substituted with 1 to 5 independently selected
R3S.
78. The compound according to claim 73, wherein R7 is -C(=O)NR9R10, optionally
substituted with one or more independently selected R44.
79. The compound according to claim 73, wherein R' is -Y-(aryi), optionally substituted
with 1 to 5 independently selected R38.
80. The compound according to claim 73, wherein R7 is -Y-(heteroaryl)., optionally
substituted with 1 to 5 independently selected R3S.
81. The compound according to claim 73, wherein R3S is selected from the group consisting
of halogen. -OR37, CrC6alkyl, -(CH2)n-(5 to 10 membered heterocyclyl), -
(CH2)jNR39(CH2)nR36, -(CH2)jNR39(CH2)iNR36R39, -(CH^-heteroaryl, -C(O)NR36R39, -
(CK2)nO(CH2)i integer ranging from 0 to 63 j is an integer ranging from 0 to 2, j is an integer ranging from 1 to
6 and wherein the alkyl, heteroaryl and heterocyclyl moieties of the foregoing R38 groups are
optionally substituted by one or more substituents independently selected from the group
consisting of halo, cyano, nitro, trifluoromefoyl, azido, -OH, -C(O)R40> -C(O)OR40, -OC(O)R40,
-OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -(CH2)[lNR36R39) CrC6 alkyl, C3-C10 cycloalkyl, -
(CH2)n(C6-Cio aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)iOR37, and -
(CH^nOR3', wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6.
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WO 2006/010264 PCT/CA2005/001177
82. The compound according to claim 73, wherein R38 is selected from the group consisting
of-OR37, Ci-C6alkyl, -(CH2)n(5 to 10 membered heterocyclyl) and -(CH2)nO(CH2)j(5 tolO
membered heterocyclyl).
83. The compound according to claim 73, wherein R9 and R10 are independently selected
from the group consisting of H, Ct-Cs alkyl, -Ci-Ce heteroalkyl, -Y-(aryl), -Y-(heterocyclyl), -
Y-(heteroaryl), -Y-O-R11 and Y-C(O)OR37, wherein a C.-C6 alkyl, CrC6 heteroalkyl, aryl,
heterocyclcyi and heteroaryl are each optionally substituted with 1 or more independently
selected R44.
84. The compound according to claim 73, wherein R44 is selected from the group consisting
of Cj-C6 alkyl, -OR37, -C(O)NR36R39 and ~C(0)OR46.
85. The compound according to claim 73, wherein R36 is selected from the grouip
consisting of H, CrC6 alkyl, -(CH2)nOR37 and -(CH2)n(heteroryclyl).
86. The compound according to claim 73, wherein R39 is H or Ci-Q alkyl.
87. The compound according to claim 73, wherein Ri> is H or Ci-Ce alkyl.
88. The compound according to claim 73, wherein R20 is selected from the group consisting
of K, halogen, -OR17 and -C(O)OR17.
89. The compound according to claim 73, wherein R17 is H or Ci-Cs alkyl.
90. The compound according to claim 73, wherein R20 is halogen.
91. The compound according to claim 73, wherein R20 is CJ or F.
92. The compound according to claim 73, wherein R6a is -(CZ5Z6)u-aryl.
93. The compound according to claim 73. wherein R7 is selected from the group consisting
of H, halogen, CrC6 alkyl, -CONR9^0, -SO2NH2, -SO2NR9R10, -Y-heterocyclyl, -Y-
heteroaryl, -S-aryl, -S-Ci-C6 a0 is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl,
and heteroaryl are unsubstituted or are substituted with one or two of allcoxy, alkyl, or
haloalkyl.
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WO 2006/010264 PCT/CA2005/001177
94. The compound according to claim 73, wherein R7 is selected from the group
consisting of H, halogen, Ci-C6 alkyl, -SO2NReRi0, -C(=O)(heterocyclyl), -Y-(heterocyclyl), -
Y-(heteroaryl), -S-aryl. -S-CrC6 alkyl, -SO-CrC6 alkyl, or -SO2-Ci-C6 alkyl, wherein CrC6
alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the
heteroeyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy,
alkyl, or haloalkyl.
255
95. The compound according to claim 77, wherein R9 and R10 are independently selected
from the group consisting of H, C]~C6 alkyl. d-C6 heteroalkyl, -Y-O-R11, -Y-(heterocycIe), -Y-
CO2-RU, -Y-(aryl) and'Y-(heteroaryl),^vherein Ci-C vvitli one or two of hydroxy or halogen, and the heterocyclyL aryl and heteroaryl are
unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
96. The compound according to claim 77, wherein R9 and R10 are taken together with the
nitrogen to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with
one or two of alkoxy, alky!, or haloallcyi.
97. The compound according to claim 77, wherein NR9R10 is selected from the group
consistisng of:



98. The compound according to claim 73, wherein R7 is unsubstituted heteroaryl.
99. The compound according to claim 73, wherein R7 is thiazolyl, pyridinyl, pyrimidinyl,
and imidazolyl, each of which is preferably unsubstituted or is substituted with one or two of
alkoxy, or alkyl.
100. The compound according to claim 73, wherein R7 is Ci-Ce alkyl, unsubstituted or
substituted with hydroxy.
101. The compound according to claim 73, wherein X and X! are both H.
102. The compound according to claim 73, wherein R17 is selected from the group consisting
of H and CrC6 alkyl.
103. The compound according to claim 73, wherein R38 is selected from the group consisting
of-OR37, Ci-C-6 alkyl and -(CH2)n(5 to 10 membered heterocylic), wherein n is an integer
ranging from 0 to 6.
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WO 2006/010264 PCT/CA2005/O01177
104. The compound according to claim 73, wherein R37 is selected from the group consisting
ofHandCi-Qalkyl.
105. The compound according to claim 1, represented by the formula A-2:

and pbarmaceutically acceptable salts and complexes thereof, wherein
R; is selected from the group consisting of hydrogen, halo, C|-C'6 alkyl, Cz-Ct, alkenyl or C2-Q alkyiryl, wherein Cj-C$ alkyl, C2-Cg alkenyl and Ca-C K" is selected from the group consisting of H and halogen;
R7 is selected from the group consisting of H, halogen, Cj-Ce a)kyl. -C(=G)NR9R!0, -
C(=O)(ary1)= -C(=O)(heterocyclyl), -C(-O)(heteroaryl), -Y-(aiyl)s -Y~(heterocyclyl), -Y-Cheteroaryl), -S-atyl, -S-Cj-C6 alkyl, -SO-Cj-C* alkyl, -SOz-CrC6 alkyl, -Y-NR9Ri0, -SO;>NR9R!0 and CO2R95 wherein Ci-C6 alkyl, aryl, heterocycle and heteroaryl are each independently optionally substituted with 1 to 5 independently selected R38;
R9 and Ri0 are independently selected from the group consisting of H, C1-C6 alkyi, -Y-
(cyctoalkyl), -Y-(aryl), -Y-(heterocycly]), -Y-(heteroaryl), -Y-O-Y^O-R11, -Yl-CO2-Ru and -Y-O-Ru, wherein C1-C6 allcyl, cycloalkyl, aryl. heterocycle, and heteroarjd are each optionally substituted with one or more independently selected R44, or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9 heterocycfyl ring or a heteroaryl ring, wherein said ring is optionally substituted;
Y is a bond or is -(C(Ru)(H))r, wherein t is an integer from 1 to 6;
Yjis-CCCR^CH^and
Ru at each occurrence is independently H or Ci-Ce alkyl, wherein Q-Q alkyl is optionally
substituted.
106. The compound according to claim 104, wherein R1 is hydrogen or halogen.
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107. The compound according to claim 104, wherein R1 is fluorine.
108. The compound according to claim 104, wherein R4 is selected from the group consisting
of H and halogen.
109. The compound according to claim 104, wherein R4 is fluorine.
110. The compound according to claim 104, wherein R' is selected from the group consisting
of H, halogen, CrC6 alkyl, -C(=O)NR9R10, -SO2NH2, -SO2NR9R10, -Y-heterocyclyl -Y-
heteroaryl, -S-aryl, -S-Cj-C6 alkyl, -SO-Ci-C6 alkyl and ~SO2-C)-C6 alkyl, wherein CrC6 alkyl,
heterocyclyl, heteroaryl and aryl are^ach optionally-substituted with-1 to 5-independently
selected R38.
111. The compound according to claim 104, wherein R7 is selected from the group consisting
of H, halogen, C,-C6 alkyl, -C(=O)NR9R10, -SO2NH2, -SO2NR9R10, -Y-heterocyclyl -Y-
heteroaryl, -S-aryl, -S-CrC6 alkyl, -SO-CrC6 alkyl and -SO2-Ci-C6 alkyl, wherein Ci-C6 alkyl
is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl,
and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, haioalkyl or
(CH2)iNR39(CH2)nO(CH2)iOR37.
112. The compound according to claim 104, wherein R7 is selected from the group consisting
of H, halogen, CrC6 alkyl, -SO2NR9R10, -C(0)(heterocyclyl), -Y-(heterocyclyl), -Y-
(heteroaryl), -S-aryl, -S-Ci-C6 alkyl, -SO-CrC6 alkyl, or -SO2-Ci-C6 alkyi, wherein Ci-C6 alkyl
is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl,
and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, haioalkyl or
(CH2)jNR39(CH2)nO(CH2)iOR37.
113. The compound according to claim 104, wherein R7 is selected from the group consisting
of Ci-C6 alkyl, -C(=0)NR9Rio, -Y-(heterocyclyl, -Y-(heteroaryl)3 -S-CrC6 alkyl and -SO-Q-
C halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or
two of alkoxy, alkyl, haioalkyl or (C^jNRjgCCH^OCCH^iORsT.
114. The compound according to claim 104, wherein R7 is CONR9Ri0.
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115. The compound according to claim 113, wherein R9 and R10 are independently selected
from the group consisting of H, Cj-C6 alkyl, -Y-O-R11, -Y-(heterocyde), -Y'-CCVR11 and -Y-
(aryl), wherein the alkyl, heterocyclyl and aryl moieties of the foregoing R9 and R10 groups are
optionally substituted with 1 or more substituents independently selected from R44.
116. The compound according to claim 113, wherein R9 and R! ° are independently selected
from the group consisting of H, CrC6 alkyl, -Y-O-R1', -Y-(heterocycle), -Y1-CO2-RU and -Y-
(aryl), wherein Ci-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or
halogen, and the heterocyclyi, and aryl are unsubstituted or are substituted with one or two of
alkoxy, alkyl; haJoalkyl or (C^jNfogCCHolnOCCHaXORsv.
117. The compound according to claim 113, wherein Rs and R!0 taken together with the
nitrogen to which they are attached form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein
said ring is optionally substituted.
118. The compound according to claim 113, wherein R9 and R!0 are taken together with the
nitrogen to which they are attached to form a pyrrolidinyl, piperidirryl, piperazinyl,
morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with
one or two of alkoxy, alky!, or haloalkyl.
119. The compound according to claim 113, wherein NR9R10 is selected from the group
consisting of:

120. The compound according to claim 1, represented by the formula A-3 :
259

WO 2006/010264 PCT/CA2005/001177

and pharmaceutically acceptable salts and complexes thereof, wherein
R7 is selected from the group consisting of H, -Y-(aryl) and -Y-(heteroaryl), wherein -Y-(aryl)
and_-Y-(heteroaryl) are optionally substituted with 1 to 5 independently selected R38; R! is selected from the group consisting of hydrogen, halo, Ci-Q alkyl, C1-C6 alkenyl and C2-
Q alkynyl, wherein Q-Cb alkyl, C2-C substituted; R12 is selected from the group consisting of H, Q-C6 allcyl, -O(Ci-C6 alkyl) and -Y-(aryl),
wherein Cj-Cg alkyl and aryl are optionally substituted; Y is a bond or is -(C(Rn)(H))r. wherein t is an integer from 1 to 6; R" is H or Ci-Ce aikyl, wherein Cj-C^ alkyi is optionally substituted: and each R2o is independently selected from the group consisting of H and halogen.
121. The compound according to claim 119, wherein R1 is hydrogen or halogen.
122. The compound according to claim 119, wherein R1 is fluorine.
123. The compound according to claim 119, wherein R12 is unsubsiituted C1-C3 alkyl or
unsubstituted -Y-phenyl.
124. The compound according to claim 119, wherein R20 is Cl.
125. The compound according to claim 1, represented by the formula A-4:

and pharmaceutically acceptable salts and complexes thereof, wherein
260

WO 2006/010264 PCT/CAZM5/001177
Z is O or S;
X and X1 are independently selected from the group consisting of H, Cj-C6 alkyl, halo, cyano
and aitro, wherein Cj-Q alkyl is optionally substituted; R1, R2, R3, R4, R3 and R6 are independently selected from the group consisting of hydrogen,
halo, CrC6 alkyl, Q2-C(> alkenyl, C2-C6 alkynyl andNR17R18, wherein CrC6 alkyl, C2~
C(, alkenyl and C2-C6 alkynyl are optionally substituted; R!7 and R18 are independently d-Cealkyl; Q is O, S, NH, N(CrC6 alkyl), or N-Y-(aryl); DisCR11, orNj L is N, or CR, wherein R is selected from the group consisting of H, halo, -CN, Cj-C C2-C6- alkenyl and C2-C6 alkynyl, wherein CrC6 alkyi, C2-C6 alkenyl, and C2-C6 alkynyl
are optionally substituted; and
R13 is heterocyclyl or heteroaryl, wherein heterocyclyl and heteroaryl ai"e optionally substituted with 1 to 5 independently selected R3S;
Y is a bond or is -(C(Ru)(H))r, wherein t is an integer from 1 to 6; and R*" at each occurrence is independently H or Ci-Q aikyl, wherein C'I-C^ a'ikyi is optionally
substituted.
126. The compound according to claim 124, wherein X and X1 are both hydrogen.
127. The compound according to claim 124, wherein R1, R2, R3 and R4 are independently H
or halogen.
128. The compound according to claim 124, wherein R1 is hydrogen or halogen.
3 29. The compound according to claim 124, wherein R1 is fluorine or chlorine.

130. The compound according to claim 124, wherein R4 is hydrogen or halogen.
131. The compound according to claim 124, wherein R* is fluorine or chlorine.
132. The compound according to claim 124, wherein R2, R3, R5, and R6 are each hydrogen.
133. The compound according to claim 124, wherein Q is selected from the group consisting
of S, N(Ci-C6 alkyl) and N-Y-(aryl).
134. The compound according to claim 124, wherein Q is S.
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WO 2006/010264 PCT/CA2005/001177
135. The compound according to claim 124, wherein D is CRU.
136. The compound according to claim 124, wherein R1! is H.
137. The compound according to claim 124, wherein L is CH or N.
138. The compound according to claim 124, wherein L is CH.
139. The compound according to claim 124, wherein Z is sulfur.
140. The compound according to claim 124, wherein R38 is selected from C(O)OR40 and
NR^R39,
141. The compound according to claim 124, wherein R40 is H or Ci-Cio alkyl.
142. The compound according to claim 124, wherein R36 and R39 are independently Cj-Ce
alkyl,
143. The compound according to claim 1, represented by the formula A-5:

and pharmaceutically acceptable salts and complexes thereof, wherein
R7 is selected from the group consisting of H, -C(O)NR42R4\ -Y-(aryl), -Y-(heteroaryl), -C(O)-
(C3-C10 cycloalkyl), -C(O)-(heterocyclyl), -C(O)-(C6-C10 aryl) and -C(O)-(heteroaryl),
wherein the aforementioned R7 groups other than H are optionally substituted with 1 to
5 independently selected R38;
R4 is selected from the group consisting of H and halogen; and T is selected from the group consisting of cycioalkyl, heterocyclyl, aryl, heteroaryl and
arylalkyl, each of which is optionally substituted with 1 to 3 independently selected R20;
144. The compound according to claim 142, wherein R' is selected from the group consisting
of H, C(O)NR42R43 and -Y-(heteroaryl), wherein -Y-(heteroaryl) is optionally substituted with
1 to 5 independently selected R38.
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145. The compound according to claim 142, wherein R7 is C(O)NR42R43.
146. The compound according to claim 142, wherein R42 and R43 taken together with the
nitrogen to which they are attached form a C5-C9 heterocyclyi ring, wherein said ring is
optionally substituted with 1 to 5 independently selected R44 substituents, with the proviso that
R42 and R43 are not both bonded to the nitrogen directly through and oxygen.
147. The compound according to claim 142, wherein R4 is halogen.
148. The compound according to claim 142, wherein R4 is fluorine.
149. The compound according to claim 1, represented by the formula A-6:

sisd pharmaceulicaliy acceptable salts and complexes thereof; wherein
R1 is selected from the group consisting of hydrogen., halo, Ci-Ca alkyl, C2-C6 alkenyl Gr C2-C6 alkynyl, wherein C1-C6 alkyl, CrQ aikenyl and C2-C5 alkynyl are optionally substituted;
R7 is selected from the group consisting of H, halogen, Ci-Q alkyl, -C(=O)NR?R10, -
C(O)(aryll -C(=O)(heterocyclyl), -C(=O)(heteroary3), -Y-(aryl), -Y-(heterocycly]), -Y-Cheteroaryl), ~SR6a, -S-aryl, -S-(heteroaryl), -S-Ci-Cg alkyl, -SO-Cj-Q alkyl, -SO2-Cj-Ce alkyl, -Y-NR9R10, -SO2NR9R10, CO2R9, -CHC-(CR45R45)n-R46 and -C(=NR42)NR3'RZ|35 wherein n is an integer ranging from 0 to 6 and wherein. Ci-Cg alkyl. aryl, heterocycle and heteroaryl are each independently optionally substituted with 1 to 5 independently selected R3S;
R9 arid R30 are independently selected from the group consisting of H, Cj-Cg alkyl, -Y~
(cycloalkyi), -Y-(Ci-C6heteroalkyl), -Y-(aryl), -Y-(heterocycIyl), -Y-(heteroaryl), -Y-O-Y}-O-Rn, -Y'-CQz-R11, Y~C(O)OR37 and -Y-O-R11, wherein said C,-C6 alk)7l,heteroalkyl, cycloalkyi, aryl, heterocycle, and heteroaryl are each optionally substituted with one or more independently selected R44. or
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WO 2006/010264 PCT/CA2005/001177
R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44;
each R20 is independently selected from the group consisting of H, halo, -OR17 and -C(O)OR17;
Y is a bond or is -(C(R! ')(H))t-5 wherein t is an integer from 1 to 6;
Y1 is -( C(Rn)(H))r; and
Rn at each occurrence is independently H or Ci-Q alkyl, wherein Q-C6 alkyl is optionally substituted.
150. The compound according to claim 148, wherein R7 is selected from the group consisting
of H, C(O)NR9R10 and -Y-(heteroaryl), wherein -Y-(heteroaryl) is optionally substituted with 1
to 5 independently selected R38.
151. The compound according to claim 148, wherein R7 is C(O)NR9R10.
152. The compound according to claim 148, wherein R9 and R10 taken together with the
nitrogen to which they are attached form a C5-C9 heterocyclyl ring, wherein said ring is
optionally substituted with 1 to 5 independently selected R44 substituents.
153. The compound according to claim 148, wherein R7 is -Y-(heteroaryl), wherein said -Y- .
(heteroaryl) is optionally substituted with 1 to 5 independently selected R38.
154. The compound according to claim 148, wherein R7 is -Y-(heteroaryl), wherein said -Y-
(heteroaryl) is optionally substituted with one Cj-Q alkyl.
155. The compound according to claim 148, wherein R! is halogen.
156. The compound according to claim 148, wherein R is fluorine.
157. The compound according to claim 148, wherein R17 is selected from the group
consisting of H and Ci-Ce allcyl.
158. The compound according to claim 148, wherein R3S is selected from the group
consisting of-OR37, Ci-Q alkyl and -(CH2)n(5 to 10 membered heterocylic), wherein n is an
integer ranging from 0 to 6.
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WO 2006/010264 PCT/CA2005/001177
159. Tlie compound according to claim 148, wherein R37 is selected from the group
consisting of H and Cj-Ce alkyl.
160. The compound according to claim 148, wherein each R20 is independently selected from
the group consisting of H, halogen and -O-(Ci-C6)alkyl.
161. The compound according to claim 148, wherein two R20 are H and the third R2G is
selected from the group consisting of H, halogen and -O-(Ci-C 162. A compound of the formula (B), that are inhibitors of VEGF receptor signaling and
HGF receptor signaling:
and pharrnaceutically acceptable salts and complexes thereof, wherein
T is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein
each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 1 to 3
RM;
each R20 is independently selected from the group consisting of -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR17, -OCF3j -NRi7R18? -S(O)0-2R17, -S(O)2NR17R17, -C(O)OR17, -C(O)NR17R17, -N(R17)SO2R17, -N(RI7)C(O)Rn, ~N(R!7)C(O)ORn5 -C(O)R17, -C(O)SRn, Ci-Q alkoxy, C;-C4 alkylthio, -O(CB2)natyl -O(CH2)nheteroaryI, -(CH2)o-5(aryi), -(CH2)o-5(heteroaryI)5 CrC6 alkyl, C2-Q alkenyl, C2-Q alkynyl, -CH2(CH2)0^-T25 an optionally substituted CM alkylcarbonyl, CM alkoxy, an amino optionally substituted by CM alkyl optionally substituted by CM aikoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe2, -NHEt and -NEt2, and wherein the aryl, heteroaryl, Cj-Cg alkyl, C2-C6 aikenyl, and C2-C6 alkynyl are optionally substituted;
W is selected from the group consisting of 0, S and NH;
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WO 2006/010264 PCI7CA2005/0OI177
Z is selected from the group consisting of O, or S and NH;
X and X1 are independently selected from the group consisting of H, Ci-Cg alkyl, halo, cyano, or nitro, wherein Cj-C6 alkyl is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C7 cyeloalkyl;
R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, halo,
trihaiomethyi, -CN, -NO2, -NH2, -OR17, -NR17R18, -C(G)ORl\ -C(O)R", d~C4 alkoxy, C1-C4 alicylthio, CVC6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein Ci-C$ alkyl, C2-Ce alkenyl and C2-C6 alkynyl are optionally substituted;
R17 is-selectedXrom the group consisting of H and R18;
R1S is selected from the group consisting of a Q-Cealkyl, an aryl, a, aryl(Ci-C6alkyl), a
heterocyclyl and a heterocyclyl(Ci-C6alkyl), each of which is optionally substituted, or
R17 and R18, taken together with a common nitrogen to which they are attached, form an
optionally substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from the group consisting of N, O, S and P;
R's is selected from the group consisting of-H, -CN, -(CK2)o-5(aryl), -(CK2)o-5(heteroaryl), CV Ce alkyi, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)o-4-T2, an optionally substituted C4-4 alkylcarbonyl, and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe2j -NHEt and -NEt2, and wherein the aryl, heteroaryl, Ci-C6 allcyl, C2-Q5 alkenyl, and C0-C6 alkynyl are optionally substituted;
D is selected from the group consisting of Oh, O, S, NH, N-(Ci-Ce alkyl), or N-Y-(aryl), -N-
OMe, -NCH2OMe and -N-Bn;
Q is selected from the group consisting of C-E and N;
L is N, or CR, wherein R is selected from the group consisting of -H, halo, -CN, Ci-Ce alkyl, C2-C0 alkenyl, and C2-C6 allcynyl, wherein Ci-Cg alkyi, C2-C6 alkenyl. and C2-C6 alkynyl are optionally substituted; and
E is selected from the group consisting of E , E and E , wherein
E1 is selected from the group consisting of -H, halogen, nitro, azido, Cj-Q allcyl, C3-C10 cyeloalkyl, -C(O)NR42R43, -Y-NR42R43, -NR42C(=O)R43, -SO2R42, -SO2NR42R43, -NR37SO2R42, -NR37SO2NR42R43, -C(=N-OR42)R43, -C(=NR42)R43.. -NR37C(=NR42)R43, -
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WO 2006/010264 PCT/CA2005/O01177
C(=NR42)NR37R43, -NR37C(=NR42)NR37R43, -C(O)R42, -CO2R42, -C(O)(heterocyclyl)5 -C(0)(C6-Cio aryl), -C(O)(heteroaryl), -Y-(C6-Cio aryl), -Y-(heteroaryl), -Y- 267

WO 2006/010264 PCT/CA2005/0OII77
membered heterocyclyl), -(CH2)n0(CH2)j0R37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;
each R42 and R43 is independently selected from the group consisting of H, C-i-Q alkyl, Ci-C6 heteroalkyi, -Y-(C3-C10 cycloalkyl), -Y-(C6-C!0 aryl), -Y-(C6-Cio heteroaryl), -Y-(5-10 membered heterocyclic), -Y-O-Y^OR37, -Y1-CO2-R37, and -Y-OR37, wherein the alkyl, heteroalkyi, cycloalkyl, aryl, heteroaryi and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or more substituents independently selected from R44, wherein
Y is a bond or is -(€{R37)(H))n, -
n is an integer ranging from 1 to 6, and
Y'is-CCCR^XH^or
R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1 to 5 R44 substituents, with the proviso that R42 andR4j are not both bonded to the nitrogen directly through an oxygen;
each R44 is independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, ~C(O)R4C', -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR3dC(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, -SO2R36, -NR36SO2R39, -NR36SO2NR37R4!, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C[0 cycloalkyl, -CrC6 alkylamino, -(CHz^OCCH^iNR3^39, ~(CH2)nO(CH2)iOR37, -(CPI2)nOR37, -S(O)j(CrC6 alkyl), -(CH2)n(C6-C]0 aryl), -(CH2)n(5-10 membered heterocyclic), -C(O)(CH2)n(C6-C10 aryl), -(CH2)nO(CH2)j(C6-C10 aryl), -(CH2)nO(CH2),(5 to 10 membered heterocyclic), -C(O)(CH2)n(5 to 10 membered heterocyclic), -(CH2)jNR39(CH2)iNR36R39, -(CH2)JNR39CH2C(O)NR36R39, -(CH2)jNR39(CH2)iNR37C(O)R4V(CH2)jNR39(CH2))10(CH2)iOR37,-(CH2)iNR39(CH2)iS(O)J(CrC6 alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-C10 aryl), and -SO2(CH2)n(5 to 10 membered heterocyclic) wherein, j is an integer from 0 to 2, n is an integer from 0 to 6 and i is an integer ranging from 2 to 6, the -(CH2)i- and -(CH2)nr moieties of the foregoing R44 groups optionally include a carbon-carbon double or triple bond wherein n is an integer from 2 to 6. and the alkyl, aryl and heterocyclic moieties of the foregoing R"" groups are optionally substituted by 1 or more substituents
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WO 2006/010264 PCT/CA2005/001177
independently selected from the group consisting of halo, cyano, nitro, trifiuoromethyl, azido, -OH, -C(O)R40, ~C(O)OR40, -OC(O)R40, -OC(O)OR40,-NR36C(O)R39, -C(O)NR36R39, -(CH2)nNR36R39, -SO2R36, -SO2NR36R39, CrC6 alkyl C3-C,o cycloalkyl, -(CH2)n(C6"Cio aryl), -(CH2)n(5 to 10 membered heterocyclic), -(CH2)nO(CH2)jOR37 and -(CH^nOR37, wherein n is an integer from 0 to 6 and i is an integer from 2 to 6: and
each R40 is independently selected from H, Ci-Cio aikyl, -(eH2)n(C6-Cio aryl), C3-C10
cycloalkyl, and -(CH2)O(5-10 membered heterocydic). wherein n is an integer ranging from 0 to 6;
eachR36 and R39 is independently selected from the. group consisting of H, -OH, Gi-Cg alkyl, "~ C3-C10 eyciualkyl, -(CHaMCs-Cio aryl), -(CH?.),j(5-iG membered heterocyclic), -(CH2)n0(CH2)i0R37? -(CH2)nCN{CH2)f;OR373 -(CH2);]CN(CH3)nR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6", and the alky!, aryi and heterocyelic moieties of the foregoing R?o ana R39 groups are optionally substituted by one or more substituents indepeiidently selected from -OH, halo, cyano, nitro, triiiuoiomelhy], azido, -C(O)R40, -0(0)0^, -CO(O)R40, -OC(O)OR48. -NR37C(O)R41, -C^NR37^", 'NR37R41, -CrC6 alkyj, -(CH^fA-Cio aryl}, -(CH2)n(5 to 10 membered heterocyclic), -(CH2)DO(CH2)jOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that when Rj6 and R39 are both attached to the same nitrogen, then R36 and R39 are not both bonded to the nitrogen directly through an oxygen;
each R37 and R41 is independently selected from the group consisting of K, OR36, Ci-Ce alkyl
at'd C3-C10 cycloalkj'l;
each R6a and R6b is independently selected from the group consisting of hydrogen, -(CZ:!Z6)U-(C3-C6)cycloalkyla-(CZ5Z6)u-(C5-C6)cycloalkenyl,-(CZ5Zfl)u-aryl,-(CZ5Z6)u-heterocycle, (C2-C6)alkenyl, and (Cj-C6)alkyl, which is optionally substituted with 1 to 3 independently selected Y3 groups, where u is 0,1,2, or 3, and wherein when u is 2 or 3, the CZ5Z6 "units may be the same or different, or
R6a and R6b taken together with adjacent atoms can form a heterocycle;
each Z33 Z4, Z5 and Z6 is independently selected from the group consisting of H, F and (Ci-C6)alkyl, or
each Z3 and Z4, or Z5 and Z6 are selected together to form a carbocycle, or
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WO 2006/010264 PCT/CA2005/001111
two ZJ groups on adjacent carbon atoms are selected together to optionally form a carbocycle;
each Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, rnethylguanidino, azido, -C(O)Z7, -OC(O)NH2;, -OC(O) NHZ7, -OC(O)NZ7Z8, -NHC(O)Z7, -NHC(O)NH2, -NHC(O)NHZ7, -NHC(O)NZ7Z8, -C(O)OH, -C(O)OZ7, -C(O)NH2, -C(O)NHZ7,-C(O)NZ7Z8, -P(O)3H2? -P(O)3(Z7)2, -S(O)3H, -S(O)Z7, -S(O)2Z\ -S(O)3Z7, -Z7, -OZ75 -OH, -NH2, -NHZ7, -NZ7Z8, -C(=NH)NH2,-C(=NOH)NH2, -N-morpholino, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)haloalkyl, (C2-C6)haloalkenyl, (C2-C5)haloalkynyl, (CrC6)haLoalkoxy, -(CZ^^NH^-CCZ^NHZ^^^^
X6(CZ9Z10)r(C5-C8)cycloalkenyl, -X6(CZ9Z10)raryI and -X6(CZ9Z!0)rheterocycle, wherein
ris 1,2, 3 or 4;
X6 is selected from the group consisting of O, S, NH, -C(O)-; -C(O)NH-, -C(O)O-, -S(O>, -S(O)2-and-S(O)3-;
Z' and Z" are independently selected from the group consisting of an alky! of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms, an aikynyi of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8 carbon atoms, a cycioaikenyl of 5 to 8 carbon atoms, an aryi of 6 to 14 carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15 carbon atoms, and a heteroaralfcyl of 5 to 14 ring atoms, or
Z7 and Z8 together may optionally form a heterocycle;
Z9 and Z10 are independently selected from the group consisting of H, F, a (Ci-Ci2)alkyl, a (C6-C} Z9 and Z10 are taken together form a carbocycle, or
two Z9 groups on adjacent carbon atoms are taken together to form a carbocycle; or
any two Y2 or Y3 groups attached to adjacent carbon atoms may be taken together to be -O[C(Z9)(ZI0)]rO or -O[C(Z9)(Z10)]r+1, or
any two Y2 or Y3 groups attached to the same or adjacent carbon atoms may be selected together to form a carbocycle or heterocycle; and wherein
any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halogen, SO or SO2 group or to a N, O or S
270

WO 2006/01026-4 PCT7CA2005/001177
atom optionally bears on said group a substituent selected from hydroxy, halogen, (Q-C4)alkyl, (CrC4)alkoxy and an -N[(Ci-C4)alkyl3[(Cl-C4)alIcyl];
E2 is -OCH or -C=C-(CR45R45)n-R46;
R45 is independently selected from the gi"oup consisting of H, a (Ci-C6)alkyl and a (C3-Cs)cycloalkyl;
R46 is selected from the group consisting of heterocyclyl, -N(R47)-C(O)-N(R47)(R48)5 -N(R47)-C(S)-N(R47)(R48), -N(R47)-C(O)-OR4S; -N(R47)-C(O)-(CH2)n~R48, -N(R47)-SO2R47, -(CH2)nNR47R48, ~(CH2)ftOR48, -(CH2)nSR49, -(CH2)nS(O)R49, -(CH2)nS(O)2R49, -OC(O)R49, -OC(O)OR49, -C(O)NR47R48, heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C$)alkoxy, -NO2, (CrC6)alkyl, -CN, -SO2R50 and -(CH2)nNR50R51, and aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-Ca)alkoxy, -NO2} (Ci-C6)alk>i -CN, -SO2R50 and -(CH2)nNR50R31;
R47 and R4S are independently selected from the group consisting of H, (Cj-C6)allcyl, (C3-
C8)cycloallcyl, heterocyclyl, -(CH2)nNR50R51, -(CH2)nORs0! -(CH2)nC(O)R49, -C(O)2R49.. -(CH2/V,SR49>-(CH2)nS(O)R49,-(CII2)nS(O)2R49, -(CH2)nK9, -(CH2)nCN, ar>'loptionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-Cfi^lkoxy, -NO2, (C-Cejalkyi, -CN, -(CH2)nOR49, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2R50 and -(CH2)nNR50R51, and heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy; -NO2, (Ci-C6)alkyl, -CN, -(CH2)nOR4S, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2R50 and -(CH2)nNR50R51, or
R4' and R48, together with the atom to which they are attached, form a 3-8 membered ring;
R49 is selected from the group consisting of (Ci-C6)all 271

WO 2006/010264 PCT/CA2005/001177
-(CH2)nNR50R5i, and heteroaryl optionally substituted with one or more substituents
selected from the group consisting of halo, -CF3, (Ci-Q)alkoxy, -NO2, (C[-C6)alkyl, -
CN, -SO2R50 and -(CH2)QNR5OR51; R50 and R51 are independently selected from the group consisting of H, (C1-C6)alkyl, (C3-
C8)cycloalkyl and -C(O)R45, or
R3U and RJI, together with the atom to which they are attached, form a 3-8 membered ring; and E3 is the group defined by -(Zll)-(Z12)m~(Zn)rah wherein Z11 is heterocyclyl or heterocyclylene;
- Z12^is selected from theLgxoupconsisting_oiOC(O3, OC(S) and C(O); Z13 is selected from the group consisting of heterocyclyl, aralkyl, N(H)R52, (C]-C3)alkyl, -OR52,
halo, S(O)2R56, (CrC3)hydi-oxyalkyi and (CrC3)haloaUcyl; misO or 1; ml isOor 1; R52 is selected from the group consisting of H, -(CH2)qS(O)2R545 R55NR53R535 (Ci-C3)alkyl, -
(CH2)qOR53, -C(O)R54 and -C(O)OR53; q is 0,1,2, 3 or 4; R53is(C,-C3)alkyl;
R54 is (CrC3)alkyi or N(H)R53;
R55is(Ci-C6)allcyl;and
R5° is selected from the group consisting of NH2, (Ci-C3)alkyl and OR52.
163. The compound according to claim 161, represented by the formula B-0:

and pharmaceutically acceptable salts and complexes thereof, wherein Z is O or S;
X and XJare independently selected from the group consisting of H, Ci-Ce alkyl, halo, cyano, or nitro, wherein Q-Ce alkyl is optionally substituted;
272

WO 2006/010264 PCT/CA2005/001177
R1, R2, R3, R4, R5 and Rb are independently selected from the group consisting of hydrogen,
halo, Ci-Co alkyl, C2-C6 alkenyl and C2-Q alkynyl, wherein Cj-Ce alkyl, C2-C6 alkenyi
and C^-Ce alkynyl are optionally substituted; Q is O, S, NH, N(CrC6 alkyl), or N-Y-(aryl); L is N, or CR, wherein R is halo, -CN, Cf-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein
Cj-Cs aik>'l, C2-C6 alkenyl, and Ci-C-6 alkynyl are optionally substituted; and R7 is selected from the group consisting of H, halogen, Cj-Q alkyl, -C(=O)NR9R10, -
C(=O)(aryl), -C(=O)(heterocyclyl), -C(=O)(heteroaryl), -Y-(aryl), -Y-(heterocyclyl), -
Y-(heteroaryl), -Y-NR9R10, -SO?NR9R10 and CO2R9, wherein A-C6 alkyl, aryl,
heterocyclyl and heteroaryl are each optionally substituted; R^ aad R10 are independently selected from the group consisting of H, Cj-Ce alkyl, -Y-
(cycloalkyl), -Y-(aryl), -Y-(heterocycIyl), -Y-(heteroaryl), -Y-O-Y^O-R11, -Y'-CO2-
R11, and -Y-O-R11, wherein Cj-Cg alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl
are each optionally substituted, or R9 and R10 are taken together with the nitrogen to which they are attached to form a C5-C9
heterocyclyl ring or a heteroaryi ring, wherein said ring is optionally substituted; R8 is selected from the group consisting of H, halo and Ci-Cg alkyl, wherein C1-C6 alkyl is
optionally substituted;
Y is a bond or is -(C(RI')(H))r, wherein t is an integer from 1 to 6; Y1is-(C(R")(H))r,and Ru at each occurrence is independently H or Ci-Q alkyi, wherein CrC-e alkyl is optionally
substituted.
164. The compound according to claim 162, wherein X and X1 are both hydrogen.
165. The compound according to claim 162, wherein R1 is hydrogen or halogen.
166. The compound according to claim 162, wherein R1 is fluorine.
167. The compound according to claim 162, wherein R4 is hydrogen or halogen.
168. The compound according 10 claim 162, wherein R4 is fluorine.
169. The compound according to claim 162, wherein R2, R3, R5S and R6 are each hydrogen.
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WO 2006/010264 PCT/CA2005/001177
170. The compound according to claim 162, wherein Q is S, N(Cj -Q alkyl), or N-Y-(aryl).
171. The compound according to claim 162, wherein L is CH or N.
172. The compound according to claim 162, wherein R8 is selected from the group consisting
of H, halo and Cj-C6 alkyl, wherein CrC6 alkyl is optionally substituted with OH or NRI4R15}
where R14 and R15 are independently H or Cr-C* alkyl, or R14 and R15 are taken together with
the nitrogen to which they are attached to form a C5-C9 heterocyclyl ring or a heteroaryl ring,
wherein said ring is optionally substituted.
- - 173. -The compound-according to-claimJ625 wherein R7 is_ selected from thgLgroup consisting of a halogen, d-C6 alkyl, -CONR9R10, -SO2NH2, -SO2NR9R10, -Y-heterocycle -Y-heteroaryl, -S-aryl, -S-Ci-Ce alkyl, -SO-CrC6 alkyl and -SO2-CrC6 alkyl, wherein Cj-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocycle, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
174. The compound according to claim 162, wherein R7 is -CONR9R10.
175. The compound according to claim 173, wherein R and R1 are independently selected
from the group consisting of H, CrC6 alkyl, -Y-O-R11, ~Y-(heterocyeie), -Y1-CO2-RU and -Y-
(aryl), wherein Ci-Ce alkyl is unsubstituted or is substituted with one or two of hydroxy or
halogen, and the heterocycle, and aryl are unsubstituted or are substituted with one or two of
alkoxy, alkyl, or haloalkyl.
176. The compound according to claim 173, wherein R9 and R10 are taken together with the
nitrogen lo which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with
one or two of alkoxy, alkyl, or haloalkyl.
177. The compound according to claim 162, wherein R7 is selected from the group consisting
of H, halogen, C,-C6 alkyf, -SO2NR9R10, -C(-O)(heterocyclyl)3 -Y-(heterocyclyl), -Y-
(heteroaryl), -S-aryl, -S-Cj-C6 alkyl, -SO-Cj-C6 alkyl and -SO2-CrC6 alkyl, wherein Ci-C6
alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the
heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy,
alkyl, or haloalkyl.
274

WO 2006/010264 PCT/CA2005/001I77
178. The compound according to claim 162, wherein Z is sulfur.
179. The compound according to claim 16], represented by the formula B-1:

and pharmaceutically acceptable salts and complexes thereof, wherein
R1 is selected from the group consisting of hydrogen, halo. Ci-Cg alkyl, C2-C Q alkynyl, wherein Ci-C6 alkyl, C2-Q alkeny! and C2-Q alkynyl are optionally
substituted; R7 is selected from the group consisting of H, halogen, Ci-C6 alkyl, -C(-0)NR9Rio5 -
C(=O)(aryl), -C(=O)(heterocyclyl), -C(=0)(heteroaryl), -Y-(aryi), -Y-(heterocyciyl), -
Y-Cheteroaiyl), -Y-NR9Rl0! ~SO2NRSR1() a.id CO2R9, wherein C-rC6 alkyl, aryl5
heterocycle and heteroaryl are each independently optiop.a!jy_sub5tiruted; R9 and R10 are independently selected from the group consisting of H, Cj-Cg alkyl, -Y-
(oycloalkyl), -Y-(aiyl)s -Y-(iieterocyciyl), -Y-(heleroaiyl), -Y-O-Y'-O-R", -Y1-CO2~
Rl\ and -Y-O-R'1, wherein CrQ alkyl, cycloalkyl, aryl, heterocj'cle, and heteroaryl
are each optionally substituted, or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Y is a bond or is ~(C(Ru)(H))r, -wherein t is an integer from 1 to 6; Yiis-(C(R!I)(H))r; R!1 at each occurrence is independently H or Cj-Ce alkyl, wherein Ci-C^ alkyl is optionally
substituted; and R12 is selected from the group consisting of EL Ci-Ct alkyl and -Y-(aryl), wherein C1-C6 alkyl
and aryl are optionally substituted.
180. The compound according to claim 178, wherein R1 is hydrogen or halogen.
181. The compound according to claim 178, wherein R1 is fluorine.
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WO 2006/010264 PCT/CA2005/001177
182. The compound according to claim 178, wherein R12 is unsubstituted C1-C3 alkyl or
unsubstituted benzyl.
183. The compound according to claim 178, wherein R7 is -C(O)NR9Ri0.
184. The compound according to claim 178, wherein R7 is selected from the group consisting
of

wherein the members of said group are optionally substituted by 1 to 3 independently selected R38.
276
185. The compound according to claim 178, wherein R7 is selected from the group consisting of


WO 2006/030264 PCT/CA2005/001177

wherein the members of said group are optionally substituted with 1 to 3 independently selected R38.
186. A pharmaceutical composition comprising the compound according to claim 1 and a
pharmaceutically acceptable carrier.
187. A pharmaceutical compositioin comprising the compound according to claim 161 and a
pharmaceutically acceptable carrier.
188. A method of inhibiting VEGF receptor signaling and HGF receptor signaling, the
method comprising contacting the receptor with a receptor inhibiting amount of a compound
according to claim 1.
189. A method of inhibiting VEGF receptor signaling and HGF receptor signaling, the
method comprising contacting the receptor with a receptor inhibiting amount of a compound
according to claim 161.
190. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in a cell,
the method comprising contacting the cell with a receptor inhibiting amount of a compound
according to claim 1.
191. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in a cell,
the method comprising contacting the cell with a receptor inhibiting amount of a composition
according to claim 185.
192. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in a cell,
the method comprising contacting the cell with a receptor inhibiting amount of a compound
according to claim 161.
193. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in a cell,
the method comprising contacting the cell with a receptor inhibiting amount of a composition
according to claim 186.
277

WO 2006/010264 PCT/CA2005/001177
194. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in an
animal, the method comprising administering to the animal a receptor inhibiting amount of a
composition according to claim 185.
195. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in an
animal, the method comprising administering to the animal a receptor inhibiting amount of a
composition according to claim 186.
196. The method of claim 193, wherein the animal is a human.
197. Themethodofclaim-194, wherein the animal is ahuman. _ ._
198. A method of inhibiting proliferative activity of a cell, the method comprising contacting
the cell with an effective proliferative inhibiting amount of a compound according to claim 1.
199. A method of inhibiting proliferative activity of a cell, the method comprising contacting
the cell with an effective proliferative inhibiting amount of a compound according to claim
161.
200. A method of treating a cell proliferative disease in a patient, the method comprising
administering to the patient in need of such treatment an effective therapeutical amount of a
composition according to claim 185.
201. A method of treating a cell proliferative disease in a patient, the method comprising
administering to the patient in need of such treatment an effective therapeutical amount of a
composition according to claim 186.
202. The method of claim 199, wherein the patient is a human.
203. The method of claim 201, wherein the cell proliferative disease is cancer.
204. The method of claim 200, wherein the patient is a human.
205. The method of claim 203, wherein the ceil proliferative disease is cancer.
206. A method of inhibiting tumor growth in a patient, the method comprising administering
to the patient in need thereoof an effective therapeutical amount of a composition according to
claim 185.
278

WO 2006/010264 PCT/CA2005/001177
207. A method of inhibiting tumor growth in a patient, the method comprising administering
to the patient in need thereof an effective therapeutical amount of a composition according to
claim 186.
208. The method of claim 205, wherein the patient is a human.
209. The method of claim 206, wherein the patient is a human.

279

The invention rolates to the inhibition of vascular endthellal growth factor (VEGF) receptor signaling and hep-atocyre growth fetor (HGF) receptor signaling The Invention provides eompounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

Documents:

00305-kolnp-2007-assignment-1.1.pdf

00305-kolnp-2007-correspondence-1.1.pdf

00305-kolnp-2007-form-3-1.1.pdf

0305-kolnp-2007-abstract.pdf

0305-kolnp-2007-assignment.pdf

0305-kolnp-2007-claims.pdf

0305-kolnp-2007-correspondence others.pdf

0305-kolnp-2007-description (complete).pdf

0305-kolnp-2007-form1.pdf

0305-kolnp-2007-form3.pdf

0305-kolnp-2007-form5.pdf

0305-kolnp-2007-international publication.pdf

0305-kolnp-2007-international search authority report.pdf

0305-kolnp-2007-pct form.pdf

0305-kolnp-2007-priority document.pdf

305-KOLNP-2007-ABSTRACT 1.1.pdf

305-KOLNP-2007-AMANDED CLAIMS.pdf

305-KOLNP-2007-AMANDED PAGES OF SPECIFICATION.pdf

305-KOLNP-2007-ASSIGNMENT 1.1.pdf

305-KOLNP-2007-ASSIGNMENT 1.2.pdf

305-KOLNP-2007-ASSIGNMENT.pdf

305-KOLNP-2007-CERTIFIED COPIES(OTHER COUNTRIES).pdf

305-KOLNP-2007-CORRESPONDENCE 1.1.pdf

305-KOLNP-2007-CORRESPONDENCE-1.1.pdf

305-KOLNP-2007-CORRESPONDENCE.pdf

305-KOLNP-2007-DESCRIPTION (COMPLETE) 1.1.pdf

305-KOLNP-2007-EXAMINATION REPORT REPLY RECIEVED.pdf

305-KOLNP-2007-EXAMINATION REPORT.pdf

305-KOLNP-2007-FORM 1-1.1.pdf

305-KOLNP-2007-FORM 1-1.2.pdf

305-KOLNP-2007-FORM 13 1.1.pdf

305-KOLNP-2007-FORM 13-1.1.pdf

305-KOLNP-2007-FORM 13.pdf

305-KOLNP-2007-FORM 18 1.1.pdf

305-kolnp-2007-form 18.pdf

305-KOLNP-2007-FORM 2-1.1.pdf

305-KOLNP-2007-FORM 2.pdf

305-KOLNP-2007-FORM 3-1.1.pdf

305-KOLNP-2007-FORM 3-1.2.pdf

305-KOLNP-2007-FORM 3-1.3.pdf

305-KOLNP-2007-FORM 3.pdf

305-KOLNP-2007-FORM 5 1.1.pdf

305-KOLNP-2007-FORM 5-1.1.pdf

305-KOLNP-2007-FORM 5.pdf

305-KOLNP-2007-FORM 6 1.1.pdf

305-KOLNP-2007-FORM 6-1.1.pdf

305-KOLNP-2007-FORM 6.pdf

305-KOLNP-2007-GPA.pdf

305-KOLNP-2007-GRANTED-ABSTRACT.pdf

305-KOLNP-2007-GRANTED-CLAIMS.pdf

305-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

305-KOLNP-2007-GRANTED-FORM 1.pdf

305-KOLNP-2007-GRANTED-FORM 2.pdf

305-KOLNP-2007-GRANTED-SPECIFICATION.pdf

305-KOLNP-2007-OTHERS 1.1.pdf

305-KOLNP-2007-OTHERS-1.2.pdf

305-KOLNP-2007-OTHERS.pdf

305-KOLNP-2007-PA.pdf

305-KOLNP-2007-PETITION UNDER RULE 137-1.1.pdf

305-KOLNP-2007-PETITION UNDER RULE 137.pdf

305-KOLNP-2007-REPLY TO EXAMINATION REPORT 1.1.pdf

abstract-00305-kolnp-2007.jpg


Patent Number 251921
Indian Patent Application Number 305/KOLNP/2007
PG Journal Number 16/2012
Publication Date 20-Apr-2012
Grant Date 17-Apr-2012
Date of Filing 25-Jan-2007
Name of Patentee METHYLGENE, INC.
Applicant Address 7220 FREDERICK-BANTING, ST. LAURENT, QUEBEC, H4S 2A1 CANADA
Inventors:
# Inventor's Name Inventor's Address
1 ZHAN, LIJIE 2540, COTE-VERTU, MONTREAL, QUEBEC H4R 1P5
2 VAISBURG, ARKADLL 10 RIVERWOOD GROVE, KIRKLAND, QUEBEC H9J 2X2
3 RAEPPEL, FRANK 5582, GATINEAU AVENUE, MONTREAL, QUEBEC H3T 1X7
4 SAAVEDRA, OSCAR MARIO 749, AVENUE OUTREMONT, OUTREMONT, QUEBEC H2V 3N2
5 BERSTEIN, NAOMY 6635, CH MACKLE, #604 COTE SAINTE-LUC, QUEBEC H4W 2Z7
6 GRANGER, MARIE-CLAUDE 250, RUE BROSSEAU, LAPRAIRIE, QUEBEC J5R 4M5
7 WILLIAM, STEPHEN 443 NORTE-DAME H., #2 MONTREAL, QUEBEC H2Y 1C9
PCT International Classification Number C07D495/04; A61K31/4355; A61K31/4365
PCT International Application Number PCT/CA2005/001177
PCT International Filing date 2005-07-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/592,913 2004-07-30 U.S.A.
2 60/683,038 2005-05-20 U.S.A.