WO2005051906A2 - Heterocyclic inhibitors of mek and methods of use thereof - Google Patents

Heterocyclic inhibitors of mek and methods of use thereof Download PDF

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Publication number
WO2005051906A2
WO2005051906A2 PCT/US2004/039053 US2004039053W WO2005051906A2 WO 2005051906 A2 WO2005051906 A2 WO 2005051906A2 US 2004039053 W US2004039053 W US 2004039053W WO 2005051906 A2 WO2005051906 A2 WO 2005051906A2
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Prior art keywords
heteroaryl
alkyl
aryl
halogen
cycloalkyl
Prior art date
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PCT/US2004/039053
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French (fr)
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WO2005051906A3 (en
Inventor
Eli Wallace
Jeongbeob Seo
Joseph P. Lyssikatos
Hong Woon Yang
T. Brian Hurley
Jim Blake
Allison L. Marlow
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Array Biopharma Inc.
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Publication date
Application filed by Array Biopharma Inc. filed Critical Array Biopharma Inc.
Priority to AU2004293436A priority Critical patent/AU2004293436B2/en
Priority to JP2006541579A priority patent/JP4842137B2/en
Priority to CA002546486A priority patent/CA2546486A1/en
Priority to EP04811721A priority patent/EP1689406A4/en
Publication of WO2005051906A2 publication Critical patent/WO2005051906A2/en
Publication of WO2005051906A3 publication Critical patent/WO2005051906A3/en

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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to a series of novel heterocyclic compounds that are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals.
  • This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
  • MAP kinase pathways are important regulator of cell growth, proliferation and differentiation.
  • growth factors through receptor activation (i.e. PDGF or EGF and others), activate MAP kinase pathways.
  • PDGF receptor activation
  • MAP kinase pathways One of the most important and most well understood MAP kinase pathways involved in normal and uncontrolled cell growth is the Ras/Raf kinase pathway. Active GTP -bound Ras results in the activation and indirect phosphorylation of Raf kinase.
  • Raf then phosphorylates MEKl and 2 on two serine residues (S218 and S222 for MEKl and S222and S226 for MEK2) (Aim et al, Methods in Enzymology, 2001, 332, 417-431).
  • Activated MEK then phosphorylates its only known substrates, the MAP kinases, ERKl and 2.
  • ERK phosphorylation by MEK occurs on Y204 and T202 for ERKl and Y185 and T183 for ERK2 (Ahn et al, Methods in Enzymology, 2001, 332, 417-431).
  • ERK Phosphorylated ERK dimerizes and then translocates to the nucleus where it accumulates (Khokhlatchev et al, Cell, 1998, 93, 605-615). In the nucleus, ERK is involved in several important cellular functions, including but not limited to nuclear transport, signal transduction, DNA repair, nucleosome assembly and translocation, and mRNA processing and translation (Ahn et al, Molecular Cell, 2000, 6, 1343-1354). Overall, treatment of cells with growth factors leads to the activation of ERKl and 2 which results in proliferation and, in some cases, differentiation (Lewis et al, Adv. Cancer Res., 1998, 74, 49-139).
  • bRaf mutations have been identified in more than 60% of malignant melanoma (Davies, H. et al, Nature, 2002, 417, 949-954). These mutations in bRaf result in a constitutively active MAP kinase cascade. Studies of primary tumor samples and cell lines have also shown constitutive or overactivation of the MAP kinase pathway in cancers of pancreas, colon, lung, ovary and kidney (Hoshino, R. et al, Oncogene, 1999, 18, 813-822). Hence, there is a strong correlation between cancers and an overactive MAP kinase pathway resulting from genetic mutations.
  • MEK is a key player in this pathway as it is downstream of Ras and Raf. Additionally, it is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERKl and 2. Inhibition of MEK has been shown to have potential therapeutic benefit in several studies.
  • small molecule MEK inhibitors have been shown to inhibit human tumor growth in nude mouse xenografts, (Sebolt-Leopold et al, Nature-Medicine, 1999, 5 (7), 810-816; Trachet et al., AACR April 6-10, 2002, Poster #5426; Tecle, H., IBC 2 nd International Conference of Protein Kinases, September 9-10, 2002), block static allodynia in animals (WO 01/05390 published January 25, 2001) and inhibit growth of acute myeloid leukemia cells (Milella et al, J. Clin. Invest., 2001, 108 (6), 851-859).
  • This invention provides for novel heterocyclic compounds, and pharmaceutically acceptable salts and prodrugs thereof that are useful in the treatment of hype ⁇ roliferative diseases. Specifically, one aspect the present invention relates to compounds of Formulas I-V that act as MEK inhibitors.
  • one embodiment of the present invention provides compounds of the Formulas I-V:
  • R 6 is trifluoromethyl, Ci-Cio alkyl, C 3 -C l0 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl
  • R 11 , R 12 , R 13 or R 14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0022] W is heteroaryl, heterocyclyl, -C(O)OR 3 , -C(O)NR 3 R 4 , -C(O)NR 4 OR 3 , - C(O)R OR 3 , -C(O)NR 4 SO 2 R 3 , -C
  • j is 0, 1 or 2.
  • compositions that inhibit MEK comprising compounds of Formulas I-V.
  • the invention is also directed to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of compounds of Formula I-V. Methods of making the compounds of Formula I-V are also described.
  • the present invention provides a method of using the compounds of this invention to treat diseases or medical conditions mediated by MEK, such as cancer.
  • this invention provides a method for treatment of a hype ⁇ roliferative disorder or an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of Formulas I-V or a pharmaceutically acceptable salt or prodrug thereof in an amount effective to treat said hype ⁇ roliferative disorder.
  • the present invention provides methods for treating or preventing an MEK-mediated condition, comprising administering to a human or animal in need thereof a pharmaceutical composition comprising a compound of Formula I-V, or a pharmaceutically-acceptable salt or in vivo cleavable prodrug thereof, in an amount effective to treat or prevent said MEK-mediated condition.
  • inventive compounds may further be used advantageously in combination with other known therapeutic agents.
  • inventive compounds may further be used advantageously in combination with other known therapeutic agents.
  • Yet another embodiment of the present invention provides pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formulas I-V or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
  • An additional aspect of the invention is the use of a compound of Formula I,
  • Formula II, Formula III, Formula IV or Formula V in the preparation of a medicament for the treatment or prevention of a disease or medical condition mediated by MEK in a warmblooded animal, preferably a mammal, more preferably a human, suffering from such disorder. More particularly, the invention includes the use of a compound of the invention in the preparation of a medicament for the treatment or prevention of a hype ⁇ roliferative disorder or an inflammatory condition in a mammal.
  • Figure 1 shows a reaction scheme for the synthesis of compounds 6-8 and 10.
  • Figure 2 shows a reaction scheme for the synthesis of compounds 11-17.
  • Figure 3 shows a reaction scheme for the synthesis of compounds 22-25.
  • Figure 4 shows a reaction scheme for the synthesis of compound 27.
  • Figure 5 shows a reaction scheme for the synthesis of compounds 28-33.
  • Figure 6 shows a reaction scheme for the synthesis of compounds 35-37.
  • Figure 7 shows a reaction scheme for the synthesis of compound 40.
  • Figure 8 shows a reaction scheme for the synthesis of compound 43.
  • Figure 9 shows a reaction scheme for the synthesis of compounds 44-45.
  • Figure 10 shows a reaction scheme for the synthesis of compound 46.
  • Figure 11 shows a reaction scheme for the synthesis of compound 47.
  • Figure 12 shows a reaction scheme for the synthesis of compound 38.
  • Figure 13 shows a reaction scheme for the synthesis of compound 38.
  • Figure 14 shows a reaction scheme for the synthesis of compound 55.
  • Figure 15 shows a reaction scheme for the synthesis of compound 59.
  • Figure 16 shows a reaction scheme for the synthesis of compound 62.
  • Figure 17 shows a reaction scheme for the synthesis of compounds 63-68.
  • Figure 18 shows a reaction scheme for the synthesis of compounds 69-70.
  • Figure 19 shows a reaction scheme for the synthesis of compounds 75-78.
  • Figure 20 shows a reaction scheme for the synthesis of compounds 81-84.
  • Figure 21 shows a reaction scheme for the synthesis of compounds 85-91.
  • Figure 22 shows a reaction scheme for the synthesis of compounds 93-98.
  • Figure 23 shows a reaction scheme for the synthesis of compounds 99-104.
  • Figure 24 shows a reaction scheme for the synthesis of compounds 105-111.
  • inventive compounds of the Formulas I-V and the pharmaceutically acceptable salts and prodrugs thereof of this invention are useful in the treatment of hype ⁇ roliferative diseases.
  • one aspect the present invention relates to compounds of Formula I-V that act as MEK inhibitors. More specifically, one embodiment of the invention provides compounds, including pharmaceutically acceptable salts, prodrugs and solvates thereof, having the general Formula I:
  • Y is NR 15 , O, S, S(O), S(O) 2 , C(O) or CH 2 ;
  • Z is C or N
  • R , R , R , and R are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR 11 , -OR 3 , -C(O)R 3 , -C(O)OR 3 , -NR 4 C(O)OR 6 , -OC(O)R 3 , -NR 4 SO 2 R 6 , -SO 2 NR 3 R 4 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 , -NR 3 R 4 , Ci-Cio alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C ⁇ 0 alkynyl, C3-C10 cycloal
  • alkyl C 2 -C ⁇ 0 alkenyl, C 2 -C ⁇ 0 alkynyl, C 3 -Ci 0 cycloalkyl, C 3 -C ⁇ 0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR u SO 2 R 14
  • R 3 and R 4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR n SO 2 R 14 , -SO 2 NR n R 12 , -C(O)R ⁇ , C(O)OR H , -OC(O)R u , - NR"C(O)OR 14 , -NR ⁇ C(O)R 12 , -C(O)NR ⁇ R 12 , -SR 1 1 , -S(O)R 14 , -SO 2 R 14 , -NR U R 12 , -NR n C(O)NR 12 R 13 , -NR ⁇
  • R 4 and R 5 independently are hydrogen or C ⁇ -C 6 alkyl, or
  • R 4 and R 5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR n SO 2 R 14 , -SO 2 R n R 12 , -C(O)R u , C(O)OR ⁇ , -OC(O)R ⁇ , - NR"C(O)OR 14 , -NR u C(O)R 12 , -C(O)NR"R 12 , -SR 1 1 , -S(O)R 14 , -SO 2 R 14 , -NR ⁇ R 12 , -NR n C(O)NR 12 R 13 ,
  • C(O)R 4 OR 3 -C(O)NR 4 SO 2 R 3 , -C(O)(C 3 -C, 0 cycloalkyl), -C(O)(C ⁇ -C, 0 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR 3 OR 3 , wherein any of said heteroaryl, heterocyclyl, -C(O)OR 3 , -C(O)NR 3 R 4 , -C(O)NR 4 OR 3 , -C(O)R 4 OR 3 , -C(O)NR 4 SO 2 R 3 , -C(O)(C 3 -C ⁇ o cycloalkyl), -C(O)(C r C 10 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocycly
  • j is 0, 1 or 2.
  • W is selected from
  • Figures 1 -2 show non-limiting examples of the synthesis of compounds of this invention having the general Formula I.
  • this invention further includes compounds of the general Formula II:
  • Y is NR 15 , O, S, S(O), S(O) 2 , C(O) or CH 2 ;
  • R 1 , R 2 , R 8 , R 9 , R 10 and R 20 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR 11 , -OR 3 , -C(O)R 3 , -C(O)OR 3 , -NR 4 C(O)OR 6 , -OC(O)R 3 , -NR SO 2 R 6 , -SO 2 NR 3 R 4 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 , -NR 3 R 4 ,
  • R 4 and R 5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR ⁇ SO 2 R 14 , -S0 2 NR"R 12 , -C(O)R ⁇ , C(O)OR ⁇ , -OC(O)R 1 !
  • -NR n C(O)OR 14 , -NR"C(O)R 12 , -C(O)NR ⁇ R 12 , -SR 1 1 , -S(O)R 14 , -SO 2 R 14 , -NR ⁇ R 12 , -NR ⁇ C(O)NR 12 R 13 , -NR ⁇ C(NCN)NR ,2 R 13 , -OR 1 1 , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
  • R 6 is trifluoromethyl, Ci-Cio alkyl, C 3 -C ⁇ o cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR SO 2 R , -SO 2 NR R , -C(O)R", C(O)OR ⁇ , -OC(O)R", -NR"C(O)OR 14 , -NR n
  • W is heteroaryl, heterocyclyl, -C(O)OR 3 , -C(O)NR 3 R 4 , -C(O)NR 4 OR 3 , -
  • C2-C10 alkenyl, C 2 -C ⁇ o alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR 3 R 4 and -OR 3 ;
  • R 15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl;
  • m is 0, 1, 2, 3, 4 or 5;
  • this invention relates to compounds of the general Formula III:
  • Y is NR 15 , O, S, S(O), S(O) 2 , C(O) or CH 2 ;
  • R 1 , R 2 , R 8 , R 9 , R 10 and R 20 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR 11 , -OR 3 , -C(O)R 3 , -C(O)OR 3 , -NR 4 C(0)OR 6 , -OC(O)R 3 , -NR 4 SO 2 R 6 , -SO 2 NR 3 R 4 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 , -NR J R 4 , d-Cio alkyl, C 2 -C10 alkenyl, C 2 -C,o alkynyl, C 3 , -
  • R 3 is hydrogen, trifluoromethyl, d-Cio alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C) 0 alkynyl,
  • R 4 and R 5 independently are hydrogen or C]-C 6 alkyl, or
  • R 4 and R 5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR u SO 2 R 14 , -S0 2 NR"R 12 , -C(O)R n , C(O)OR n , -OC(O)R n , - NR n C(O)OR 14 , -NR ⁇ C(O)R 12 , -C(O)NR ⁇ R 12 , -SR 1 1 , -S(O)R 14 , -SO 2 R 14 , -NR ⁇ R 12 , -NR"C(O)NR ,2 R
  • -C(O)R 4 OR 3 , -C(O)NR 4 SO 2 R 3 , -C(O)(C 3 -C ⁇ 0 cycloalkyl), -C(O)(C ⁇ -C, 0 alkyl), -C(O)(aryl), -C( ⁇ heteroaryl), -C(O)fheterocyclyl) or CR 3 OR 3 , wherein any of said heteroaryl, heterocyclyl, -C(O)OR 3 , -C(O)NR 3 R 4 , -C(O)NR 4 OR 3 , -C(O)R 4 OR 3 , -C(O)NR 4 SO 2 R 3 , -C(O)(C 3 -C ⁇ o cycloalkyl), -C(O)(C ⁇ -C ⁇ 0 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heter
  • j is 0, 1 or 2.
  • Figures 6-18 show non-limiting examples of the synthesis of compounds of this invention having the general Fo ⁇ nula III.
  • this invention relates to compounds of the general
  • R 1 , R 2 , R 8 , R 9 and R 10 are independently hydrogen, hydroxy, halogen, cyanc nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethox) trifluoromethoxy, azido, -SR 1 1 , -OR 3 , -C(O)R 3 , -C(O)OR 3 , -NR 4 C(O)OR 6 , -OC(O)R 2 -NR SO 2 R 6 , -SO 2 NR 3 R 4 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R
  • R 3 is hydrogen, trifluoromethyl, C_-C.o alkyl, -Cio alkenyl, C 2 -C ⁇ o alkynyl,
  • R 4 and R 5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR ⁇ SO 2 R 14 , -SO 2 NR u R 12 , -C(O)R n , C(O)OR u , -OC(O)R n , - NR"C(O)OR 14 , -NR"C(0)R 12 , -C(O)NR u R 12 , -SR", -S(O)R 14 , -SO 2 R 14 , -NR"R 12 , -NR u C(O)NR 12 R 13 , -NR"C(
  • m is 0, 1, 2, 3, 4 or 5;
  • j is 0, 1 or 2.
  • Figures 19-21 show non- limiting examples of the synthesis of compounds of this invention having the general Formula IV.
  • this invention relates to compounds of the general
  • Y is NR 15 , O, S, S(O), S(O) 2 , C(O) or CH 2 ;
  • R , R , R , R and R are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR n , -OR 3 , -C(O)R 3 , -C(O)OR 3 , -NR 4 C(O)OR 6 , -OC(O)R 3 , -NR 4 SO 2 R 6 , -SO 2 NR 3 R 4 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 , -NR 3 R 4 , Ci-do alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C ⁇ 0 alkynyl, C 3 -C ⁇ 0 alkyn
  • R 7 is hydrogen, trifluoromethyl, Ci-Cio alkyl, C 2 -C ⁇ 0 alkenyl, -Cio alkynyl,
  • R 3 and R 4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO 2 R 14 , -SO 2 NR M R 12 , -C(O)R n , C(O)OR u , -OC(O)R", - NR"C(O)OR 14 , -NR u C(O)R 12 , -C(O)NR l l R 12 , -SR 1 1 , -S(O)R 14 , -SO 2 R 14 , -NR ⁇ R 12 , -NR"C(0)NR 12 R 13 , -NR"C(NCN)
  • R 4 and R 5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO 2 R 14 , -SO 2 NR ⁇ R 12 , -C(O)R n , C(O)OR n , -OC(O)R n , - NR ⁇ C(O)OR 14 , -NR"C(O)R 12 , -C(O)NR u R 12 , -SR U , -S(O)R 14 , -SO 2 R 14 , -NR U R 12 , -NR"C(O)NR 12 R 13 , -NR
  • m is 0, 1, 2, 3, 4 or 5;
  • j is 0, 1 or 2.
  • Figures 22-24 show non-limiting examples of the synthesis of compounds of this invention having the general Formula V.
  • the terms "Ci-Cio alkyl”, “alkyl” and “lower alkyl” as used herein refer to a saturated linear or branched-chain monovalent hydrocarbon radical having one to ten carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described below.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, heptyl, octyl, and the like.
  • d-Cio alkenyl refers to linear or branched-chain monovalent hydrocarbon radical having two to 10 carbon atoms and at least one double bond, and include, but is not limited to, ethenyl, propenyl, l-but-3-enyl, l-pent-3- enyl, l-hex-5-enyl and the like, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • d-Cio alkynyl refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentyn- 2-yl and the like, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or any substituent as defined herein, wherein the allyl may be optionally substituted independently with one or more substituents described herein.
  • the terms "carbocycle,” “carbocyclyl,” “cycloalkyl” or “C 3 -C 10 cycloalkyl” refer to saturated or partially unsaturated cyclic hydrocarbon radical having from three to ten carbon atoms.
  • cycloalkyl includes monocyclic and polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated cycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • the cycloalkyl may be optionally substituted independently in one or more substitutable positions with various groups.
  • such cycloalkyl groups may be optionally substituted with, for example, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C ⁇ -C 6 )alkylamino, di(C ⁇ -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 haloalkoxy, amino(C ⁇ -C 6 )alkyl, mono(d- C 6 )alkylamino(C ⁇ -C 6 )alkyl or di(C ⁇ -C 6 )alkylamino(C ⁇ -C ⁇ )alkyl.
  • heteroalkyl refers to saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms, wherein at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S, and wherein the radical may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical).
  • the heteroalkyl radical may be optionally substituted independently with one or more substituents described herein.
  • heteroalkyl encompasses alkoxy and heteroalkoxy radicals.
  • heterocycloalkyl refers to a saturated or partially unsaturated carbocyclic radical of 3 to 10 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms being C, where one or more ring atoms may be optionally substituted independently with one or more substituent described below.
  • the radical may be a carbon radical or heteroatom radical.
  • the term further includes bicyclic and tricyclic fused ring systems which include a heterocycle fused to one or more carbocyclic or heterocyclic rings.
  • Heterocycloalkyl also includes radicals where heterocycle radicals are fused with aromatic or heteroaromatic rings.
  • heterocycloalkyl rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, mo ⁇ holino, thiomo ⁇ holino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- pyrrolinyl,
  • Spiro moieties are also included within the scope of this definition.
  • the foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible.
  • a group derived from py ⁇ ole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N- attached) or imidazol-3-yl (C-attached).
  • heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • such heterocycle groups may be optionally substituted with, for example, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C ⁇ -C 6 )alkylamino, di(C r C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, d- C 6 haloalkyl, C ⁇ -C 6 haloalkoxy, amino(C ⁇ -C 6 )alkyl, mono(C ⁇ -C 6 )alkylamino(C ⁇ -C 6 )alkyl or di(C i -C 6 )alkylamino(C i -C 6 )alkyl.
  • aryl refers to a monovalent aromatic carbocyclic radical having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, and hydroxy.
  • heteroaryl refers to a monovalent aromatic radical of 5-, 6-, or 7- membered rings which includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur.
  • heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, py ⁇ olyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazo
  • Heteroaryl groups are optionally mono-, di-, or trisubstituted with, e.g., substituents including, but not limited to, halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.
  • halogen represents fluorine, bromine, chlorine, and iodine.
  • arylalkyl means an alkyl moiety (as defined above) substituted with one or more aryl moiety (also as defined above). More preferred arylalkyl radicals are aryl-C ⁇ . -alkyls. Examples include benzyl, phenylethyl, and the like.
  • heteroarylalkyl means an alkyl moiety (as defined above) substituted with a heteroaryl moiety (also as defined above). More prefe ⁇ ed heteroarylalkyl radicals are 5- or 6-membered heteroaryl-C ⁇ - -alkyls. Examples include oxazolylmethyl, pyridylethyl and the like.
  • heterocyclylalkyl means an alkyl moiety (as defined above) substituted with a heterocyclyl moiety (also defined above). More prefe ⁇ ed heterocyclylalkyl radicals are 5- or 6-membered heterocyclyl-C] -3 -alkyls. Examples include tetrahydropyranylmethyl.
  • cycloalkylalkyl means an alkyl moiety (as defined above) substituted with a cycloalkyl moiety (also defined above). More prefe ⁇ ed heterocyclyl radicals are 5- or 6-membered cycloalkyl-C ⁇ -3 -alkyls. Examples include cyclopropylmethyl.
  • Me means methyl
  • Et means ethyl
  • Bu means butyl
  • Ac means acetyl.
  • amino acid residue includes, but is not limited to, the 20 naturally occu ⁇ ing amino acids commonly designated by three letter symbols, and also includes 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta- alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Formulas I-V may be optionally substituted by one or more substituents.
  • substituents suitable for pu ⁇ oses of this invention include, but are not limited to, oxo (with the proviso that the oxo substituent is not on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -N 4 SU 2 R 6 , -SO 2 NR 3 R 4 , -C(O)R 3 , -C(O)OR 3 , -OC(O)R 3 , -NR 4 C(O)OR 6 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , -NR 3 R 4 , -NR 5 C(O)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 , -OR 3 , aryl, heteroaryl, arylalkyl, heteroary
  • the term (CR 4 R 5 ) m may equal -CH CH 2 - or -CH(CH 3 )C(CH 2 CH 3 )(CH 2 CH 2 CH 3 )- or any number of similar moieties falling within the scope of the definitions of R 4 and R 5 .
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers, diastereomers mixtures, racemic or otherwise, thereof.
  • this invention also includes all such isomers, including diastereomeric mixtures and pure enantiomers of the Formulas I-V.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomer mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the co ⁇ esponding pure enantiomers.
  • an appropriate optically active compound e.g., alcohol
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 1992).
  • This invention also encompasses pharmaceutical compositions containing a compound of Formula I-V and methods of treating proliferative disorders, or abnormal cell growth, by administering compounds of the present invention.
  • Compounds of the present invention having free amino, amido, hydroxy or carboxylic groups can be converted into pharmaceutically acceptable prodrugs.
  • a "pharmaceutically acceptable prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • One prefe ⁇ ed prod prodrug of this invention is a compound of Formula I-V covalently joined to a valine residue.
  • Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • compounds of this invention comprising free hydroxy groups may be derivatized as prodrugs by converting the hydroxy group to a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (Ci -C 6 )alkanoyloxymethyl, l-((C ⁇ -C 6 )alkanoyloxy)ethyl, 1-methyl-l- ((C ⁇ -C 6 )alkanoyloxy)ethyl, (Ci-G alkoxycarbonyloxymethyl, N-(d-
  • each ⁇ -aminoacyl group is independently selected from the naturally occu ⁇ ing L-amino acids, P(O)(OH)2, -P(O)(O(d- C 6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
  • Free amines can also be derivatized as amides, sulfonamides or phosphonamides.
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci -C ⁇ o)alkyl, (C -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl-natural ⁇ -aminoacyl, -C(OH)C(O)OY wherein Y is H, (C, -C 6 )alkyl or benzyl, -C(OY 0 )Y ⁇ wherein Y 0 is (C .
  • Yj is (Ci -C 6 )alkyl, carboxy(C ⁇ -C 6 )alkyl, amino(C ⁇ -C 4 )alkyl or mono-N- or di- N,N- (Ci -C ⁇ )alkylaminoalkyl, -C(Y 2 )Y wherein Y is H or methyl and Y is mono-N- or di- N,N-(C ⁇ -C ⁇ )alkylamino, mo ⁇ holino, piperidin-1-yl or pyrrolidin-1-yl.
  • prodrug moieties may inco ⁇ orate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • the invention also includes solvates, pharmaceutically active metabolites, and pharmaceutically acceptable salts of compounds of Formulas I-V.
  • solvate refers to an aggregate of a molecule with one or more solvent molecules.
  • a "pharmaceutically active metabolite” is a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein.
  • Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art.
  • Various forms of prodrugs are known in the art.
  • prodrug derivatives see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p. 113-191 (1991); c) H.
  • a "pharmaceutically acceptable salt” as used herein, unless otherwise indicated, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable sale.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitromenzoates, hydroxybenzoates, methoxybenzoates
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an acidic compound, particularly an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alphahydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base.
  • Prefe ⁇ ed inorganic salts are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium.
  • Prefe ⁇ ed organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2- hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzyl- ethylenediamine, and the like salts.
  • salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglusoamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.
  • Fo ⁇ nula III, Fo ⁇ nula IV and Fo ⁇ nula V are provided as further features of the invention.
  • the inventive compounds may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available or can be synthesized using methods known in the art.
  • Illustrations of the preparation of compounds of the present invention are shown in Figures 1-24.
  • Oxidation of imidazopyridine 1 can be accomplished using m-CPBA in suitable organic solvent or H 2 O 2 in water or water/organic solvent systems.
  • the intermediate N-oxide can then be chlorinated with POCl , or thionyl chloride, or oxalyl chloride or PC1 5 , or MsCl in DMF.
  • Most preferable is the use of m-CPBA in methylene chloride at or near room temperature followed by treatment with neat POCl 3 .
  • alkylation of the imidazo[4,5-b]pyridine 2 is accomplished by use of an alkylating agent such as an alkyl halide and base such as LiH, NaH, or K 2 CO 3 in suitable organic solvent such as DMF, MeCN, or THF at temperatures ranging from 0 to 80 °C.
  • an alkylating agent such as an alkyl halide and base such as LiH, NaH, or K 2 CO 3 in suitable organic solvent such as DMF, MeCN, or THF at temperatures ranging from 0 to 80 °C.
  • suitable organic solvent such as DMF, MeCN, or THF at temperatures ranging from 0 to 80 °C.
  • the alkylation gives a mixture of NI and N3 products 3 and 4 that are separable by standard techniques, including, for example, chromatography, trituration, and crystallization.
  • the 5-methyl group of the N3- alkylsubstitured imidazo[4,5-b]pyridines 3 or 4 can be oxidized by standard method, including but not limited to KMnO 4 in water, SeO 2 in organic solvent such as dioxane, xylene, or pyridine, NaOCl/RuCl 3 , CrO 3 in aqueous H 2 SO 4 , K2Cr 2 O , and Na 2 Cr 2 O 7 in water. Preferably this transformation is achieved with KMnO 4 in water.
  • Inco ⁇ oration of the appropriate aniline moiety to give carboxylic acid 6 can be accomplished by S N A ⁇ reaction.
  • Carboxylic acid 6 can also be prepared by treating imidazopyridine 5 with the appropriate aniline in the presence of Cul, Cu(OAc) 2 , or Zn-Cu and a suitable base such as K2CO 3 , Na2CO , or TEA. Additionally, preparation of carboxylic acid 6 can be achieved in a three-step sequence; esterification followed by palladium mediated cross-coupling reaction with the appropriate aniline (when R 8 is not Br or I) and then basic hydrolysis.
  • amide base such as LDA, LiHMDS, NaHMDS or KHMDS
  • Esterification can be achieved by standard methods including but not to limited to Fisher esterification (MeOH, H 2 SO 4 ), reaction with TMSCHN 2 or TMSC1 in MeOH.
  • a suitable aniline is coupled with the intermediate ester by use of palladium catalyst, including not to limited to Pd(OAc) 2 , Pd 2 (dba) 3 , or PdCl 2 , and a ligand, such as BINAP, dppf, (o-tol) 3 P, or (t-Bu) 3 P, along with a base such as t-BuONa, t-BuOK, LiHMDS, or Cs CO 3 , in a suitable organic solvent, DME, dioxane, toluene, xylene, THF, or DMF at temperatures ranging from 50 to 120 °C.
  • palladium catalyst including not to limited to Pd(OAc) 2 , Pd 2 (dba) 3 , or PdCl 2 , and
  • the aniline moiety can be further functionalized if desired by standard methods known to those skilled in the art such as halogenation.
  • the ester is hydrolyzed by standard saponification conditions.
  • the N3 -substituted acid 6 is then converted to the N3-substituted amide analog 7 or hydroxamate analog 8 by standard coupling procedures including but not limited to EDCI, HOBt, or PyBOP and the appropriate amine or hydroxylamine in suitable organic solvents such as DMF, THF or dichloromethane.
  • the amine or hydroxylamine used in the coupling reaction contains a standard protecting group. In those cases, the protecting group can be removed by standard conditions known in the art.
  • the co ⁇ esponding NI -substituted imidazo[4,5-b]pyridine analog 10 can be prepared by the procedures described above after the separation step.
  • Figure 2 illustrates the preparation of compounds of Formula I where W is heteroaryl or heterocyclic.
  • the thiadiazole 12 can be prepared from the carboxylic acid 6 by treatment with thiosemicarbazide using standard EDCI coupling conditions followed by cyclization of the intermediate 11 employing PPh 3 , TEA, and CC1 4 in dichloromethane.
  • the N-3 substituted acid 6 can be converted to the hydrazide 13 by standard coupling procedures including but not limited to EDCI, HOBt, or PyBOP and hydrazine in suitable organic solvents such as DMF, THF or dichloromethane.
  • suitable organic solvents such as DMF, THF or dichloromethane.
  • the desired derivative can then be prepared by cyclization with an appropriate reagent.
  • aminooxadiazole 14 the hydrazide 13 is treated with BrCN and base such as NaHCO , in a suitable biphasic solvent system such as dioxane and water at room temperature.
  • the triazole 15 can be prepared by reaction of the hydrazide 13 with an appropriate coupling agent, such as cyanamide or ethyl acetimidate, followed by cyclization using PPh , TEA, and CC1 4 in dichloromethane.
  • an appropriate coupling agent such as cyanamide or ethyl acetimidate
  • the hydrazide 13 is first cyclized to the oxadiazolone 16 using either CDI, phosgene or a phosgene equivalent in a suitable organic solvent such as DMF, PhMe, methylene chloride or mixtures thereof.
  • cyclization to form oxadiazolone 16 is accomplished by treating hydrazide 13 with CDI in DMF at room temperature.
  • the aminooxadiazole 17 is then prepared by addition of an appropriate amine followed by re-cyclization of the intermediate obtained using PPh 3 , TEA, and CC1 in dichloromethane.
  • the co ⁇ esponding NI -substituted imidazo[4,5-b]pyridine analogs, where W is heteroaryl or heterocyclyl, can be prepared by the procedures described above. [00180] In Figure 3, preparation of compounds of the Formula II is depicted.
  • Pyrazolopyrimidine ester 20 can be prepared by the condensation of aminopyrazole 18 and ester 19 with acid (such as AcOH, HCl, ZnCl 2 , HBr or p-TsOH) or base (such as alkylamine such as piperidine) or without acidic or basic conditions in a suitable organic solvent such as EtOH, toluene, DMF, MeCN or AcOH at elevated temperatures (80 to 120 °C).
  • acid such as AcOH, HCl, ZnCl 2 , HBr or p-TsOH
  • base such as alkylamine such as piperidine
  • the condensation is achieved by treating the aminopyrazole 18 with ester 19 in AcOH and heating to 120 °C.
  • Chlorination of the pyrazolopyrimidine ester 20 can be accomplished with POCl 3 , thionyl chloride, oxalyl chloride or PC1 5 .
  • this transformation is achieved with POCl 3 neat or in the presence of an amine such as triethylamine at room temperature.
  • an amine such as triethylamine at room temperature.
  • a fluorination step can be inco ⁇ orated at this stage.
  • Fluorination of pyrazolopyrimidine ester 21 (where R 9 is Cl) can be accomplished with KF in the presence of 18-Crown-6 or in the presence of an amine such as trimethylamine in a suitable organic solvent such as MeCN, DMF, DMSO at the elevated temperature.
  • this reaction is canied out with KF in the presence of 18-crown-6 in MeCN at the appropriate temperature.
  • hydroxamate 23 or amide 25 can be prepared using one the following routes.
  • the first route involves palladium mediated cross- coupling with appropriately substituted aniline and the chloro (or bromo) pyrazolopyrimidine 21 where R 5 is CO 2 Et (and X is Cl or Br) to prepare ester 22.
  • the cross-coupling can be done in a suitable organic solvent such as toluene, DME, DMF, THF, or dioxane in the presence of a base such as NaOt-Bu, KOt-Bu, K2CO 3 , Cs 2 CO , Na 2 CO , a phosphine ligands such as BINAP, DPPF, and (o-tol) 3 P and a palladium catalysts such as Pd(OAc) 2 , PdCl 2 (dppf), Pd(dba) 2 , and Pd 2 (dba) 3 at elevated temperature (50 to 120 °C).
  • this cross-coupling reaction is accomplished by treating the chloro (or bromo) pyrazolopyrimidine 21 with aniline (R 8 is not Br or I), Cs 2 CO , BINAP, and Pd(OAc) 2 in toluene and heating to about 80 °C.
  • aniline moiety can be further functionalized if desired by standard methods known to those skilled in the art such as halogenation.
  • Hydroxamates 23 is then prepared from ester 22 using standard coupling procedures. This can be done in a suitable organic solvent such as THF using an amide base such as LiHMDS, NaHMDS or KHMDS at appropriate temperatures (0 °C to room temperature).
  • the hydroxylamine is added to LiHMDS in THF at low temperature (0 °C) followed by the addition of ester 22 and the reaction mixture is warm to room temperature.
  • Ester 22 can also be converted to acid 24 by basic hydrolysis under standard conditions using either LiOH or NaOH in standard mixed aqueous/organic solvent systems.
  • Carboxylic acid 24 can then be converted to the amide 25 or hydroxamate 23 by standard coupling procedures including but not limited to EDCI, HOBt, or PyBOP and the appropriate amine or hydroxylamine in suitable organic solvents such as DMF, THF or dichloromethane.
  • an alternative second route includes a two-step procedure to carboxylic acid 24 is available when R 5 is Me through oxidation followed by S N A ⁇ reaction with appropriate aniline.
  • oxidation of chloro (or bromo) pyrazolopyrimidine 21 where R 5 is Me (and X is Cl or Br) can be accomplished using standard methods including but not limited to KMO 4 , NaOCl/RuCl 3 or Na 2 Cr 2 O 7 /HCl.
  • Inco ⁇ oration of the aniline moiety is accomplished by S N AT reaction. This can be done in a suitable organic solvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78 °C to room temperature).
  • the aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80 °C).
  • the carboxylic acid intermediate is then added and the reaction mixture is warmed to room temperature to generate carboxylic acid 24.
  • the hydroxamate 23 or amide 25 is then prepared as described above.
  • the amine or hydroxylamine used in the coupling reaction contains a standard protecting group. In those cases, the protecting group can be removed by standard conditions known in the art.
  • Figure 4 outlines the synthesis of compounds of Formula II wherein the R 9 group is incorporated into the starting ethyl ester 26.
  • pyrazolopyrimidine ester 27 can be achieved by the condensation of aminopyrazole 18 and the ester 26 in the presence of base such as an alkylamine such as piperidine in a suitable organic solvent such as MeCN, EtOH, DMF or toluene at the appropriate temperature. Pyrazolopyrimidine ester 27 can then be carried forward to hydroxamate 23 or amide 25 as described in Figure 3.
  • base such as an alkylamine such as piperidine
  • a suitable organic solvent such as MeCN, EtOH, DMF or toluene
  • acid catalyzed deprotection of 34 can be accomplished by standard conditions including TFA in a suitable organic solvent such as methylene chloride or HCl in a suitable organic solvent such as dioxane.
  • Hydroxamate 36 and amide 37 can be prepared using standard coupling procedures, including but not limited to EDCI, HOBt, or PyBOP and the appropriate amine or hydroxylamine in suitable organic solvents such as DMF, THF, or methylene chloride. Additionally, hydroxamate 36 and amide 37 can be prepared in two steps by initial conversion to the acid chloride by standard methods followed by addition of the appropriate amine or hydroxylamine.
  • imidazo[l,2-b] ⁇ yridazine ester 34 can be directly converted to hydroxamate 36 in a suitable organic solvent such as THF using the appropriate hydroxylamine and an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature).
  • a suitable organic solvent such as THF
  • an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature).
  • the amine or hydroxylamine used in the coupling reaction contains a standard protecting group. In those cases, the protecting group can be removed by standard conditions known in the art.
  • Figures 7-11 several syntheses of imidazo[l,2-b]pyridazine ester 34, which is utilized as the starting material in Figure 6, are depicted, depending on the identity of R .
  • Figure 7 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R 10 is H.
  • An appropriately functionalized 6-chloro-4-phenylaminopyridazine ester 38 (synthesized as shown in Figures 12-17) is converted to 6-amino-4-phenylaminopyridazine ester 39 in two steps.
  • sodium azide is added to 38 in an appropriate solvent, including but not limited to DMF.
  • the 6-amino-4-phenylaminopyridazine ester 39 is prepared by reduction of the azide under standard conditions including but not limited to Zn dust/ AcOH, Pt/C or Pt ⁇ 2 in the presence of H 2 gas, Ph P or SnCl 2 /MeOH.
  • the azide reduction is accomplished by treatment with Zn dust in a mixture of methylene chloride and acetic acid.
  • Cyclization to form imidazo[l,2-b]pyridazine 40 can be accomplished by treatment with chloroacetaldehyde or bromoacetaldehyde in suitable organic solvent such as DMF or EtOH at elevated temperatures (50 to 120 °C).
  • cyclization is realized by treatment with chloroacetaldehyde in EtOH at 70 °C.
  • Figure 8 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R 10 is Me.
  • l-Aminopropan-2-ol is added to an appropriately functionalized 6-chloro-4- phenylaminopyridazine ester 38 (synthesized as shown in Figures 12-17) in the presence of an appropriate base, such as NEt , in an organic solvent, such as CH CN to provide 41.
  • Oxidation of 41 can be accomplished with an appropriate oxidizing agent, including, but not limited to TPAP and NMO, PCC, KMnO 4 , CrO 3 , Na 2 Cr 2 O 7 .
  • Acid catalyzed cyclization of 42 to form imidazo[l,2-b]pyridazine 43 can be accomplished with an appropriate acid, including, but not limited to H 2 SO 4 .
  • Figure 9 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R 10 is aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, alkynyl, amino or anilinyl.
  • Halogenation of imidazo[l,2-b]pyridazine 40 can be accomplished by treatment with either NBS, NIS or NCS in DMF, MeCN or mixed solvent systems to form halogenated intermediate 44.
  • R 10 is aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, alkynyl, amino or anilinyl
  • Pd mediated cross-coupling conditions where R 8 is not Br or I.
  • R 10 is alkenyl or alkynyl
  • these groups can be further reduced using the appropriate reducing agent to provide alkyl substituents at R 10 .
  • this chemistry can be accomplished using a wide variety of Pd catalysts and ligands, with or without added base, in a suitable organic solvent such as DMF, PhMe, DME, THF, CH 3 CN at elevated temperature.
  • the coupling partner will depend on the nature of R .
  • Pd mediated cross-couplings are well documented in the literature and are known by those skilled in the art.
  • Figure 10 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R 10 is NR 3 R 4 .
  • An appropriately functionalized 6-amino-4-phenylaminopyridazine ester 39 in a suitable organic solvent such as dichloromethane or dichloro ethane is treated with a Lewis acid such as zinc bromide and condensation product as disclosed by Katritzky et al. (J. Org. Chem., 2003, 68, 4935-4937: J. Org. Chem., 1990, 55, 3209-3213) to provide the 3- dialkyamino-3-imidazo[l,2-b]pyridazine ring system 46.
  • Condensation products i.e., condensation of a glyoxal, benzotriazole and a secondary amine
  • condensation products can be generated using benzotriazole, glyoxal and any appropriate secondary amine including, but not limited to dimethylamine, diethylamine, py ⁇ olidine, piperidine, mo ⁇ holine, 1-methylpiperazine, N- methyl allylamine, diallyamine, and N-methylbenzylamine as described by Katritzky et al.
  • Figure 11 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R 10 is CH 2 NR R 4 .
  • 3-aminomethylimidazo[l,2-b]pyridazine 47 can be accomplished using the modified Mannich reaction procedure developed by Kercher et al. (manuscript in preparation) as illustrated.
  • the reaction is generally canied out by combining 37% aqueous formaldehyde and a suitable amine in a mixture of acetonitrile/water.
  • secondary amines can be employed, including but not limited to pyrrolidine, piperadine, mo ⁇ holine, dimethylamine, N-BOC-piperazine and 1-methylpiperazine.
  • FIGS. 12-17 depict the synthesis of an appropriately functionalized 6-chloro- 4-phenylaminopyridazine ester 38, which is utilized as the starting material in Figures 7 and 8.
  • Figure 12 depicts the synthesis of the 6-chloropyridazine core where R 9 is H, F, or Cl.
  • 4,6-Dichloropyridazine-3-carboxylic acid ethyl ester 48 can be synthesized as described in WO 04/031174, which is inco ⁇ orated herein by reference.
  • Basic hydrolysis of 48 using standard saponification conditions such as LiOH or NaOH in standard mixed aqueous/organic solvent systems provides acid 49.
  • Formation of 50 can be accomplished in two steps. The first step involves the coupling of the properly substituted aniline moiety and pyridazine acid 49 by S N AT reaction. This can be achieved in a suitable organic solvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature).
  • the aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80 °C).
  • Pyridazine acid 49 is then added and the mixture is sti ⁇ ed at low temperature to generate the coupled product.
  • Esterification to give the methyl ester 50 can be canied out under standard conditions, including but not limited to Fisher esterification (MeOH, H 2 SO 4 ), TMSC1 in MeOH or TMSCHN 2 in suitable organic solvents such as PhMe/MeOH. If a compound where R 9 is Cl or F is desired, a chlorination or fluorination step can be inco ⁇ orated at this stage.
  • Chlorination of pyridazine ester 50 can be accomplished with NCS in a suitable organic solvent such as DMF, MeCN or mixed solvent systems at room temperature.
  • a suitable organic solvent such as DMF, MeCN or mixed solvent systems at room temperature.
  • Fluorination is achieved by treating pyridazine ester 50 with [l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) in the presence of base in a suitable organic solvent at the appropriate temperature.
  • Most preferable is the use of LiOH as base and MeCN as solvent at approximately 85 °C.
  • Figure 13 depicts an alternative synthesis of the 6-chloropyridazine core
  • R H, F, or Cl.
  • Addition of an appropriately substituted aniline to 4,6-dichloropyridazine- 3-carboxylic acid ethyl ester 48 in an appropriate organic solvent such as PhMe, xylenes, NMP or DMA from 0 °C to elevated temperature can directly provide the coupled product 50.
  • an appropriate organic solvent such as PhMe, xylenes, NMP or DMA from 0 °C to elevated temperature
  • a chlorination or fluorination step can be inco ⁇ orated at this stage to provide 38.
  • Chlorination of the pyridazine ester 50 can be accomplished with NCS in a suitable organic solvent such as DMF, MeCN or mixed solvent systems at room temperature. Preferably the reaction is canied out in DMF.
  • Fluorination is achieved by treating pyridazine ester 50 with [l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) in the presence of base in a suitable organic solvent at the appropriate temperature. Most preferable is the use of LiOH as base and MeCN as solvent at approximately 85 °C. [00193] Figure 14 depicts the synthesis of the 6-chloropyridazine core where R 9 is Cl.
  • 4,6-Dihydroxypyridazine-3-carboxylic acid ethyl ester 51 can be synthesized as described in WO 04/031174. Chlorination of pyridazine ester 51 can be accomplished with NCS in a suitable organic solvent such as DMF, MeCN or mixed solvent systems at room temperature to yield monochloropyridazine ester 52. Preferably the reaction is carried out in DMF. Pyridazine ester 52 can be further chlorinated using an appropriate reagent such as POCl , oxalyl chloride or thionyl chloride. In one embodiment, chlorination is accomplished with neat POCl 3 or in the presence of Et 3 N at elevated temperatures.
  • Fluorination of pyridazine ester 51 can be accomplished with [l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) in the presence of base in a suitable organic solvent at the appropriate temperature to yield monofluoro pyridazine ester 56.
  • base a suitable organic solvent at the appropriate temperature
  • Most preferable is the use of LiOH as base and MeCN as solvent at approximately 85 °C.
  • Pyridazine ester 56 can be chlorinated using an appropriate reagent such as POCl , oxalyl chloride or thionyl chloride. In one embodiment, chlorination is accomplished with neat POCl or in the presence of Et N at elevated temperatures.
  • Figure 16 depict the synthesis of the 6-chloropyridazine core where R 9 is Me.
  • Dichloro-5-methylpyridazine-3-carboxylic acid ethyl ester 60 can be prepared by minor modification of the method described in WO 04/031174. Hydrolysis of the resulting diichloropyridazine ester 60 to provide compound 61 can be performed under standard conditions. Addition of the appropriately substituted aniline to either 60 or 61 can be accomplished as described for the reaction schemes in Figures 12 and 13 detailed above to provide 6-chloro-5-methyl-4-phenylaminopyridazine-3 -carboxylic acid ester 62. 100196] The preparation of compounds of Formula III where W is heteroaryl or heterocyclic is shown in Figures 17 and 18.
  • Figure 19 illustrates the synthesis of compounds of Formula IV of the present invention.
  • a fluorination step can be introduced in a three step protocol starting from tetrachloropyridine-2-carboxylic acid 71 by esterification, fluorination and saponification.
  • Esterification of 71 can be achieved by standard methods including but not to limited to Fisher esterification (MeOH, H 2 SO 4 ), reaction with TMSCHN2 or TMSC1 in MeOH.
  • Fluorination can be accomplished through substitution of the chloride intermediate by heating with KF in DMSO, KF and 18-Crown-6 in NMP, or CsF in MeCN.
  • carboxylic acid is prepared by standard saponification methods such as LiOH or NaOH in standard mixed aqueous/organic solvent systems.
  • Dichloro-4-fluoro-3- phenylaminopyridine-2-carboxylic acid 72 can be prepared by either S N A ⁇ reaction or a copper mediated coupling.
  • the S N AT chemistry can be achieved by treating the carboxylic acid with the desired aniline in a suitable organic solvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78 °C to room temperature).
  • the copper mediated coupling can be achieved by treating the carboxylic acid with the desired aniline in a suitable organic solvent in the presence of Cu or CuO and a suitable base such as K 2 CO; . , or Na2CO .
  • a suitable base such as K 2 CO; . , or Na2CO .
  • the acetylene derivative 73 can be prepared by Sonagashira palladium mediated cross- coupling using an appropriately substituted acetylene, Cul, an amine base, palladium catalyst and organic solvent such as DME, THF, or DMF at temperatures between 25 to 100 °C (R 8 is not Br or I).
  • Suitable palladium catalysts include, but are not limited to, PdCl 2 (dp ⁇ f), Pd(Ph 3 P) , and Pd 2 dba 3 /dppf.
  • Suitable amine bases include, but are not limited, to Et_N, Et 2 NH, Hunig's base, and diisopropyl amine.
  • carboxylic acid 71 can be taken directly into the S N AT reaction or the copper mediated coupling followed by esterification under standard methods including but not to limited to Fisher esterification (MeOH, H 2 SO 4 ), reaction with TMSCHN 2 or TMSC1 in MeOH to generate ester 74. If a compound where R 9 is alkyl is desired, the alkyl group be inco ⁇ orated by the procedure of Shiota et al (J. Org. Chem.
  • acetylene 73 is then prepared by the palladium mediated cross-coupling procedure described above. [00199] With continued reference to Figure 19, regardless of the nature of R 9 , acetylene 73 can be canied forward in an analogous manner.
  • Acetylene 73 can be hydrolyzed to the co ⁇ esponding ketone by standard methods including but not limited to H 2 SO 4 , TFA, trifluorosulfonamide, FeCl 3 , or HgSO 4 /H 2 SO 4 .
  • the ketone can then be converted to the isoxazolo[4,5-b]pyridine 75 in a two-step procedure.
  • Addition of the potassium salt of acetone oxime in a suitable organic solvent such as THF or E12O at temperatures ranging from -78 to 5 °C is followed by acid catalyzed cyclization.
  • the acetone oxime addition is most easily performed by addition of a THF solution of the ketone intermediate to the salt at 0 °C.
  • the cyclization can be performed under a variety of acidic aqueous conditions at a range of temperatures. If a compound is desired where R is Br or I, then the halide of interest may be inco ⁇ orated at this stage. This may be accomplished by standard aromatic halogenation chemistry including but not limited to NIS or NBS in DMF with or without catalytic aqueous acid. Basic hydrolysis under standard saponification conditions such as LiOH or NaOH in standard mixed aqueous/organic solvent systems can then provide carboxylic acid 76.
  • Amide 77 and hydroxamate 78 can be prepared using standard coupling procedures, including but not limited to EDCI, HOBt, or PyBOP and the appropriate amine or hydroxylamine in suitable organic solvents such as DMF, THF, or methylene chloride.
  • ester 75 can be directly converted to hydroxamate 78 in a suitable organic solvent such as THF using the appropriate hydroxylamine and an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature).
  • the amine or hydroxylamine used in the coupling reaction contains a standard protecting group. In those cases, the protecting group can be removed by standard conditions known in the art.
  • 5,6- dichloro-3-phenylaminopyridine-2-carboxylic acid 79 can be esterified by standard methods including but not to limited to Fisher esterification (MeOH, H 2 SO 4 ), reaction with TMSCHN 2 or TMSC1 in MeOH.
  • Nitrile 80 can then be prepared by palladium mediated coupling of the chloroester intermediate with zinc cyanide in a suitable organic solvent such as DMA, NMP or DMF at elevated temperatures ranging from 50 to 120 °C (R 8 is not Br or I).
  • palladium catalysts may be employed including but not limited to Pd(PPh 3 ) 4 , PdCl 2 (dp ⁇ f), or Pd 2 dba 3 with ligands such as dppe, dppp, dppf or BINAP.
  • Preparation of aminoisoxazolo[4,5-b]pyridine 81 can be accomplished in a two-step procedure from nitrile 80 by the addition of the potassium salt of acetone oxime followed by acid mediated cyclization as described above in Figure 19.
  • the analogs 83 and 84 can be prepared from the intermediates 81 or 82 by the procedures described in Figure 19.
  • the preparation of compounds of Formula IV where W is heteroaryl or heterocyclyl is shown in Figure 21.
  • the preparation of these analogs from carboxylic acid 76 is accomplished as described for the reaction schemes in Figure 2 detailed above.
  • Figure 22 illustrates the synthesis of compounds of Formula V of the present invention.
  • the 6-acetyl-5-chloropyridine methyl ester 92 can be prepared from the acetylene 73 as described in Figure 19.
  • the ketone 92 can then be converted to a mixture of NI and N2-substituted pyrazolo[4,3-b]pyridines 93 and 94 in an manner analogous to the preparation of benzisoxazole 75 by employing the potassium salt of acetone hydrazone in place of acetone oxime in the cyclization step.
  • the cyclization can also be performed by heating with hydrazine in a suitable organic solvent such as DMF or EtOH at temperature ranging from 0 to 150 °C. Alkylation and separation can be accomplished as described for Figure 1.
  • ester 93 can be converted directly to hydroxamate 97 in a suitable organic solvent such as THF using the appropriate hydroxylamine and an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature).
  • Figure 23 illustrates the synthesis of NI and N2-substituted 3- aminopyrazolo[4,3-b]pyridine of Formula V. Cyclization of nitrile 80 can be achieved as described in Figures 19 and 22. Alkylation and separation can be accomplished as described for Figure 1. As outlined in Figure 23, 3-aminopyrazolo[4,3-b]pyridines 99 and 100 can be further converted to the final 3-aminopyrazolo[4,3-b]pyridine analogs 102, 103, and 104 by the procedures described for Figure 19 above.
  • ester 99 can be converted directly to hydroxamate 103 in a suitable organic solvent such as THF using the appropriate hydroxylamine and an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature).
  • a suitable organic solvent such as THF
  • an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature).
  • the compounds of Formula V where W is heteroaryl or heterocyclic can be prepared from the carboxylic acid 95 by the methods described in Figure 2.
  • the co ⁇ esponding Nl-susbtituted pyrozolo[4,3-b]pyridine analogs can also be prepared in the same manner from the co ⁇ esponding carboxylic acid.
  • the invention also relates to a pharmaceutical composition for the treatment of a hype ⁇ roliferative disorder in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable canier.
  • said pharmaceutical composition is for the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, esophageal, testicular, gynecological or thyroid cancer.
  • said pharmaceutical composition is for the treatment of a non-cancerous hype ⁇ roliferative disorder such as benign hype ⁇ lasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hype ⁇ roliferative disorder such as benign hype ⁇ lasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • the invention also relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes- induced renal disease) or the treatment of pain in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable canier.
  • the invention also relates to a pharmaceutical composition for the prevention of blastocyte implantation in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable ca ⁇ ier.
  • the invention also relates to a pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable canier.
  • said pharmaceutical composition is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease or other inflammatory condition such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease or other inflammatory condition such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma
  • diabetes diabetic retinopathy, retinopathy of prematurity, age
  • the invention also relates to a method of treating a hype ⁇ roliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • said method relates to the treatment of cancer such as brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, esophageal, testicular, gynecological or thyroid cancer.
  • said method relates to the treatment of a non-cancerous hype ⁇ roliferative disorder such as benign hype ⁇ lasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hype ⁇ roliferative disorder such as benign hype ⁇ lasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • the invention also relates to a method for the treatment of a hype ⁇ roliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti- androgens.
  • an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti- androgens.
  • the invention also relates to a method of treating pancreatitis or kidney disease in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pha ⁇ naceutically acceptable salt, prodrug or hydrate thereof.
  • the invention also relates to a method of preventing blastocyte implantation in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • the invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma
  • diabetes diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangio
  • the invention also relates to a pharmaceutical composition for treating a disease or condition related to inflammatory disease, autoimmune disease, destructive bone disorders, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable canier.
  • diseases and/or conditions include but is not limited to rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes and diabetic complications, diabetic retinopathy, retinopathy of prematurity, age- related macular degeneration, hemangioma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, allergic responses including asthma allergic rhinitis and atopic dermatitis, renal disease and renal failure, polycystic kidney disease, acute coronary syndrome, congestive heart failure, osteoarthritis, neurofibromatosis, organ transplant rejection, cachexia and pain.
  • Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salts, prodrugs and hydrates of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or
  • This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, salt, solvate, or prodrug, and of the chemotherapeutic are together effective in inhibiting abnormal cell growth.
  • chemotherapeutics are presently known in the art.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • This invention further relates to a method for inhibiting abnormal cell growth in a mammal or treating a hype ⁇ roliferative disorder which method comprises administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiation therapy, wherein the amounts of the compound, salt, solvate, or prodrug, is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hype ⁇ roliferative disorder in the mammal.
  • Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.
  • the administration of the compound of the invention in this combination therapy can be determined as described herein.
  • this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt or solvate or prodrug thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation.
  • the amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
  • the invention also relates to a method of and to a pharmaceutical composition of inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, a prodrug thereof, or an isotopically-labeled derivative thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
  • Anti-angiogenesis agents such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of the present invention and pharmaceutical compositions described herein.
  • MMP-2 matrix-metalloprotienase 2
  • MMP-9 matrix-metalloprotienase 9
  • COX-II cyclooxygenase II
  • Examples of useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.
  • Prefened MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More prefened, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
  • abnormal cell growth and “hype ⁇ roliferative disorder” are used interchangeably in this application.
  • Abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition).
  • tumor cells tumor cells
  • tumors tumor cells
  • any tumors that proliferate by receptor tyrosine kinases any tumors that proliferate by abenant serine/threonine kinase activation
  • benign and malignant cells of other proliferative diseases in which abenant serine/theroine kinase activation occurs benign and malignant cells of other proliferative diseases in which abenant serine/theroine kinase activation occurs.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • the amount of a given agent that will conespond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e. g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • Treating is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is affected, at least in part, by the activity of MEK, and includes, but is not limited to, preventing the disease condition from occuning in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but has not yet been diagnosed as having it; modulating and/or inhibiting the disease condition; and/or alleviating the disease condition.
  • a compound of the Formula I-V or a pharmaceutically acceptable salt or prodrug thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • a pharmaceutical composition that comprises a compound of the Formula I-V, or a pharmaceutically acceptable salt or prodrug thereof, as defined hereinbefore in association with a pharmaceutically acceptable diluent or carrier.
  • a therapeutically or prophylactically effective amount of a compound of Formula I-V or a pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.
  • a canier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
  • Suitable earners include any and all solvents, dispersion media, adjuvants, coatings, antibacterial and antifungal agents, isotonic and abso ⁇ tion delaying agents, sweeteners, stabilizers (to promote long term storage), emulsifiers, binding agents, thickening agents, salts, preservatives, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and abso ⁇ tion delaying agents, flavoring agents, and miscellaneous materials such as buffers and absorbents that may be needed in order to prepare a particular therapeutic composition.
  • suitable earners include any and all solvents, dispersion media, adjuvants, coatings, antibacterial and antifungal agents, isotonic and abso ⁇ tion delaying agents, sweeteners, stabilizers (to promote long term storage), emulsifiers, binding agents, thickening agents, salts, preservatives, solvents, dispersion media, coatings, antibacterial and antifungal agents, isot
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular dosing or as a
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent abso ⁇ tion of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose.
  • dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxy
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be. for example, naturally-occu ⁇ ing gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally- acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • Topical formulations such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedures well known in the art.
  • compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 ⁇ m or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable caniers such as lactose.
  • the powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
  • compositions for administration by inhalation may be in the form of a conventional pressurized aerosol ananged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently ananged to dispense a metered quantity of active ingredient.
  • the amount of a compound of this invention that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the subject treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically inco ⁇ orated herein by reference.
  • Formula I-V will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • the compounds of this invention may be used alone in combination with other drugs and therapies used in the treatment of disease states which would benefit from the inhibition of MEK. Such treatment may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti -tumor agents: [00245] (i) antiproliferative/anti-neoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example, cis-platin, carboplatin, cyclophosphamide, nitorgen mustard, melphalan, chlorambucil, busulphan and nitorsoureas); anti-metabolites (for example, antifolates such as such as fluoropyrimidines like 5- fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinside, hydroxyurea, or, one of the prefened anti-metabolites disclosed in European Patent Application No.
  • alkylating agents for example, cis-platin, carboplatin, cyclophosphamide, nitorgen mustard, melphalan, chlorambucil, busulphan and n
  • cytostatic agents such as antiestrogens (for example, anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example, vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like eptoposide and teniposide, amsacrine, topotecan and 5 campothecin): [00246] (ii) cytostatic agents such as antiestrogens (for example, anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and
  • LHRH antagonists or LHRH agonists for example, goserelin, leuporelin and buserelin
  • progestogens for example, megestrol acetate
  • aromatase inhibitors for example, asanastrozole, letrozole, vorazole and exemestane
  • inhibitors of 5 ⁇ -reductase such as finasteride; [00247] (iii) agents which inhibit cancer cell invasion (for example, metalloproteinase
  • inhibitors like marimastat and inhibitors of urokinase plasminogne activator receptor function [00248] (iv) inhibitors of growth factor function like growth factor antibodies, growth factor receptor antibodies (for example, the anti-erbB2 antibody trastumuzab [HerceptinTM] and the anti-erbBl antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine
  • kinase inhibitors and serine-threonine kinase inhibitors for example, inhibitors of the epidermal growth factor family tyrosine kinases such as N-(3-chloro-4-fluorophenyl)-7- methoxy-6-(3-mo ⁇ holinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-mo ⁇ holinopropoxy)quinazolin-4-amine (CI
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (for example, the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in PCT Publication
  • antisense therapies for example, those which are directed to the targets listed above such as ISIS 2503, and anti-ras antisense);
  • gene therapy approaches including for example GVAXTM, approaches to replace abenant genes such as abenant p53 or abenant BRCA1 or BRCA2, GDEPT (gene- directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
  • GVAXTM abenant genes
  • GDEPT gene- directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches to using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of treatment.
  • Such combination products employ the compounds of this invention within the dose range described hereinbefore and the other pharmaceutically active agent within its approved dose range.
  • a pharmaceutical product comprising a compound of Formula I-V as defined hereinbefore and an additional anti-tumor agent as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds of Formula I-V are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of MEK.
  • the activity of the compounds of the present invention may be determined by the following procedure. N-terminal 6 His-tagged, constitutively active MEK-1 (2-393) is expressed in E. coli and protein is purified by conventional methods (Ahn et al, Science 1994, 265, 966-970). The activity of MEKl is assessed by measuring the inco ⁇ oration of ⁇ - 33 P-phosphate from ⁇ - 33 P-ATP onto N-terminal His tagged ERK2, which is expressed in E. coli and is purified by conventional methods, in the presence of MEK-1.
  • the assay is carried out in 96-well polypropylene plate.
  • the incubation mixture (100 ⁇ L) comprises of 25 mM Hepes, pH 7.4, 10 mM MgCl 2 , 5 mM ⁇ -glycerolphosphate, 100 ⁇ M Na-orthovanadate, 5 mM DTT, 5 nM MEKl, and 1 ⁇ M ERK2.
  • Inhibitors are suspended in DMSO, and all reactions, including controls are performed at a final concentration of 1% DMSO. Reactions are initiated by the addition of 10 ⁇ M ATP (with 0.5 ⁇ Ci ⁇ - 33 P-ATP/well) and incubated at ambient temperature for 45 minutes.
  • reaction flasks are typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware is oven dried and/or heat dried.
  • ⁇ -NMR spectra were obtained as CDC1 3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm). Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiple.), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).
  • Step A Preparation of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine 4- oxide: To a solution of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent)
  • Step B Preparation of 6-bromo-7-chloro-5-methyl-3H-imidazo 4,5- blpyridine: A solution of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine 4-oxide (1.00 equivalent) in POCl 3 (excess) is sti ⁇ ed at 80 °C for 16 hours. The reaction mixture is concentrated in vacuo to give the crude material that is poured into ice-water. The resulting aqueous solution is neutralized with saturated aqueous NaHCO 3 and extracted with EtOAc. The organic layer is dried over MgSO 4 , filtered, and concentrated in vacuo to afford the desired product. The product is purified by trituration or flash column chromatography if further purification is necessary.
  • Step C Preparation of 6-bromo-7-fluoro-5-methyl-3H-imidazo[4,5- blpyridine: To a solution of 6-bromo-7-chloro-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) in NMP is added KF (3.00 equivalents) and 18-crown-6 (0.20 equivalents) at room temperature. The resulting mixture is refluxed with stining for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO 4 , filtered, and concentrated in vacuo to afford the desired product that is purified by flash column chromatography as necessary.
  • Step D Preparation of 6-bromo-7-fluoro-3,5-dimethyl-3H-imidazo[4,5- blpyridine: To a solution of 6-bromo-7-fluoro-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) in DMF is added iodomethane (1.20 equivalents) and K CO 3 (1.50 equivalents) at room temperature. The resulting mixture is stined at 75 °C for 1 hour. The reaction mixture is diluted with EtOAc and washed with water and brine.
  • Step E Preparation of 6-bromo-7-fluoro-3-methyl-3H-imidazo r 4.5- blpyridine-5-carboxylic acid: To a boiling suspension of 6-bromo-7-fluoro-3,5-dimethyl-3H- imidazo[4,5-b]pyridine (1.00 equivalent) and Na CO 3 (1.00 equivalent) in water is added powered KMnO (3.00 equivalents) in small portions. After refluxing for 3 hours, the reaction mixture is cooled to room temperature and filtered.
  • the filtrate is concentrated in vacuo to a half of the original volume and acidified with 6 N aqueous HCl.
  • the precipitates are washed with water and dried in vacuo to afford the desired product.
  • the desired product is purified by trituration or re-crystallization as necessary.
  • Step F Preparation of 6-bromo-7-fluoro-3-methyl-3H-imidazo
  • Step G Preparation of 7-fluoro-6-(2-fluorophenylamino)-3-methyl-3H- imidazo[4,5-blpyridine-5-carboxylic acid methyl ester: A mixture of 6-bromo-7-fluoro-3- methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.00 equivalent), 2- fluoroaniline (1.00 equivalent), Pd(OAc) 2 (0.10 equivalents), rac-BINAP (0.15 equivalents), and Cs 2 CO 3 (1.50 equivalents) in toluene in a sealed tube is stined at 80 °C for 16 hours.
  • reaction mixture is cooled to room temperature and diluted with EtOAc.
  • the resulting precipitate is filtered off and washed with EtOAc.
  • the filtrate is diluted with EtOAc and washed with water.
  • the organic layer is dried over MgSO 4 , filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product.
  • Step H Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl- 3H-imidazo[4,5-b1pyridine-5-carboxylic acid methyl ester: To a solution of 7-fluoro-6-(2- fluorophenylamino)-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.00 equivalent) in DMF is added NBS (1.20 equivalents) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO 4 , filtered, and concentrated in v ⁇ cwo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
  • Step I Preparation of 6-(4-bomo-2-fluorophenylamino)-7-fluoro-3-methyl-
  • Step J Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-
  • Step K Preparation of 6-(4-bromo-2-fluorophenylaminoV7-fluoro-3-methyl-
  • Step A Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl- 3H-imidazo[4,5-b1pyridine-5-carboxylic acid hydrazide: To a solution of 6-(4-bromo-2- fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.00 equivalent) and HOBt (3.00 equivalents) is added EDCI (3.00 equivalents) at room temperature. After stining for 1 hour, hydrazine (3.00 equivalents) and TEA (3.00 equivalents) are added.
  • reaction mixture is stined for 1 hour and diluted with EtOAc.
  • the resulting mixture is washed with saturated aqueous NH 4 C1, brine, saturated aqueous NaHCO , and brine.
  • the organic layer is dried over MgSO 4 , filtered, and concentrated in vacuo to give the crude material that is used directly without further purification.
  • Step B Preparation of r5-(5-amino-[l ,3,41oxadiazol-2-ylV7-fluoro-3-methyl- 3H-imidazo 4.5-blpyridin-6-yll-(4-bromo-2-fluorophenyl)-amine: To a suspension of 6-(4- bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid hydrazide (1.00 equivalent) in 1,4-dioxane at room temperature is added BrCN (2.0 equivalents) followed by a solution of NaHCO 3 (1.0 equivalents) in H 2 O.
  • Step A Preparation of 6-chloro-5-methylpyrazolo[l,5-a)pyrimidin-7-ol.
  • a mixture of 3-aminopyrazole (10.0 g, 120.3 mmol), 2-chloro-3-oxo-butyric acid ethyl ester (16.7 mL, 120.3 mmol), and glacial acetic acid (103 mL) was heated to 120 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOH and concentrated. Trituration with Et 2 O gave 20.7 g (94%) desired product.
  • Step B Preparation of 6 -dichloro-5-methylpyrazolo[l,5-a]pyrimidine.
  • Potassium permanganate (2.00 equivalents) is added to 6-chloro-7-fluoro-5- methylpyrazolo[l,5-a]pyrimidine (1.00 equivalent) in water, and the mixture is heated at 100 °C. After 3 hours, the reaction mixture is cooled to room temperature, and the precipitated oxides of manganese are filtered and washed with hot water. The filtrate is concentrated under reduced pressure, diluted with EtOAc, washed with 10% aqueous HCl solution, dried (MgSO 4 ), and concentrated. The product may be triturated with an appropriate solvent such as diethyl ether or dichloromethane if further purification is necessary.
  • an appropriate solvent such as diethyl ether or dichloromethane if further purification is necessary.
  • Step E Preparation of 6-(4-bromo-2-fluorophenylamino -7- fluoropyrazolori ,5-alpyrimidine-5-carboxylic acid.
  • i-Pr 2 NH 3.50 equivalents
  • n-BuLi 3.50 equivalents, 2.5 M solution in hexanes.
  • 4-Bromo-2-fluorophenylamine 2.50 equivalents
  • Step F Preparation of 6-(4-bromo-2-fluorophenylaminoV7- fluoropyrazolo
  • Step A Preparation of 6-chloro-7-methylpyrazolo[1.5-a]pyrimidine-5- carboxylic acid ethyl ester.
  • Step B Preparation of 6-(2-fluoro-4-methylsulfanyl-phenylamino)-7- methylpyrazolo ⁇ ,5-a1pyrimidine-5-carboxylic acid ethyl ester.
  • 2-Fluoro-4-methylsulfanyl- phenylamine (1.01 equivalents), palladium (II) acetate (0.10 equivalents), rac-2,2- bis(diphenylphosphino)-l,l '-binaphthyl (0.15 equivalents), and cesium carbonate (1.50 equivalents) are added to a solution of 6-chloro-7-methylpyrazolo[l,5-a]pyrimidine-5- carboxylic acid ethyl ester (1.00 equivalent) in toluene in a sealed vial. After stirring 10 minutes, the mixture is heated to 80 °C. After 24 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc.
  • Step C Preparation of 6-(2-fluoro-4-methylsulfanyl- ⁇ henylamino)-7- methylpyrazolo
  • Step A Preparation of 6-(4-bromo-2-fluorophenylamino)-7- fluoropyrazolo[T,5-a " lpyrimidine-5-carboxylic acid hydrazide.
  • Step B Preparation of .5-(5-amino- ⁇ .3.4]oxadiazol-2-vn-7- fluoropyrazolo[1.5-a1pyrimidin-6-yl1-(4-bromo-2-fluorophenyl)-amine.
  • Cyanogen bromide (2.02 equivalents) is added to a suspension of 6-(4-bromo-2-fluorophenylamino)-7- fluoropyrazolo[l, 5 -a]pyrimidine-5 -carboxylic acid hydrazide (1.00 equivalent) in dioxane followed by an aqueous NaHCO 3 solution (1.01 equivalents). After 17 hours, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO ) and concentrated under reduced pressure. The product is purified by flash chromatography as necessary.
  • Step A Preparation of 4.6-dichloropyridazine-3-carboxylic acid ethyl ester:
  • 4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester is prepared from 3-oxo-pentanedioic acid diethyl ester according to the procedure described in WO 04/031174.
  • Step B Preparation of 4.6-dichloropyridazine-3-carboxylic acid: To a solution of 4,6-dichloropyridazine-3-carboxylic acid ethyl ester (1.00 equivalent) in 4:1 v/v THF/MeOH is added aqueous 1 M NaOH (5.00 equivalents). The reaction mixture is stined at room temperature for 1 hour.
  • reaction mixture is acidified to pH 1-2 with aqueousl M HCl, diluted with water, and extracted with ethyl acetate/THF.
  • the organic layer is washed with water, saturated NaCl, is dried (Na 2 SO 4 ), and is concentrated under reduced pressure to afford the desired product.
  • Step C Preparation of 4-(4-bromo-2-fluorophenylamino)-6-chloro- pyridazine-3 -carboxylic acid: LiHMDS (1.0 M solution in hexanes, 3.20 equivalents) is added dropwise to a stined solution of 4-bromo-2-fluorophenylamine (2.10 equivalents) in THF cooled to -78 °C. After one hour, 4,6-dichloropyridazine-3-carboxylic acid (1.00 equivalent) is added dropwise as a solution in THF. The reaction mixture is allowed to warm to room temperature slowly and is stined for 16 hours.
  • Step D The reaction mixture is quenched with water, diluted with ethyl acetate and acidified with aqueousl M HCl. The layers are separated and the aqueous phase is extracted with ethyl acetate (3x). The combined organic phases are dried (Na 2 SO 4 ) and concentrated under reduced pressure to give the desired product. The product may be triturated with an appropriate solvent such as diethyl ether or dichloromethane if further purification is necessary. [00293] Step D.
  • Step E The organic layer is washed with 10% K CO 3 and saturated NaCl, dried (Na 2 SO 4 ), and concentrated in vacuo.
  • the crude product is redissolved in dichloromethane and the resulting white solid is removed by filtration (urea byproduct). The filtrate is concentrated under reduced pressure to provide the desired product.
  • the product may be purified by flash column chromatography if further purification is necessary.
  • Step F Preparation of 6-amino-4-(4-bromo-2-fluorophenylamino)-pyridazine-
  • Step G Preparation of 7-(4-bromo-2-fluorophenylamino)-imidazo[l,2- blpyridazine-6-carboxylic acid: Chloroacetaldehyde (50% aqueous solution, 5.00 equivalents) is added to a suspension of 6-amino-4-(4-bromo-2-fluorophenylamino)- pyridazine-3 -carboxylic acid tert-butyl ester (1.00 equivalent) in ethanol contained in a sealed tube. The reaction mixture is heated at 80 °C for two days and then cooled to room temperature. The reaction mixture is concentrated and then diluted with ethyl acetate.
  • Step H The organic layer is washed with saturated NaCl, dried (Na 2 SO 4 ) and concentrated under reduced pressure to provide the desired product.
  • the product may be triturated with an appropriate solvent such as diethyl ether or dichloromethane if further purification is necessary.
  • Step I After the reaction mixture is stined for 16 hours at room temperature, it is diluted with EtOAc and washed with saturated NH 4 C1 solution, saturated NaHCO 3 solution and saturated NaCl. The organic layer is dried (Na2SO 4 ) and concentrated under reduced pressure to yield the desired product. The product may be purified by flash column chromatography if further purification is necessary. [00298] Step I.
  • Example 7 6-(5-Amino-[l,3,4]oxadiazo_-2-y_)-imidazo[l,2-b]pyridazin-7-y_]-(4-bromo-2- fluorophenyl)-amine [00299] Step A.
  • Step B Preparation r6-(5-amino-[l,3,41oxadiazol-2-yl)-imidazori.2- b1pyridazin-7-yn-(4-bromo-2-fluorophenyl)-amine.
  • Step A Preparation of 3A5,6-tetrachloropyridine-2-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step F of Example 1.
  • Step B Preparation of 3,5,6-trichloro-4-fluoropyridine-2-carboxyric acid methyl ester: To a solution of 3,4,5,6-tetrachloropyridine-2-carboxylic acid methyl ester (1.00 equivalent) in MeCN is added CsF (1.00 equivalent) at room temperature. The resulting mixture is refluxed with stirring for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO 4 , filtered, and concentrated in vacuo to afford the desired product that is purified by flash column chromatography as necessary.
  • Step C Preparation of 3,5,6-trichloro-4-fluoropyridine-2-carboxylic acid:
  • Step D Preparation of 5.6-dichloro-4-fluoro-3-(2-fluorophenylamino)- pyridine-2-carboxylic acid: To a solution of 4-fluoraniline (2.00 equivalents) in THF at -78 °C is added LiHMDS (3.00 equivalents, 1 M solution in THF). After complete addition, the resulting mixture is stined for 1 hour at -78 °C. A solution of 3,5,6-trichloro-4- fluoropyridine-2-carboxylic acid (1.00 equivalent) is added at -78 °C. The reaction mixture is slowly warmed to room temperature and stined for 16 hours.
  • Step E Preparation of 5,6-dichloro-4-fluoro-3-(2-fluorophenylaminoV pyridine-2-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step F of Example 1.
  • Step F Preparation of 5-chloro-4-fluoro-3-(2-fluorophenylamino -6- trimethylsilanylethvnyl-pyridine-2-carboxylic acid methyl ester: A mixture of 5,6-dichloro- 4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent), TMS-acetylene (1.20 equivalents), Pd(PPh 3 ) 2 Cl 2 (0.10 equivalents), Cul (0.10 equivalents), and i-Pr 2 NH (2.00 equivalents) in THF is stined for 16 hours at room temperature. THF is evaporated in vacuo.
  • Step G Preparation of 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)- pyridine-2-carboxylic acid methyl ester: A mixture of 5-chloro-4-fluoro-3-(2- fluorophenylamino)-6-trimethylsilanylethynyl-pyridine-2-carboxylic acid methyl ester (1.00 equivalent), HgSO 4 (1.00 equivalent), and cone.
  • Step H Preparation of 7-fluoro-6-(2-fluorophenylaminoV3-methyl- isoxazolo[ " 4,5-b1pyridine-5-carboxylic acid methyl ester: To a solution of acetone oxime (2.20 equivalents) at room temperature is added t-BuOK (2.20 equivalents, 1.0 M solution in THF). After stirring for 30 minutes room temperature, the reaction mixture is cooled to 0 °C. A solution 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent) in THF is added.
  • Step I Preparation of 6-(4-bromo-2-fluorophenylamino -7-fluoro-3-methyl- isoxazolo[4,5-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step H of Example 1.
  • Step J Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3- methylisoxazolo 4,5-b pyridine-5-carboxylic acid: The title compound is prepared by the procedure previously described in Step I of Example 1.
  • Step K Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3- methylisoxazolo[ " 4,5-b1pyridine-5-carboxylic acid cyclopropylmethoxyamide: The title compound is prepared using O-cyclopropylmethyl-hydroxylamine by the method previously described in Step J of Example 1.
  • Example 9
  • Step A Preparation of 5-chloro-6-cvano-4-fluoro-3-(2-fluorophenylamino)- pyridine-2-carboxylic acid methyl ester: A mixture of 5,6-dichloro-4-fluoro-3-(2- fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent) (prepared in Example 8), dppf (0.02 equivalents), Pd 2 dba 3 (0.01 equivalents), and Zn(CN) 2 (0.60 equivalents) in NMP is stined at 120 °C in a sealed tube.
  • reaction mixture After stining for 20 hours, the reaction mixture is cooled to room temperature and quenched with a 4:1 :4 (volume) mixture solution of saturated aqueous NH 4 Cl-conc NH OH-water. The mixture is extracted with EtOAc. The organic layer is washed with saturated aqueous NH 4 Cl/conc. NH 4 OH/water, and brine. The organic layer is dried over MgSO 4 , filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product.
  • Step B Preparation of 3-amino-7-fluoro-6-(2-fluorophenylamino)- isoxazolo( " 4,5-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by a two step procedures as described in Step H of Example 8.
  • Step C Preparation of 3-amino-6-(4-bromo-2-fluorophenylamino)-7- fluoroisoxazolo
  • Step D Preparation of 3-amino-6-(4-bromo-2-fluorophenylamino)-7- fluoroisoxazolo( " 4.5-b1pyridine-5-carboxylic acid: The title compound is prepared by the method described in step I of Example 1.
  • Step E Preparation of 3-amino-6-(4-bromo-2-fluorophenylaminoV7- fluoroisoxazolo[4,5-blpyridine-5-carboxylic acid (2-vinyloxyethoxyVamide: The title compound is prepared using O-(2-vinyloxy-ethyl)-hydroxylamine by the method described in Step J of Example 1.
  • Step F Preparation of 3-amino-6-(4-bromo-2-fluorophenylamino)-7- fluoroisoxazolo 4,5-blpyridine-5-carboxylic acid (2-hydroxyethoxy)-amide: The title compound is prepared by the method described in Step K of Example 1.
  • Example 10 Example 10
  • Step A Preparation of 7-fluoro-6-(2-fluorophenylamino)-3-methyl-2H- pyrazolo[4,3-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared from 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (prepared in Example 8) and the potassium salt of acetone hydrazone in place of the potassium salt of acetone oxime by the method previously described in step H of Example 8.
  • Step B Preparation of 7-fluoro-6-(2-fluorophenylamino)-2.3-dimethyl-2H- pyrazolol4,3-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step D of Example 1.
  • Step C Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-2,3- dimethyl-2H-pyrazolo[4,3-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step H of Example 1.
  • Step D Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-2.3- dimethyl-2H-pyrazolo[4,3-blpyridine-5-carboxylic acid: The title compound is prepared by the procedure previously described in Step I of Example 1.
  • Step E Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-2,3- dimethyl-2H-pyrazolof4,3-b]pyridine-5-carboxylic acid cyclopropylmethoxyamide: The title compound is prepared using O-cyclopropylmethyl-hydroxylamine by the procedure previously described in Step J of Example 1.
  • Example 12
  • Step A Preparation of 3-amino-7-fluoro-6-(2-fluorophenylamino)-2H- pyrazolo r 4,3-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared from 5-chloro-6-cyano-4-fluoro-3-(2-fluorophenylamino)- ⁇ yridine-2-carboxylic acid methyl ester (prepared in Example 9) and the potassium salt of acetone hydrazone in place of the potassium salt of acetone oxime by the method previously described in step H of Example 8. [00325] Step B: Preparation of 3-amino-7-fluoro-6-(2-fluorophenylaminoV2-methyl-
  • Step D Preparation of 3-amino-6-(4-bromo-2-fluorophenylaminoV7-fluoro- 2-methyl-2H-pyrazolor4,3-blpyridine-5-carboxylic acid: The title compound is prepared by the method described in Step I of Example 1.
  • Step E Preparation of 3 -amino-6-(4-bromo-2-fluorophenylamino)-7-fluoro-2- methyl-2H-pyrazolo[4,3-b]pyridine-5-carboxylic acid (2-vinyloxyethoxy -amide: The title compound is prepared using O-(2-vinyloxy-ethyl)-hydroxylamine by the method described in Step J of Example 1.
  • Step F Preparation of 3-amino-6-(4-bromo-2-fluorophenylamino)-7-fluoro-2- methyl-2H-pyrazolor4,3-b1pyridine-5-carboxylic acid (2-hydroxyethoxy)-amide: The title compound is prepared by the method described in Step K of Example 1.
  • Example 13

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Abstract

Disclosed are compounds of the Formula I and pharmaceutically acceptable salts and prodrugs thereof, wherein R1, R2, R7, R8 and R9, W, X, Y and Z are as defined in the specification. Such compounds are MEK inhibitors and are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals, and inflammatory conditions. Also disclosed are methods of using such compounds in the treatment of hyperproliferative diseases in mammals and pharmaceutical compositions containing such compounds.

Description

HETEROCYCLIC INHIBITORS OF MEK AND METHODS OF USE THEREOF
[0001] This application claims benefit of U.S. Provisional Application Serial No. 60/523,270 filed November 19, 2003, incorporated herein in its entirety by reference. BACKGROUND OF THE INVENTION
1. Field of the Invention [0002] This invention relates to a series of novel heterocyclic compounds that are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
2. Description of the state of the art
[0003] Cell signaling through growth factor receptors and protein kinases is an important regulator of cell growth, proliferation and differentiation. In normal cell growth, growth factors, through receptor activation (i.e. PDGF or EGF and others), activate MAP kinase pathways. One of the most important and most well understood MAP kinase pathways involved in normal and uncontrolled cell growth is the Ras/Raf kinase pathway. Active GTP -bound Ras results in the activation and indirect phosphorylation of Raf kinase. Raf then phosphorylates MEKl and 2 on two serine residues (S218 and S222 for MEKl and S222and S226 for MEK2) (Aim et al, Methods in Enzymology, 2001, 332, 417-431). Activated MEK then phosphorylates its only known substrates, the MAP kinases, ERKl and 2. ERK phosphorylation by MEK occurs on Y204 and T202 for ERKl and Y185 and T183 for ERK2 (Ahn et al, Methods in Enzymology, 2001, 332, 417-431). Phosphorylated ERK dimerizes and then translocates to the nucleus where it accumulates (Khokhlatchev et al, Cell, 1998, 93, 605-615). In the nucleus, ERK is involved in several important cellular functions, including but not limited to nuclear transport, signal transduction, DNA repair, nucleosome assembly and translocation, and mRNA processing and translation (Ahn et al, Molecular Cell, 2000, 6, 1343-1354). Overall, treatment of cells with growth factors leads to the activation of ERKl and 2 which results in proliferation and, in some cases, differentiation (Lewis et al, Adv. Cancer Res., 1998, 74, 49-139). [0004] In proliferative diseases, genetic mutations and or overexpression of the growth factor receptors, downstream signaling proteins, or protein kinases involved in the ERK kinase pathway lead to uncontrolled cell proliferation and, eventually, tumor formation. For example, some cancers contain mutations which result in the continuous activation of this pathway due to continuous production of growth factors. Other mutations can lead to defects in the deactivation of the activated GTP -bound Ras complex, again resulting in activation of the MAP kinase pathway. Mutated, oncogenic forms of Ras are found in 50% of colon and >90% pancreatic cancers as well as many others types of cancers (Kohl et al, Science, 1993, 260, 1834-1837). Recently, bRaf mutations have been identified in more than 60% of malignant melanoma (Davies, H. et al, Nature, 2002, 417, 949-954). These mutations in bRaf result in a constitutively active MAP kinase cascade. Studies of primary tumor samples and cell lines have also shown constitutive or overactivation of the MAP kinase pathway in cancers of pancreas, colon, lung, ovary and kidney (Hoshino, R. et al, Oncogene, 1999, 18, 813-822). Hence, there is a strong correlation between cancers and an overactive MAP kinase pathway resulting from genetic mutations.
[0005] As constitutive or overactivation of MAP kinase cascade plays a pivotal role in cell proliferation and differentiation, inhibition of this pathway is believed to be beneficial in hyperproliferative diseases. MEK is a key player in this pathway as it is downstream of Ras and Raf. Additionally, it is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERKl and 2. Inhibition of MEK has been shown to have potential therapeutic benefit in several studies. For example, small molecule MEK inhibitors have been shown to inhibit human tumor growth in nude mouse xenografts, (Sebolt-Leopold et al, Nature-Medicine, 1999, 5 (7), 810-816; Trachet et al., AACR April 6-10, 2002, Poster #5426; Tecle, H., IBC 2nd International Conference of Protein Kinases, September 9-10, 2002), block static allodynia in animals (WO 01/05390 published January 25, 2001) and inhibit growth of acute myeloid leukemia cells (Milella et al, J. Clin. Invest., 2001, 108 (6), 851-859).
[0006] Small molecule inhibitors of MEK have been disclosed, including in U.S.
Patent Publication Nos. 2003/0232869, 2004/0116710, and 2003/0216460, and U.S. Patent Application Serial Nos. 10/654,580 and 10/929,295, each of which is hereby incoφorated by reference. At least fifteen additional patent applications have appeared in the last several years. See, for example: U.S. Patent No. 5,525,625; WO 98/43960; WO 99/01421; WO 99/01426; WO 00/41505; WO 00/42002; WO 00/42003; WO 00/41994; WO 00/42022; WO 00/42029; WO 00/68201; WO 01/68619; WO 02/06213; WO 03/077914; and WO 03/077855. SUMMARY OF THE INVENTION [0007] This invention provides for novel heterocyclic compounds, and pharmaceutically acceptable salts and prodrugs thereof that are useful in the treatment of hypeφroliferative diseases. Specifically, one aspect the present invention relates to compounds of Formulas I-V that act as MEK inhibitors.
]0008] More specifically, one embodiment of the present invention provides compounds of the Formulas I-V:
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
Figure imgf000005_0001
IV
Figure imgf000005_0002
[0009] and pharmaceutically accepted salts, prodrugs and solvates thereof, wherein: [00101 X is C or N; [0011] Y is NR15, O, S, S(O), S(O)2, C(O) or CH2; [0012] Z is C or N; [0013] R1, R2, R8, R9, R10 and R20 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluσromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR11, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, Ci-Cio alkyl, C2-C10 alkenyl, C2-C,0 alkynyl, C3-C,0 cycloalkyl, C3-C10 cycloalkylalkyl, -S(O)j(d-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R°, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, di fluoromethyl, trifluoromethyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; [0014] R7 is hydrogen, trifluoromethyl, C Cι0 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-Ci0 cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NRnR12, -C(O)Rπ, C(O)ORπ, -OC(O)Rπ, -NRuC(O)OR14, -NRuC(O)R12, -C(O)NRπR12, -SR11, -S(O)R14, -SO2R14, -NRπR12, -NRuC(O)NR12R13, -NRUC(NCN)NR12R13, -OR11, Cι-C,0 alkyl, C2-C,0 alkenyl, C -Cι0 alkynyl, C3-Cι0 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, C2-C4 alkenyl, C -C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; [0015] R3 is hydrogen, trifluoromethyl, Cι-C10 alkyl, C2-Cι0 alkenyl, C2-C10 alkynyl, C -Cιo cycloalkyl, C3-Cι0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRuSO2R14, -SO2NRuR12, -C(O)Rπ, C(O)ORn, -OC(O)Rn, -NRπC(O)OR14, - NRπC(O)R12, -C(O)NRuR12, -SR", -S(O)R14, -SO2R14, -NRπR12, -NRuC(O)NR12R13, - NRUC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0016] or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO^R12, -C(O)Rn, C(O)ORu, -OC(O)RH, - NRnC(O)OR14, -NRπC(O)R12, -C(O)NRuR12, -SR11, -S(O)R14, -SO2R14, -NRπR12, -NRπC(O)NRl 2R13, -NRnC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0017] R4 and R5 independently are hydrogen or C C6 alkyl, or [0018] R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRnSO2R14, -SO2NRnR12, -C(O)Ru, C(O)ORn, -OC(O)R1 !, - NRnC(O)OR14, -NRuC(O)R12, -C(O)NRπR12, -SR1 1, -S(O)R14, -SO2R14, -NRπR12, -NRuC(O)NR12R13, -NRUC(NCN)NR12R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0019] R6 is trifluoromethyl, Ci-Cio alkyl, C3-Cl0 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRuSO2R14, -SO2NRuR12, -C(O)Rn, C(O)OR", -OC(O)R", -NRnC(O)OR14, -NRuC(O)R12, -C(O)NRnR12, -SR11, -S(O)R14, -SO2R14, -NRπR12, -NRnC(O)NR12R13, -NRnC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0020] Rπ, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl;
[0021] or any two of R11, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0022] W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, - C(O)R OR3, -C(O)NR4SO2R3, -C(O)(C3-C10 cycloalkyl), -C(O)(C,-C10 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR3OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C,o cycloalkyl), -C(O)(C,-C,0 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR3OR3 are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR3R4, -OR3, C1-C10 alkyl, C2-Cι0 alkenyl, C2-C10 alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said Cι-C)0 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR R and -OR ; [0023] R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; [0024] m is 0, 1, 2, 3, 4 or 5; and
[0025] j is 0, 1 or 2.
[0026] In a further aspect the present invention provides compositions that inhibit MEK comprising compounds of Formulas I-V.
[0027] The invention is also directed to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of compounds of Formula I-V. Methods of making the compounds of Formula I-V are also described. [0028] In a further aspect the present invention provides a method of using the compounds of this invention to treat diseases or medical conditions mediated by MEK, such as cancer. For example, this invention provides a method for treatment of a hypeφroliferative disorder or an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of Formulas I-V or a pharmaceutically acceptable salt or prodrug thereof in an amount effective to treat said hypeφroliferative disorder.
[0029] In a further aspect the present invention provides methods for treating or preventing an MEK-mediated condition, comprising administering to a human or animal in need thereof a pharmaceutical composition comprising a compound of Formula I-V, or a pharmaceutically-acceptable salt or in vivo cleavable prodrug thereof, in an amount effective to treat or prevent said MEK-mediated condition.
[0030] The inventive compounds may further be used advantageously in combination with other known therapeutic agents. [0031] Yet another embodiment of the present invention provides pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formulas I-V or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof. [0032] An additional aspect of the invention is the use of a compound of Formula I,
Formula II, Formula III, Formula IV or Formula V in the preparation of a medicament for the treatment or prevention of a disease or medical condition mediated by MEK in a warmblooded animal, preferably a mammal, more preferably a human, suffering from such disorder. More particularly, the invention includes the use of a compound of the invention in the preparation of a medicament for the treatment or prevention of a hypeφroliferative disorder or an inflammatory condition in a mammal.
[0033] Additional advantages and novel features of this invention shall be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following specification or may be learned by the practice of the invention. The advantages of the invention may be realized and attained by means of the instrumentalities, combinations, compositions, and methods particularly pointed out in the appended claims. BRIEF DESCRIPTION OF THE FIGURES [0034] The accompanying drawings, which are incoφorated herein and form a part of the specification, illustrate non-limiting embodiments of the present invention, and together with the description, serve to explain the principles of the invention. In the Figures:
[0035] Figure 1 shows a reaction scheme for the synthesis of compounds 6-8 and 10.
[0036] Figure 2 shows a reaction scheme for the synthesis of compounds 11-17. [0037] Figure 3 shows a reaction scheme for the synthesis of compounds 22-25.
[0038] Figure 4 shows a reaction scheme for the synthesis of compound 27.
[0039] Figure 5 shows a reaction scheme for the synthesis of compounds 28-33.
[0040] Figure 6 shows a reaction scheme for the synthesis of compounds 35-37.
[0041] Figure 7 shows a reaction scheme for the synthesis of compound 40. [0042] Figure 8 shows a reaction scheme for the synthesis of compound 43.
[0043] Figure 9 shows a reaction scheme for the synthesis of compounds 44-45.
[0044] Figure 10 shows a reaction scheme for the synthesis of compound 46. [0045] Figure 11 shows a reaction scheme for the synthesis of compound 47. [0046] Figure 12 shows a reaction scheme for the synthesis of compound 38. [0047] Figure 13 shows a reaction scheme for the synthesis of compound 38. [0048] Figure 14 shows a reaction scheme for the synthesis of compound 55. [0049] Figure 15 shows a reaction scheme for the synthesis of compound 59. [0050] Figure 16 shows a reaction scheme for the synthesis of compound 62. [0051] Figure 17 shows a reaction scheme for the synthesis of compounds 63-68. [0052] Figure 18 shows a reaction scheme for the synthesis of compounds 69-70. [0053] Figure 19 shows a reaction scheme for the synthesis of compounds 75-78. [0054] Figure 20 shows a reaction scheme for the synthesis of compounds 81-84. [0055] Figure 21 shows a reaction scheme for the synthesis of compounds 85-91. [0056] Figure 22 shows a reaction scheme for the synthesis of compounds 93-98. [0057] Figure 23 shows a reaction scheme for the synthesis of compounds 99-104. [0058] Figure 24 shows a reaction scheme for the synthesis of compounds 105-111. DETAILED DESCRIPTION OF THE INVENTION
[0059] The inventive compounds of the Formulas I-V and the pharmaceutically acceptable salts and prodrugs thereof of this invention are useful in the treatment of hypeφroliferative diseases. Specifically, one aspect the present invention relates to compounds of Formula I-V that act as MEK inhibitors. More specifically, one embodiment of the invention provides compounds, including pharmaceutically acceptable salts, prodrugs and solvates thereof, having the general Formula I:
Figure imgf000010_0001
I and pharmaceutically acceptable salts, prodrugs and solvates thereof, where: [0060] X is C or N;
[0061] Y is NR15, O, S, S(O), S(O)2, C(O) or CH2;
[0062] Z is C or N;
[0063] R , R , R , and R are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR11, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, Ci-Cio alkyl, C2-Cι0 alkenyl, C2-Cι0 alkynyl, C3-C10 cycloalkyl, C3-C,0 cycloalkylalkyl, -S(O)j(C C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C alkyl, C -C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; [0064] R7 is hydrogen, trifluoromethyl, C_-Cιo alkyl, C2-C10 alkenyl, C2-CIQ alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NR"R'2, -C(O)Ru, C(O)ORπ, -OC(O)Rn, -NRπC(O)OR14, -NRuC(O)R12, -C(O)NRΠR12, -SR1 1, -S(O)R14, -SO2R14, -NRπR12, -NR" C(0)NR12R13, -NR"C(NCN)NR12R13, -OR", Ci-C.o alkyl, C2-Cιo alkenyl, C2-C10 alkynyl, C -Cιo cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; [0065] R3 is hydrogen, trifluoromethyl, Cι-C.0 alkyl, C2-Cι0 alkenyl, C2-Cι0 alkynyl, C3-Ci0 cycloalkyl, C3-Cι0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRuSO2R14, -SO2NRuR12, -C(O)Rn, C(O)ORu, -OC(O)Ru, -NRnC(O)OR14, - NRuC(O)R12, -C(O)NRnR12, -SR1 1, -S(O)R14, -SO2R14, -NRnR12, -NRnC(O)NR12R13, - NRπC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
[0066] or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRnSO2R14, -SO2NRnR12, -C(O)Rπ, C(O)ORH, -OC(O)Ru, - NR"C(O)OR14, -NRπC(O)R12, -C(O)NRπR12, -SR1 1, -S(O)R14, -SO2R14, -NRUR12, -NRnC(O)NR12R13, -NRπC(NCN)NR12R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
[0067] R4 and R5 independently are hydrogen or Cι-C6 alkyl, or
[0068] R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRnSO2R14, -SO2 RnR12, -C(O)Ru, C(O)ORπ, -OC(O)Rπ, - NR"C(O)OR14, -NRuC(O)R12, -C(O)NR"R12, -SR1 1, -S(O)R14, -SO2R14, -NRπR12, -NRnC(O)NR12R13, -NRl lC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0069] R6 is trifluoromethyl, Ci-Cio alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR SO2R , -SO2NR R , -C(O)R", C(O)ORπ, -OC(O)R", -NRπC(O)OR14, -NRnC(O)R12, -C(O)NRπR12, -SR11, -S(O)R14, -SO2R14, -NRπR12, -NRπC(O)NR12R13, -NRπC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0070] R11, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl; [0071] or any two of R11, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0072] W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -
C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C,0 cycloalkyl), -C(O)(Cι-C,0 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR3OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-Cιo cycloalkyl), -C(O)(CrC10 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR3OR3 are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR3R4, -OR3, Cι-Cι0 alkyl, C2-Cι0 alkenyl, C2-Cιo alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said Cj-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR3R4 and -OR3; [0073] R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; [0074] m is 0, 1, 2, 3, 4 or 5; and
[0075] j is 0, 1 or 2.
[0076] In one preferred embodiment, W is selected from
Figure imgf000013_0001
Figure imgf000014_0001
[0077] Figures 1 -2 show non-limiting examples of the synthesis of compounds of this invention having the general Formula I.
[0078] In addition to compounds of the general Formula I, this invention further includes compounds of the general Formula II:
Figure imgf000014_0002
II
[0079] and pharmaceutically accepted salts, prodrugs and solvates thereof, where:
[0080] Y is NR15, O, S, S(O), S(O)2, C(O) or CH2; [0081] R1, R2, R8, R9, R10 and R20 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR11, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, Ci-Ci0 alkyl, C2-Cιo alkenyl, C2-C,o alkynyl, C3-C10 cycloalkyl, C3-C]0 cycloalkylalkyl, -S(O)j(C,-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, CrC4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; [0082] R3 is hydrogen, trifluoromethyl, d-Cio alkyl, C2-C10 alkenyl, C2-Cι0 alkynyl,
C3-Cιo cycloalkyl, C3-Cι0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRnSO2R14, -SO2NRuR12, -C(O)Rn, C(O)ORπ, -OC(O)Rπ, -NRuC(O)OR14, - NRuC(O)R12, -C(O)NRuR12, -SR11, -S(O)R14, -SO2R14, -NRUR12, -NRuC(O)NR12R13, - NRπC(NCN)NR12R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0083] or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NRπR12, -C(O)Rπ, C(O)ORπ, -OC(O)Ru, - NRnC(O)OR14, -NRπC(O)R12, -C(O)NRπR12, -SR11, -S(O)R14, -SO2R14, -NRnR12, -NRuC(O)NR12R13, -NRπC(NCN)NR,2R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0084] R4 and R5 independently are hydrogen or Cι-C6 alkyl, or
[0085] R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -S02NR"R12, -C(O)RΠ, C(O)ORπ, -OC(O)R1 !, - NRnC(O)OR14, -NR"C(O)R12, -C(O)NRπR12, -SR1 1, -S(O)R14, -SO2R14, -NRπR12, -NRπC(O)NR12R13, -NRπC(NCN)NR,2R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
[0086] R6 is trifluoromethyl, Ci-Cio alkyl, C3-Cιo cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR SO2R , -SO2NR R , -C(O)R", C(O)ORπ, -OC(O)R", -NR"C(O)OR14, -NRnC(O)R12, -C(O)NRπR12, -SR11, -S(O)R14, -SO2R14, -NRπR12, -NRnC(O)NR12R13, -NRnC(NCN)NR1 R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0087] R11, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl; [0088] or any two of Rn, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
10089] W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -
C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C10 cycloalkyl), -C(O)(C,-Cι0 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR OR , wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C10 cycloalkyl), -C(O)(d-C10 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR3OR3 are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR R , -OR , d~C10 alkyl, C2-C 10 alkenyl, C2-Cιo alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said d-C10 alkyl,
C2-C10 alkenyl, C2-Cιo alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR3R4 and -OR3;
[0090] R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl;
[0091] m is 0, 1, 2, 3, 4 or 5; and
[0092] j is 0, 1 or 2. [0093] Figures 3-5 show non-limiting examples of the synthesis of compounds of this invention having the general Formula II.
[0094] In another embodiment, this invention relates to compounds of the general Formula III:
Figure imgf000017_0001
[0095] and phaπnaceutically accepted salts, prodrugs and solvates thereof, where: [0096] Y is NR15, O, S, S(O), S(O)2, C(O) or CH2;
[0097] R1, R2, R8, R9, R10 and R20 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR11, -OR3, -C(O)R3, -C(O)OR3, -NR4C(0)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NRJR4, d-Cio alkyl, C2-C10 alkenyl, C2-C,o alkynyl, C3-Cιo cycloalkyl, C3-C 10 cycloalkylalkyl, -S(O)j(d-C6 alkyl), -S(O)j(CR 44TR.53Λ)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -S02NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C alkyl, d-d alkenyl, d-C4 alkynyl, C -C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3;
[0098] R3 is hydrogen, trifluoromethyl, d-Cio alkyl, C2-Cι0 alkenyl, C2-C)0 alkynyl,
C3-Cιo cycloalkyl, C -Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSθ2R14, -SO2NRπR12, -C(O)Ru, C(O)ORn, -OC(O)Rπ, -NRπC(O)OR14, - NRuC(O)R12, -C(O)NRπR12, -SR11, -S(O)R14, -SO2R14, -NRnR12, -NRπC(O)NRl2R13, - NRnC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [0099] or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NRnR12, -C(O)Rπ, C(O)ORu, -OC(O)Rπ, - NRuC(O)OR14, -NRuC(O)R12, -C(O)NRuR12, -SR11, -S(O)R14, -SO2R14, -NRUR12, -NRπC(O)NR12R13, -NRπC(NCN)NR12R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
[00100] R4 and R5 independently are hydrogen or C]-C6 alkyl, or
[00101] R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRuSO2R14, -S02NR"R12, -C(O)Rn, C(O)ORn, -OC(O)Rn, - NRnC(O)OR14, -NRπC(O)R12, -C(O)NRΠR12, -SR1 1, -S(O)R14, -SO2R14, -NRΠR12, -NR"C(O)NR,2R13, -NRΠC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00102] R6 is trifluoromethyl, Cι-Cιo alkyl, C3-C,o cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO R14, -Sθ2N πR12, -C(O)R", C(O)ORπ, -OC(O)R", -NR"C(O)OR14, -NR"C(O)R12, -C(O)NRΠR12, -SR11, -S(O)R14, -SO2R14, -NRUR12, -NRuC(O)NR12R13, -NRnC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00103] R11, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl; [00104] or any two of R11, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00105] W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3,
-C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-Cι0 cycloalkyl), -C(O)(Cι-C,0 alkyl), -C(O)(aryl), -C(θχheteroaryl), -C(O)fheterocyclyl) or CR3OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-Cιo cycloalkyl), -C(O)(Cι-Cι0 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR OR are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR3R4, -OR3, Ci-Cio alkyl, -Cio alkenyl, -Cio alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said Ci-Cio alkyl, -Cio alkenyl, -Cio alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR3R4 and -OR3; [00106] R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; [00107] m is 0, 1, 2, 3, 4 or 5; and
[00108] j is 0, 1 or 2.
[00109] Figures 6-18 show non-limiting examples of the synthesis of compounds of this invention having the general Foπnula III.
[00110] In another embodiment, this invention relates to compounds of the general
Formula IV:
Figure imgf000019_0001
[00111] and pharmaceutically accepted salts, prodrugs and solvates thereof, where: [00112] Y is NR15, O, S, S(O), S(O)2, C(O) or CH2; [00113] R1, R2, R8, R9 and R10 are independently hydrogen, hydroxy, halogen, cyanc nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethox) trifluoromethoxy, azido, -SR1 1, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R2 -NR SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4 -NR3R4, Ci-Cio alkyl, C2-Cιo alkenyl, C2-C10 alkynyl, C3-Cι0 cycloalkyl, C3-Cι, cycloalkylalkyl, -S(O)j(CrC6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, C2-C4 alkenyl, d-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3;
[00114] R3 is hydrogen, trifluoromethyl, C_-C.o alkyl, -Cio alkenyl, C2-Cιo alkynyl,
C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NRπR12, -C(O)Ru, C(O)ORu, -OC(O)Ru, -NRuC(O)OR14, - NRπC(O)R12, -C(O)NRuR12, -SR11, -S(O)R!4, -SO2R14, -NRnR12, -NRuC(O)NR12R13, - NRUC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00115] or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRnSO2R1 , -SO2NRnR12, -C(O)Rπ, C(O)ORu, -OC(O)Ru, - NRuC(O)OR14, -NRnC(O)R12, -C(O)NRuR12, -SR11, -S(O)R14, -SO2R14, -NRnR12, -NRnC(O)NR12R13, -NRπC(NCN)NR12R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00116] R4 and R5 independently are hydrogen or C]-C6 alkyl, or
[00117] R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NRuR12, -C(O)Rn, C(O)ORu, -OC(O)Rn, - NR"C(O)OR14, -NR"C(0)R12, -C(O)NRuR12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NRuC(O)NR12R13, -NR"C(NCN)NR12R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00118] R6 is trifluoromethyl, Ci-Cio alkyl, C3-Cl0 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NR"R'2, -C(O)R", C(O)OR", -OC(O)R", -NRnC(O)OR14, -NRuC(O)R12, -C(O)NRπR12, -SR11, -S(O)R14, -SO2R14, -NR"R12, -NR"C(O)NR12R13, -NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00119] R1 1, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl; [00120] or any two of R1 1, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00121] W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, - C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C10 cycloalkyl), -C(O)(C,-C10 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR3OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO R3, -C(O)(C3-Cιo cycloalkyl), -C(O)(C,-C,o alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR3OR3 are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR3R4, -OR3, Ci-Cio alkyl, d-Cio alkenyl, -Cio alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said Ci-Cio alkyl, d-Cio alkenyl, -Cio alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR3R4 and -OR3; [00122] R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl;
[00123] m is 0, 1, 2, 3, 4 or 5; and
[00124] j is 0, 1 or 2.
[00125] Figures 19-21 show non- limiting examples of the synthesis of compounds of this invention having the general Formula IV. [00126] In another embodiment, this invention relates to compounds of the general
Formula V:
Figure imgf000022_0001
[00127] and pharmaceutically accepted salts, prodrugs and solvates thereof, where: [00128] Y is NR15, O, S, S(O), S(O)2, C(O) or CH2;
[00129] R , R , R , R and R are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SRn, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, Ci-do alkyl, C2-Cι0 alkenyl, C2-Cι0 alkynyl, C3-Cι0 cycloalkyl, C3-Cιo cycloalkylalkyl, -S(O)j(C,-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, d-C alkyl, C2-C4 alkenyl, d-C4 alkynyl, C -C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3;
[00130] R7 is hydrogen, trifluoromethyl, Ci-Cio alkyl, C2-Cι0 alkenyl, -Cio alkynyl,
C3-Cιo cycloalkyl, C -Cι0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NRuSO2R14, -SO2NRnR12, -C(O)Rn, C(O)ORH, -OC(O)Rn,
-NR"C(O)OR14, -NR"C(O)R12, -C(O)NR"R12, -SR" , -S(O)R14, -SO2R14, -NR"R12,
-NR"C(O)NR12R13, -NRUC(NCN)NR12R13, -OR", d-do alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C alkyl, d-C alkenyl, C2-C alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; [00131] R3 is hydrogen, trifluoromethyl, C.-Cio alkyl, C2-Cι0 alkenyl, C2-Cιo alkynyl,
C3-C]0 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NRuR12, -C(O)R", C(O)ORU, -OC(O)Rπ, -NRUC(O)OR14, - NR"C(O)R12, -C(0)NR"R12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(O)NR12R13, - NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
[00132] or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -SO2NRMR12, -C(O)Rn, C(O)ORu, -OC(O)R", - NR"C(O)OR14, -NRuC(O)R12, -C(O)NRl lR12, -SR1 1, -S(O)R14, -SO2R14, -NRπR12, -NR"C(0)NR12R13, -NR"C(NCN)NRI 2R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00133] R4 and R5 independently are hydrogen or Cι-C6 alkyl, or
[00134] R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -SO2NRΠR12, -C(O)Rn, C(O)ORn, -OC(O)Rn, - NRπC(O)OR14, -NR"C(O)R12, -C(O)NRuR12, -SRU, -S(O)R14, -SO2R14, -NRUR12, -NR"C(O)NR12R13, -NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00135] R6 is trifluoromethyl, C1-C10 alkyl, C3-Cι0 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR SO2R , -SO2NR R , -C(O)R", C(O)OR", -OC(O)R", -NR"C(O)OR14, -NR"C(O)R12, -C(O)NRnR12, -SR11, -S(O)R14, -SO2R14, -NR"R12, -NR"C(O)NR12R13, -NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00136] R11, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl; [00137] or any two of R1 1, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; [00138] W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR OR3, - C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C,0 cycloalkyl), -C(O)(d-C,0 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR3OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-Cιo cycloalkyl), -C(O)(C,-Cl0 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR OR are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR3R4, -OR3, C Cιo alkyl, C2-C10 alkenyl, -Cio alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said Ci-Cio alkyl, d-Cio alkenyl, d-Cio alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR3R4 and -OR3; [00139] R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl;
[00140] m is 0, 1, 2, 3, 4 or 5; and
[00141] j is 0, 1 or 2.
[00142] Figures 22-24 show non-limiting examples of the synthesis of compounds of this invention having the general Formula V. [00143] The terms "Ci-Cio alkyl", "alkyl" and "lower alkyl" as used herein refer to a saturated linear or branched-chain monovalent hydrocarbon radical having one to ten carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described below. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, heptyl, octyl, and the like. [00144] The terms "d-Cio alkenyl", "lower alkenyl" and "alkenyl" refer to linear or branched-chain monovalent hydrocarbon radical having two to 10 carbon atoms and at least one double bond, and include, but is not limited to, ethenyl, propenyl, l-but-3-enyl, l-pent-3- enyl, l-hex-5-enyl and the like, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. [00145] The terms "d-Cio alkynyl," "lower alkynyl" and "alkynyl" refer to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentyn- 2-yl and the like, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. [00146] The term "allyl" refers to a radical having the formula RC=CHCHR, wherein
R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or any substituent as defined herein, wherein the allyl may be optionally substituted independently with one or more substituents described herein. [00147J The terms "carbocycle," "carbocyclyl," "cycloalkyl" or "C3-C10 cycloalkyl" refer to saturated or partially unsaturated cyclic hydrocarbon radical having from three to ten carbon atoms. The term "cycloalkyl" includes monocyclic and polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated cycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The cycloalkyl may be optionally substituted independently in one or more substitutable positions with various groups. For example, such cycloalkyl groups may be optionally substituted with, for example, Cι-C6 alkyl, Cι-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(Cι-C6)alkylamino, di(Cι-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, Cι-C6 haloalkyl, Cι-C6 haloalkoxy, amino(Cι-C6)alkyl, mono(d- C6)alkylamino(Cι-C6)alkyl or di(Cι-C6)alkylamino(Cι-Cδ)alkyl. [00148] The term "heteroalkyl" refers to saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms, wherein at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S, and wherein the radical may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical). The heteroalkyl radical may be optionally substituted independently with one or more substituents described herein. The term "heteroalkyl" encompasses alkoxy and heteroalkoxy radicals. [00149] The terms "heterocycloalkyl," "heterocycle" or "hetercyclyl" refer to a saturated or partially unsaturated carbocyclic radical of 3 to 10 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms being C, where one or more ring atoms may be optionally substituted independently with one or more substituent described below. The radical may be a carbon radical or heteroatom radical. The term further includes bicyclic and tricyclic fused ring systems which include a heterocycle fused to one or more carbocyclic or heterocyclic rings. "Heterocycloalkyl" also includes radicals where heterocycle radicals are fused with aromatic or heteroaromatic rings. Examples of heterocycloalkyl rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, moφholino, thiomoφholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Spiro moieties are also included within the scope of this definition. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyπole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N- attached) or imidazol-3-yl (C-attached). An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo (=O) moieties is 1,1-dioxo-thiomoφholinyl. The heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heterocycle groups may be optionally substituted with, for example, Cι-C6 alkyl, Cι-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(Cι-C6)alkylamino, di(CrC6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, d- C6 haloalkyl, Cι-C6 haloalkoxy, amino(Cι-C6)alkyl, mono(Cι-C6)alkylamino(Cι-C6)alkyl or di(C i -C6)alkylamino(C i -C6)alkyl. [00150] The term "aryl" refers to a monovalent aromatic carbocyclic radical having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, and hydroxy. [00151] The term "heteroaryl" refers to a monovalent aromatic radical of 5-, 6-, or 7- membered rings which includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyπolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiro moieties are also included within the scope of this definition. Heteroaryl groups are optionally mono-, di-, or trisubstituted with, e.g., substituents including, but not limited to, halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.
[00152] The term "halogen" represents fluorine, bromine, chlorine, and iodine.
[00153] The term "arylalkyl" means an alkyl moiety (as defined above) substituted with one or more aryl moiety (also as defined above). More preferred arylalkyl radicals are aryl-Cι. -alkyls. Examples include benzyl, phenylethyl, and the like. [00154] The term "heteroarylalkyl" means an alkyl moiety (as defined above) substituted with a heteroaryl moiety (also as defined above). More prefeπed heteroarylalkyl radicals are 5- or 6-membered heteroaryl-Cι- -alkyls. Examples include oxazolylmethyl, pyridylethyl and the like. [00155] The term "heterocyclylalkyl" means an alkyl moiety (as defined above) substituted with a heterocyclyl moiety (also defined above). More prefeπed heterocyclylalkyl radicals are 5- or 6-membered heterocyclyl-C]-3-alkyls. Examples include tetrahydropyranylmethyl. [00156] The term "cycloalkylalkyl" means an alkyl moiety (as defined above) substituted with a cycloalkyl moiety (also defined above). More prefeπed heterocyclyl radicals are 5- or 6-membered cycloalkyl-Cι-3-alkyls. Examples include cyclopropylmethyl. [00157] The term "Me" means methyl, "Et" means ethyl, "Bu" means butyl and "Ac" means acetyl.
[00158] The term "amino acid residue" includes, but is not limited to, the 20 naturally occuπing amino acids commonly designated by three letter symbols, and also includes 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta- alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.
[00159] In general, the various moieties or functional groups of the compounds of
Formulas I-V may be optionally substituted by one or more substituents. Examples of substituents suitable for puφoses of this invention include, but are not limited to, oxo (with the proviso that the oxo substituent is not on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -N 4SU2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where R3, R4, R5 and R6 are as defined herein. [00160] It is to be understood that in instances where two or more radicals are used in succession to define a substituent attached to a structure, the first named radical is considered to be terminal and the last named radical is considered to be attached to the structure in question. Thus, for example, the radical arylalkyl is attached to the structure in question by the alkyl group. [00161] In the compounds of the present invention, where a term such as (CR4R5)m is used, R and R5 may vary with each iteration of m above 1. For instance, where m is 2, the term (CR4R5)m may equal -CH CH2- or -CH(CH3)C(CH2CH3)(CH2CH2CH3)- or any number of similar moieties falling within the scope of the definitions of R4 and R5. [00162] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers, diastereomers mixtures, racemic or otherwise, thereof. Accordingly, this invention also includes all such isomers, including diastereomeric mixtures and pure enantiomers of the Formulas I-V. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the coπesponding pure enantiomers. The methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 1992).
[00163] This invention also encompasses pharmaceutical compositions containing a compound of Formula I-V and methods of treating proliferative disorders, or abnormal cell growth, by administering compounds of the present invention. Compounds of the present invention having free amino, amido, hydroxy or carboxylic groups can be converted into pharmaceutically acceptable prodrugs.
[00164] A "pharmaceutically acceptable prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. One prefeπed prodrug of this invention is a compound of Formula I-V covalently joined to a valine residue. [00165] Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. As another example, compounds of this invention comprising free hydroxy groups may be derivatized as prodrugs by converting the hydroxy group to a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., 1996, 39, 10. More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (Ci -C6)alkanoyloxymethyl, l-((Cι -C6)alkanoyloxy)ethyl, 1-methyl-l- ((Cι-C6)alkanoyloxy)ethyl, (Ci-G alkoxycarbonyloxymethyl, N-(d-
C6)alkoxycarbonylaminomethyl, succinoyl, (Cι-C6)alkanoyl, α-amino(Cι -C4)alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occuπing L-amino acids, P(O)(OH)2, -P(O)(O(d- C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate). [00166] Free amines can also be derivatized as amides, sulfonamides or phosphonamides. For example, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci -Cιo)alkyl, (C -C7)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, -C(OH)C(O)OY wherein Y is H, (C, -C6)alkyl or benzyl, -C(OY0)Yι wherein Y0 is (C. -C4) alkyl and Yj is (Ci -C6)alkyl, carboxy(Cι -C6)alkyl, amino(Cι-C4)alkyl or mono-N- or di- N,N- (Ci -Cό)alkylaminoalkyl, -C(Y2)Y wherein Y is H or methyl and Y is mono-N- or di- N,N-(Cι -Cό)alkylamino, moφholino, piperidin-1-yl or pyrrolidin-1-yl. [00167] All of these prodrug moieties may incoφorate groups including but not limited to ether, amine and carboxylic acid functionalities. [00168] In addition, the invention also includes solvates, pharmaceutically active metabolites, and pharmaceutically acceptable salts of compounds of Formulas I-V. [00169] The term "solvate" refers to an aggregate of a molecule with one or more solvent molecules. [00170] A "pharmaceutically active metabolite" is a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. [00171] Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al, Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull, 32: 692 (1984), each of which is specifically incoφorated herein by reference.
[00172] A "pharmaceutically acceptable salt" as used herein, unless otherwise indicated, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable sale. Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitromenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, pheylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates. Since a single compound of the present invention may include more than one acidic or basic moieties, the compounds of the present invention may include mono, di or tri-salts in a single compound.
[00173] If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an acidic compound, particularly an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alphahydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. [00174] If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base. Prefeπed inorganic salts are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Prefeπed organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2- hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzyl- ethylenediamine, and the like salts. Other salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglusoamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. [00175] Processes for the manufacture of the compounds of Formula I, Formula II,
Foπnula III, Foπnula IV and Foπnula V are provided as further features of the invention. The inventive compounds may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available or can be synthesized using methods known in the art. [00176] Illustrations of the preparation of compounds of the present invention are shown in Figures 1-24. [00177] Figure 1 illustrates the synthesis of compounds of Formula I of the present invention. 6-Bromo-7-chloro-5-methyl-3H-imidazo[4,5-b]pyridine (compound 2 where R9 = Cl) can be prepared in a two-step procedure from the known bromoimidazo[4,5-b]pyridine 1 (Graboyes et al J. Am. Chem. Soc. 1957, 79, 6421-6426). Oxidation of imidazopyridine 1 can be accomplished using m-CPBA in suitable organic solvent or H2O2 in water or water/organic solvent systems. The intermediate N-oxide can then be chlorinated with POCl , or thionyl chloride, or oxalyl chloride or PC15, or MsCl in DMF. Most preferable is the use of m-CPBA in methylene chloride at or near room temperature followed by treatment with neat POCl3. If a compound where R9 is F is desired (compound 2 where R9 is F), fluorination is accomplished through substitution of the chloride 2 (R9 is Cl) intermediate by heating with either KF in DMSO, or KF and 18-Crown-6 in NMP, or CsF in MeCN. [00178] With continued reference to Figure 1, regardless of the nature of R9 (R9 is Me is known, Graboyes et al J. Am. Chem. Soc. 1957, 79, 6421-6426), alkylation of the imidazo[4,5-b]pyridine 2 is accomplished by use of an alkylating agent such as an alkyl halide and base such as LiH, NaH, or K2CO3 in suitable organic solvent such as DMF, MeCN, or THF at temperatures ranging from 0 to 80 °C. The alkylation gives a mixture of NI and N3 products 3 and 4 that are separable by standard techniques, including, for example, chromatography, trituration, and crystallization. The 5-methyl group of the N3- alkylsubstitured imidazo[4,5-b]pyridines 3 or 4 can be oxidized by standard method, including but not limited to KMnO4 in water, SeO2 in organic solvent such as dioxane, xylene, or pyridine, NaOCl/RuCl3, CrO3 in aqueous H2SO4, K2Cr2O , and Na2Cr2O7 in water. Preferably this transformation is achieved with KMnO4 in water. Incoφoration of the appropriate aniline moiety to give carboxylic acid 6 can be accomplished by SNAΓ reaction. This can be done in a suitable organic solvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78 °C to room temperature). Carboxylic acid 6 can also be prepared by treating imidazopyridine 5 with the appropriate aniline in the presence of Cul, Cu(OAc)2, or Zn-Cu and a suitable base such as K2CO3, Na2CO , or TEA. Additionally, preparation of carboxylic acid 6 can be achieved in a three-step sequence; esterification followed by palladium mediated cross-coupling reaction with the appropriate aniline (when R8 is not Br or I) and then basic hydrolysis. Esterification can be achieved by standard methods including but not to limited to Fisher esterification (MeOH, H2SO4), reaction with TMSCHN2 or TMSC1 in MeOH. In the second step, a suitable aniline is coupled with the intermediate ester by use of palladium catalyst, including not to limited to Pd(OAc)2, Pd2(dba)3, or PdCl2, and a ligand, such as BINAP, dppf, (o-tol)3P, or (t-Bu)3P, along with a base such as t-BuONa, t-BuOK, LiHMDS, or Cs CO3, in a suitable organic solvent, DME, dioxane, toluene, xylene, THF, or DMF at temperatures ranging from 50 to 120 °C. The aniline moiety can be further functionalized if desired by standard methods known to those skilled in the art such as halogenation. Finally, the ester is hydrolyzed by standard saponification conditions. The N3 -substituted acid 6 is then converted to the N3-substituted amide analog 7 or hydroxamate analog 8 by standard coupling procedures including but not limited to EDCI, HOBt, or PyBOP and the appropriate amine or hydroxylamine in suitable organic solvents such as DMF, THF or dichloromethane. In some instances, the amine or hydroxylamine used in the coupling reaction contains a standard protecting group. In those cases, the protecting group can be removed by standard conditions known in the art. The coπesponding NI -substituted imidazo[4,5-b]pyridine analog 10 can be prepared by the procedures described above after the separation step. [00179] Figure 2 illustrates the preparation of compounds of Formula I where W is heteroaryl or heterocyclic. The thiadiazole 12 can be prepared from the carboxylic acid 6 by treatment with thiosemicarbazide using standard EDCI coupling conditions followed by cyclization of the intermediate 11 employing PPh3, TEA, and CC14 in dichloromethane. Furthermore, the N-3 substituted acid 6 can be converted to the hydrazide 13 by standard coupling procedures including but not limited to EDCI, HOBt, or PyBOP and hydrazine in suitable organic solvents such as DMF, THF or dichloromethane. The desired derivative can then be prepared by cyclization with an appropriate reagent. For aminooxadiazole 14 the hydrazide 13 is treated with BrCN and base such as NaHCO , in a suitable biphasic solvent system such as dioxane and water at room temperature. The triazole 15 can be prepared by reaction of the hydrazide 13 with an appropriate coupling agent, such as cyanamide or ethyl acetimidate, followed by cyclization using PPh , TEA, and CC14 in dichloromethane. For the preparation of the substituted aminooxadiazole 17, the hydrazide 13 is first cyclized to the oxadiazolone 16 using either CDI, phosgene or a phosgene equivalent in a suitable organic solvent such as DMF, PhMe, methylene chloride or mixtures thereof. Preferably, cyclization to form oxadiazolone 16 is accomplished by treating hydrazide 13 with CDI in DMF at room temperature. The aminooxadiazole 17 is then prepared by addition of an appropriate amine followed by re-cyclization of the intermediate obtained using PPh3, TEA, and CC1 in dichloromethane. The coπesponding NI -substituted imidazo[4,5-b]pyridine analogs, where W is heteroaryl or heterocyclyl, can be prepared by the procedures described above. [00180] In Figure 3, preparation of compounds of the Formula II is depicted.
Pyrazolopyrimidine ester 20 can be prepared by the condensation of aminopyrazole 18 and ester 19 with acid (such as AcOH, HCl, ZnCl2, HBr or p-TsOH) or base (such as alkylamine such as piperidine) or without acidic or basic conditions in a suitable organic solvent such as EtOH, toluene, DMF, MeCN or AcOH at elevated temperatures (80 to 120 °C). Preferably the condensation is achieved by treating the aminopyrazole 18 with ester 19 in AcOH and heating to 120 °C. Chlorination of the pyrazolopyrimidine ester 20 can be accomplished with POCl3, thionyl chloride, oxalyl chloride or PC15. Preferably this transformation is achieved with POCl3 neat or in the presence of an amine such as triethylamine at room temperature. If a compound wherein R9 is F is desired, a fluorination step can be incoφorated at this stage. Fluorination of pyrazolopyrimidine ester 21 (where R9 is Cl) can be accomplished with KF in the presence of 18-Crown-6 or in the presence of an amine such as trimethylamine in a suitable organic solvent such as MeCN, DMF, DMSO at the elevated temperature. Preferably this reaction is canied out with KF in the presence of 18-crown-6 in MeCN at the appropriate temperature. [00181] With continued reference to Figure 3, hydroxamate 23 or amide 25 can be prepared using one the following routes. The first route involves palladium mediated cross- coupling with appropriately substituted aniline and the chloro (or bromo) pyrazolopyrimidine 21 where R5 is CO2Et (and X is Cl or Br) to prepare ester 22. In this case, the cross-coupling can be done in a suitable organic solvent such as toluene, DME, DMF, THF, or dioxane in the presence of a base such as NaOt-Bu, KOt-Bu, K2CO3, Cs2CO , Na2CO , a phosphine ligands such as BINAP, DPPF, and (o-tol)3P and a palladium catalysts such as Pd(OAc)2, PdCl2(dppf), Pd(dba)2, and Pd2(dba)3 at elevated temperature (50 to 120 °C). Preferably this cross-coupling reaction is accomplished by treating the chloro (or bromo) pyrazolopyrimidine 21 with aniline (R8 is not Br or I), Cs2CO , BINAP, and Pd(OAc)2 in toluene and heating to about 80 °C. The aniline moiety can be further functionalized if desired by standard methods known to those skilled in the art such as halogenation. Hydroxamates 23 is then prepared from ester 22 using standard coupling procedures. This can be done in a suitable organic solvent such as THF using an amide base such as LiHMDS, NaHMDS or KHMDS at appropriate temperatures (0 °C to room temperature). Preferably, the hydroxylamine is added to LiHMDS in THF at low temperature (0 °C) followed by the addition of ester 22 and the reaction mixture is warm to room temperature. Ester 22 can also be converted to acid 24 by basic hydrolysis under standard conditions using either LiOH or NaOH in standard mixed aqueous/organic solvent systems. Carboxylic acid 24 can then be converted to the amide 25 or hydroxamate 23 by standard coupling procedures including but not limited to EDCI, HOBt, or PyBOP and the appropriate amine or hydroxylamine in suitable organic solvents such as DMF, THF or dichloromethane. [00182] With continued reference to Figure 3, an alternative second route includes a two-step procedure to carboxylic acid 24 is available when R5 is Me through oxidation followed by SNAΓ reaction with appropriate aniline. In this case, oxidation of chloro (or bromo) pyrazolopyrimidine 21 where R5 is Me (and X is Cl or Br) can be accomplished using standard methods including but not limited to KMO4, NaOCl/RuCl3 or Na2Cr2O7/HCl. Incoφoration of the aniline moiety is accomplished by SNAT reaction. This can be done in a suitable organic solvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78 °C to room temperature). Preferably, the aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80 °C). The carboxylic acid intermediate is then added and the reaction mixture is warmed to room temperature to generate carboxylic acid 24. The hydroxamate 23 or amide 25 is then prepared as described above. Regardless of the route incoφorated, in some instances, the amine or hydroxylamine used in the coupling reaction contains a standard protecting group. In those cases, the protecting group can be removed by standard conditions known in the art. [00183] Figure 4 outlines the synthesis of compounds of Formula II wherein the R9 group is incorporated into the starting ethyl ester 26. Preparation of pyrazolopyrimidine ester 27 can be achieved by the condensation of aminopyrazole 18 and the ester 26 in the presence of base such as an alkylamine such as piperidine in a suitable organic solvent such as MeCN, EtOH, DMF or toluene at the appropriate temperature. Pyrazolopyrimidine ester 27 can then be carried forward to hydroxamate 23 or amide 25 as described in Figure 3.
[00184] The preparation of compounds of Formula II where W is heteroaryl or heterocyclyl is shown in Figure 5. The preparation of these analogs from carboxylic acid 24 is accomplished as described for the reaction schemes in Figure 2 detailed above. [00185] In Figure 6, synthesis of compounds of Formula III is depicted. Imidazo[l,2- bjpyridazine ester 34, which can be synthesized as shown in Figures 7-11, can be converted to carboxylic acid 35, using standard saponification conditions such as LiOH or NaOH in standard mixed aqueous/organic solvent systems, when R = Me or Et. When a t-butyl ester is used, acid catalyzed deprotection of 34 can be accomplished by standard conditions including TFA in a suitable organic solvent such as methylene chloride or HCl in a suitable organic solvent such as dioxane. Hydroxamate 36 and amide 37 can be prepared using standard coupling procedures, including but not limited to EDCI, HOBt, or PyBOP and the appropriate amine or hydroxylamine in suitable organic solvents such as DMF, THF, or methylene chloride. Additionally, hydroxamate 36 and amide 37 can be prepared in two steps by initial conversion to the acid chloride by standard methods followed by addition of the appropriate amine or hydroxylamine. Alternatively imidazo[l,2-b]ρyridazine ester 34 can be directly converted to hydroxamate 36 in a suitable organic solvent such as THF using the appropriate hydroxylamine and an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature). In some instances, the amine or hydroxylamine used in the coupling reaction contains a standard protecting group. In those cases, the protecting group can be removed by standard conditions known in the art. [00186] In Figures 7-11, several syntheses of imidazo[l,2-b]pyridazine ester 34, which is utilized as the starting material in Figure 6, are depicted, depending on the identity of R . Figure 7 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R10 is H. An appropriately functionalized 6-chloro-4-phenylaminopyridazine ester 38 (synthesized as shown in Figures 12-17) is converted to 6-amino-4-phenylaminopyridazine ester 39 in two steps. In the first step, sodium azide is added to 38 in an appropriate solvent, including but not limited to DMF. The 6-amino-4-phenylaminopyridazine ester 39 is prepared by reduction of the azide under standard conditions including but not limited to Zn dust/ AcOH, Pt/C or Ptθ2 in the presence of H2 gas, Ph P or SnCl2/MeOH. In one embodiment, the azide reduction is accomplished by treatment with Zn dust in a mixture of methylene chloride and acetic acid. Cyclization to form imidazo[l,2-b]pyridazine 40 can be accomplished by treatment with chloroacetaldehyde or bromoacetaldehyde in suitable organic solvent such as DMF or EtOH at elevated temperatures (50 to 120 °C). In one embodiment, cyclization is realized by treatment with chloroacetaldehyde in EtOH at 70 °C.
[00187] Figure 8 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R10 is Me. l-Aminopropan-2-ol is added to an appropriately functionalized 6-chloro-4- phenylaminopyridazine ester 38 (synthesized as shown in Figures 12-17) in the presence of an appropriate base, such as NEt , in an organic solvent, such as CH CN to provide 41. Oxidation of 41 can be accomplished with an appropriate oxidizing agent, including, but not limited to TPAP and NMO, PCC, KMnO4, CrO3, Na2Cr2O7. Acid catalyzed cyclization of 42 to form imidazo[l,2-b]pyridazine 43 can be accomplished with an appropriate acid, including, but not limited to H2SO4.
[00188] Figure 9 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R10 is aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, alkynyl, amino or anilinyl. Halogenation of imidazo[l,2-b]pyridazine 40 can be accomplished by treatment with either NBS, NIS or NCS in DMF, MeCN or mixed solvent systems to form halogenated intermediate 44. Conversion of 44 to compound 45 where R10 is aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, alkynyl, amino or anilinyl can be achieved using Pd mediated cross-coupling conditions (where R8 is not Br or I). When R10 is alkenyl or alkynyl, these groups can be further reduced using the appropriate reducing agent to provide alkyl substituents at R10. In general, this chemistry can be accomplished using a wide variety of Pd catalysts and ligands, with or without added base, in a suitable organic solvent such as DMF, PhMe, DME, THF, CH3CN at elevated temperature. The coupling partner will depend on the nature of R . These Pd mediated cross-couplings are well documented in the literature and are known by those skilled in the art.
[00189] Figure 10 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R10 is NR3R4. An appropriately functionalized 6-amino-4-phenylaminopyridazine ester 39 in a suitable organic solvent such as dichloromethane or dichloro ethane is treated with a Lewis acid such as zinc bromide and condensation product as disclosed by Katritzky et al. (J. Org. Chem., 2003, 68, 4935-4937: J. Org. Chem., 1990, 55, 3209-3213) to provide the 3- dialkyamino-3-imidazo[l,2-b]pyridazine ring system 46. Condensation products (i.e., condensation of a glyoxal, benzotriazole and a secondary amine) can be generated using benzotriazole, glyoxal and any appropriate secondary amine including, but not limited to dimethylamine, diethylamine, pyπolidine, piperidine, moφholine, 1-methylpiperazine, N- methyl allylamine, diallyamine, and N-methylbenzylamine as described by Katritzky et al. [00190] Figure 11 depicts the synthesis of imidazo[l,2-b]pyridazine ester 34 where R10 is CH2NR R4. The preparation of 3-aminomethylimidazo[l,2-b]pyridazine 47 can be accomplished using the modified Mannich reaction procedure developed by Kercher et al. (manuscript in preparation) as illustrated. The reaction is generally canied out by combining 37% aqueous formaldehyde and a suitable amine in a mixture of acetonitrile/water. Several secondary amines can be employed, including but not limited to pyrrolidine, piperadine, moφholine, dimethylamine, N-BOC-piperazine and 1-methylpiperazine. The Mannich reaction is preferentially catalyzed by a group IIIA lanthanide triflate, preferably scandium triflate, though alternatively it may be performed using an excess of protic acid (AcOH or HCl) or elevated temperatures. [00191] Figures 12-17 depict the synthesis of an appropriately functionalized 6-chloro- 4-phenylaminopyridazine ester 38, which is utilized as the starting material in Figures 7 and 8. Figure 12 depicts the synthesis of the 6-chloropyridazine core where R9 is H, F, or Cl. 4,6-Dichloropyridazine-3-carboxylic acid ethyl ester 48 can be synthesized as described in WO 04/031174, which is incoφorated herein by reference. Basic hydrolysis of 48 using standard saponification conditions such as LiOH or NaOH in standard mixed aqueous/organic solvent systems provides acid 49. Formation of 50 can be accomplished in two steps. The first step involves the coupling of the properly substituted aniline moiety and pyridazine acid 49 by SNAT reaction. This can be achieved in a suitable organic solvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature). Preferably the aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80 °C). Pyridazine acid 49 is then added and the mixture is stiπed at low temperature to generate the coupled product. Esterification to give the methyl ester 50 can be canied out under standard conditions, including but not limited to Fisher esterification (MeOH, H2SO4), TMSC1 in MeOH or TMSCHN2 in suitable organic solvents such as PhMe/MeOH. If a compound where R9 is Cl or F is desired, a chlorination or fluorination step can be incoφorated at this stage. Chlorination of pyridazine ester 50 can be accomplished with NCS in a suitable organic solvent such as DMF, MeCN or mixed solvent systems at room temperature. Preferably the reaction is carried out in DMF. Fluorination is achieved by treating pyridazine ester 50 with [l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) in the presence of base in a suitable organic solvent at the appropriate temperature. Most preferable is the use of LiOH as base and MeCN as solvent at approximately 85 °C.
[00192] Figure 13 depicts an alternative synthesis of the 6-chloropyridazine core where
R = H, F, or Cl. Addition of an appropriately substituted aniline to 4,6-dichloropyridazine- 3-carboxylic acid ethyl ester 48 in an appropriate organic solvent such as PhMe, xylenes, NMP or DMA from 0 °C to elevated temperature can directly provide the coupled product 50. If a compound where R is Cl or F is desired, a chlorination or fluorination step can be incoφorated at this stage to provide 38. Chlorination of the pyridazine ester 50 can be accomplished with NCS in a suitable organic solvent such as DMF, MeCN or mixed solvent systems at room temperature. Preferably the reaction is canied out in DMF. Fluorination is achieved by treating pyridazine ester 50 with [l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) in the presence of base in a suitable organic solvent at the appropriate temperature. Most preferable is the use of LiOH as base and MeCN as solvent at approximately 85 °C. [00193] Figure 14 depicts the synthesis of the 6-chloropyridazine core where R9 is Cl.
4,6-Dihydroxypyridazine-3-carboxylic acid ethyl ester 51 can be synthesized as described in WO 04/031174. Chlorination of pyridazine ester 51 can be accomplished with NCS in a suitable organic solvent such as DMF, MeCN or mixed solvent systems at room temperature to yield monochloropyridazine ester 52. Preferably the reaction is carried out in DMF. Pyridazine ester 52 can be further chlorinated using an appropriate reagent such as POCl , oxalyl chloride or thionyl chloride. In one embodiment, chlorination is accomplished with neat POCl3 or in the presence of Et3N at elevated temperatures. Hydrolysis of the resulting trichloropyridazine ester 53 to provide compound 54 can be performed under standard conditions. Addition of the appropriately substituted aniline to either 53 or 54 can be accomplished as described for the reaction schemes in Figures 12 and 13 detailed above to provide 55. [00194] Figure 15 depicts the synthesis of the 6-chloropyridazine core where R9 is F.
Fluorination of pyridazine ester 51 can be accomplished with [l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) in the presence of base in a suitable organic solvent at the appropriate temperature to yield monofluoro pyridazine ester 56. Most preferable is the use of LiOH as base and MeCN as solvent at approximately 85 °C. Pyridazine ester 56 can be chlorinated using an appropriate reagent such as POCl , oxalyl chloride or thionyl chloride. In one embodiment, chlorination is accomplished with neat POCl or in the presence of Et N at elevated temperatures. Hydrolysis of the resulting pyridazine ester 57 to provide compound 58 can be performed under standard conditions. Addition of the appropriately substituted aniline to either 57 or 58 can be accomplished as described for the reaction schemes in Figures 12 and 13 detailed above to provide 59.
[00195] Figure 16 depict the synthesis of the 6-chloropyridazine core where R9 is Me.
Dichloro-5-methylpyridazine-3-carboxylic acid ethyl ester 60 can be prepared by minor modification of the method described in WO 04/031174. Hydrolysis of the resulting diichloropyridazine ester 60 to provide compound 61 can be performed under standard conditions. Addition of the appropriately substituted aniline to either 60 or 61 can be accomplished as described for the reaction schemes in Figures 12 and 13 detailed above to provide 6-chloro-5-methyl-4-phenylaminopyridazine-3 -carboxylic acid ester 62. 100196] The preparation of compounds of Formula III where W is heteroaryl or heterocyclic is shown in Figures 17 and 18. The preparation of these analogs from carboxylic acid 35 is accomplished as described for the reaction schemes in Figure 2 detailed above. [00197] Figure 19 illustrates the synthesis of compounds of Formula IV of the present invention. If a compound where R9 is F is desired, a fluorination step can be introduced in a three step protocol starting from tetrachloropyridine-2-carboxylic acid 71 by esterification, fluorination and saponification. Esterification of 71 can be achieved by standard methods including but not to limited to Fisher esterification (MeOH, H2SO4), reaction with TMSCHN2 or TMSC1 in MeOH. Fluorination can be accomplished through substitution of the chloride intermediate by heating with KF in DMSO, KF and 18-Crown-6 in NMP, or CsF in MeCN. Finally, the carboxylic acid is prepared by standard saponification methods such as LiOH or NaOH in standard mixed aqueous/organic solvent systems. Dichloro-4-fluoro-3- phenylaminopyridine-2-carboxylic acid 72 can be prepared by either SNAΓ reaction or a copper mediated coupling. The SNAT chemistry can be achieved by treating the carboxylic acid with the desired aniline in a suitable organic solvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78 °C to room temperature). The copper mediated coupling can be achieved by treating the carboxylic acid with the desired aniline in a suitable organic solvent in the presence of Cu or CuO and a suitable base such as K2CO;., or Na2CO . Following esterification under standard conditions, the acetylene derivative 73 can be prepared by Sonagashira palladium mediated cross- coupling using an appropriately substituted acetylene, Cul, an amine base, palladium catalyst and organic solvent such as DME, THF, or DMF at temperatures between 25 to 100 °C (R8 is not Br or I). Suitable palladium catalysts include, but are not limited to, PdCl2(dpρf), Pd(Ph3P) , and Pd2dba3/dppf. Suitable amine bases include, but are not limited, to Et_N, Et2NH, Hunig's base, and diisopropyl amine.
[00198] With continued reference to Figure 19, alternatively when R9 is not F, carboxylic acid 71 can be taken directly into the SNAT reaction or the copper mediated coupling followed by esterification under standard methods including but not to limited to Fisher esterification (MeOH, H2SO4), reaction with TMSCHN2 or TMSC1 in MeOH to generate ester 74. If a compound where R9 is alkyl is desired, the alkyl group be incoφorated by the procedure of Shiota et al (J. Org. Chem. 1999, 64, 453-457) using the regioselective cross-coupling of the chloroester 74 with an appropriate alkyl organozinc and a suitable additive such as LiCl, LiBr, Lil, NaCl, or MgBr2 in DMF. The alkyl group of interest may also be incoφorated by use of alkyl magnesium halide as described by Troya et al (New J. Chem., 2002, 26, 1308-1313). The acetylene 73 is then prepared by the palladium mediated cross-coupling procedure described above. [00199] With continued reference to Figure 19, regardless of the nature of R9, acetylene 73 can be canied forward in an analogous manner. Acetylene 73 can be hydrolyzed to the coπesponding ketone by standard methods including but not limited to H2SO4, TFA, trifluorosulfonamide, FeCl3, or HgSO4/H2SO4. The ketone can then be converted to the isoxazolo[4,5-b]pyridine 75 in a two-step procedure. Addition of the potassium salt of acetone oxime in a suitable organic solvent such as THF or E12O at temperatures ranging from -78 to 5 °C is followed by acid catalyzed cyclization. The acetone oxime addition is most easily performed by addition of a THF solution of the ketone intermediate to the salt at 0 °C. The cyclization can be performed under a variety of acidic aqueous conditions at a range of temperatures. If a compound is desired where R is Br or I, then the halide of interest may be incoφorated at this stage. This may be accomplished by standard aromatic halogenation chemistry including but not limited to NIS or NBS in DMF with or without catalytic aqueous acid. Basic hydrolysis under standard saponification conditions such as LiOH or NaOH in standard mixed aqueous/organic solvent systems can then provide carboxylic acid 76. Amide 77 and hydroxamate 78 can be prepared using standard coupling procedures, including but not limited to EDCI, HOBt, or PyBOP and the appropriate amine or hydroxylamine in suitable organic solvents such as DMF, THF, or methylene chloride. Alternatively, ester 75 can be directly converted to hydroxamate 78 in a suitable organic solvent such as THF using the appropriate hydroxylamine and an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature). In some instances, the amine or hydroxylamine used in the coupling reaction contains a standard protecting group. In those cases, the protecting group can be removed by standard conditions known in the art.
[00200] The preparation of compounds of Formula IV is shown in Figure 20. 5,6- dichloro-3-phenylaminopyridine-2-carboxylic acid 79 can be esterified by standard methods including but not to limited to Fisher esterification (MeOH, H2SO4), reaction with TMSCHN2 or TMSC1 in MeOH. Nitrile 80 can then be prepared by palladium mediated coupling of the chloroester intermediate with zinc cyanide in a suitable organic solvent such as DMA, NMP or DMF at elevated temperatures ranging from 50 to 120 °C (R8 is not Br or I). Several palladium catalysts may be employed including but not limited to Pd(PPh3)4, PdCl2(dpρf), or Pd2dba3 with ligands such as dppe, dppp, dppf or BINAP. Preparation of aminoisoxazolo[4,5-b]pyridine 81 can be accomplished in a two-step procedure from nitrile 80 by the addition of the potassium salt of acetone oxime followed by acid mediated cyclization as described above in Figure 19. The analogs 83 and 84 can be prepared from the intermediates 81 or 82 by the procedures described in Figure 19. [00201] The preparation of compounds of Formula IV where W is heteroaryl or heterocyclyl is shown in Figure 21. The preparation of these analogs from carboxylic acid 76 is accomplished as described for the reaction schemes in Figure 2 detailed above.
[00202] Figure 22 illustrates the synthesis of compounds of Formula V of the present invention.
[00203] The 6-acetyl-5-chloropyridine methyl ester 92 can be prepared from the acetylene 73 as described in Figure 19. The ketone 92 can then be converted to a mixture of NI and N2-substituted pyrazolo[4,3-b]pyridines 93 and 94 in an manner analogous to the preparation of benzisoxazole 75 by employing the potassium salt of acetone hydrazone in place of acetone oxime in the cyclization step. Alternatively, the cyclization can also be performed by heating with hydrazine in a suitable organic solvent such as DMF or EtOH at temperature ranging from 0 to 150 °C. Alkylation and separation can be accomplished as described for Figure 1. As outlined in Figure 22, the NI or N2-substituted pyrazolo[4,3- bjpyridine analogs 96, 97, and 98 can be prepared by the methods described for Figure 19 above. Additionally (as described above) ester 93 can be converted directly to hydroxamate 97 in a suitable organic solvent such as THF using the appropriate hydroxylamine and an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature).
[00204] Figure 23 illustrates the synthesis of NI and N2-substituted 3- aminopyrazolo[4,3-b]pyridine of Formula V. Cyclization of nitrile 80 can be achieved as described in Figures 19 and 22. Alkylation and separation can be accomplished as described for Figure 1. As outlined in Figure 23, 3-aminopyrazolo[4,3-b]pyridines 99 and 100 can be further converted to the final 3-aminopyrazolo[4,3-b]pyridine analogs 102, 103, and 104 by the procedures described for Figure 19 above. Additionally (as described above) ester 99 can be converted directly to hydroxamate 103 in a suitable organic solvent such as THF using the appropriate hydroxylamine and an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (-78 °C to room temperature). [00205] As shown in Figure 24, the compounds of Formula V where W is heteroaryl or heterocyclic can be prepared from the carboxylic acid 95 by the methods described in Figure 2. The coπesponding Nl-susbtituted pyrozolo[4,3-b]pyridine analogs can also be prepared in the same manner from the coπesponding carboxylic acid. [00206] The invention also relates to a pharmaceutical composition for the treatment of a hypeφroliferative disorder in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable canier. In one embodiment, said pharmaceutical composition is for the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, esophageal, testicular, gynecological or thyroid cancer. In another embodiment, said pharmaceutical composition is for the treatment of a non-cancerous hypeφroliferative disorder such as benign hypeφlasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
[00207] The invention also relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes- induced renal disease) or the treatment of pain in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable canier.
[00208] The invention also relates to a pharmaceutical composition for the prevention of blastocyte implantation in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable caπier.
[00209] The invention also relates to a pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable canier. In one embodiment, said pharmaceutical composition is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease or other inflammatory condition such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
[00210] The invention also relates to a method of treating a hypeφroliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof. In one embodiment, said method relates to the treatment of cancer such as brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, esophageal, testicular, gynecological or thyroid cancer. In another embodiment, said method relates to the treatment of a non-cancerous hypeφroliferative disorder such as benign hypeφlasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)). [00211] The invention also relates to a method for the treatment of a hypeφroliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti- androgens.
[00212] The invention also relates to a method of treating pancreatitis or kidney disease in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a phaπnaceutically acceptable salt, prodrug or hydrate thereof.
[00213] The invention also relates to a method of preventing blastocyte implantation in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
[00214] The invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof. In one embodiment, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer. [00215] The invention also relates to a pharmaceutical composition for treating a disease or condition related to inflammatory disease, autoimmune disease, destructive bone disorders, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable canier. Examples of the above diseases and/or conditions include but is not limited to rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes and diabetic complications, diabetic retinopathy, retinopathy of prematurity, age- related macular degeneration, hemangioma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, allergic responses including asthma allergic rhinitis and atopic dermatitis, renal disease and renal failure, polycystic kidney disease, acute coronary syndrome, congestive heart failure, osteoarthritis, neurofibromatosis, organ transplant rejection, cachexia and pain.
[00216] Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salts, prodrugs and hydrates of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas). [00217] This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, salt, solvate, or prodrug, and of the chemotherapeutic are together effective in inhibiting abnormal cell growth. Many chemotherapeutics are presently known in the art. In one embodiment, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
[00218] This invention further relates to a method for inhibiting abnormal cell growth in a mammal or treating a hypeφroliferative disorder which method comprises administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiation therapy, wherein the amounts of the compound, salt, solvate, or prodrug, is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hypeφroliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.
[00219] It is believed that the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for puφoses of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt or solvate or prodrug thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation. The amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein. [00220] The invention also relates to a method of and to a pharmaceutical composition of inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, a prodrug thereof, or an isotopically-labeled derivative thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents. [00221] Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of the present invention and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloprotienase inhibitors are described in WO 96/33172, WO 96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 606,046, EP 931788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864, U.S. Patent No. 5,863,949, U.S. Patent No. 5,861,510, and EP 780,386, all of which are incoφorated herein in their entireties by reference. Prefened MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More prefened, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
[00222] The terms "abnormal cell growth" and "hypeφroliferative disorder" are used interchangeably in this application. [00223] "Abnormal cell growth," as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes, for example, the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which abenant tyrosine kinase activation occurs; (3) any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that proliferate by abenant serine/threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases in which abenant serine/theroine kinase activation occurs. [00224] The term "treating," as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment," as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. [00225] The amount of a given agent that will conespond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e. g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art. "Treating" is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is affected, at least in part, by the activity of MEK, and includes, but is not limited to, preventing the disease condition from occuning in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but has not yet been diagnosed as having it; modulating and/or inhibiting the disease condition; and/or alleviating the disease condition. [00226] In order to use a compound of the Formula I-V or a pharmaceutically acceptable salt or prodrug thereof, for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. According to this aspect of the invention there is provided a pharmaceutical composition that comprises a compound of the Formula I-V, or a pharmaceutically acceptable salt or prodrug thereof, as defined hereinbefore in association with a pharmaceutically acceptable diluent or carrier. [00227] To prepare the pharmaceutical compositions according to this invention, a therapeutically or prophylactically effective amount of a compound of Formula I-V or a pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof (alone or together with an additional therapeutic agent) is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A canier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. Examples of suitable earners include any and all solvents, dispersion media, adjuvants, coatings, antibacterial and antifungal agents, isotonic and absoφtion delaying agents, sweeteners, stabilizers (to promote long term storage), emulsifiers, binding agents, thickening agents, salts, preservatives, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absoφtion delaying agents, flavoring agents, and miscellaneous materials such as buffers and absorbents that may be needed in order to prepare a particular therapeutic composition. The use of such media and agents with pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with a compound of Formula I-V, its use in the therapeutic compositions and preparations is contemplated. Supplementary active ingredients can also be incoφorated into the compositions and preparations as described herein. [00228] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular dosing or as a suppository for rectal dosing). For example, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. [00229] Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absoφtion of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
[00230] Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. [00231] Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose. methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pynolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). [00232] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. [00233] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present. [00234] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be. for example, naturally-occuπing gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.
[00235] Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent. [00236] The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally- acceptable diluent or solvent, for example a solution in 1,3-butanediol.
[00237] Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. [00238] Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedures well known in the art. [00239] Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 μm or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable caniers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
[00240] Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol ananged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently ananged to dispense a metered quantity of active ingredient.
[00241] For further information on formulations, see Chapter 25.2 in Volume 5 of
Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incoφorated herein by reference. [00242] The amount of a compound of this invention that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the subject treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. For further information on routes of administration and dosage regimes, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incoφorated herein by reference.
[00243] The size of the dose for therapeutic or prophylactic puφoses of a compound of
Formula I-V will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. [00244] The compounds of this invention may be used alone in combination with other drugs and therapies used in the treatment of disease states which would benefit from the inhibition of MEK. Such treatment may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti -tumor agents: [00245] (i) antiproliferative/anti-neoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example, cis-platin, carboplatin, cyclophosphamide, nitorgen mustard, melphalan, chlorambucil, busulphan and nitorsoureas); anti-metabolites (for example, antifolates such as such as fluoropyrimidines like 5- fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinside, hydroxyurea, or, one of the prefened anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)- L-glutamic acid); antitumor antibiotics (for example, anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example, vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like eptoposide and teniposide, amsacrine, topotecan and 5 campothecin): [00246] (ii) cytostatic agents such as antiestrogens (for example, tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor down regulators (for example, fulvestratrant) antiandrogens (for example, bicalutamide, flutamide, nilutamide, cyproxerone acetate and Casodex™ (4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-
10 methyl-3'-(trifluoromethyl)propionanilide)), LHRH antagonists or LHRH agonists (for example, goserelin, leuporelin and buserelin), progestogens (for example, megestrol acetate), aromatase inhibitors (for example, asanastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; [00247] (iii) agents which inhibit cancer cell invasion (for example, metalloproteinase
15 inhibitors like marimastat and inhibitors of urokinase plasminogne activator receptor function); [00248] (iv) inhibitors of growth factor function like growth factor antibodies, growth factor receptor antibodies (for example, the anti-erbB2 antibody trastumuzab [Herceptin™] and the anti-erbBl antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine
20 kinase inhibitors and serine-threonine kinase inhibitors (for example, inhibitors of the epidermal growth factor family tyrosine kinases such as N-(3-chloro-4-fluorophenyl)-7- methoxy-6-(3-moφholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-moφholinopropoxy)quinazolin-4-amine (CI
25 1033)), inhibitors of the platelet-derived growth factor family and inhibitors of the hepatocyte growth factor family; [00249] (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (for example, the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in PCT Publication
30 Nos. WO 97/22596, WO 97/30035, WO 97/32856, and WO 98/13354) and compounds that work by other mechanisms (for example, linomide, inhibitors of integrin αvβ3 function, MMP inhibitors, COX-2 inhibitors and angiostatin); [00250] (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in PCT Publication Nos. WO 99/02166, WO 0/40529, WO 00/41669, WO 01/92224, WO 02/04434, and WO 02/08213;
[00251] (vii) antisense therapies (for example, those which are directed to the targets listed above such as ISIS 2503, and anti-ras antisense);
[00252] (viii) gene therapy approaches, including for example GVAX™, approaches to replace abenant genes such as abenant p53 or abenant BRCA1 or BRCA2, GDEPT (gene- directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; [00253] (ix) interferon; and
[00254] (x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches to using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.
[00255] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of treatment. Such combination products employ the compounds of this invention within the dose range described hereinbefore and the other pharmaceutically active agent within its approved dose range. [00256] According to this aspect of the invention there is provided a pharmaceutical product comprising a compound of Formula I-V as defined hereinbefore and an additional anti-tumor agent as defined hereinbefore for the conjoint treatment of cancer. [00257] Although the compounds of Formula I-V are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of MEK. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. [00258] The activity of the compounds of the present invention may be determined by the following procedure. N-terminal 6 His-tagged, constitutively active MEK-1 (2-393) is expressed in E. coli and protein is purified by conventional methods (Ahn et al, Science 1994, 265, 966-970). The activity of MEKl is assessed by measuring the incoφoration of γ- 33P-phosphate from γ-33P-ATP onto N-terminal His tagged ERK2, which is expressed in E. coli and is purified by conventional methods, in the presence of MEK-1. The assay is carried out in 96-well polypropylene plate. The incubation mixture (100 μL) comprises of 25 mM Hepes, pH 7.4, 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM Na-orthovanadate, 5 mM DTT, 5 nM MEKl, and 1 μM ERK2. Inhibitors are suspended in DMSO, and all reactions, including controls are performed at a final concentration of 1% DMSO. Reactions are initiated by the addition of 10 μM ATP (with 0.5 μCi γ-33P-ATP/well) and incubated at ambient temperature for 45 minutes. Equal volume of 25% TCA is added to stop the reaction and precipitate the proteins. Precipitated proteins are trapped onto glass fiber B filteφlates, and excess labeled ATP washed off using a Tomtec MACH III harvestor. Plates are allowed to air-dry prior to adding 30 μL/well of Packard Microscint 20, and plates are counted using a Packard TopCount. In this assay, compounds of the invention exhibited an IC50 of less than 50 micromolar. [00259] Representative compounds of the present invention, which are encompassed by the present invention include, but are not limited to the compounds of the examples and their pharmaceutically acceptable acid or base addition salts or prodrugs thereof. The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way. [00260] The disclosures in this application of all articles and references, including patents, are incoφorated herein by reference. EXAMPLES [00261] In order to illustrate the invention, the following examples are included.
However, it is to be understood that these examples do not limit the invention and are only meant to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other MEK inhibitors of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention. [00262] In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents are purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and are used without further purification unless otherwise indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane, toluene, dioxane and 1,2-difluoroethane can be purchased from Aldrich in Sure seal bottles and used as received. [00263] The reactions set forth below are done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks are typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware is oven dried and/or heat dried.
[00264] Column chromatography was done on a Biotage system (Manufacturer: Dyax
Coφoration) having a silica gel column or on a silica SepPak cartridge (Waters). [00265] Η-NMR spectra were recorded on a Varian instrument operating at 400 MHz.
Η-NMR spectra were obtained as CDC13 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm). Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiple.), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz). Example 1
Figure imgf000058_0001
6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b[pyridine-5- carboxylic acid (2-hydroxyethoxy)-amide [00266] Step A: Preparation of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine 4- oxide: To a solution of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent)
(Graboyes et al J. Am. Chem. Soc 1957, 79, 6421-6426) in CH2C12 is added m-CPBA (1.50 equivalents). The resulting solution is stined at room temperature for 16 hours. The precipitate is filtered off, washed with ether, and dried in vacuo to afford the desired product. The product is purified by re-crystallization if further purification is necessary. [00267] Step B: Preparation of 6-bromo-7-chloro-5-methyl-3H-imidazo 4,5- blpyridine: A solution of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine 4-oxide (1.00 equivalent) in POCl3 (excess) is stiπed at 80 °C for 16 hours. The reaction mixture is concentrated in vacuo to give the crude material that is poured into ice-water. The resulting aqueous solution is neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product. The product is purified by trituration or flash column chromatography if further purification is necessary.
[00268] Step C: Preparation of 6-bromo-7-fluoro-5-methyl-3H-imidazo[4,5- blpyridine: To a solution of 6-bromo-7-chloro-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) in NMP is added KF (3.00 equivalents) and 18-crown-6 (0.20 equivalents) at room temperature. The resulting mixture is refluxed with stining for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product that is purified by flash column chromatography as necessary. [00269] Step D: Preparation of 6-bromo-7-fluoro-3,5-dimethyl-3H-imidazo[4,5- blpyridine: To a solution of 6-bromo-7-fluoro-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) in DMF is added iodomethane (1.20 equivalents) and K CO3 (1.50 equivalents) at room temperature. The resulting mixture is stined at 75 °C for 1 hour. The reaction mixture is diluted with EtOAc and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product. [00270] Step E: Preparation of 6-bromo-7-fluoro-3-methyl-3H-imidazor4.5- blpyridine-5-carboxylic acid: To a boiling suspension of 6-bromo-7-fluoro-3,5-dimethyl-3H- imidazo[4,5-b]pyridine (1.00 equivalent) and Na CO3 (1.00 equivalent) in water is added powered KMnO (3.00 equivalents) in small portions. After refluxing for 3 hours, the reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated in vacuo to a half of the original volume and acidified with 6 N aqueous HCl. The precipitates are washed with water and dried in vacuo to afford the desired product. The desired product is purified by trituration or re-crystallization as necessary. [00271] Step F: Preparation of 6-bromo-7-fluoro-3-methyl-3H-imidazo|"4,5- blpyridine-5-carboxylic acid methyl ester: To a solution of 6-bromo-7-fluoro-3-methyl-3H- imidazo[4,5-b]ρyridine-5-carboxylic acid (1.00 equivalent) in THF-MeOH at 0 °C is added TMSCHN2 (1.30 equivalents, 2 M solution in hexanes). The resulting mixture is warmed to room temperature and stined for 2 hours. The reaction is quenched with AcOH. The reaction mixture is diluted with EtOAc. The organic layer is washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product that is used directly without further purification. [00272] Step G: Preparation of 7-fluoro-6-(2-fluorophenylamino)-3-methyl-3H- imidazo[4,5-blpyridine-5-carboxylic acid methyl ester: A mixture of 6-bromo-7-fluoro-3- methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.00 equivalent), 2- fluoroaniline (1.00 equivalent), Pd(OAc)2 (0.10 equivalents), rac-BINAP (0.15 equivalents), and Cs2CO3 (1.50 equivalents) in toluene in a sealed tube is stined at 80 °C for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc. The resulting precipitate is filtered off and washed with EtOAc. The filtrate is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product. [00273] Step H: Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl- 3H-imidazo[4,5-b1pyridine-5-carboxylic acid methyl ester: To a solution of 7-fluoro-6-(2- fluorophenylamino)-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.00 equivalent) in DMF is added NBS (1.20 equivalents) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vαcwo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
[00274] Step I: Preparation of 6-(4-bomo-2-fluorophenylamino)-7-fluoro-3-methyl-
3H-imidazo("4,,5-b]pyridine-5-carboxylic acid: To a solution of 6-(4-bromo-2- fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.00 equivalent) in THF-MeOH is added 1 N aqueous LiOH (2.00 equivalents) at 0 °C. The resulting mixture is warmed to room temperature and stined for 3 hours. The reaction mixture is neutralized with 1 N aqueous HCl and extracted with EtOAc. The organic layer is washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is used directly without further purification.
[00275] Step J: Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-
3H-imidazo[4,5-b1ρyridine-5-carboxylic acid (2-vinyloxyethoxy)-amide: To a solution of 6- (4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.00 equivalent) and HOBt (1.50 equivalents) is added EDCI (1.50 equivalents) at room temperature. After stining for 1 hour, O-(2-vinyloxy-ethyl)-hydroxylamine (1.10 equivalents) and TEA (1.20 equivalents) are added. The reaction mixture is stined for 1 hour and diluted with EtOAc. The resulting mixture is washed with saturated aqueous NH4C1, brine, saturated aqueous NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is used directly without further purification.
[00276] Step K: Preparation of 6-(4-bromo-2-fluorophenylaminoV7-fluoro-3-methyl-
3H-imidazo|"4,5-b]pyridine-5-carboxylic acid (2-hvdroxyethoxy)-amide: To a solution of 6- (4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (2-vinyloxyethoxy)-amide (1.00 equivalent) in THF-EtOH is added 1 N aqueous HCl (2.0 equivalents) at room temperature. After stining for 1 hour at room temperature, the reaction mixture is neutralized with saturated aqueous NaHCO3 and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO , filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H- imidazo[4,5-b]pyridine-5-carboxylic acid (2-hydroxyethoxy)-amide. Example 2
Figure imgf000061_0001
[5-(5-Amino-[l,3,4]oxadiazol-2-yl)-7-nuoro-3-methyl-3H-imidazo[4,5-b]pyridin-6-yI]-(4- bromo-2-fluorophenyl)-amine
[00277] Step A: Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl- 3H-imidazo[4,5-b1pyridine-5-carboxylic acid hydrazide: To a solution of 6-(4-bromo-2- fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.00 equivalent) and HOBt (3.00 equivalents) is added EDCI (3.00 equivalents) at room temperature. After stining for 1 hour, hydrazine (3.00 equivalents) and TEA (3.00 equivalents) are added. The reaction mixture is stined for 1 hour and diluted with EtOAc. The resulting mixture is washed with saturated aqueous NH4C1, brine, saturated aqueous NaHCO , and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is used directly without further purification. [00278] Step B: Preparation of r5-(5-amino-[l ,3,41oxadiazol-2-ylV7-fluoro-3-methyl- 3H-imidazo 4.5-blpyridin-6-yll-(4-bromo-2-fluorophenyl)-amine: To a suspension of 6-(4- bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid hydrazide (1.00 equivalent) in 1,4-dioxane at room temperature is added BrCN (2.0 equivalents) followed by a solution of NaHCO3 (1.0 equivalents) in H2O. After stining for 3 hours at room temperature, the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford [5-(5-amino-[l,3,4]oxadiazol-2-yl)-7-fluoro-3-methyl-3H- imidazo[4,5-b]pyridin-6-yl]-(4-bromo-2-fluorophenyl)-amine. Example 3
Figure imgf000062_0001
6-(4-Bromo-2-fluorophenylamino)-7-fluoropyrazolo[l,5-a]pyrimidine-5-carboxylic acid amide
[00279] Step A: Preparation of 6-chloro-5-methylpyrazolo[l,5-a)pyrimidin-7-ol. A mixture of 3-aminopyrazole (10.0 g, 120.3 mmol), 2-chloro-3-oxo-butyric acid ethyl ester (16.7 mL, 120.3 mmol), and glacial acetic acid (103 mL) was heated to 120 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOH and concentrated. Trituration with Et2O gave 20.7 g (94%) desired product. MS APCI (+) m/z 184, 186 (M+, Cl pattern) detected; Η NMR (400 mHz, CD3OD) δ 7.90 (d, IH), 6.17 (d, IH), 2.53 (s, 3H).
[00280] Step B: Preparation of 6 -dichloro-5-methylpyrazolo[l,5-a]pyrimidine.
Phosphorous oxychloride (excess) is added to 6-chloro-5-methylpyrazolo[l,5-a]pyrimidin-7- ol (1.00 equivalent) and heated to 80 °C. After 2 hours, the reaction mixture is concentrated under reduced pressure. The resulting residue is poured onto ice and, carefully neutralized with saturated NaHCO3 (pH 8), and diluted with EtOAc. After stining for 17 hours, the organic layer was separated and the aqueous layer was re-extracted with EtOAc, repeatedly. The combined organic extracts are dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary. [00281] Step C: Preparation of 6-chloro-7-fluoro-5-methylpyrazolori,5-a1pyrimidine.
A mixture of 6,7-dichloro-5-methylpyrazolo[l,5-a]pyrimidine (1.00 equivalent), 18-crown-6 (5 mol %), and KF (3.00 equivalents) in MeCN is heated under reflux with stining. After 17 hours, the reaction mixture is poured into water, extracted with EtOAc, dried (MgSO4), and concentrated. The product is purified by flash chromatography as necessary. [00282] Step D: Preparation of 6-chloro-7-fluoropyrazolori,5-a1pyrimidine-5- carboxylic acid. Potassium permanganate (2.00 equivalents) is added to 6-chloro-7-fluoro-5- methylpyrazolo[l,5-a]pyrimidine (1.00 equivalent) in water, and the mixture is heated at 100 °C. After 3 hours, the reaction mixture is cooled to room temperature, and the precipitated oxides of manganese are filtered and washed with hot water. The filtrate is concentrated under reduced pressure, diluted with EtOAc, washed with 10% aqueous HCl solution, dried (MgSO4), and concentrated. The product may be triturated with an appropriate solvent such as diethyl ether or dichloromethane if further purification is necessary. [00283] Step E: Preparation of 6-(4-bromo-2-fluorophenylamino -7- fluoropyrazolori ,5-alpyrimidine-5-carboxylic acid. To a solution of i-Pr2NH (3.50 equivalents) in THF at 0 °C is added n-BuLi (3.50 equivalents, 2.5 M solution in hexanes). After stining 15 minutes, the mixture is cooled to -78 °C. 4-Bromo-2-fluorophenylamine (2.50 equivalents) is added. After vigorous stining for 10 minutes, a mixture of the 6-chloro- 7-fluoropyrazolo[l,5-a]pyrimidine-5-carboxylic acid (1.00 equivalent) in THF is added. The dry-ice bath is removed after 30 minutes, and the reaction mixture is stined for 17 hours at room temperature. The reaction mixture is treated with a 10%> aqueous HCl solution, extracted with EtOAc, dried (MgSO4), and concentrated. Trituration with methylene chloride give desired product. [00284] Step F: Preparation of 6-(4-bromo-2-fluorophenylaminoV7- fluoropyrazolo|'1.5-a]pyrimidine-5-carboxylic acid amide. A mixture of 6-(4-bromo-2- fluorophenylamino)-7-fluoropyrazolo[l,5-a]pyrimidine-5-carboxylic acid (1.00 equivalent), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMF is stined for 30 minutes. NH C1 (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After 1 hour, the reaction mixture is diluted with EtOAc and washed with saturated NH4C1 solution, saturated NaHCO3 solution and brine. The organic layer is dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary. Example 4
Figure imgf000064_0001
6-(2-Fluoro-4-methylsulfanyl-phenylamino)-7-methylpyrazolo[l,5-a]pyrimidine-5- carboxylic acid ethoxyamide [00285] Step A: Preparation of 6-chloro-7-methylpyrazolo[1.5-a]pyrimidine-5- carboxylic acid ethyl ester. 3-Chloro-2,4-dioxo-pentanoic ethyl ester (0.325 g, 1.685 mmol) is added to a solution of 3-aminopyrazole (0.14 g, 1.685 mmol) and piperidine (0.18 mL, 1.85 mmol) in MeCN (15 mL), and the reaction mixture heated at 90 °C for 17 hours. After cooling to room temperature, the reaction mixture is diluted with EtOH and concentrated. Purification by flash chromatography (0.5% MeOH in methylene chloride) gives 80 mg (20%) desired product. Η NMR (400 niHz, CD3OD) δ 8.27 (d, IH), 6.84 (d, IH), 4.48 (q, 2H), 2.97 (s, 3H), 1.42 (t, 3H).
[00286] Step B: Preparation of 6-(2-fluoro-4-methylsulfanyl-phenylamino)-7- methylpyrazoloπ,5-a1pyrimidine-5-carboxylic acid ethyl ester. 2-Fluoro-4-methylsulfanyl- phenylamine (1.01 equivalents), palladium (II) acetate (0.10 equivalents), rac-2,2- bis(diphenylphosphino)-l,l '-binaphthyl (0.15 equivalents), and cesium carbonate (1.50 equivalents) are added to a solution of 6-chloro-7-methylpyrazolo[l,5-a]pyrimidine-5- carboxylic acid ethyl ester (1.00 equivalent) in toluene in a sealed vial. After stirring 10 minutes, the mixture is heated to 80 °C. After 24 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc. The resulting precipitate is filtered and washed with EtOAc. The filtrate is diluted with EtOAc and washed with water. The aqueous layer is re-extracted with EtOAc. The combined organic layers are washed with brine, dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary. [00287] Step C: Preparation of 6-(2-fluoro-4-methylsulfanyl-ρhenylamino)-7- methylpyrazolo|'l,5-alpyrimidine-5-carboxylic acid ethoxyamide. O-Ethyl-hydroxylamine HCl salt (2.50 equivalents) is added to a solution of 6-(2-fluoro-4-methylsulfanyl- phenylamino)-7-methylpyrazolo[l,5-a]pyrimidine-5-carboxylic acid ethyl ester (1.00 equivalent) in THF. The solution is cooled to 0 °C and lithium bis(trimethylsilyl)amide (6.00 equivalents, 1.0 M solution in hexanes) is added dropwise. The reaction mixture is warmed to room temperature. After stining for 1 hour, the reaction is quenched by addition of a saturated aqueous solution of NaHCO3 and partitioned between EtOAc and brine. The aqueous layer is re-extracted with EtOAc. The combined organic extracts is dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary. Example 5
Figure imgf000065_0001
[5-(5-Amino-[l,3,4]oxadiazol-2-yl)-7-fluoropyrazolo[l,5-a]pyrimidin-6-yl]-(4-bromo-2- fluorophenyl)-amine [00288] Step A: Preparation of 6-(4-bromo-2-fluorophenylamino)-7- fluoropyrazolo[T,5-a"lpyrimidine-5-carboxylic acid hydrazide. A mixture of 6-(4-bromo-2- fluorophenylamino)-7-fluoropyrazolo[l,5-a]pyrimidine-5-carboxylic acid (1.00 equivalent), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMF is stined for 30 minutes. Hydrazine (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After 3 hours, the reaction mixture is diluted with EtOAc and washed with saturated NH4C1 solution, saturated NaHCO3 solution and brine. The organic layer is dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary.
[00289] Step B: Preparation of .5-(5-amino-π.3.4]oxadiazol-2-vn-7- fluoropyrazolo[1.5-a1pyrimidin-6-yl1-(4-bromo-2-fluorophenyl)-amine. Cyanogen bromide (2.02 equivalents) is added to a suspension of 6-(4-bromo-2-fluorophenylamino)-7- fluoropyrazolo[l, 5 -a]pyrimidine-5 -carboxylic acid hydrazide (1.00 equivalent) in dioxane followed by an aqueous NaHCO3 solution (1.01 equivalents). After 17 hours, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO ) and concentrated under reduced pressure. The product is purified by flash chromatography as necessary. Example 6
Figure imgf000066_0001
7-(4-Bromo-2-fluorophenylamino)-imidazo[l ,2-b]pyridazine-6-carboxylic acid (2- hydroxy ethoxy)-amide
[00290] Step A. Preparation of 4.6-dichloropyridazine-3-carboxylic acid ethyl ester:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester is prepared from 3-oxo-pentanedioic acid diethyl ester according to the procedure described in WO 04/031174. [00291] Step B. Preparation of 4.6-dichloropyridazine-3-carboxylic acid: To a solution of 4,6-dichloropyridazine-3-carboxylic acid ethyl ester (1.00 equivalent) in 4:1 v/v THF/MeOH is added aqueous 1 M NaOH (5.00 equivalents). The reaction mixture is stined at room temperature for 1 hour. The reaction mixture is acidified to pH 1-2 with aqueousl M HCl, diluted with water, and extracted with ethyl acetate/THF. The organic layer is washed with water, saturated NaCl, is dried (Na2SO4), and is concentrated under reduced pressure to afford the desired product.
[00292] Step C. Preparation of 4-(4-bromo-2-fluorophenylamino)-6-chloro- pyridazine-3 -carboxylic acid: LiHMDS (1.0 M solution in hexanes, 3.20 equivalents) is added dropwise to a stined solution of 4-bromo-2-fluorophenylamine (2.10 equivalents) in THF cooled to -78 °C. After one hour, 4,6-dichloropyridazine-3-carboxylic acid (1.00 equivalent) is added dropwise as a solution in THF. The reaction mixture is allowed to warm to room temperature slowly and is stined for 16 hours. The reaction mixture is quenched with water, diluted with ethyl acetate and acidified with aqueousl M HCl. The layers are separated and the aqueous phase is extracted with ethyl acetate (3x). The combined organic phases are dried (Na2SO4) and concentrated under reduced pressure to give the desired product. The product may be triturated with an appropriate solvent such as diethyl ether or dichloromethane if further purification is necessary. [00293] Step D. Preparation of 4-(4-bromo-2-fluorophenylamino)-6-chloro- pyridazine-3 -carboxylic acid tert-butyl ester: 2-tert-Butyl-l,3-diisopropylisourea (5.50 equivalents) is added to 4-(4-bromo-2-fluorophenylamino)-6-chloro-pyridazine-3-carboxylic acid (1.00 equivalent) in THF. The reaction mixture is stined for 5 hours at reflux. The reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer is washed with 10% K CO3 and saturated NaCl, dried (Na2SO4), and concentrated in vacuo. The crude product is redissolved in dichloromethane and the resulting white solid is removed by filtration (urea byproduct). The filtrate is concentrated under reduced pressure to provide the desired product. The product may be purified by flash column chromatography if further purification is necessary. [00294] Step E. Preparation of 6-azido-4-(4-bromo-2-fluorophenylamino)-pyridazine- 3-carboxylic acid tert-butyl ester: Sodium azide (2.00 equivalents) is added to a solution of 4-(4-bromo-2-fluorophenylamino)-6-chloro-pyridazine-3-carboxylic acid tert-butyl ester (1.00 equivalent) in DMF and the reaction mixture is stined at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and washed with water, saturated NaHCO3 and saturated NaCl. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to provide the desired product. The product may be purified by flash column chromatography if further purification is necessary. [00295] Step F. Preparation of 6-amino-4-(4-bromo-2-fluorophenylamino)-pyridazine-
3-carboxylic acid tert-butyl ester: Zinc powder (5.00 equivalents) is added portion- wise to a suspension of 6-6-azido-4-(4-bromo-2-fluorophenylamino)-pyridazine-3-carboxylic acid tert- butyl ester (1.00 equivalent) in 3:1 v/v dichloromethane/acetic acid. After fifteen minutes, the reaction mixture is poured into ethyl acetate. The organic layer is washed with water, saturated NaHCO3 and saturated NaCl. The organic layer is dried (Na SO ) and concentrated under reduced pressure to provide the desired product. The product may be triturated with an appropriate solvent such as diethyl ether or dichloromethane if further purification is necessary.
[00296] Step G. Preparation of 7-(4-bromo-2-fluorophenylamino)-imidazo[l,2- blpyridazine-6-carboxylic acid: Chloroacetaldehyde (50% aqueous solution, 5.00 equivalents) is added to a suspension of 6-amino-4-(4-bromo-2-fluorophenylamino)- pyridazine-3 -carboxylic acid tert-butyl ester (1.00 equivalent) in ethanol contained in a sealed tube. The reaction mixture is heated at 80 °C for two days and then cooled to room temperature. The reaction mixture is concentrated and then diluted with ethyl acetate. The organic layer is washed with saturated NaCl, dried (Na2SO4) and concentrated under reduced pressure to provide the desired product. The product may be triturated with an appropriate solvent such as diethyl ether or dichloromethane if further purification is necessary. [00297] Step H. Preparation of 7-(4-bromo-2-fluorophenylamino)-imidazo[l,2- blpyridazine-6-carboxylic acid (2-vinyloxyethoxy)-amide: A mixture of 7-(4-bromo-2- fluorophenylamino)-imidazo[l,2-b]pyridazine-6-carboxylic acid (1.00 equiv), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMA is stined for 30 minutes at room temperature under N2. O-(2-vinyloxy-ethyl)-hydroxylamine (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After the reaction mixture is stined for 16 hours at room temperature, it is diluted with EtOAc and washed with saturated NH4C1 solution, saturated NaHCO3 solution and saturated NaCl. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to yield the desired product. The product may be purified by flash column chromatography if further purification is necessary. [00298] Step I. Preparation of 7-(4-bromo-2-fluorophenylamino)-imidazo|T,2- b]pyridazine-6-carboxylic acid (2-hydroxyethoxy)-amide: To a solution of 7-(4-bromo-2- fluorophenylamino)-imidazo[l,2-b]pyridazine-6-carboxylic acid (2-vinyloxyethoxy)-amide (1.00 equivalent) in ethanol is added aqueous 2 M HCl (5.00 equivalents). The reaction mixture is stined for 16 hours at room temperature. The reaction mixture is adjusted with aqueous 1 M NaOH until the pH is 7. The reaction mixture is diluted with EtOAc and H2O. The organic layer is separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure to yield the desired product. The product may be purified by flash column chromatography if further purification is necessary. Example 7
Figure imgf000069_0001
]6-(5-Amino-[l,3,4]oxadiazo_-2-y_)-imidazo[l,2-b]pyridazin-7-y_]-(4-bromo-2- fluorophenyl)-amine [00299] Step A. Preparation of 7-(4-bromo-2-fluorophenylamino)-imidazo|T,2- b"|pyridazine-6-carboxylic acid hydrazide: A mixture of 7-(4-bromo-2-fluorophenylamino)- imidazo[l,2-b]pyridazine-6-carboxylic acid (1.00 equiv), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMA is stined for 30 minutes at room temperature under N2. Hydrazine (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After the reaction mixture is stined for 16 hours at room temperature, it is diluted with EtOAc and washed with saturated NH4C1 solution, saturated NaHCO3 solution and saturated NaCl. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to yield the desired product. The product may be purified by flash column chromatography if further purification is necessary. [00300] Step B: Preparation r6-(5-amino-[l,3,41oxadiazol-2-yl)-imidazori.2- b1pyridazin-7-yn-(4-bromo-2-fluorophenyl)-amine. 7-(4-Bromo-2-fluorophenylamino)- imidazo[l,2-b]pyridazine-6-carboxylic acid hydrazide (1.00 equivalent) is suspended in dioxane. Cyanogen bromide (1.01 equivalents) is added, followed by a solution of sodium bicarbonate (1.00 equivalent) in H2O. The reaction mixture is stined at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate and washed with water and saturated aqueous NaCl. The organic layer is dried (Na2SO ) and concentrated under reduced pressure to yield the desired product. The product may be purified by flash column chromatography if further purification is necessary. Example 8
Figure imgf000069_0002
6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-isoxazoio[4,5-b]pyridine-5- carboxylic acid cyclopropylmethoxyamide
[00301] Step A: Preparation of 3A5,6-tetrachloropyridine-2-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step F of Example 1.
[00302] Step B: Preparation of 3,5,6-trichloro-4-fluoropyridine-2-carboxyric acid methyl ester: To a solution of 3,4,5,6-tetrachloropyridine-2-carboxylic acid methyl ester (1.00 equivalent) in MeCN is added CsF (1.00 equivalent) at room temperature. The resulting mixture is refluxed with stirring for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product that is purified by flash column chromatography as necessary.
[00303] Step C: Preparation of 3,5,6-trichloro-4-fluoropyridine-2-carboxylic acid:
The title compound is prepared by the procedure previously described in Step I of Example 1. [00304] Step D: Preparation of 5.6-dichloro-4-fluoro-3-(2-fluorophenylamino)- pyridine-2-carboxylic acid: To a solution of 4-fluoraniline (2.00 equivalents) in THF at -78 °C is added LiHMDS (3.00 equivalents, 1 M solution in THF). After complete addition, the resulting mixture is stined for 1 hour at -78 °C. A solution of 3,5,6-trichloro-4- fluoropyridine-2-carboxylic acid (1.00 equivalent) is added at -78 °C. The reaction mixture is slowly warmed to room temperature and stined for 16 hours. The reaction is quenched with 10% aqueous HCl at 0 °C, acidified to pH 1, warmed to room temperature, and stined for 1 hour. The precipitates are filtered, and washed with ether to yield the desired product that is directly used without further purification. [00305] Step E: Preparation of 5,6-dichloro-4-fluoro-3-(2-fluorophenylaminoV pyridine-2-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step F of Example 1.
[00306] Step F: Preparation of 5-chloro-4-fluoro-3-(2-fluorophenylamino -6- trimethylsilanylethvnyl-pyridine-2-carboxylic acid methyl ester: A mixture of 5,6-dichloro- 4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent), TMS-acetylene (1.20 equivalents), Pd(PPh3)2Cl2 (0.10 equivalents), Cul (0.10 equivalents), and i-Pr2NH (2.00 equivalents) in THF is stined for 16 hours at room temperature. THF is evaporated in vacuo. The reaction mixture is diluted with EtOAc and washed with saturated aqueous NH4C1 and brine. The organic layer is dried over MgSO , filtered, and concentrated to give the crude material that is purified by flash column chromatography to afford the desired product. [00307] Step G: Preparation of 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)- pyridine-2-carboxylic acid methyl ester: A mixture of 5-chloro-4-fluoro-3-(2- fluorophenylamino)-6-trimethylsilanylethynyl-pyridine-2-carboxylic acid methyl ester (1.00 equivalent), HgSO4 (1.00 equivalent), and cone. H2SO4 (2.00 equivalents) in acetone-water is refluxed with stirring for 3 hours. The reaction mixture is concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vauco to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
[00308] Step H: Preparation of 7-fluoro-6-(2-fluorophenylaminoV3-methyl- isoxazolo["4,5-b1pyridine-5-carboxylic acid methyl ester: To a solution of acetone oxime (2.20 equivalents) at room temperature is added t-BuOK (2.20 equivalents, 1.0 M solution in THF). After stirring for 30 minutes room temperature, the reaction mixture is cooled to 0 °C. A solution 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent) in THF is added. After stining for 1 hour at 0 - 5 °C, the reaction mixture is quenched with saturated aqueous NH4C1 and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO , concentrated in vacuo to give 6- acetyl-4-fluoro-3-(2-fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester that is used directly. A mixture of 6-acetyl-4-fluoro-3-(2- fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester in 5% aqueous MeOH is refluxed with stining for 1 hour. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product.
[00309] Step I: Preparation of 6-(4-bromo-2-fluorophenylamino -7-fluoro-3-methyl- isoxazolo[4,5-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step H of Example 1. [00310] Step J: Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3- methylisoxazolo 4,5-b pyridine-5-carboxylic acid: The title compound is prepared by the procedure previously described in Step I of Example 1. 100311] Step K: Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3- methylisoxazolo["4,5-b1pyridine-5-carboxylic acid cyclopropylmethoxyamide: The title compound is prepared using O-cyclopropylmethyl-hydroxylamine by the method previously described in Step J of Example 1. Example 9
Figure imgf000072_0001
3-Amino-6-(4-bromo-2-fluorophenylamino)-7-fluoroisoxazolo[4,5-b]pyridine-5- carboxylic acid (2-hydroxyethoxy)-amide
[00312] Step A: Preparation of 5-chloro-6-cvano-4-fluoro-3-(2-fluorophenylamino)- pyridine-2-carboxylic acid methyl ester: A mixture of 5,6-dichloro-4-fluoro-3-(2- fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent) (prepared in Example 8), dppf (0.02 equivalents), Pd2dba3 (0.01 equivalents), and Zn(CN)2 (0.60 equivalents) in NMP is stined at 120 °C in a sealed tube. After stining for 20 hours, the reaction mixture is cooled to room temperature and quenched with a 4:1 :4 (volume) mixture solution of saturated aqueous NH4Cl-conc NH OH-water. The mixture is extracted with EtOAc. The organic layer is washed with saturated aqueous NH4Cl/conc. NH4OH/water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product. [00313] Step B: Preparation of 3-amino-7-fluoro-6-(2-fluorophenylamino)- isoxazolo("4,5-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by a two step procedures as described in Step H of Example 8.
[00314] Step C: Preparation of 3-amino-6-(4-bromo-2-fluorophenylamino)-7- fluoroisoxazolo|"4,5-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by the method described in Step H of Example 1. [00315] Step D: Preparation of 3-amino-6-(4-bromo-2-fluorophenylamino)-7- fluoroisoxazolo("4.5-b1pyridine-5-carboxylic acid: The title compound is prepared by the method described in step I of Example 1. [00316] Step E: Preparation of 3-amino-6-(4-bromo-2-fluorophenylaminoV7- fluoroisoxazolo[4,5-blpyridine-5-carboxylic acid (2-vinyloxyethoxyVamide: The title compound is prepared using O-(2-vinyloxy-ethyl)-hydroxylamine by the method described in Step J of Example 1. [00317] Step F: Preparation of 3-amino-6-(4-bromo-2-fluorophenylamino)-7- fluoroisoxazolo 4,5-blpyridine-5-carboxylic acid (2-hydroxyethoxy)-amide: The title compound is prepared by the method described in Step K of Example 1. Example 10
Figure imgf000073_0001
[5-(5-Amino-[l,3,4]oxadiazol-2-yl)-7-fluoro-3-methyl-isoxazolo[4,5-b]pyridin-6-yl]-(4- bromo-2-fluorophenyl)-amine
[00318] The title compound is prepared using 6-(4-bromo-2-fluorophenylamino)-7- fluoro-3-methyl-isoxazolo[4,5-b]pyridine-5-carboxylic acid (prepared in Example 8) by the procedures previously described in Steps A and B of Example 2. Example 11
Figure imgf000073_0002
6-(4-Bromo-2-fluorophenylamino)-7-fluoro-2,3-dimethyI-2H-pyrazolo[4,3-b]pyridine-5- carboxylic acid cyclopropylmethoxyamide [00319] Step A: Preparation of 7-fluoro-6-(2-fluorophenylamino)-3-methyl-2H- pyrazolo[4,3-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared from 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (prepared in Example 8) and the potassium salt of acetone hydrazone in place of the potassium salt of acetone oxime by the method previously described in step H of Example 8. [00320] Step B: Preparation of 7-fluoro-6-(2-fluorophenylamino)-2.3-dimethyl-2H- pyrazolol4,3-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step D of Example 1.
[00321] Step C: Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-2,3- dimethyl-2H-pyrazolo[4,3-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step H of Example 1.
[00322] Step D: Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-2.3- dimethyl-2H-pyrazolo[4,3-blpyridine-5-carboxylic acid: The title compound is prepared by the procedure previously described in Step I of Example 1.
[00323] Step E: Preparation of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-2,3- dimethyl-2H-pyrazolof4,3-b]pyridine-5-carboxylic acid cyclopropylmethoxyamide: The title compound is prepared using O-cyclopropylmethyl-hydroxylamine by the procedure previously described in Step J of Example 1. Example 12
Figure imgf000074_0001
3-Amino-6-(4-bromo-2-fluorophenyIamino)-7-fluoro-2-methyl-2H-pyrazolo[4,3- b]pyridine-5-carboxylic acid (2-hydroxyethoxy)-amide
[00324] Step A: Preparation of 3-amino-7-fluoro-6-(2-fluorophenylamino)-2H- pyrazolor4,3-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared from 5-chloro-6-cyano-4-fluoro-3-(2-fluorophenylamino)-ρyridine-2-carboxylic acid methyl ester (prepared in Example 9) and the potassium salt of acetone hydrazone in place of the potassium salt of acetone oxime by the method previously described in step H of Example 8. [00325] Step B: Preparation of 3-amino-7-fluoro-6-(2-fluorophenylaminoV2-methyl-
2H-pyrazolo[4,3-b1pyridine-5-carboxylic acid methyl ester: The title compound is prepared by the procedure previously described in Step D of Example 1. [00326] Step C: Preparation of 3-amino-6-(4-bromo-2-fluorophenylamino)-7-fluoro-
2-methyl-2H-pyrazolo[4,3-b]pyridine-5-carboxylic acid methyl ester: The title compound is prepared by the method described in Step H of Example 1. [00327] Step D: Preparation of 3-amino-6-(4-bromo-2-fluorophenylaminoV7-fluoro- 2-methyl-2H-pyrazolor4,3-blpyridine-5-carboxylic acid: The title compound is prepared by the method described in Step I of Example 1. [00328] Step E: Preparation of 3 -amino-6-(4-bromo-2-fluorophenylamino)-7-fluoro-2- methyl-2H-pyrazolo[4,3-b]pyridine-5-carboxylic acid (2-vinyloxyethoxy -amide: The title compound is prepared using O-(2-vinyloxy-ethyl)-hydroxylamine by the method described in Step J of Example 1. [00329] Step F: Preparation of 3-amino-6-(4-bromo-2-fluorophenylamino)-7-fluoro-2- methyl-2H-pyrazolor4,3-b1pyridine-5-carboxylic acid (2-hydroxyethoxy)-amide: The title compound is prepared by the method described in Step K of Example 1. Example 13
Figure imgf000075_0001
[5-(5- Amino- [1 ,3 ,4] oxadiazol-2-y_)-7-fluoro-2,3-dimethyl-2H-pyrazolo [4,3-b] pyridin-6- yl]-(4-bromo-2-fluorophenyl)-amine [00330] The title compound is prepared using 6-(4-bromo-2-fluorophenylamino)-7- fluoro-2,3-dimethyl-2H-pyrazolo[4,3-b]pyridine-5-carboxylic acid (prepared in Example 11) by the methods previously described in Steps A and B of Example 2.
[00331] The foregoing description is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable modifications and equivalents may be resorted to falling within the scope of the invention as defined by the claims that follow.
[00332] The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

Claims

What is claimed is:
1. A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound having the Formula:
Figure imgf000076_0001
where X is C or N; Y is NR15, O, S, S(O), S(O)2, C(O) or CH2; Z is C or N; R1, R2, R8, and R9 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR1 1, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cι0 alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, -S(O)j(Cι-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, d-C4 alkenyl, d-C alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; R7 is hydrogen, trifluoromethyl, Ci-Cio alkyl, C2-C10 alkenyl, C2-Cι0 alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -SO2NR"R12, -C(O)Rπ, C(O)OR", -OC(O)R", -NR"C(0)0R14, -NRuC(O)R12, -C(0)NR"R12, -SR", -S(O)R14, -SO2R14, -NRπR12, -NR"C(0)NR12R13, -NR"C(NCN)NR12R13, -OR11, C1-C10 alkyl, C2-Cι0 alkenyl, d-Cio alkynyl, C3-C,0 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, d-C4 alkenyl, d-C4 alkynyl, C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; R3 is hydrogen, trifluoromethyl, C1-C10 alkyl, d-Cio alkenyl, -Cio alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR"SO2R14, -Sθ2NR"R12, -C(O)R", C(O)OR", -OC(O)Rπ, -NR"C(0)0R14, - NR"C(O)R12, -C(0)NR"R12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(O)NR12R13, - NRnC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"S02R14, -S02NR"R12, -C(O)RΠ, C(O)ORπ, -OC(O)Rπ, - NR"C(O)OR14, -NRuC(O)R12, -C(O)NR"R'2, -SR", -S(O)R14, -SO2R14, -NRnR12, -NR"C(0)NR12R13, -NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 and R5 independently are hydrogen or Cι-C6 alkyl, or R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -S02NR"R12, -C(O)Rπ, C(O)ORπ, -OC(O)Rπ, - NR"C(O)OR14, -NR"C(O)R12, -C(0)NR"R12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NRnC(O)NR12R13, -NR"C(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R6 is trifluoromethyl, Cι-C)0 alkyl, C -Cιo cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -S02NR"R12, -C(O)R", C(O)OR", -OC(O)R", -NRΠC(O)OR14, -NR"C(0)R12, -C(O)NRuR12, -SR11, -S(O)R14, -SO2R14, -NR"R'2, -NR"C(O)NR12R13, -NR"C(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R11, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl; or any two of R11, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C,0 cycloalkyl), -C(O)(d-C,0 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR3OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C,o cycloalkyl), -C(O)(C,-Cιo alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR3OR3 are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR R , -OR , CpCio alkyl, d-Cio alkenyl, C2-Cιo alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said d-Cio alkyl, C2-Cιo alkenyl, d-Cio alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR R and -OR ; R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; m is 0, 1, 2, 3, 4 or 5; and j is 0, 1 or 2.
2. The compound of claim 1, where Y is NH.
3. The compound of claim 2, where X is C and Z is N.
4. The compound of claim 2, where R9 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl.
5. The compound of claim 4, where W is selected from heteroaryl, C(O)OR ,
C(O)NR3R4, C(O)NR4OR3 and C(O)NR4S(O)2R3, wherein any of said heteroaryl, C(O)OR3, C(O)NR3R4, C(O)NR4OR3 or C(O)NR4S(O)2R3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, CpC4 alkyl, d-C4 alkenyl, d-C4 alkynyl, C3-C6 cycloalkyl and C -C6 heterocycloalkyl, wherein any of said Cι-C4 alkyl, d-C4 alkenyl, C2-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR3R4 and OR3.
6. The compound of claim 4, where W is selected from C(O)OR3, C(O)NHR3, and C(O)NHOR3, wherein any of said C(O)OR3, C(O)NHR3, and C(O)NHOR3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, d-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C -C6 cycloalkyl and C -C6 heterocycloalkyl, wherein any of said Cι-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR3R4 and OR3; and R3 is selected from hydrogen, C.-C alkyl, C2-C4 alkenyl, C2-C alkynyl, C3-C6 cycloalkyl and C -C6 heterocycloalkyl, wherein any of said d-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted with one or more groups selected from NR3R4 and OR3.
7. The compound of claim 6, where R7 is Cι-C alkyl, C2-C4 alkenyl or C2-C4 alkynyl, wherein said C C4 alkyl, C2-C4 alkenyl and C2-C alkynyl, may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3.
8. The compound of claim 7, where R and R are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR1 1.
9. The compound of claim 8, where R1 is halogen or methyl, R2 is hydrogen and R8 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SR11.
10. The compound of claim 9, where R1 is halogen, R8 is halogen, R9 is alkyl or halogen, and R is in the position adjacent to Y, where R is hydrogen.
11. The compound of claim 4, where W is selected from N"N , NH , H"N, l 'N , N'N , and
Figure imgf000080_0001
12. The compound of claim 11, where R7 is Cι-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, wherein said Cι-C alkyl, C2-C4 alkenyl and C2-C alkynyl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3.
13. The compound of claim 12, where R1 and R2 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR .
14. The compound of claim 13, where R is halogen or methyl, R is hydrogen and R is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SR1 x . 1 "7 8
15. The compound of claim 14, where R is halogen, R is hydrogen, R is hal
R > 9 i ■s alkyl or halogen, and R is in the position adjacen „+t j t.o_ Y - τ-, _ w,, ,1h,e „„re„ T Ri is hydrogen.
16. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A composition comprising a compound of claim 6 and a pharmaceutically acceptable canier.
18. A composition comprising a compound of claim 11 and a pharmaceutically acceptable canier.
19. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 1 in an amount effective to inhibit said MEK activity.
20. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 1 in an amount effective to treat said hypeφroliferative disorder.
21. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 1 in an amount effective to treat said inflammatory condition.
22. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 6 in an amount effective to inhibit said MEK activity.
23. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 6 in an amount effective to treat said hypeφroliferative disorder.
24. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 6 in an amount effective to treat said inflammatory condition.
25. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 11 in an amount effective to inhibit said MEK activity.
26. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 11 in an amount effective to treat said hypeφroliferative disorder.
27. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 11 in an amount effective to treat said inflammatory condition.
28. A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound having the formula:
Figure imgf000082_0001
where Y is NR15, O, S, S(O), S(O)2, C(O) or CH2; R1, R2, R8, R9, R10 and R20 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR11, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, Ci-Cio alkyl, C2-C,0 alkenyl, C2-C,0 alkynyl, C3-C10 cycloalkyl, C3-C,0 cycloalkylalkyl, -S(O)j(C,-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, d-C4 alkenyl, d-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; R3 is hydrogen, trifluoromethyl, Ci-do alkyl, d-Cio alkenyl, -Cio alkynyl, C3-Cιo cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR"S02R14, -SO2NR"R12, -C(O)R", C(O)ORΠ, -OC(O)Rn, -NRΠC(O)OR14, - NR"C(O)R12, -C(O)NR"R'2, -SR", -S(O)R14, -SO2R14, -NRnR12, -NR"C(0)NR12R13, - NRπC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -S02NR"R12, -C(O)RΠ, C(O)ORU, -OC(O)RΠ, -
NR"C(O)OR14, -NR"C(O)R12, -C(O)NR"R12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(0)NR12R13, -NR"C(NCN)NR12RI 3, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 and R5 independently are hydrogen or Cι-C6 alkyl, or R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -S02NR"R12, -C(O)RΠ, C(O)ORΠ, -OC(O)RU, -
NR"C(O)OR14, -NR"C(O)R12, -C(O)NR"R12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(O)NR12R13, -NRnC(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R6 is trifluoromethyl, Ci-Cio alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2RI4, -SO2NRπR12, -C(O)R", C(O)OR", -OC(O)Rn, -NRnC(O)OR14, -NRnC(O)R12, -C(0)NR"R12, -SR11, -S(O)R14, -SO2R14, -NR"R'2, -NR"C(0)NR12R13, -NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R , R and R independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, or and arylalkyl; or any two of R1 ', R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C,0 cycloalkyl), -C(O)(Cι-Cι0 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR3OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-Cιo cycloalkyl), -C(O)(C,-C,0 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR3OR3 are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR R , -OR , CpCio alkyl, C2-Cιo alkenyl, C2-Cιo alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said Ci-Cio alkyl, -Cio alkenyl, C2-Cιo alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR R and -OR ; R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; m is 0, 1, 2, 3, 4 or 5; and j is O, 1 or 2.
29. The compound of claim 28, where Y is NH.
30. The compound of claim 29, where R9 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl.
31. The compound of claim 30, where W is selected from heteroaryl, C(O)OR3, C(O)NR3R4, C(O)NR4OR3 and C(O)NR4S(O)2R3, wherein any of said heteroaryl, C(O)OR3, C(O)NR3R4, C(O)NR4OR3 or C(O)NR4S(O) R3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, Cι-C4 alkyl, d-C4 alkenyl, d-C4 alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, wherein any of said Cι-C4 alkyl, d-C4 alkenyl, d-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR3R4 and OR3.
32. The compound of claim 30, where W is selected from C(O)OR3, C(O)NHR3, and C(O)NHOR3, wherein any of said C(O)OR3, C(O)NHR3, and C(O)NHOR3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, Cι-C alkyl, d-C4 alkenyl, d-C4 alkynyl, C3-C6 cycloalkyl and C -C6 heterocycloalkyl, wherein any of said Cι-C4 alkyl, C -C4 alkenyl, d-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR3R4 and OR3; and R3 is selected from hydrogen, C^- alkyl, C2-C alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, wherein any of said CpC4 alkyl, C2-C alkenyl, d-C4 alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted with one or more groups selected from NR3R4 and OR3.
33. The compound of claim 32, where R7 is C i -C alkyl, C2-C4 alkenyl or d-C4 alkynyl, wherein said CpC4 alkyl, C2-C4 alkenyl and C2-C alkynyl, may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, C2-C4 alkenyl, d-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3.
34. The compound of claim 33, where R1 and R2 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR11.
35. The compound of claim 34, where R1 is halogen or methyl, R2 is hydrogen and R8 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SR11.
36. The compound of claim 35, where R1 is halogen, R2 is hydrogen, R8 is halogen, R is alkyl or halogen, and R2 is in the position adjacent to Y, where R2 is hydrogen.
37. The compound of claim 30, where W is selected from
Figure imgf000086_0001
38. The compound of claim 37, where R7 is Cι-C alkyl, C2-C4 alkenyl or d-C4 alkynyl, wherein said C C alkyl, d-C alkenyl and C2-C4 alkynyl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, d-C4 alkyl, d-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3.
39. The compound of claim 38, where R1 and R2 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR1 ' . 1 9 8
40. The compound of claim 39, where R is halogen or methyl, R is hydrogen and R is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SR11.
41. The compound of claim 40, where R1 is halogen, R2 is hydrogen, R8 is halogen, R9 is alkyl or halogen, and R2 is in the position adjacent to Y, where R2 is hydrogen.
42. A composition comprising a compound of claim 28 and a pharmaceutically acceptable carrier.
43. A composition comprising a compound of claim 32 and a pharmaceutically acceptable canier.
44. A composition comprising a compound of claim 37 and a phaπnaceutically acceptable canier.
45. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 28 in an amount effective to inhibit said MEK activity.
46. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 28 in an amount effective to treat said hypeφroliferative disorder.
47. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 28 in an amount effective to treat said inflammatory condition.
48. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 32 in an amount effective to inhibit said MEK activity.
49. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 32 in an amount effective to treat said hypeφroliferative disorder.
50. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 32 in an amount effective to treat said inflammatory condition.
51. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 37 in an amount effective to inhibit said MEK activity.
52. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 37 in an amount effective to treat said hypeφroliferative disorder.
53. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 37 in an amount effective to treat said inflammatory condition.
54. A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound having the formula:
Figure imgf000088_0001
where Y is NR15, O, S, S(O), S(O)2, C(O) or CH2; R1, R2, R8, R9, R10 and R20 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR11, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4 -NR3R4, Ci-Cio alkyl, -Cio alkenyl, C2-C,0 alkynyl, C3-Cι0 cycloalkyl, C3-C,0 cycloalkylalkyl, -S(O),(d-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR (CR R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, d-C4 alkenyl, d-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; R is hydrogen, trifluoromethyl, d-Cio alkyl, -Cio alkenyl, -Cio alkynyl, C -Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR"SO2R14, -SO2NRΠR12, -C(O)R", C(O)OR", -OC(O)R", -NR"C(O)OR14, - NR"C(O)R12, -C(O)NR"R12, -SR", -S(O)R14, -SO2R14, -NRUR12, -NRΠC(O)NR12R13, - NR"C(NCN)NR12R'3, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NR"R'2, -C(O)Rπ, C(O)ORπ, -OC(O)Rn, - NR"C(O)OR14, -NR"C(O)R12, -C(O)NR"R12, -SR", -S(O)R14, -SO2R14, -NRUR12, -NR"C(0)NR12R13, -NR"C(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 and R5 independently are hydrogen or Cι-C6 alkyl, or R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -S02NR"R12, -C(O)Rπ, C(O)ORπ, -OC(O)Rπ, - NRuC(O)OR14, -NR"C(0)R12, -C(O)NR"R'2, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(0)NR12R13, -NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R6 is trifluoromethyl, Ci-Cio alkyl, C3-Cιo cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRuSθ2R14, -S02NR"R12, -C(O)R", C(O)OR", -OC(O)R", -NR"C(O)OR14, -NRnC(O)R12, -C(O)NR"R12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(O)NR12R13, -NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R11, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl; or any two of R1 1, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-C,0 cycloalkyl), -C(O)(C,-Cι0 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-Cιo cycloalkyl), -C(O)(Cι-Cιo alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR3OR3 are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR R , -OR , Ci-Cio alkyl, -Cio alkenyl, C2-Cι0 alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said Ci-Cio alkyl, -Cio alkenyl, -Cio alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR R and -OR ; R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; m is 0, 1, 2, 3, 4 or 5; and j is 0, 1 or 2.
55. The compound of claim 54, where Y is NH.
56. The compound of claim 55, where R9 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl.
57. The compound of claim 56, where W is selected from heteroaryl, C(O)OR3, C(O)NR3R4, C(O)NR4OR3 and C(O)NR4S(O)2R3 wherein any of said heteroaryl, C(O)OR3, C(O)NR3R4, C(O)NR4OR3 or C(O)NR4S(O)2R3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, Cι-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl and C -C6 heterocycloalkyl, wherein any of said Cι-C4 alkyl, d-C4 alkenyl, d-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR3R4 and OR3.
58. The compound of claim 56, where W is selected from C(O)OR3, C(O)NHR3, and C(O)NHOR3, wherein any of said C(O)OR3, C(O)NHR3, and C(O)NHOR3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, Cι-C alkyl, d-C4 alkenyl, d-C4 alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, wherein any of said Cι-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR3R4 and OR3; and R3 is selected from hydrogen, Cι-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, wherein any of said d-C4 alkyl, C2-C4 alkenyl, d-C4 alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted with one or more groups selected from NR3R4 and OR3.
59. The compound of claim 58, where R7 is C C4 alkyl, C2-C alkenyl or d-C4 alkynyl, wherein said Cι-C alkyl, d-d alkenyl and d-C4 alkynyl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3.
60. The compound of claim 59, where R and R are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR1 ' .
61. The compound of claim 60, where R1 is halogen or methyl, R2 is hydrogen and R8 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SR11.
62. The compound of claim 61, where R1 is halogen, R2 is hydrogen, R8 is halogen, R is alkyl or halogen, and R2 is in the position adjacent to Y, where R2 is hydrogen.
63. The compound of claim 56, where W is selected from
Figure imgf000092_0001
64. The compound of claim 63, where R7 is Cι-C alkyl, C2-C4 alkenyl or d-d alkynyl, wherein said d-C alkyl, C2-C4 alkenyl and d-d alkynyl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, d-d alkenyl, C2-d alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3. 1
65. The compound of claim 64, where R and R are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR '.
66. The compound of claim 65, where R1 is halogen or methyl, R2 is hydrogen and R8 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SRU. 1 R
67. The compound of claim 66, where R is halogen, R is hydrogen, R is halogen, R9 is alkyl or halogen, and R2 is in the position adjacent to Y, where R2 is hydrogen.
68. A composition comprising a compound of claim 54 and a pharmaceutically acceptable canier.
69. A composition comprising a compound of claim 58 and a phaπnaceutically acceptable canier.
70. A composition comprising a compound of claim 63 and a pharmaceutically acceptable canier.
71. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 54 in an amount effective to inhibit said MEK activity.
72. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 54 in an amount effective to treat said hypeφroliferative disorder.
73. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 54 in an amount effective to treat said inflammatory condition.
74. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 58 in an amount effective to inhibit said MEK activity.
75. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 58 in an amount effective to treat said hypeφroliferative disorder.
76. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 58 in an amount effective to treat said inflammatory condition.
77. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 63 in an amount effective to inhibit said MEK activity.
78. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 63 in an amount effective to treat said hypeφroliferative disorder.
79. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 63 in an amount effective to treat said inflammatory condition.
80. A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound having the formula:
Figure imgf000094_0001
where Y is NR15, O, S, S(O), S(O)2, C(O) or CH2; R1, R2, R8, R9 and R10 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR11, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, Ci-Cio alkyl, C2-C,0 alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C3-C,0 cycloalkylalkyl, -S(O)j(Cι-C6 alkyl), -S(O)j(CR R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)ff-aryl, -O(CR R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C4 alkyl, d-C alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, d-C6 heterocycloalkyl, NR3R4 and OR3; R3 is hydrogen, trifluoromethyl, Ci-Cio alkyl, C2-Cι0 alkenyl, C2-Cιo alkynyl, C3-Cιo cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR"SO2R14, -S02NR"R12, -C(O)R", C(O)OR", -OC(O)R", -NR"C(O)OR14, - NR"C(O)R12, -C(0)NR"R12, -SR", -S(O)R14, -SO2R14, -NR"R'2, -NR"C(0)NR12R13, - NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -SO2NR"R'2, -C(O)RΠ, C(O)ORπ, -OC(O)RΠ, - NR"C(O)OR14, -NR"C(O)R12, -C(0)NR"R12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(O)NR'iR'J, -NR"C(NCN)NR12R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 and R5 independently are hydrogen or d-C6 alkyl, or R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRuSO2R14, -SO2NRΠR12, -C(O)Rπ, C(O)ORU, -OC(O)RΠ, - NR"C(O)OR14, -NRΠC(O)R12, -C(O)NR"R12, -SR", -S(O)R14, -SO2R14, -NRnR12, -NR1 'C(O)NR12R13, -NR"C(NCN)NR12R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R6 is trifluoromethyl, Ci-Cio alkyl, C -Cιo cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NR"R'2, -C(O)R", C(O)ORn, -OC(O)Ru, -NRuC(O)OR14, -NRuC(O)R12, -C(O)NRi lR12, -SRn, -S(O)R14, -SO2R14, -NRπR12, -NR"C(0)NR12R13, -NRΠC(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R1 ' , R1 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl; or any two of R11, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-Cιo cycloalkyl), -C(O)(C,-C,0 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR3OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(d-Cιo cycloalkyl), -C(O)(C,-Cι0 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR3OR3 are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR R , -OR , Ci-Cio alkyl, C2-Cιo alkenyl, C2-do alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said d-Cio alkyl, d-Cio alkenyl, d-Cio alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR3R4 and -OR3; R15 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; m is 0, 1, 2, 3, 4 or 5; and j is O, 1 or 2.
81. The compound of claim 80, where Y is NH.
82. The compound of claim 81 , where R9 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl.
83. The compound of claim 82, where W is selected from heteroaryl, C(O)OR3, C(O)NR3R4, C(O)NR4OR3 and C(O)NR4S(O)2R3, wherein any of said heteroaryl, C(O)OR3, C(O)NR3R4, C(O)NR4OR3 or C(O)NR4S(O)2R3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, Cι-C4 alkyl, d-C4 alkenyl, d-d alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, wherein any of said Cι-C4 alkyl, d-d alkenyl, d-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR3R4 and OR3.
84. The compound of claim 82, where W is selected from C(O)OR3, C(O)NHR3, and C(O)NHOR3, wherein any of said C(O)OR3, C(O)NHR3, and C(O)NHOR3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, Cι-C4 alkyl, d-C4 alkenyl, d-C4 alkynyl, C -C6 cycloalkyl and C -C6 heterocycloalkyl, wherein any of said Cι-C4 alkyl, d-d alkenyl, d-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR3R4 and OR3; and R3 is selected from hydrogen, C.-C alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, wherein any of said C C alkyl, C2-C4 alkenyl, C2-C alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted with one or more groups selected from NR3R4 and OR3.
85. The compound of claim 84, where R7 is d-C alkyl, C2-C alkenyl or C2-C4 alkynyl, wherein said d-C alkyl, C2-C4 alkenyl and C2-d alkynyl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C alkyl, C2-C4 alkenyl, C2-d alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3.
86. The compound of claim 85, where R1 and R2 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR11.
87. The compound of claim 86, where R1 is halogen or methyl, R2 is hydrogen and R8 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SR11.
88. The compound of claim 87, where R1 is halogen, R2 is hydrogen, R8 is halogen, R is alkyl or halogen, and R2 is in the position adjacent to Y, where R2 is hydrogen.
89. The compound of claim 82, where W is selected from
Figure imgf000098_0001
90. The compound of claim 89, where R7 is Cι-C4 alkyl, C2-C4 alkenyl or d-C4 alkynyl, wherein said C C4 alkyl, C2-C4 alkenyl and C2-C4 alkynyl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, C(-C alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3.
91. The compound of claim 90, where R1 and R2 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR11.
92. The compound of claim 91, where R1 is halogen or methyl, R2 is hydrogen and R8 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SRU.
93. The compound of claim 92, where R is halogen, R is hydrogen, R is halogen, R9 is alkyl or halogen, and R2 is in the position adjacent to Y, where R2 is hydrogen.
94. A composition comprising a compound of claim 80 and a phaπnaceutically acceptable carrier.
95. A composition comprising a compound of claim 84 and a pharmaceutically acceptable canier.
96. A composition comprising a compound of claim 89 and a pharmaceutically acceptable carrier.
97. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 80 in an amount effective to inhibit said MEK activity.
98. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 80 in an amount effective to treat said hypeφroliferative disorder.
99. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 80 in an amount effective to treat said inflammatory condition.
100. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 84 in an amount effective to inhibit said MEK activity.
101. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 84 in an amount effective to treat said hypeφroliferative disorder.
102. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 84 in an amount effective to treat said inflammatory condition.
103. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 89 in an amount effective to inhibit said MEK activity.
104. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 89 in an amount effective to treat said hypeφroliferative disorder.
105. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 89 in an amount effective to treat said inflammatory condition.
106. A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound having the formula:
Figure imgf000100_0001
where Y is NR15, O, S, S(O), S(O)2, C(O) or CH2; R1, R2, R8, R9 and R10 are independently hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR11, -OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, Ci-Cio alkyl, C2-C10 alkenyl, C2-C,0 alkynyl, C3-C10 cycloalkyl, C3-Cιo cycloalkylalkyl, -S(O)j(d-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or -NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, C C alkyl, C2-C alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; R7 is hydrogen, trifluoromethyl, Ci-Cio alkyl, d-Cio alkenyl, C2-Cι0 alkynyl, C -Cι0 cycloalkyl, d-Cio cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -SO2NRuR12, -C(O)Rn, C(O)ORn, -OC(O)Ru, -NR"C(0)0R14, -NR"C(0)R12, -C(O)NR"R'2, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(0)NR12R13, -NR"C(NCN)NR12R13, -OR1', CI-CIO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be further substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, d-C4 alkyl, C2-d alkenyl, C2-C4 alkynyl, C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3; R3 is hydrogen, trifluoromethyl, d-Cio alkyl, d-Cio alkenyl, d-Cio alkynyl, C3-Cι0 cycloalkyl, C3-Cιo cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphate or an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR"SO2R14, -SO2NR"R12, -C(O)R", C(O)OR", -OC(O)R", -NR"C(O)OR14, - NRnC(O)R12, -C(O)NRnR12, -SR11, -S(O)R14, -SO2R14, -NRUR12, -NR"C(0)NR12R13, - NR"C(NCN)NR12R13, -OR1 1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R3 and R4 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NRπSO2R14, -S02NR"R12, -C(O)RU , C(O)ORΠ , -OC(O)Rn, - NRυC(O)OR14, -NRnC(O)R12, -C(O)NRuR12, -SRΠ, -S(O)R14, -SO2R14, -NRnR12, -NR1 'C(O)NR!2R13, -NR"C(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 and R5 independently are hydrogen or Cι-C6 alkyl, or R4 and R5 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -SO2NR"RI2, -C(O)Rπ, C(O)ORπ, -OC(O)Rπ, - NR"C(O)OR14, -NR"C(O)R12, -C(O)NR"R12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(O)NR12R13, -NR"C(NCN)NR12R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R6 is trifluoromethyl, Ci-Cio alkyl, C3-Cι0 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR"SO2R14, -S02NR"R12, -C(O)R", C(O)OR", -OC(O)R", -NR"C(O)OR14, -NR"C(O)R12, -C(O)NRUR12, -SR", -S(O)R14, -SO2R14, -NR"R12, -NR"C(0)NR12R13, -NR"C(NCN)NR, 2R13, -OR", aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R11, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R14 is lower alkyl, lower alkenyl, aryl or arylalkyl; or any two of R11, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-Cιo cycloalkyl), -C(O)(Cι-C10 alkyl), -C(O)(aryl), - C(O)(heteroaryl), -C(O)(heterocyclyl) or CR3OR3, wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)R4OR3, -C(O)NR4SO2R3, -C(O)(C3-Cιo cycloalkyl), -C(O)(d-C,0 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) and CR3OR3 are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR3R4, -OR3, Ci-Cio alkyl, C -C10 alkenyl, C2-Cιo alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said C1-C10 alkyl, C2-C 10 alkenyl, d-Cio alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR3R4 and -OR3; R 3 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; m is O, 1, 2, 3, 4 or 5; and j is 0, 1 or 2.
107. The compound of claim 106, where Y is NH.
108. The compound of claim 107, where R9 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl.
109. The compound of claim 107, where W is selected from heteroaryl, C(O)OR3, C(O)NR3R4, C(O)NR4OR3 and C(O)NR4S(O)2R3, wherein any of said heteroaryl, C(O)OR3, C(O)NR3R4, C(O)NR4OR3 or C(O)NR4S(O)2R3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, Ci- alkyl, d-d alkenyl, d-d alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, wherein any of said Cι-C alkyl, d-d alkenyl, C2-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR3R4 and OR3.
110. The compound of claim 107, where W is selected from C(O)OR3, C(O)NHR3, and C(O)NHOR3, wherein any of said C(O)OR3, C(O)NHR3, and C(O)NHOR3 are optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, Cι-C4 alkyl, d-d alkenyl, d-d alkynyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, wherein any of said Cι-C4 alkyl, C2-C4 alkenyl, d-C4 alkynyl, cycloalkyl or heterocycloalkyl can be further optionally substituted with one or more groups selected from NR R4 and OR ; and R3 is selected from hydrogen, Cι-C4 alkyl, C2-C4 alkenyl, G2-C4 alkynyl, C -C6 cycloalkyl and C3-C6 heterocycloalkyl, wherein any of said CpC4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted with one or more groups selected from NR3R4 and OR3.
111. The compound of claim 110, where R7 is CpC4 alkyl, d-d alkenyl or C2-C4 alkynyl, wherein said d-C4 alkyl, C2-d alkenyl and d-C4 alkynyl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cj-C4 alkyl, d-C alkenyl, C2-C alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3.
112. The compound of claim 111, where R and R are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR11.
113. The compound of claim 112, where R1 is halogen or methyl, R2 is hydrogen and R8 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SR11.
114. The compound of claim 113, where R1 is halogen, R2 is hydrogen, R8 is halogen, R9 is alkyl or halogen, and R2 is in the position adjacent to Y, where R2 is hydrogen.
115. The compound of claim 107, where W is selected from 00~ .NR3R4 o > H H .R1 fi_ .NR3R4 M _<°γ" . ^ r N'N , * VNH , * VN, * VN , V , and NR3R4
116. The compound of claim 115, where R .7 i ■s CpC alkyl, d-d alkenyl or d-C4 alkynyl, wherein said Cj-C4 alkyl, d-d alkenyl and d-d alkynyl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, Cι-C alkyl, d-C4 alkenyl, C2-C4 alkynyl, C -d cycloalkyl, C3-C6 heterocycloalkyl, NR3R4 and OR3.
117. The compound of claim 116, where R1 and R2 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethyl, ethoxy or SR1 ' .
118. The compound of claim 117, where R1 is halogen or methyl, R2 is hydrogen and R8 is hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or SR11.
119. The compound of claim 118, where R1 is halogen, R2 is hydrogen, R8 is halogen, R9 is alkyl or halogen, and R2 is in the position adjacent to Y, where R2 is hydrogen.
120. A composition comprising a compound of claim 106 and a pharmaceutically acceptable carrier.
121. A composition comprising a compound of claim 110 and a pharmaceutically acceptable caπier.
122. A composition comprising a compound of claim 115 and a phaπnaceutically acceptable canier.
123. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 106 in an amount effective to inhibit said MEK activity.
124. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 106 in an amount effective to treat said hypeφroliferative disorder.
125. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 106 in an amount effective to treat said inflammatory condition.
126. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 110 in an amount effective to inhibit said
MEK activity.
127. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 110 in an amount effective to treat said hypeφroliferative disorder.
128. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 110 in an amount effective to treat said inflammatory condition.
129. A method of inhibiting MEK activity in a mammal comprising administrating to said mammal one or more compounds of claim 115 in an amount effective to inhibit said MEK activity.
130. A method for treatment of a hypeφroliferative disorder in a mammal comprising administrating to said mammal one or more compounds of claim 115 in an amount effective to treat said hypeφroliferative disorder.
131. A method for treatment of an inflammatory condition in a mammal comprising administrating to said mammal one or more compounds of claim 115 in an amount effective to treat said inflammatory condition.
132. A compound according to any one of claims 1, 6, 11, 28, 32, 37, 54, 58 and 63 for use as a medicament.
133. A compound according to any one of claims 80, 84, 89, 106, 110 and 115 for use as a medicament. 5 134. A compound according to any one of claims 1, 6, 11, 28, 32, 37, 54, 58 and 63 for use as a medicament for the treatment of a hypeφroliferative disorder or an inflammatory condition. 135. A compound according to any one of claims 80, 84, 89, 106, 110 and 115 for use as a medicament for the treatment of a hypeφroliferative disorder or an inflammatory
10 condition. 136. The use of a compound according to any one of claims 1, 6, 11, 28, 32, 37, 54, 58 and 63 in the manufacture of a medicament for the treatment of a hypeφroliferative disorder or an inflammatory condition. 137. The use of a compound according to any one of claims 80, 84, 89, 106, 110 and 15 115 in the manufacture of a medicament for the treatment of a hypeφroliferative disorder or an inflammatory condition. 138. A method for preparing a compound of foπnula 7
Figure imgf000107_0001
7 wherein0 R1 , R2 and R9 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or Cι-C6 alkyl; R3 and R7 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or5 heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising: (a) reacting a compound of formula 5
Figure imgf000108_0001
5 with an aniline derivative to provide a compound of formula 6
Figure imgf000108_0002
6 ; and (b) reacting a compound of formula 6 with an amine to provide a compound of formula 7. 139. A method for preparing a compound of formula 8
Figure imgf000108_0003
wherein R , R2 and R9 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R >4 i •s hydrogen or Cι-C6 alkyl; R3 and R7 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1 , ethyl, or ethoxy; said method comprising: (a) reacting a compound of formula 5
Figure imgf000109_0001
5 with an aniline derivative to provide a compound of formula 6
Figure imgf000109_0002
6 ; and (b) reacting a compound of formula 6 with a hydroxylamine to provide a compound of formula 8. 140. A method for preparing a compound of formula 8
Figure imgf000109_0003
wherein R1, R2 and R9 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or Cι-C6 alkyl; R3 and R7 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising: (a) reacting a compound of formula 9
Figure imgf000110_0001
9 with an aniline derivative to provide a compound of formula 10
Figure imgf000110_0002
10 ; and (b) reacting a compound of formula 10 with a hydroxylamine to provide a compound of formula 8. 141. A method for preparing a compound of formula 23
Figure imgf000111_0001
wherein R1, R2, R9 and R20 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or d-C6 alkyl; R3 and R1 ' are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising: (a) reacting a compound of formula 21
Figure imgf000111_0002
where A is Cl or Br, with an aniline derivative to provide a compound of formula 22
Figure imgf000111_0003
(b) reacting a compound of formula 22 with a hydroxylamine to provide a compound of formula 23. 142. A method for preparing a compound of formula 25
Figure imgf000112_0001
wherein R1, R2, R9 and R20 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or Cι-C alkyl; R3 and R11 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising: (a) reacting a compound of formula 21
Figure imgf000112_0002
where A is Cl or Br, with an aniline derivative to provide a compound of formula 22
Figure imgf000113_0001
(b) reacting a compound of formula 22 with a base to provide a compound of formula 24
Figure imgf000113_0002
24 ; and (c) reacting a compound of formula 24 with an amine to provide a compound of formula 25. 143. A method for preparing a compound of formula 36
Figure imgf000113_0003
wherein R1, R2, R9 and R20 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or Cι-C6 alkyl; R and R are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising reacting a compound of formula 34 or 35
Figure imgf000114_0001
with a hydroxylamine to provide a compound of formula 36. 144. A method for preparing a compound of formula 37
Figure imgf000114_0002
wherein Rl, R2, R9 and R20 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or CpC6 alkyl; R3 and R10 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising reacting a compound of formula 35
Figure imgf000115_0001
with an amide aniline derivative to provide a compound of formula 37. 145. A method for preparing a compound of formula 77
Figure imgf000115_0002
77 wherein R1, R2, R9 and R10 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or Cι-C6 alkyl; R3 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising: (a) reacting a compound of formula 75
Figure imgf000116_0001
75
with a base to provide a compound of formula 76
Figure imgf000116_0002
76 ; and
(b) reacting a compound of formula 76 with an amine to provide a compound of formula 77. 146. A method for preparing a compound of formula 78
Figure imgf000116_0003
wherein R1, R2, R9 and R10 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or C C6 alkyl; R3 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising: (a) reacting a compound of formula 75
Figure imgf000117_0001
75
with a base to provide a compound of formula 76
Figure imgf000117_0002
76 ; and
(b) reacting a compound of formula 76 with a hydroxylamine to provide a compound of formula 78. 147. A method for preparing a compound of formula 102
Figure imgf000117_0003
wherein R1, R2 and R9 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or Cι-C6 alkyl; R3 and R7 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R8 is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising: (a) reacting a compound of formula 99
Figure imgf000118_0001
with a base to provide a compound of formula 101
Figure imgf000118_0002
(b) reacting a compound of formula 101 with an amine to provide a compound of formula 102. 148. A method for preparing a compound of foπnula 103
Figure imgf000119_0001
103 wherein R1, R2 and R9 are independently hydrogen, halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl; R4 is hydrogen or d-C6 alkyl;
R3 and R7 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R is halogen, hydroxyl, cyano, nitro, azido, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, SR1, ethyl, or ethoxy; said method comprising: (a) reacting a compound of formula 99
Figure imgf000119_0002
with a base to provide a compound of formula 101
Figure imgf000120_0001
(b) reacting a compound of formula 101 with a hydroxylamine to provide a compound of formula 103.
119
W.DE - 80248/0031 - 220905 vl
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