WO2005121125A1 - Ether-linked heteroaryl compounds - Google Patents

Ether-linked heteroaryl compounds Download PDF

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Publication number
WO2005121125A1
WO2005121125A1 PCT/IB2005/001849 IB2005001849W WO2005121125A1 WO 2005121125 A1 WO2005121125 A1 WO 2005121125A1 IB 2005001849 W IB2005001849 W IB 2005001849W WO 2005121125 A1 WO2005121125 A1 WO 2005121125A1
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Prior art keywords
alkyl
aryl
cycloalkyl
membered
membered heteroaryl
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PCT/IB2005/001849
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French (fr)
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Pei-Pei Kung
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Pfizer Inc.
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Publication of WO2005121125A1 publication Critical patent/WO2005121125A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention relates to heteroaryl compounds useful as tyrosine kinase inhibitors. More particularly, the invention provides ether-linked heteroaryl compounds that are c-MET (HGFR) inhibitors. Such compounds are useful in the treatment of c-MET (HGFR) mediated disorders, such as cancers.
  • HGFR c-MET
  • RTK hepatocyte growth factor
  • HGFR can be activated through overexpression or mutations in various human cancers including small cell lung cancer (SCLC) (Ma, P.C., Kijima, T., Maulik, G., Fox, E.A., Sattler, M., Griffin, J.D., Johnson, B.E. & Saigia, R. (2003a). Cancer Res, 63, 6272-6281).
  • SCLC small cell lung cancer
  • c-MET is a receptor tyrosine kinase that is encoded by the Met proto-oncogene and transduces the biological effects of hepatocyte growth factor (HGF), which is also referred to as scatter factor (SF).
  • HGF hepatocyte growth factor
  • SF scatter factor
  • c-MET and HGF are expressed in numerous tissues, although their expression is normally confined predominantly to cells of epithelial and mesenchymal origin, respectively.
  • c-MET and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation, and organization of 3-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.).
  • HGF/SF has been reported to be an angiogenic factor, and c-MET signaling in endothelial cells can induce many of the cellular responses necessary for angiogenesis (proliferation, motility, invasion).
  • the c-MET receptor has been shown to be expressed in a number of human cancers.
  • c-Met and its ligand, HGF have also been shown to be co-expressed at elevated levels in a variety of human cancers (particularly sarcomas).
  • c-MET signaling is most commonly regulated by tumor-stroma (tumor-host) interactions.
  • c-MET gene amplification, mutation, and rearrangement have been observed in a subset of human cancers. Families with germline mutations that activate c-MET kinase are prone to multiple kidney tumors as well as tumors in other tissues. Numerous studies have correlated the expression of c-MET and/or HGF/SF with the state of disease progression of different types of cancer
  • c-MET has been shown to correlate with poor prognosis and disease outcome in a number of major human cancers including lung, liver, gastric, and breast.
  • c-MET has also been directly implicated in cancers without a successful treatment regimen such as pancreatic cancer, glioma, and hepatocellular carcinoma.
  • HGFR novel c-MET
  • L is N or CR 5 ; when L is N, A represents a fused 5 or 6-membered aryl or heteroaryl group, and when L is CR 5 , A represents a fused 5-membered heteroaryl group; and each hydrogen in A is optionally substituted by an R 6 group;
  • X and Y are independently N or CR 7 ; each R , R 2 , R 3 , R 5 and R 7 is independently hydrogen, halogen, C ⁇ -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C ⁇ 2 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0) m R 8 , -S0 2 NR 8 R 9 , S(0) 2 OR B , -N0 2 , -NR B R a , -CN, -C(0)R B , -OC(0)R B
  • R 6 is halogen, C ⁇ Cu * alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C ⁇ 2 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0) m R 8 , -S0 2 NR 8 R 9 , -S(0) 2 OR 8 , -N0 2 , -NR 8 R 9 ,
  • R 4 is C C i2 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C ⁇ 2 cycloalkyl, C 6 -C ⁇ 2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, S(0) m R , -S0 2 NR ⁇ R 1d , -S ⁇ OR 1 1 2 -NO, -NR 12 R 13 ,
  • each hydrogen in R 4 is optionally substituted by an R 17 group; each R 8 , R 9 , R 10 and R i1 is independently hydrogen, halogen, C r C 12
  • R 4 is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C ⁇ 2 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C ⁇ 2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR 14 R 5 ) n OR 12 , -(CR 14 R 15 ) n C(0)R 12 , -(CR 14 R 15 ) n C(S)R 12 , -(CR 14 R 15 ) n C(0)NR 12 R 13 , -(CR 14 R 15 ) n C(S)NR 12 R 13 ,
  • each hydrogen in R 4 is optionally substituted by an R 17 group.
  • each R 17 is independently halogen, C ⁇ -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, -C(0)R 19 , -C(0)OR 19 -C(0)NR 19 R 2 °, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C 1 -C 12 ajkyl, -0-(CH 2 ) n C 3 -C 12 cycloalkyl, -0-(CH 2 ) n C 6 -C 12 aryl, -0-(CH 2 ) n (3-12 membered heteroalicyclic) or -0-(CH 2 ) n (5-12 membered heteroaryl), and each hydrogen in R 17 is optionally substituted by an R 18 group, wherein each R 18 is independently -H, halogen, C C 12 alkyl, C
  • each R 18 is optionally substituted by a group selected from halogen, -OH, -CN, -C 1 .
  • each R 19 and R 20 which may be the same or different, is independently selected from -H, halogen, C ⁇ C ⁇ alkyl, C ⁇ C ⁇ alkoxy, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R 19 and R 20 is optionally substituted by a group selected from halogen, -OH, -CN, -C ⁇ .
  • L is selected from N and CR 5 ; when L is N, A represents a fused 5 or 6-membered aryl or heteroaryl group, and when L is CR 5 , A represents a fused 5-membered heteroaryl group; and A is optionally substituted by from 1-4 R 6 groups;
  • X and Y are independently selected from N and CR 7 ';
  • R 1 , R 2 , R 3 , R 5 and R 7 which may be the same or different, are each independently selected from hydrogen, halogen, C r C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C ⁇ 2 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C ⁇ 2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S0 2 NR 8 R 9 , -S(0) 2 OR 8 , -N0 2 , -NR 8 R 9 , -(CR 10 R 11 )
  • R 4 is selected from -H, C C 12 alkyl, C 2 -C ⁇ 2 alkenyl, C 2 -C 12 alkynyl, C 3 -C ⁇ 2 cycloalkyl, C 6 -C ⁇ 2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR 14 R 15 ) n OR 12 , -(CR 14 R 15 ) n C(0)R 12 ,
  • each W is optionally substituted by from 1 to 6 R 17 groups; each R 8 , R 9 , R 10 and R 11 , which may be the same or different, is independently selected from hydrogen, halogen, C r C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, and 5-12 membered heteroaryl; or any two of R 8 , R 9 , R 10 and R 11 bound to the same nitrogen atom may, together with the nitrogen to which they
  • each R 17 is optionally substituted by from 1 to 6 R 18 groups; each R 18 , which may be the same or different, is independently selected from -H, halogen, C C 2 alkyl, C C ⁇ 2 alkoxy, C 3 -C ⁇ 2 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C C 12 alkyl, -0-(CH 2 ) n C 3 -C 12 cycloalkyl, -0-(CH 2 )
  • each R 19 and R 20 which may be the same or different, is independently selected from -H, halogen, C r C 12 alkyl, C ⁇ -C ⁇ 2 alkoxy, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R 19 and R 20 is optionally substituted by a group selected from halogen, -OH, -CN, -C ⁇ 2 alkyl which may be partially or fully halogenated, -0-C r C ⁇ 2 alkyl which may be partially or fully halogenated, and -S0 3 H; or R 19 and R 20 , taken together with the nitrogen atom to which they are attached, may form a 3-12 membered heteroalicyclic ring optionally substitute
  • L is CR 5 .
  • X is CR 7 .
  • Y is CR 7 .
  • L is CR 5
  • X is CR 7 and Y is CR 7 .
  • L is N and Y is CR 7 .
  • R 6 is selected from 5-12 membered heteroaryl and -(CR 1 °R 11 ) n 0R 8 .
  • R 4 is selected from -(CR 14 R 15 ) n C(0)R 12 , -(CR 14 R 15 ) n C(S)R 12 , -(CR 1 R 15 ) n C(0)NR 12 R 13 and -(CR 1 R 15 ) n C(S)NR 12 R 13 .
  • X is CR 7
  • Y is CR 7
  • R 6 is selected from 5-12 membered heteroaryl and -(CR 10 R 11 ) n OR 8
  • R 4 is selected from -(CR 14 R 15 ) n C(0)R 12 , -(CR 14 R 15 ) n C(S)R 12 , -(CR 14 R 15 ) n C(0)NR 12 R 13 or -(CR 1 R 15 ) n C(S)NR 12 R 13 .
  • each R 7 is H.
  • R 3 is H.
  • R and R which may be the same or different, are independently selected from H and halogen.
  • the invention provides compounds of formula 2
  • X and Y are independently N or CR 7 ; each R 1 , R 2 , R 3 and R 7 is independently hydrogen, halogen, CrC 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 1 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl,
  • R 4 is C C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C ⁇ 2 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR 14 R 15 ) n OR 12 ,
  • each hydrogen in R 4 is optionally substituted by an R 17 group.
  • each R 17 is independently halogen, C ⁇ -C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, -C(0)R 19 , -C(0)OR 19 -C(0)NR 19 R 2 °, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C ⁇ -C ⁇ 2 alkyl, -0-(CH 2 ) n C 3 -C ⁇ 2 cycloalkyl, -0-(CH 2 ) ⁇ C 6 -C 12 aryl, -0-(CH 2 ) conflict(3-12 membered heteroalicyclic) or -0-(CH 2 ) n (5-12 membered heteroaryl), and each hydrogen in R 17 is optionally substituted by an R 18 group, wherein each R 19 and R 20 , which may be the same or different, is independently selected from
  • X and Y are independently N or CR 7 ; each of R 1 , R 2 , R 3 and R 7 , which may be the same or different, is independently selected from hydrogen, halogen, C 1 -C ⁇ 2 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S0 2 NR 8 R 9 , -S(0) 2 OR 8 , -N0 2 , -NR 8 R 9 , -(CR 10 R 11 ) n OR 8 , -CN, -C(0)R 8 , -OC(0)R 8 , -O(CR 10 R 11 ) n R 8 , -NR 8 C(0)R 9 , -(CR 10 R 11 ) n C(O)OR 8 , -(CR 10 R 11 ) n
  • i2 alkyl which may be partially or fully halogenated, -0-C r C 12 alkyl which may be partially or fully halogenated, and -S0 3 H; or R 19 and R 20 , taken together with the nitrogen atom to which they are attached, may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R 18 groups; and n is O, 1, 2, 3 or 4; and q is 1 , 2, 3 or 4; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • Y is CR 7 .
  • X is CR 7 .
  • At least one R 6 group is -(CR 10 R 11 ) n OR 8 .
  • at least two R 6 groups are -(CR 10 R 11 ) ⁇ OR 8 .
  • R 4 is selected from -(CR 14 R 15 ) ⁇ C(0)R 12 , -(CR 14 R 15 ) n C(S)R 12 , -(CR 1 R 15 ) n C(0)NR 12 R 13 and -(CR 14 R 15 ) n C(S)NR 12 R 13 .
  • the compound has formula 2a
  • Z 1 is O or S and Z 2 is O or S.
  • the compound has formula 2a, and Z 1 is O and Z 2 is O.
  • the compound has formula 2a, and Z 1 is O and Z 2 is S.
  • the compound has formula 2a, and Z 1 is S and Z 2 is O.
  • the compound has formula 2a, and Z 1 is S and Z 2 is S.
  • each R 7 is H.
  • R 3 is H.
  • R 1 and R 2 are independently H or halogen.
  • the invention provides a compound formula 3
  • X and Y are independently N or CR each R 1 , R 2 , R 3 , R 5 and R 7 is independently hydrogen, halogen, C-
  • R 4 is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C ⁇ 2 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C ⁇ 2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR 14 R 15 ) n OR 12 , -(CR 14 R 15 ) n C(0)R 12 , -(CR 14 R 15 ) n C(S)R 12 , -(CR 14 R 15 ) n C(0)NR 12 R 13 , -(CR 1 R 15 ) n C(S)NR 12 R 13 ,
  • each hydrogen in R 4 is optionally substituted by an R 17 group.
  • each R 17 is independently halogen, C r C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C 2 -C 12 alkynyl, C 3 -C ⁇ 2 cycloalkyl, C 6 -C 12 aryl, -C(0)R 19 , -C(0)OR 19 -C(0)NR 19 R 2 °, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C r C 12 alkyl, -0-(CH 2 ) n C 3 -C ⁇ 2 cycloalkyl, -0-(CH 2 ) n C 6 -C 12 aryl, -0-(CH 2 ) n (3-12 membered heteroalicyclic) or -0-(CH 2 ) n (5-12 membered heteroaryl), and each hydrogen in R 17 is optionally substituted by an R 18 group, wherein each R 8 is independently -H, halogen, C ⁇ -C 12 alkyl, C 2 -C ⁇
  • each R 18 is optionally substituted by a group selected from halogen, -OH, -CN, -C 1-12 alkyl which may be partially or fully halogenated, -0-C 1 -C 12 alkyl which may be partially or fully halogenated, and -S0 3 H; and each R 19 and R 20 , which may be the same or different, is independently selected from -H, halogen, C r C ⁇ 2 alkyl, C C 2 alkoxy, C 3 -C 12 cycloalkyl, C 6 -O-Ci-C ⁇ alkyl, -0-(CH 2 ) n C 3 -C 12 cycloalkyl, -0-(CH 2 ) n C 6 -C 12 aryl, -0-(CH 2 ) n (3-12 membered heteroalicyclic), or -0-(CH 2 ) n (5-12 membered heteroaryl), and each R 18 is optionally substituted by a group selected from halogen, -
  • X and Y are independently N or CR 7 ; each R 1 , R 2 , R 3 , R 5 and R 7 , which may be the same or different, is independently selected from hydrogen, halogen, C r C ⁇ 2 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S0 2 NR 8 R 9 , -S(0) 2 OR' -N0 2 , -NR 8 R 9 ,
  • each R 6 which may be the same or different, is independently selected from halogen, C- ⁇ -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S0 2 NR 8 R 9 , -S(0) 2 OR 8 , -N0 2 , -NR 8 R 9 , -(CR 10 R 11 ) n OR 8 , -CN, -C(0)R 8
  • each R 18 is optionally substituted by from 1 to 6 R 17 groups; each R 17 , which may be the same or different, is independently selected from halogen, C C ⁇ 2 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, -C(0)R 19 , -C(0)OR 19 -C(0)NR 19 R 20 , 3- 12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C C ⁇ 2 alkyl, -0-(CH 2 ) n C 3 -C ⁇ 2 cycloalkyl, -O-
  • each R 17 is optionally substituted by from 1 to 6 R 18 groups; each R 18 , which may be the same or different, is independently selected from -H, halogen, C C 12 alkyl, C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C r C 12 alkyl, -0-(CH 2 ) n C 3 -C 12 cycloalkyl, -0-(CH 2 ) n C 6 -C 12 aryl, -0-(CH 2 ) ⁇ (3-12 membered heteroalicyclic), and -0-(CH 2 ) ⁇ (5-12 membered heteroaryl), and
  • R 4 is selected from -(CR 14 R 15 ) n C(0)R 12 , -(CR 14 R 15 ) ⁇ C(S)R 12 , -(CR 14 R 15 ) n C(0)NR 12 R 13 and -(CR 14 R 15 ) n C(S)NR 12 R 13 .
  • R 4 is -C(0)NR 12 R 13 .
  • R 4 is -C(S)NR 12 R 13 .
  • each R 7 is H.
  • R 3 is H.
  • R 1 and R 2 are independently H or halogen.
  • the invention provides a compound selected from the group consisting of:
  • the invention provides a compound selected from the group consisting of: and pharmaceutically acceptable salts, solvates and hydrates thereof.
  • Preferred compounds of the invention include those having c-MET inhibitory activity as defined by any one or more of IC 50 , Ki, or percent inhibition (%l).
  • IC 50 IC 50 , Ki, or percent inhibition (%l).
  • %l percent inhibition
  • particularly preferred compounds have a c- MET IC 50 of less than 10 ⁇ M, or less than 5 ⁇ M, or less than 3 ⁇ M.
  • particularly preferred compounds have a c-MET Ki of less than 5 ⁇ M or less than 2 ⁇ M, or less than 1 ⁇ M, or less than 500 nM. In another embodiment, particularly preferred compounds have a c-MET inhibition at 1 ⁇ M of at least 10% or at least 20% or at least 30% or at least 40% or at least 50% or at least 60% or at least 70% or at least 80% or at least 90%. Methods for measuring c-MET/HGFR activity are described in the Examples herein.
  • the invention provides a method of treating abnormal cell growth in a mammal, including a human, the method comprising administering to the mammal any of the pharmaceutical compositions of the invention.
  • the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvi
  • said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
  • the invention provides a method of treating an HGFR mediated disorder in a mammal, including a human, the method comprising administering to the mammal any of the pharmaceutical compositions of the invention.
  • the method further comprises administering to the mammal an amount of one or more substances selected from anti- tumor agents, anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth.
  • substances include those disclosed in PCT Publication Nos.
  • anti-tumor agents include mitotic inhibitors, for example vinca alkaloid derivatives such as vinblastine vinorelbine, vindescine and vincristine; colchines allochochine, halichondrine, N- benzoyltrimethyl-methyl ether colchicinic acid, dolastatin 10, maystansine, rhizoxine, taxanes such as taxol (paclitaxel), docetaxel (Taxotere), 2'-N-[3-(dimethylamino)propyl]glutaramate (taxol derivative), thiocholchicine, trityl cysteine, teniposide, methotrexate, azathioprine, fluorouricil, cytocine arabinoside, 2'2'- difluorodeoxycytidine (gemcitabine), adriamycin and mitamycin.
  • mitotic inhibitors for example vinca alkaloid derivatives such as vinblastine vinorelbine,
  • Alkylating agents for example cis-platin, carboplatin oxiplatin, iproplatin, Ethyl ester of N-acetyl-DL-sarcosyl-L-leucine (Asaley or Asalex), 1,4- cyclohexadiene-1 ,4-dicarbamic acid, 2,5 -bis(1-azirdinyl)-3,6-dioxo-, diethyl ester (diaziquone), 1 ,4- bis(methanesulfonyloxy)butane (bisulfan or leucosulfan) chlorozotocin, clomesone, cyanomorpholinodoxorubicin, cyclodisone, dianhydroglactitol, fluorodopan, hepsulfam, mitomycin C, hycantheonemitomycin C, mitozolamide, 1-(2-chloroethyl)-4-(3-chloroprop
  • DNA anti-metabolites for example 5-fluorouracil, cytosine arabinoside, hydroxyurea, 2-[(3hydroxy-2- pyrinodinyl)methylene]-hydrazinecarbothioamide, deoxyfluorouridine, 5-hydroxy-2-formylpyridine thiosemicarbazone, alpha-2'-deoxy-6-thioguanosine, aphidicolin glycinate, 5-azadeoxycytidine, beta- thioguanine deoxyriboside, cyclocytidine, guanazole, inosine glycodialdehyde, macbecin II, pyrazolimidazole, cladribine, pentostatin, thioguanine, mercaptopurine, bleomycin, 2-chlorodeoxyadenosine, inhibitors of thymidylate synthase such as raltitrexed and pemetrexed disodium, clofarabine, flox
  • DNA RNA antimetabolites for example, L-alanosine, 5-azacytidine, acivicin, aminopterin and derivatives thereof such as N-[2-chloro-5-[[(2, 4-diamino-5-methyl-6-quinazolinyl)methyl]amino]benzoyl]-L- aspartic acid, N-[4-[[(2, 4-diamino-5-ethyl-6-quinazolinyl)methyl]amino]benzoyl]-L-aspartic acid, N -[2-chloro- 4-[[(2, 4-diaminopteridinyl)methyl]amino]benzoyl]-L-aspartic acid, soluble Baker's antifol, dichloroallyl lawsone, brequinar, ftoraf, dihydro-5-azacytidine, methotrexate, N-(phosphonoacetyl)-L-aspartic acid t
  • Anti-angiogenesis agents include MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix- metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors.
  • MMP-2 matrix-metalloprotienase 2
  • MMP-9 matrix- metalloprotienase 9
  • COX-II cyclooxygenase II
  • useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.
  • Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No.
  • MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases ⁇ i.e.
  • MMP inhibitors include AG-3340, RO 32-3555, RS 13-0830, and the following compounds: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]- propionic acid; 3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3- carboxylic acid hydroxyamide; (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3- methyl-piperidine-2-carboxyIic acid hydroxyamide; 4-[4-(4-(4-
  • signal transduction inhibitors include agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM (Genentech, Inc. of South San Francisco, California, USA).
  • EGFR inhibitors are described in, for example in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998), and United States Patent 5,747,498 (issued May 5, 1998).
  • EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, New York, USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck & Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusetts).
  • VEGF inhibitors for example SU-5416 and SU-6668 (Sugen Inc.
  • VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued August 11 , 1998), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 99/16755 (published April 8, 1999), and WO 99/16755 (published April 8, 1999), and
  • VEGF inhibitors include IM862 (Cytran Inc. of Kirkland, Washington, USA); anti-VEGF monoclonal antibody bevacizumab (Genentech, Inc. of South San Francisco, California); and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California).
  • ErbB2 receptor inhibitors such as GW -282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), may be administered in combination with the composition.
  • Such erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issued March 2, 1999), each of which is herein incorporated by reference in its entirety.
  • ErbB2 receptor inhibitors useful in the present invention are also described in United States Provisional Application No. 60/117,341 , filed January 27, 1999, and in United States Provisional Application No.
  • antiproliferative agents include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following United States patent applications: 09/221946 (filed December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed February 9, 2000); 09/539930 (filed March 31, 2000); 09/202796 (filed May 22, 1997); 09/384339 (filed August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds disclosed and claimed in the following United States provisional patent applications: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21 , 2000); 60/168217 (filed November 30, 1999), and 60/200834 (filed May 1 , 2000).
  • compositions of the invention can also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors.
  • CTLA4 cytotoxic lymphocite antigen 4
  • anti-proliferative agents such as other farnesyl protein transferase inhibitors.
  • Specific CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application 60/113,647 (filed December 23, 1998) which is herein incorporated by reference in its entirety. Definitions Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below.
  • Alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms (i.e. C 1 -C 12 alkyl), more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • “Lower alkyl” refers specifically to an alkyl group with 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, n- butyl, /so-butyl, fert-butyl, pentyl, and the like. Alkyl may be substituted or unsubstituted.
  • Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, silyl, amino and -NR x R y , where R x and R y are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-member heteroalicyclic ring.
  • Cycloalkyl refers to a 3 to 12 member all-carbon monocyclic ring (i.e. Ca-C ! 2 cycloalkyl), an all- carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system.
  • cycloalkyl groups examples, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like.
  • a cycloalkyl group may be substituted or unsubstituted.
  • Typical substituent groups include alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O- carboxy, O-carbamyl, N-carbamyl, C-amido, N-amido, nitro, amino and -NR x R y , with R x and R y as defined above.
  • Illustrative examples of cycloalkyl are derived from, but not limited to, the following:
  • Alkenyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond (e.g. C 2 -C ⁇ 2 alkenyl). Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • Alkynyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond (e.g. C 2 -C ⁇ 2 alkynyl).
  • Aryl refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system (i.e. C 6 -C- ⁇ 2 aryl). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
  • Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and -NR x R y , with R and R y as defined above.
  • Heteroaryl refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, and S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system.
  • unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole.
  • the heteroaryl group may be substituted or unsubstituted.
  • Typical substituents include alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, amino and -NR x R y with R x and R y as defined above.
  • a pharmaceutically acceptable heteroaryl is one that is sufficiently stable to be attached to a compound of the invention, formulated into a pharmaceutical composition and subsequently administered to a patient in need thereof. Examples of typical monocyclic heteroaryl groups include, but are not limited to:
  • i ff N is oxazole isothiazole thiazolyl 1 ,2,3-triazole (isoxazolyl) (oxazolyl) (isothiazolyl) (thiazolyl) (1 ,2,3-triazolyl)
  • fused ring heteroaryl groups include, but are not limited to: ben2 ⁇ tria2 ⁇ le pyrrolo[2,3-b]pyridine pyrrolo[2,3-c]pyridine pyrrolo[3,2-c]pyridine (ben2 ⁇ tria2 ⁇ lyl) (pyrrolo[2,3-b]pyridinyl) (pyrrolo[2,3-c]pyridinyl) (pyrrolo[3,2-c]pyridinyl)
  • pyra2olo[1 ,5-a]pyridine pyrrolo[1 ,2-b]pyrida2ine imida2o[1 ,2-c]pyrimidine (pyra2 ⁇ lo[1 ,5-a]pyridinyl) (pyrrolo[1-2,b]pyrida2inyl) (imida2o[1 ,2-cJpyrimidinyl)
  • Heteroalicyclic refers to a monocyclic or fused ring group having in the ring(s) of 3 to 12 ring atoms, in which one or two ring atoms are heteroatoms selected from N, O, and S(0) n (where n is 0, 1 or 2), the remaining ring atoms being C.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • suitable saturated heteroalicyclic groups include, but are not limited to: H ⁇ ⁇ N D° D s D N oxirane thiarane aziridine oxetane thiatane azetidine tetrahyd Orofuran (oxiranyl) (thiaranyl) (aziridinyl) (oxetanyl) (thiatanyl) (azetidinyl) (tetrahydrofuranyl)
  • piperazine 1 ,4-azathiane oxepane thiepane azepane piperazinyl (1 ,4-azathianyl) (oxepanyl) (thiepanyl) (azepanyl)
  • suitable partially unsaturated heteroalicyclic groups include, but are not limited to: 3,4-dihydro-2H-pyran 5,6-di ydro-2H-pyran 2H-pyran (3,4-dihydro-2H-pyranyl) (5,6-dihydro-2H-pyranyl) (2H-pyranyl)
  • heterocycle group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, or mono or dialkylamino.
  • substituents independently selected from halo, lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, or mono or dialkylamino.
  • Hydroxyloxy refers to an -OH group.
  • Alkoxy refers to both an -O-(alkyl) or an -0-(unsubstituted cycloalkyl) group.
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Haloalkoxy refers to an -O-(haloalkyl) group. Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.
  • Aryloxy refers to an -O-aryl or an -O-heteroaryl group, as defined herein.
  • Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
  • Mercapto refers to an -SH group.
  • Alkylthio refers to an -S-(alkyl) or an -S-(unsubstituted cycloalkyl) group.
  • Arylthio refers to an -S-aryl or an -S-heteroaryl group, as defined herein.
  • Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like and derivatives thereof.
  • Acyl or “carbonyl” refers to a -C(0)R” group, where R" is selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halo and -NR x R y groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substitutents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NR x R y groups and heteroalicyclic (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NR
  • acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like
  • Aldehyde refers to an acyl group in which R" is hydrogen.
  • Thioacyl or thiocarbonyl refers to a -C(S)R” group, with R" as defined above.
  • a “thiocarbonyl” group refers to a -C(S)R” group, with R” as defined above.
  • a “C-carboxy” group refers to a -C(0)OR” group, with R" as defined above.
  • An “O-carboxy” group refers to a -OC(0)R” group, with R" as defined above.
  • Ester refers to a -C(0)OR” group with R" as defined herein except that R" cannot be hydrogen.
  • “Acetyl” group refers to a -C(0)CH 3 group.
  • “Halo” group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • Trihalomethyl refers to a methyl group having three halo substituents, such as a trifluoromethyl group.
  • Cyano refers to a -C ⁇ N group.
  • a "sulfinyl” group refers to a -S(0)R” group wherein, in addition to being as defined above, R" may also be a hydroxy group.
  • a “sulfonyl” group refers to a -S(0) 2 R" group wherein, in addition to being as defined above, R" may also be a hydroxy group.
  • S-sulfonamido refers to a -S(0) 2 NR x R y group, with R x and R y as defined above.
  • N-sulfonamido refers to a -NR x S(0) 2 R y group, with R x and R y as defined above.
  • “O-carbamyl” group refers to a -OC(0)NR R y group with R x and R y as defined above.
  • N-carbamyl refers to an R y OC(0)NR x - group, with R x and R y as defined above.
  • O-thiocarbamyl refers to a -OC(S)NR x R y group with R x and R y as defined above.
  • N-thiocarbamyl refers to a R y OC(S)NR x - group, with R y and R x as defined above.
  • Amino refers to an -NR x R y group, wherein R x and R y are both hydrogen.
  • C-amido refers to a -C(0)NR x R y group with R x and R y as defined above.
  • N-amido refers to a R x C(0)NR y - group, with R x and R y as defined above.
  • Ni refers to a -N0 2 group.
  • Haloalkyl means an alkyl, preferably lower alkyl, that is substituted with one or more same or different halo atoms, e.g., -CH 2 CI, -CF 3 , -CH 2 CF 3 , -CH 2 CCI 3 , and the like.
  • Hydroxyalkyl means an alkyl, preferably lower alkyl, that is substituted with one, two, or three hydroxy groups; e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1 ,2-, 1,3-, or ,3-dihydroxypropyl, and the like.
  • “Aralkyl” means alkyl, preferably lower alkyl, that is substituted with an aryl group as defined above; e.g., -CH 2 phenyl, -(CH 2 ) 2 phenyl, -(CH 2 ) 3 phenyl, CH 3 CH(CH 3 )CH 2 phenyl,and the like and derivatives thereof.
  • Heteroaralkyl means alkyl, preferably lower alkyl, that is substituted with a heteroaryl group; e.g., -CH 2 pyridinyl, -(CH 2 ) 2 pyrimidinyl, -(CH 2 ) 3 imidazolyl, and the like, and derivatives thereof.
  • “Monoalkylamino” means a radical -NHR where R is an alkyl or unsubstituted cycloalkyl group; e.g., methylamino, (1 -methylethyl)amino, cyclohexylamino, and the like.
  • Dialkylamino means a radical -NRR where each R is independently an alkyl or unsubstituted cycloalkyl group; dimethylamino, diethylamino, (l-methylethyl)-ethylamino, cyclohexylmethylamino, cyclopentylmethylamino, and the like.
  • "Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • heterocycle group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a “physiologically/pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • a “pharmaceutically acceptable excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • the term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the parent compound.
  • Such salts include: (i) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine,
  • PK refers to receptor protein tyrosine kinase (RTKs), non-receptor or “cellular” tyrosine kinase (CTKs) and serine-threonine kinases (STKs).
  • RTKs receptor protein tyrosine kinase
  • CTKs non-receptor or “cellular” tyrosine kinase
  • STKs serine-threonine kinases
  • modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTK, CTK or STK is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.
  • Catalytic activity refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs.
  • Contacting refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly, i.e., by interacting with the kinase itself, or indirectly, i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent.
  • Such "contacting” can be accomplished “in vitro,” i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment.
  • the ability of a particular compound to affect a PK related disorder can be determined before use of the compounds in vivo with more complex living organisms is attempted.
  • a PK related disorder i.e., the IC 50 of the compound, defined below.
  • “In vitro” refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium.
  • In vivo refers to procedures performed within a living organism such as, without limitation, a mouse, rat or rabbit.
  • PK related disorder all refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK.
  • Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs, (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth.
  • Over-activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases). Under-activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases.
  • Treatment refer to a method of alleviating or abrogating a PK mediated cellular disorder and/or its attendant symptoms.
  • Organism refers to any living entity comprised of at least one cell.
  • a living organism can be as simple as, for example, a single eukariotic cell or as complex as a mammal, including a human being.
  • “Therapeutically effective amount” refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • a therapeutically effective amount refers to that amount which has at least one of the following effects: (1 ) reducing the size of the tumor; (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis; (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.
  • Monitoring means observing or detecting the effect of contacting a compound with a cell expressing a particular PK. The observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a natural binding partner.
  • Cell phenotype refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known in the art.
  • Natural binding partner refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role in propagating a signal in a PK-mediated signal transduction process. A change in the interaction of the natural binding partner with the PK can manifest itself as an increased or decreased concentration of the PK/natural binding partner complex and, as a result, in an observable change in the ability of the PK to mediate signal transduction.
  • Detailed Description Compounds of the invention can be prepared according to the following general scheme:
  • Compounds of formula 10 can be obtained commercially, synthesized according to methods known in the art, or prepared as described in the Examples herein.
  • the heteroaryl chloride 10 is reacted with a p-aminophenol to form the corresponding amine 11.
  • the reaction is conveniently carried out in a polar aprotic solvent.
  • An aprotic solvent is any solvent that, under normal reaction conditions, does not donate a proton to a solute.
  • Polar solvents are those which have a non-uniform distribution of charge. Generally they include 1 to 3 heteroatoms such as N, S or O.
  • polar aprotic solvents examples include ethers such as tetrahydrofuran, diethylether, methyl tert-butyl ether; nitrile solvents such as acetonitrile; dimethylsulfoxide (DMSO); and amide solvents such as dimethylformamide. Mixtures of solvents may also be used.
  • Both compounds 10 and the aminophenol are introduced into a reaction vessel together with the solvent.
  • the reactants may be added in any order.
  • a reactant concentration of 0.1 to 0.5 mol/L is typical, although one skilled in the art will appreciate that the reaction may be conducted at different concentrations.
  • the reaction may be conducted at a temperature of 0 °C up to the reflux temperature of the solvent, and may be catalyzed by, for example, palladium, or in situ-formed palladium complex, or uncatalyzed.
  • the progress of the reaction may be monitored by a suitable analytical method, such as HPLC, TLC, LC/MS or NMR.
  • the amine 11 may be separated from the reaction mixture by methods known to those skilled in the art, such as, for example, crystallization, extractive workup and chromatography.
  • the compounds of formula 1a are easily formed from the amine 11 by reacting with the appropriate R 4 -containing reagent under conditions suitable to replace a hydrogen on the primary amine group in 11 by R 4 .
  • R 4 is a group of formula -C(0)NR 12 R 13 or -C(S)NR 1 R 13
  • the compound of formula 1 a is formed by reacting the compound of formula 11 with the corresponding R 4 isocyanate or thiocyanate in a suitable solvent, such as any of the polar aprotic solvents described above.
  • R 4 is a group of formula -C(0)R 2 R 13
  • the compound of formula 1a is formed by reacting the compound of formula 11 with the corresponding R 4 carboxylic acid or acid chloride in a suitable solvent, such as any of the polar aprotic solvents described above.
  • R 4 when R 4 is an alkyl or substituted alkyl, the compound of formula 1a is formed by reacting the compound of formula 11 with the corresponding R 4 reagent containing a halogen, or a mesolate, or a tosylate, in a suitable solvent, such as any of the polar aprotic solvents described above.
  • the compound of formula 1a is formed by reacting the compound of formula 11 with the corresponding R 4 sulfonyl chloride.
  • Preferred polar aprotic solvents include halogenated solvents, such as methylene chloride or chlorobenzene.
  • One skilled in the art can readily determine the appropriate R 4 - containing reagent and appropriate conditions, based on the structure of R 4 .
  • the reaction first proceeds through the chloropyridine compound 12 by reacting the compound of formula 10 with a 2-chloro-5-hydroxypyridine in a polar aprotic solvent such as those described above.
  • the resulting compound 12 is then converted to the corresponding amine 13 by reaction with the appropriate amine, protected amine, or amine equivalent.
  • the reaction may be conducted at a temperature of from ambient temperature up to the reflux temperature of the solvent, and may be catalyzed by, for example, palladium, or in situ-formed palladium complex, or uncatalyzed.
  • the progress of the reaction may be monitored by a suitable analytical method, such as HPLC, TLC, LC/MS or NMR.
  • the amine 13 may be separated from the reaction mixture by methods known to those skilled in the art, such as, for example, crystallization, extractive workup or chromatography.
  • the compound of formula 1b is readily formed from the compound of formula 13 in the same manner as described above for compound 1a.
  • references herein to the inventive compounds include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including poiymorphs, stereoisomers, and isotopically labeled versions thereof.
  • Pharmaceutically acceptable salts include acid addition and base salts (including disalts). Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • suitable salts see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002), the disclosure of which is incorporated herein by reference in its entirety.
  • a pharmaceutically acceptable salt of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when the solvent is water.
  • Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized, or non-ionized.
  • polymorphs, prodrugs, and isomers including optical, geometric and tautomeric isomers
  • inventive compounds derivatives of compounds of the invention which may have little or no pharmacological activity themselves but can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties.
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the inventive compounds with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs” by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.
  • prodrugs in accordance with the invention include: > (i) where the compound contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (d-CaJalkyl; (ii) where the compound contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (CrC ⁇ Jalkanoyloxymethyl; and (iii) where the compound contains a primary or secondary amino functionality (-NH 2 or -NHR where R ⁇ H), an amide thereof, for example, replacement of one or both hydrogens with (C r C-io)alkanoyl.
  • inventive compounds may themselves act as prodrugs of other of the inventive compounds.
  • Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. A single compound may exhibit more than one type of isomerism.
  • ail stereoisomers geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • acid addition or base salts wherein the counterion is optically active for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • racemate or the racemate of a salt or derivative
  • HPLC high pressure liquid chromatography
  • the racemate or a racemic precursor
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New).
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 3 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically-labeled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 0 and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying.
  • the compounds can be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art.
  • compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.
  • Oral Administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano- particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs.
  • Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V ⁇ _ (6), 981-986 by Liang and
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant will comprise from
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • diluents such as lactose (monohydrate, spray-d
  • Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
  • the formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma er a/, Pharmaceutical Technology On-line, 25(2), 1-14 (2001).
  • parenteral Administration The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • the solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • Topical Administration The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • Topical administration examples include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free ⁇ e.g. PowderjectTM, BiojectTM, etc.) injection.
  • formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • a suitable propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
  • a bioadhesive agent for example, chitosan or cyclodextrin.
  • the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ L to 100 ⁇ L.
  • a typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • PGLA poly(DL-lactic-coglycolic acid
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing a desired mount of the compound of the invention.
  • the overall daily dose may be administered in a single dose or, more usually, as divided doses throughout
  • Rectal/lntravaqinal Administration Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Ocular Administration Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • Other Technologies Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • Drug-cyclodextrin complexes for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties. Dosage The amount of the active compound administered will be dependent on the subject being 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 typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/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 used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.
  • kit-of-Parts Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically includes directions for administration and may be provided with a memory aid.
  • 3,4-Dimethoxyaniline (5g, 32 mmol) and diethyl (ethoxymethylene) malonate (10 mL, 50 mmol) were added to a 250 mL round bottom flask and heated in an oil bath. When the temperature of oil bath reached about 135 °C, EtOH was generated and collected with a condenser. The reaction was heated at 150 °C for 40 minutes to give A. The reaction flask was removed from the oil bath. Phenyl ether (about two times volume of the reaction mixture) was added into the flask. The reaction flask was placed in the oil bath, which was preheated to 270 °C.
  • reaction mixture was stirred and heated to 272 °C for 15 minutes (the temperature of inside the flask was 241 °C).
  • the reaction flask was removed from heating and reaction mixture was slowly poured into Acetone (1 L). The mixture was stirred at room temperature for about one hour. Ethyl 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylate was precipitated and collected by filtration.
  • Ethyl 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylate (700 mg, 2.53 mmol) was added into a solution of potassium hydroxide (450 mg, 7.6 mmol) in 20 mL of H 2 0/EtOH (1:1 ; v:v).
  • This mixture was placed in a sealed vessel (XP-500 Plus vessel) and heated by microwave (MARS 5 Microwave System) at 180°C, under 260-280 psi pressure for 50 minutes.
  • the reaction mixture was cooled to room temperature and transferred into a flask.
  • the solution was then acidified with HOAc (about 2 mL) to pH about 6, saturated with NaCI and extracted with THF (3 x 100 mL).
  • Lithium hexamethyldisilazide (1.5 mL, 1.5 mmol), tris(dibenzylideneacetone) dipalladium (0) chloroform adduct (54 mg, 0.052 mmol), and 2-(dicyclohexylphosphino) biphenyl (45 mg, 0.12 mmol) were added sequentially to a stirred solution of 4-[(6-chloropyridin-3-yl)oxy]-6,7-dimethoxyquinoline (324.4 mg, 1.02 mmol) in THF (3 mL) under a nitrogen atmosphere.
  • reaction mixture was heated at 80 °C for 12 h and then 2 M HCl (17 mL) was added and the mixture was stirred for an additional 2 h.
  • the reaction mixture was neutralized with Na 2 C0 3 and then extracted with THF (2 x 100 mL). The combined organic layers were dried over Na 2 S0 4 then concentrated under vacuum.
  • the residue was purified by flash chromatography (eiuting with 10 ⁇ 20% CH 3 OH in EtOAc) to give 5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-amine as a light brown foam (177.4 mg; 0.60 mmol; 59% yield); MS (APCI) (M+H) + 298.
  • 7-Chlorothieno[3,2-b]pyridine was prepared and isolated as described in J. Heterocycle Chemistry (1985), 22(5), 1249-1252 (Klemm, L. H. et al.), the disclosure of which is incorporated herein by reference in its entirety.
  • 7-(2-fluoro-4-nitrophenoxy)thienor3,2- ⁇ _>lpyridine 2-fluoro-4-nitrophenol (710 mg, 4.5 mmol) and DIEA (10 mL, 57 mmol) were added sequentially to a stirred solution of 7-chlorothieno[3,2-_7]pyridine (500 mg, 2.95 mmol) in chlorobenzene (6 mL). The resulting solution was heated to 140 °C for 12 h.
  • Procedure B 4-Amino-2-fluorophenol (see below) (152 mg, 1.20 mmol) and cesium carbonate (974 mg, 2.99 mmol) were added sequentially to a stirred solution of 7-chlorothieno[3,2-b]pyridine (169 mg, 0.996 mmol) in DMSO (2 mL). The reaction mixture was microwaved at 150 °C for 30 min using Smithsynthesizer. H 2 0 (20 mL) was poured to the mixture stir and EtOAc (2 x 20 mL) was added to extract the aqueous solution. The combined organic layers were dried (Na 2 S0 4 ), filtered and concentrated to give a tan oil residue.
  • Lithium hexamethyldisilazide 0.5 mL, 0.42 mmol
  • tris(dibenzylideneacetone) dipalladium (0) chloroform adduct 20 mg, 0.02 mmol
  • 2-(dicyclohexylphosphino) biphenyl 15 mg, 0.04 mmol
  • 7-[(6-chloropyridin-3-yl)oxy]-2-(1 -methyl-1 H-imidazol-2- yl)thieno[3,2-b]pyridine 120 mg, 0.35 mmol
  • THF 3 mL
  • 4-amino-2-fluorophenol 2-fluoro-4-nitrophenol (500 mg, 3.18 mmol), Pd (10% on activated carbon, 31 mg), and EtOH (20 mL) were combined and stirred under atmospheric H 2 at room temperature. After 16 h, the solution was diluted with EtOAc (20 mL), filtered through Celite, concentrated, and purified by preparative thin layer chromatography (30% EtOAc in hexanes) to afford 4-amino-2-fluorophenol as a tan solid of sufficient purity for subsequent transformations (152 mg, 1.20 mmol; 38% yield). 4-amino-3-fluorophenol:
  • 4-Chloro-6,7-dimethoxyguinazoline was prepared and isolated as described in Tetrahedron (2003), 59(9), 1413-1419 (Alexandre, F.- R. et al.), the disclosure of which is incorporated herein by reference in its entirety.
  • 4-r(6-Chloropyridin-3-yl)oxyl-6.7-dimethoxyguinazoline Potassium t-butoxide (1 mL, 1 mmol, 1 M in THF) was added to 2-chloro-5-hydroxypyridine (198 mg, 1.5 mmol) under inert atmosphere.
  • Lithium hexamethyldisilazide (3 mL, 3 mmol), tris(dibenzylideneacetone) dipalladium (0) chloroform adduct (166 mg, 0.16 mmol), and 2-(dicyclohexylphosphino) biphenyl (135 mg, 0.38 mmol) were added sequentially to a stirred solution of 4-[(6-chloropyridin-3-yl)oxy]-6,7-dimethoxyquinazoline (264 mg, 0.83 mmol) in THF (13 mL) under a nitrogen atmosphere.
  • Trans-2-phenylcyclopropyl isocyanate (0.04 g, 0.22 mmol) was added to a stirred solution of [3- fluoro-4-(thieno[3,2-i)]pyridin-7-yloxy)phenyl]amine (procedure A) (37.2 mg, 0.143 mmol) in CH 2 CI 2 (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 12 h. The solvent was evaporated to give a brown oil residue.
  • Benzoyl isocyanate (0.04 g, 0.25 mmol) was added to a solution of 5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-amine (0.04 g, 0.12 mmol) in CH 2 CI 2 (10 mL). The resulting mixture was stirred at room temperature for 12 h under inert atmosphere. The mixture was evaporated and CH 3 OH (5 mL) was added.
  • Benzoyl isothiocyanate (0.05 g, 0.3 mmol) was added to a solution of 5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-amine (0.067 g, 0.23 mmol) in CH 2 CI 2 (10 mL). The resulting mixture was stirred at room temperature for 12 h under inert atmosphere.
  • 2,6-Difluorobenzoyl isocyanate (0.05 g, 0.3 mmol) was added to a solution of 5-[(6,7- dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (0.065 g, 0.22 mmol) in CH 2 CI 2 (10 mL). The resulting mixture was stirred at room temperature for 12 h under inert atmosphere.
  • Example 9 2.6-dif luoro- ⁇ /-f [(5-(r2-(1 -methyl-1 H-imidazol-2-yl)thienor3.2-frlpyridin-7-yl1oxylpyridin-2- vPaminolcarbonvUbenzamide 2,6-Difluorobenzoyl isocyanate (12 mg, 0.05 mmol) was added to a solution of 5- ⁇ [2-(1 -methyl-1 H- imidazoI-2-yl)thieno[3,2-b]pyridin-7-yl]oxy ⁇ pyridin-2-amine (11.4 mg, 0.035 mmol) in CH 2 CI 2 (4 mL).
  • 2,6-Difluorobenzoyl isocyanate (0.05 g, 0.2 mmol) was added to a solution of 5-[(6,7- dimethoxyquinazolin-4-yl)oxy]pyridin-2-amine (0.04 g, 0.13 mmol) in CH 2 CI 2 (10 mL). The resulting mixture was stirred at room temperature for 12 h under inert atmosphere.
  • Example 14 ⁇ /-r2-(2.6-dichlorophenyl)ethyll- ⁇ /'-f5-r(6.7-dimethoxyguinolin-4-yl)oxy1pyridin-2-yl)urea: ⁇ ⁇
  • Diisopropylamine (0.2 mL, 1 mmol) and 1 ,1'-carbonyldiimidazole (200 mg, 1.2 mmol) were added to a solution of 2-pyridylacetic acid hydrochloride in 2 mL of dichloroethanne. The mixture was stirred at room temperature for 30 min under inert atmosphere. A solution of 5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-amine (150 mg, 0.5 mmol) in 2 mL of dichloroethane was added. The mixture was heated at 80°C for 12 h then cool to ambient temperature. Water (50 mL) was added to the reaction mixture to quench the reaction.
  • Piperidine 40 mg, 0.4 mmol
  • DIEA 0.2 mL, 1 mmol
  • 2-chloro- ⁇ /-[( ⁇ 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl ⁇ amino)carbonyl]acetamide 80 mg, 0.19 mmol
  • the mixture was heated at 60°C for 12 h then cool to ambient temperature.
  • Example 23 ⁇ /- ⁇ 5-r(6,7-dimethoxyquinolin-4-yl)oxylPyridin-2-yl)- ⁇ /-(2-oxo-2-pyrrolidin-1-ylethyl)urea
  • Example 25 /v g -[((5-[(6,7-dimethoxyquinolin-4-yl)oxylpyridin-2-yl ⁇ amino)carbonyl1- ⁇ / , ⁇ 1 -dimethyl- glvcinamide
  • this invention relates to novel compounds capable of modulating, regulating and/or inhibiting protein kinase activity.
  • the following assays may be employed to select those compounds demonstrating the optimal degree of the desired activity.
  • Assay Procedures The following in vitro assay may be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed along the same lines for any PK using techniques well known in the art. A literature reference is provided (Technikova-Dobrova Z, Sardanelli AM, Papa S FEBS Lett. 1991 Nov 4; 292: 69-72).
  • the general procedure is as follows: compounds and kinase assay reagents are introduced into test wells. The assay is initiated by addition of the kinase enzyme. Enzyme inhibitors reduce the measured activity of the enzyme. In the continuous-coupled spectrophotometric assay the time-dependent production of ADP by the kinase is determined by analysis of the rate of consumption of NADH by measurement of the decrease in absorbance at 340 nm. As the PK produces ADP it is re-converted to ATP by reaction with phosphoenol pyruvate and pyruvate kinase. Pyruvate is also produced in this reaction.
  • HGFR Continuous-coupled Spectrophotometric Assay This assay analyzes the tyrosine kinase activity of HGFR on the Met-2 substrate peptide, a peptide derived from the activation loop of the HGFR.
  • DB Prep Dilution Buffer (DB) for Enzyme (For 30 mL prep) 1.
  • DB final concentration is 2 mM DTT, 25 mM NaCI 2 , 5 mM MgCI 2 , 0.01% Tween-20, and 50 mM HEPES buffer, pH 7.5.
  • Into 50 mL conical vial add 60 ⁇ L of 1 M DTT, 150 ⁇ L 5M NaCI 2 , 150 ⁇ L 1 M MgCI 2 , and 30 ⁇ L of 10% Tween-20 to give total volume of 30 mL. 3.
  • reaction buffer For a 10 mL reaction buffer add 10 ⁇ L of 1M PEP, 33 ⁇ L of 100 mM NADH, 50 ⁇ L of 4M MgCI 2 , 20 ⁇ L of 1M DTT, 6 ⁇ L of 500 mM ATP, and 500 ⁇ L of 10 mM Met-2 peptide into 100 mM HEPES buffer pH 7.5 and vortex/mix. 3. Add coupling enzymes, LDH and PK, into reaction mix. Mix by gentle inversion. Running samples 1. Spectrophotometer settings: i. Absorbance wavelength ( ⁇ ): 340 nm ii. Incubation time: 10 min iii. Run time: 10 min iv. Temperature: 37°C 2.
  • a compound is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand known to activate the receptor is added.
  • the cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody recognizing the substrate of the enzymatic phosphorylation reaction. Non-substrate components of the cell lysate are washed away and the amount of phosphorylation on the substrate is detected with an antibody specifically recognizing phosphotyrosine compared with control cells that were not contacted with a test compound.
  • a DNA labeling reagent such as 5- bromodeoxyuridine (BrdU) or H 3 -thymidine is added.
  • the amount of labeled DNA is detected with either an anti-BrdU antibody or by measuring radioactivity and is compared to control cells not contacted with a test compound.
  • MET Transphosphorylation Assay This assay is used to measure phosphotyrosine levels on a poly(glutamic acid: tyrosine, 4:1) substrate as a means for identifying agonists/antagonists of met transphosphorylation of the substrate.
  • Materials and Reagents I . Corning 96-well ELISA plates, Corning Catalog # 25805-96. 2.
  • Blocking Buffer Dissolve 25 g Bovine Serum Albumin, Sigma Cat. No A-7888, in 500 mL PBS, filter through a 4 ⁇ m filter. 6. Purified GST fusion protein containing the Met kinase domain, SUGEN, Inc. 7. TBST Buffer. 8. 10% aqueous (MilliQue H 2 0) DMSO. 9. 10 mM aqueous (dH 2 0) Adenosine-5'-triphosphate, Sigma Cat. No. A-5394. 10.
  • 2X Kinase Dilution Buffer for 100 mL, mix 10 mL 1M HEPES at pH 7.5 with 0.4 mL 5% BSA/PBS, 0.2 mL 0.1 M sodium orthovanadate and 1 mL 5M sodium chloride in 88.4 mL dH 2 0. II.
  • 4X ATP Reaction Mixture for 10 mL, mix 0.4 mL 1 M manganese chloride and 0.02 mL 0.1 M ATP in 9.56 mL dH a O. 12.
  • 4X Negative Controls Mixture for 10 mL, mix 0.4 mL 1 M manganese chloride in 9.6 mL dH 2 0. 13.
  • NUNC 96-well V bottom polypropylene plates NUNC 96-well V bottom polypropylene plates, Applied Scientific Catalog # S-72092 14. 500 mM EDTA.
  • Antibody Dilution Buffer for 100 mL, mix 10 mL 5% BSA/PBS, 0.5 mL 5% Carnation ® Instant Milk in PBS and 0.1 mL 0.1 M sodium orthovanadate in 88.4 mL TBST. 16.
  • Goat anti-rabbit horseradish peroxidase conjugated antibody Biosource, Inc. 18.
  • ABTS Solution for 1 L, mix 19.21 g citric acid, 35.49 g Na 2 HP0 4 and 500 mg ABTS with sufficient dH 2 0 to make 1 L. 19. ABTS/H 2 0 2 : mix 15 mL ABST solution with 2 ⁇ L H 2 0 2 five minutes before use. 20. 0.2 M HCl Procedure: 1. Coat ELISA plates with 2 ⁇ g Poly(Glu-Tyr) in 100 ⁇ L PBS, hold overnight at 4°C. 2. Block plate with 150 ⁇ L of 5% BSA/PBS for 60 min. 3. Wash plate twice with PBS then once with 50 mM Hepes buffer pH 7.4. 4. Add 50 ⁇ L of the diluted kinase to all wells.
  • BrdU INCORPORATION ASSAYS The following assays use cells engineered to express a selected receptor and then evaluate the effect of a compound of interest on the activity of ligand-induced DNA synthesis by determining BrdU incorporation into the DNA.
  • the following materials, reagents and procedure are general to each of the following BrdU incorporation assays. Variances in specific assays are noted.
  • General Materials and Reagents 1. The appropriate ligand. 2. The appropriate engineered cells. 3.
  • BrdU Labeling Reagent 10 mM, in PBS, pH7.4(Roche Molecular Biochemicals, Indianapolis, IN). 4. FixDenat: fixation solution (Roche Molecular Biochemicals, Indianapolis, IN). 5.
  • Anti-BrdU-POD mouse monoclonal antibody conjugated with peroxidase (Chemicon,
  • TMB Substrate Solution tetramethylbenzidine (TMB, ready to use, Roche Molecular Biochemicals, Indianapolis, IN).
  • PBS Washing Solution 1 X PBS, pH 7.4.
  • Albumin, Bovine (BSA), fraction V powder Sigma Chemical Co., USA).
  • Cells are incubated overnight at 37°C in 5% CO2. 2. After 24 hours, the cells are washed with PBS, and then are serum-starved in serum free medium (0%CS DMEM with 0.1% BSA) for 24 hours. 3. On day 3, the appropriate ligand and the test compound are added to the cells simultaneously. The negative control wells receive serum free DMEM with 0.1% BSA only; the positive control cells receive the ligand but no test compound. Test compounds are prepared in serum free DMEM with ligand in a 96 well plate, and serially diluted for 7 test concentrations. 4.
  • serum free medium 0%CS DMEM with 0.1% BSA
  • diluted BrdU labeling reagent (1:100 in DMEM, 0.1% BSA) is added and the cells are incubated with BrdU (final concentration is 10 ⁇ M) for 1.5 hours. 5. After incubation with labeling reagent, the medium is removed by decanting and tapping the inverted plate on a paper towel. FixDenat solution is added (50 ⁇ l/well) and the plates are incubated at room temperature for 45 minutes on a plate shaker. 6. The FixDenat solution is removed by decanting and tapping the inverted plate on a paper towel.
  • Milk is added (5% dehydrated milk in PBS, 200 ⁇ L/well) as a blocking solution and the plate is incubated for 30 minutes at room temperature on a plate shaker. 7.
  • the blocking solution is removed by decanting and the wells are washed once with PBS.
  • Anti-BrdU-POD solution is added (1 :200 dilution in PBS, 1% BSA, 50 ⁇ Uwell) and the plate is incubated for 90 minutes at room temperature on a plate shaker.
  • the antibody conjugate is removed by decanting and rinsing the wells 5 times with PBS, and the plate is dried by inverting and tapping on a paper towel. 9.
  • TMB substrate solution is added (100 ⁇ l/well) and incubated for 20 minutes at room temperature on a plate shaker until color development is sufficient for photometric detection. 10. The absorbance of the samples are measured at 410 nm (in "dual wavelength" mode with a filter reading at 490 nm, as a reference wavelength) on a Dynatech ELISA plate reader.
  • HGF-lnduced BrdU Incorporation Assay Materials and Reagents: 1. Recombinant human HGF (Cat. No. 249-HG, R&D Systems, Inc. USA). 2. BxPC-3 cells (ATCC CRL-1687). Remaining Materials and Reagents, as above. Procedure: 1.
  • Cells are seeded at 9000 cells/well in RPMI 10% FBS in a 96 well plate. Cells are incubated overnight at 37°C in 5% C0 2 . 2. After 24 hours, the cells are washed with PBS, and then are serum starved in 100 ⁇ L serum-free medium (RPMI with 0.1% BSA) for 24 hours. 3. on day 3, 25 ⁇ L containing ligand (prepared at 1 ⁇ g/mL in RPMI with 0.1% BSA; final
  • HGF cone is 200 ng/mL
  • test compounds are added to the cells.
  • the negative control wells receive 25 ⁇ L serum-free RPMI with 0.1% BSA only; the positive control cells receive the ligand (HGF) but no test compound.
  • Test compounds are prepared at 5 times their final concentration in serum-free RPMI with ligand in a 96 well plate, and serially diluted to give 7 test concentrations. Typically, the highest final 5 concentration of test compound is 100 ⁇ M, and 1:3 dilutions are used (i.e. final test compound concentration range is 0.137-100 ⁇ M). 4.
  • Cellular HGFR Autophosphorylation Assay A549 cells (ATCC) were used in this assay. Cells were seeded in the growth media (RPMI +0 10%FBS) into 96 well plates and cultured overnight at 37 °C for attachment. Cells were exposed to the starvation media (RPMI + 0.05% BSA). Dilutions of the inhibitors were added to the plates and incubated at 37 °C for 1 hour. Cells were then stimulated by adding 40 ng/mL HGF for 15 minutes. Cells were washed once with 1mM Na 3 V0 4 in HBSS and then lysed.
  • RPMI +0 10%FBS RPMI + 0.05% BSA
  • the lysates were diluted with 1mM Na 3 V0 4 in HBSS and transferred to a 96 well goat ant-rabbit coated plate (Pierce) which was pre-coated with anti-5 HGFR antibody (Zymed Laboratories). The plates were incubated overnight at 4 °C and washed with 1% Tween 20 in PBS for seven times. HRP-PY20 (Santa Cruz) was diluted and added to the plates for 30 minutes incubation. Plates were then washed again and TMB peroxidase substrate (Kirkegaard & Perry) was added and incubated for 10 minutes. The reaction was then stopped by adding 0.09N H 2 S0 4 .

Abstract

Compounds of formula (I) are disclosed, as well as methods for synthesizing such compounds and methods of their use. Preferred compounds of formula (I) are potent inhibitors of c-MET/HGFR useful in the treatment of a variety of HGFR-mediated disorders, including cancers.

Description

Ether-Linked Heteroaryl Compounds Field of the Invention The invention relates to heteroaryl compounds useful as tyrosine kinase inhibitors. More particularly, the invention provides ether-linked heteroaryl compounds that are c-MET (HGFR) inhibitors. Such compounds are useful in the treatment of c-MET (HGFR) mediated disorders, such as cancers. Background The hepatocyte growth factor (HGF) receptor (c-MET or HGFR) receptor tyrosine kinase (RTK) has been shown in many human cancers to be involved in oncogenesis, tumor progression with enhanced cell motility and invasion, as well as metastasis (see, e.g., Ma, P.C., Maulik, G., Christensen, J. & Saigia, R. (2003b). Cancer Metastasis Rev, 22, 309-25; Maulik, G., Shrikhande, A„ Kijima, T., Ma, P.C., Morrison, P.T. & Saigia, R. (2002b). Cytokine Growth Factor Rev, 13, 41-59). c-MET (HGFR) can be activated through overexpression or mutations in various human cancers including small cell lung cancer (SCLC) (Ma, P.C., Kijima, T., Maulik, G., Fox, E.A., Sattler, M., Griffin, J.D., Johnson, B.E. & Saigia, R. (2003a). Cancer Res, 63, 6272-6281). c-MET is a receptor tyrosine kinase that is encoded by the Met proto-oncogene and transduces the biological effects of hepatocyte growth factor (HGF), which is also referred to as scatter factor (SF). Jiang et al., Crit. Rev. Oncol. Hematol. 29: 209-248 (1999). c-MET and HGF are expressed in numerous tissues, although their expression is normally confined predominantly to cells of epithelial and mesenchymal origin, respectively. c-MET and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation, and organization of 3-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.). In addition to its effects on epithelial cells, HGF/SF has been reported to be an angiogenic factor, and c-MET signaling in endothelial cells can induce many of the cellular responses necessary for angiogenesis (proliferation, motility, invasion). The c-MET receptor has been shown to be expressed in a number of human cancers. c-Met and its ligand, HGF, have also been shown to be co-expressed at elevated levels in a variety of human cancers (particularly sarcomas). However, because the receptor and ligand are usually expressed by different cell types, c-MET signaling is most commonly regulated by tumor-stroma (tumor-host) interactions. Furthermore, c-MET gene amplification, mutation, and rearrangement have been observed in a subset of human cancers. Families with germline mutations that activate c-MET kinase are prone to multiple kidney tumors as well as tumors in other tissues. Numerous studies have correlated the expression of c-MET and/or HGF/SF with the state of disease progression of different types of cancer
(including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin, and bone cancers). Furthermore, the overexpression of c-MET or HGF have been shown to correlate with poor prognosis and disease outcome in a number of major human cancers including lung, liver, gastric, and breast. c-MET has also been directly implicated in cancers without a successful treatment regimen such as pancreatic cancer, glioma, and hepatocellular carcinoma. For additional background information, see EP 860433, US 2004053908, WO 99/24440, WO 00/43366, WO 01/47890, WO 01/94353, WO 03/000194, WO 03/000660 and WO 03/106462. It would be desirable to have novel c-MET (HGFR) inhibitors, and methods of treating abnormal cell growth, such as cancers, using such compounds. Summary In one embodiment, the invention provides compounds of formula 1
Figure imgf000003_0001
wherein: L is N or CR5; when L is N, A represents a fused 5 or 6-membered aryl or heteroaryl group, and when L is CR5, A represents a fused 5-membered heteroaryl group; and each hydrogen in A is optionally substituted by an R6 group; X and Y are independently N or CR7; each R , R2, R3, R5 and R7 is independently hydrogen, halogen, Cι-C12 alkyl, C2-C12 alkenyl, C2-Cι2 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR8, -S02NR8R9, S(0)2ORB, -N02, -NRBRa,
Figure imgf000003_0002
-CN, -C(0)RB, -OC(0)RB -O(CR10R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8, -(CR10R11)nNCR8R9 -C(=NR10)NR8R9,
-NR8C(0)NR9R10, -NR8S(0)pR9 or -C(0)NR8R9, and each hydrogen in R1, R2, R3, R5 and R7 is optionally substituted by an R17 group; R6 is halogen, C^Cu* alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR8, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9,
-(CR10R11)nOR8 -CN, -C(0)R8, -OC(0)R8, -O(CR10R11)πR8, -NR8C(0)R9, (CR10R11)nC(O)OR8,
-(CR10R11)nNCR8R9, -C(=NR10)NR8R9, -NR8C(0)NR9R1°, -NR8S(0)pR9 or -C(0)NR8R9, and each hydrogen in R6 is optionally substituted by an R17 group; R4 is C Ci2 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, S(0)mR , -S02NR^R1d, -S^OR 112 -NO, -NR12R13,
-(CR14R15)nOR12, CN, -(CR14R15)πC(0)R12, -(CR14R15)nC(S)R12, -(CR14R15)nC(0)NR12R13, -(CR14R15)nC(S)NR12R13 -OC(0)R12, -0(CR14R15)nR12, -NR12C(0)R13, -(CR14R15)nC(0)OR12, -(CR14R15)nNCR1 R13, -C(=NR14)NR 2R13, -NR12C(0)NR13R14, -NR12S(0)pR13 or -C(0)NR12R13, and each hydrogen in R4 is optionally substituted by an R17 group; each R8, R9, R10 and Ri1 is independently hydrogen, halogen, CrC12 alkyl, C2-Cι2 alkenyl, C2-Cι2 alkynyl, C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R8, R9, R10 and R11 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R8, R9, R10 and R11 bound to the same carbon atom may be combined to form a C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R8, R9, R10 and Ri1 is optionally substituted by an R17 group; each R12, R13, R14 and R15 is independently hydrogen, halogen, C C12 alkyl, C2-C12 alkenyl, C2-
C12 alkynyl, C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R16 or -C(S)R16; or any two of R12, R13, R14 and R15 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5- 12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R12, R13, R 4 and R15 bound to the same carbon atom may be combined to form a C3- C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R12, R13, R14 and R15 is optionally substituted by an R17 group; R18 is hydrogen, halogen, C C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C 2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl; and each hydrogen in R16 is optionally substituted by an R17 group; each R17 is independently halogen, C1-C12 alkyl, C2-C12 alkenyl, C2-Cι2 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -0-CrC12 alkyl, -O- (CH2)nC3-C12 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)„(3-12 membered heteroalicyclic) or -0-(CH2)n(5- 12 membered heteroaryl); and each hydrogen in R17 is optionally substituted by an R18 group; each R18 is independently halogen, CrC12 alkyl, Cι-C12 alkoxy, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C1-Cι2 alkyl, -0-(CH2)nC3-C12 cycloalkyl, -O- (CH2)πC6-Cι2 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), -0-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R 8 is optionally substituted by a group selected from halogen, -OH, -CN, -C-M2 alkyl which may be partially or fully halogenated, -0-Cι-C12 alkyl which may be partially or fully halogenated, -CO, -SO and -S02; m is O, 1 or 2; n is O, 1 , 2, 3 or 4; and p is 1 or 2; or a pharmaceutically acceptable salt, solvate or hydrate thereof. In a particular aspect of this embodiment, R4 is C1-C12 alkyl, C2-C12 alkenyl, C2-Cι2 alkynyl, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR14R 5)nOR12, -(CR14R15)nC(0)R12, -(CR14R15)nC(S)R12, -(CR14R15)nC(0)NR12R13, -(CR14R15)nC(S)NR12R13,
-(CR14R15)nC(0)OR12, -(CR14R15)nNR1 R13, -C(=NR14)NR12R13, or -C(0)NR12R13, and each hydrogen in R4 is optionally substituted by an R17 group. In a particular aspect of this embodiment, each R17 is independently halogen, Cι-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, -C(0)R19, -C(0)OR19 -C(0)NR19R2°, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C1-C12 ajkyl, -0-(CH2)nC3-C12 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) or -0-(CH2)n(5-12 membered heteroaryl), and each hydrogen in R17 is optionally substituted by an R18 group, wherein each R18 is independently -H, halogen, C C12 alkyl, CrC12 alkoxy, C3-Cι2 cycloalkyl, C6-C12 aryl,
3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C Cι2 alkyl, -0-(CH2)nC3-Ci2 cycloalkyl, -0-(CH2)nC6-Cι2 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), or -0-(CH2)n(5-12 membered heteroaryl), and each R18 is optionally substituted by a group selected from halogen, -OH, -CN, -C1.12 alkyl which may be partially or fully halogenated, -0-C C12 alkyl which may be partially or fully halogenated, and -S03H; and each R19 and R20, which may be the same or different, is independently selected from -H, halogen, C^C^ alkyl, C^C^ alkoxy, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R19 and R20 is optionally substituted by a group selected from halogen, -OH, -CN, -Cι.12 alkyl which may be partially or fully halogenated, -0-C1-C12 alkyl which may be partially or fully halogenated, and -S03H, or R19 and R20, taken together with the nitrogen atom to which they are attached, may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R18 groups. In one embodiment, the invention provides compounds of formula 1
Figure imgf000005_0001
wherein: L is selected from N and CR5; when L is N, A represents a fused 5 or 6-membered aryl or heteroaryl group, and when L is CR5, A represents a fused 5-membered heteroaryl group; and A is optionally substituted by from 1-4 R6 groups; X and Y are independently selected from N and CR7'; R1, R2, R3, R5 and R7, which may be the same or different, are each independently selected from hydrogen, halogen, CrC12 alkyl, C2-C12 alkenyl, C2-Cι2 alkynyl, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)πOR8, -CN, -C(0)R8, -OC(0)R8, -O(CR10R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8, -(CR10R11)nNR8R9, -C(=NR10)NR8R9, -NR8C(0)NR9R10, and -C(0)NR8R9, wherein each of R1, R2, R3, R5 and R7 is optionally substituted by from 1 to 6 R17 groups; R6 is selected from halogen, CrC12 alkyl, C2-Cι2 alkenyl, C2-Cι2 alkynyl, C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)nOR8, -CN, -C(0)R8, -OC(0)R8, -O(CR10R11)πR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8, (CR D1l0u DR1111)nNR°Ra, -C(=NR ,110U). NR°RS, -NRBC(0)NRaR 1l0u, and -C(0)NRDRa, wherein each RD is optionally substituted by from 1 to 6 R ι17 g , roups; R4 is selected from -H, C C12 alkyl, C2-Cι2 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR14R15)nOR12, -(CR14R15)nC(0)R12,
-(CR14R15)nC(S)R12, -(CR 4R15)nC(0)NR12R13, -(CR14R1s)nC(S)NR12R13, "(CR14R15)nC(0)OR12,
Figure imgf000005_0002
and -C(0)NR 112'i DR113J, and each W is optionally substituted by from 1 to 6 R17 groups; each R8, R9, R10 and R11, which may be the same or different, is independently selected from hydrogen, halogen, CrC12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-12 membered heteroaryl; or any two of R8, R9, R10 and R11 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl ring optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R8, R9, R10 and R11 bound to the same carbon atom may be combined to form a C3-C12 cycloalkyl, C6-Cι aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring; and each of R8, R9, R10 and R11 is optionally substituted by from 1 to 6 R17 groups; each R12, R13, R14 and R15, which may be the same or different, is independently selected from hydrogen, halogen, CrC12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R16, and -C(S)R16; or any two of R 2, R13, R14 and R15 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl ring optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R12, R13, R14 and R15 bound to the same carbon atom may be combined to form a C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring; and each of R12, R13, R14 and R15 is optionally substituted by from 1 to 6 R17 groups; R16 is selected from hydrogen, halogen, Cι-Cι2 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R18, and - C(0)NR19R20; and each R16 is optionally substituted by from 1 to 6 R17 groups; each R17, which may be the same or different, is independently selected from halogen, CΪ-C^ alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-d2 aryl, -C(0)R19, -C(0)OR19 -C(0)NR19R20, 3-
12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C C12 alkyl, -0-(CH2)πC3-Cι2 cycloalkyl, -O- (CH2)nC6-Cι2 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) and -0-(CH2)n(5-12 membered heteroaryl), and each R17 is optionally substituted by from 1 to 6 R18 groups; each R18, which may be the same or different, is independently selected from -H, halogen, C C 2 alkyl, C Cι2 alkoxy, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C C12 alkyl, -0-(CH2)nC3-C12 cycloalkyl, -0-(CH2)πC6-Cι2 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), and -0-(CH2)n(5-12 membered heteroaryl), and each R18 is optionally substituted by a group selected from halogen, -OH, -CN, -Cι.12 alkyl which may be partially or fully halogenated, -0-Cι-Cι2 alkyl which may be partially or fully halogenated, and -S03H; each R19 and R20, which may be the same or different, is independently selected from -H, halogen, CrC12 alkyl, Cι-Cι2 alkoxy, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R19 and R20 is optionally substituted by a group selected from halogen, -OH, -CN, -C^2 alkyl which may be partially or fully halogenated, -0-CrCι2 alkyl which may be partially or fully halogenated, and -S03H; or R19 and R20, taken together with the nitrogen atom to which they are attached, may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R18 groups; and n is 0, 1 , 2, 3 or 4; or a pharmaceutically acceptable salt, solvate or hydrate thereof. In a particular aspect of this embodiment, and in combination with any other particular embodiment not inconsistent L is CR5. In another particular aspect of this embodiment, and in combination with any other particular embodiment not inconsistent, X is CR7. In another particular aspect of this embodiment, and in combination with any other particular embodiment not inconsistent, Y is CR7. In another particular aspect of this embodiment, and in combination with any other particular embodiment not inconsistent, L is CR5, X is CR7 and Y is CR7. In another particular aspect of this embodiment, and in combination with any other particular embodiment not inconsistent, L is N and Y is CR7. In another particular aspect of this embodiment, and in combination with any other particular embodiment not inconsistent, R6 is selected from 5-12 membered heteroaryl and -(CR1°R11)n0R8. In another particular aspect of this embodiment, and in combination with any other particular embodiment not inconsistent, R4 is selected from -(CR14R15)nC(0)R12, -(CR14R15)nC(S)R12, -(CR1 R15)nC(0)NR12R13 and -(CR1 R15)nC(S)NR12R13. > In another particular aspect of this embodiment, and in combination with any other particular embodiment not inconsistent, X is CR7, Y is CR7, R6 is selected from 5-12 membered heteroaryl and -(CR10R11)nOR8, and R4 is selected from -(CR14R15)nC(0)R12, -(CR14R15)nC(S)R12, -(CR14R15)nC(0)NR12R13 or -(CR1 R15)nC(S)NR12R13. In another particular aspect of this embodiment, and in combination with any other particular embodiment not inconsistent, each R7 is H. In another particular aspect of this embodiment and in combination with any other particular embodiment not inconsistent, R3 is H. In another particular aspect of this embodiment and in combination with any other particular 1 2 l embodiment not inconsistent, R and R , which may be the same or different, are independently selected from H and halogen. In another embodiment, the invention provides compounds of formula 2
Figure imgf000007_0001
wherein: X and Y are independently N or CR7; each R1, R2, R3 and R7 is independently hydrogen, halogen, CrC12 alkyl, C2-C12 alkenyl, C2-C1 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl,
-S(0)mR8, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)πOR8, -CN, -C(0)R8, -OC(0)R8
-O(CR10R11)nR8, -NRBC(0)Ra, -(CRπυR11)nC(0)OR -(CR10R11)nNCR8R9, -C(=NR 110U%)NRBR -NR8C(0)NR9R10, -NR8S(0)pR9 or -C(0)NR8R9, and each hydrogen in R1, R2, R3 and R7 is optionally substituted by an R 17 g . roup; R6 represents 1 , 2, 3 or 4 optional substituents selected from halogen, C C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR8, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R 1)nOR8, -CN, -C(0)R8, -OC(0)R8, -O(CR10R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8, -(CR10R11)nNCR8R9, -C(=NR10)NR8R9, -NR8C(0)NR9R10, -NR8S(0)pR9 and -C(0)NR8R9, and each hydrogen in R6 is optionally substituted by an R17 group; R4 is C Ci2 alkyl, C2-Cι2 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR12, -S02NR12R13, -S(0)20R12, -N02, -NR12R13, -(CR14R15)πOR12, -CN, -(CR14R15)nC(0)R12, -(CR14R15)nC(S)R12, -(CR14R15)nC(0)NR12R13, -(CR14R 5)nC(S)NR12R13, -OC(0)R12, -0(CR14R15)nR12, -NR12C(0)R13, -(CR14R15)nC(0)OR12, -(CR14R15)nNCR12R13, -C(=NR14)NR12R13, -NR12C(0)NR13R14, -NR12S(0)pR13, and -C(0)NR12R13, and hydrogen in R4 is optionally substituted by an R17 group; each R8, R9, R10 and R11 is independently hydrogen, halogen, C C12 alkyl, C2-C12 alkenyl, C2-Cι2 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R8, R9, R10 and R11 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R8, R9, R10 and R11 bound to the same carbon atom may be combined to form a C3-C 2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R8, R9, R10 and R11 is optionally substituted by an R17 group; each R12, R13, R14 and R15 is independently hydrogen, halogen, C Cι2 alkyl, C2-Cι2 alkenyl, C2-
C12 alkynyl, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R16 or -C(S)R16; or any two of R 2, R13, R14 and R15 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5- 12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R12, R13, R14 and R15 bound to the same carbon atom may be combined to form a C3- C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R12, R13, R14 and R15 is optionally substituted by an R17 group; R16 is hydrogen, halogen, C C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl; and each hydrogen in R16 is optionally substituted by an R17 group; each R17 is independently halogen, CrC12 alkyl, C2-C12 alkenyl, C2-C 2 alkynyl, C3-C-i2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -O-C1-C12 alkyl, -O- (CH2)nC3-C12 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) or -0-(CH2)n(5- 12 membered heteroaryl); and each hydrogen in R17 is optionally substituted by an R18 group; each R18 is independently halogen, CrC12 alkyl, &ι-C 2 alkoxy, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C Cι2 alkyl, -0-(CH2)nC3-C12 cycloalkyl, -O- (CH2)nC6-C12 aryl, -0-(CH2)π(3-12 membered heteroalicyclic), -0-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R18 is optionally substituted by a group selected from halogen, -OH, -CN, -0^2 alkyl which may be partially or fully halogenated, -0-C1-Cι2 alkyl which may be partially or fully halogenated, -CO, -SO and -S02; m is O, 1 or 2; n is O, 1 , 2, 3 or 4; and p is 1 or 2; or a pharmaceutically acceptable salt, solvate or hydrate thereof. In a particular aspect of this embodiment, R4 is C C12 alkyl, C2-C12 alkenyl, C2-Cι2 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR14R15)nOR12,
-(CR14R15)πC(0)R12, -(CR14R15)nC(S)R12, <CR14FπnC(0)NFr 12ιR-,13
Figure imgf000009_0001
-(CR14R15)nC(0)OR12, -(CR14R15)nNR 2R13, -C(=NR14)NR12R13, or -C(0)NR12R13, and each hydrogen in R4 is optionally substituted by an R17 group. In a particular aspect of this embodiment, each R17 is independently halogen, Cι-Cι2 alkyl, C2-Cι2 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, -C(0)R19, -C(0)OR19 -C(0)NR19R2°, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-Cι-Cι2 alkyl, -0-(CH2)nC3-Cι2 cycloalkyl, -0-(CH2)πC6-C12 aryl, -0-(CH2)„(3-12 membered heteroalicyclic) or -0-(CH2)n(5-12 membered heteroaryl), and each hydrogen in R17 is optionally substituted by an R18 group, wherein each R19 and R20, which may be the same or different, is independently selected from -H, halogen, C C12 alkyl, CrCι2 alkoxy, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R19 and R20 is optionally substituted by a group selected from halogen, -OH, -CN, -C1.12 alkyl which may be partially or fully halogenated, -0-CrCι2 alkyl which may be partially or fully halogenated, and -S03H, or R19 and R20, taken together with the nitrogen atom to which they are attached, may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R18 groups. In another embodiment, the invention provides compounds of formula 4
Figure imgf000009_0002
wherein: X and Y are independently N or CR7; each of R1, R2, R3 and R7, which may be the same or different, is independently selected from hydrogen, halogen, C1-Cι2 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)nOR8, -CN, -C(0)R8, -OC(0)R8, -O(CR10R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8, -(CR10R11)nNR8R9, -C(=NR10)NR8R9, -NR8C(0)NR9R1°, and -C(0)NR8R9, and each of R1, R2, R3 and R7 is optionally substituted by from 1 -6 R 17 g , roups; each R6, which may be the same or different, is independently selected from halogen, Cι-Cι2 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)nOR8, -CN, -C(0)R8, -OC(0)R8, -O(CR10R1 )πR8, -NR8C(0)R9, -(CR10R11)πC(O)OR8, -(CR10R11)nNR8R9, -C(=NR10)NR8R9, -NR8C(0)NR9R10, and -C(0)NR8R9, and each R6 is optionally substituted by from 1 to 6 R17 groups; R4 is CrC12 alkyl, C2-Cι2 alkenyl, C2-Cι2 alkynyl, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR14R15)n0R12, -(CR14R15)nC(0)R12, -(CR14R15)πC(S)R12, -(CR1 R15)nC(0)NR12R13, -(CR14R15)nC(S)NR12R13, -(CR14R15)nC(0)OR12, -(CR14R15)nNR12R13, -C(=NR14)NR12R13, or -C(0)NR12R13, and R4 is optionally substituted by from 1 to 6 R17 groups; each of R8, R9, R10 and R11, which may be the same or different, is independently selected from hydrogen, halogen, Cι-Cι2 alkyl, C2-Cι2 alkenyl, C2-C12 alkynyl, C3-C 2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, and 5-12 membered heteroaryl; or any two of R8, R9, R10 and R11 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl ring optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R8, R9, R10 and R11 bound to the same carbon atom may be combined to form a C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring; and each of R8, R9, R10 and R11 is optionally substituted by from 1-6 R17 groups; each R12, R13, R14 and R15 is independently hydrogen, halogen, Cι-C12 alkyl, C2-Cι2 alkenyl, C2- C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R16, and -C(S)R16; or any two of R12, R13, R14 and R15 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl ring optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R12, R13, R14 and R15 bound to the same carbon atom may be combined to form a C3-C-|2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring; and each hydrogen in R12, R13, R14 and R15 is optionally substituted by from 1 to 6 R17 group; each R18, which may be the same or different, is selected from hydrogen, halogen, C-[-C12 alkyl, C2-Cι2 alkenyl, C2-Cι2 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-12 membered heteroaryl; and each R16 is optionally substituted by from 1 to 6 R17 groups; each R17, which may be the same or different, is independently selected from halogen, C-ι-C12 alkyl, C2-Ci2 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, -C(0)R19, -C(0)OR19 -C(0)NR19R2°, 3- 12 membered heteroaiicyclic, 5-12 membered heteroaryl, -0-Cι-C12 alkyl, -0-(CH2)nC3-C12 cycloalkyl, -O- (CH2)nC6-Cι2 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) and -0-(CH2)n(5-12 membered heteroaryl), and each R17 is optionally substituted by from 1 to 6 R18 groups; each R18, which may be the same or different, is independently selected from -H, halogen, CrCι2 alkyl, Cι-C12 alkoxy, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -O-CrC^ alkyl, -0-(CH2)nC3-C12 cycloalkyl, -0-(CH2)nCβ-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), and -0-(CH2)n(5-12 membered heteroaryl), and each R18 is optionally substituted by a group selected from halogen, -OH, -CN, -Cι-12 alkyl which may be partially or fully halogenated, -0-CrCι2 alkyl which may be partially or fully halogenated, and -S03H; each R19 and R20, which may be the same or different, is independently selected from -H, halogen, C C12 alkyl, C Cι2 alkoxy, C3-C 2 cycloalkyl, Cβ-C12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R19 and R20 is optionally substituted by a group selected from halogen, -OH, -CN, -Cι.i2 alkyl which may be partially or fully halogenated, -0-CrC12 alkyl which may be partially or fully halogenated, and -S03H; or R19 and R20, taken together with the nitrogen atom to which they are attached, may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R18 groups; and n is O, 1, 2, 3 or 4; and q is 1 , 2, 3 or 4; or a pharmaceutically acceptable salt, solvate or hydrate thereof. In a particular aspect of this embodiment, Y is CR7. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, X is CR7. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, at least one R6 group is -(CR10R11)nOR8. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, at least two R6 groups are -(CR10R11)πOR8. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, R4 is selected from -(CR14R15)πC(0)R12, -(CR14R15)nC(S)R12, -(CR1 R15)nC(0)NR12R13 and -(CR14R15)nC(S)NR12R13. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, the compound has formula 2a
Figure imgf000011_0001
wherein Z1 is O or S and Z2 is O or S. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, the compound has formula 4a
Figure imgf000012_0001
wherein Z1 is O or S and Z2 is O or S. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, the compound has formula 2a, and Z1 is O and Z2 is O. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, the compound has formula 2a, and Z1 is O and Z2 is S. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, the compound has formula 2a, and Z1 is S and Z2 is O. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, the compound has formula 2a, and Z1 is S and Z2 is S. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, each R7 is H. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, R3 is H. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, R1 and R2 are independently H or halogen. In another embodiment, the invention provides a compound formula 3
Figure imgf000012_0002
wherein: X and Y are independently N or CR each R1, R2, R3, R5 and R7 is independently hydrogen, halogen, C-|-C12 alkyl, Ca-C 2 alkenyl, C2-
C12 alkynyl, C3-C-|2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR8, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)nOR8, -CN, -C(0)R8, -OC(0)R8, -O(CR10R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8, -(CR10R11)nNCR8R9, -C(=NR10)NR8R9, -NR8C(0)NR9R1°, -NR8S(0)pR9 or -C(0)NR8R9, and each hydrogen in R1, R2, R3, R5 and R7 is optionally substituted by an R17 group; R6 represents 1 or 2 optional substituents selected from halogen, CrC12 alkyl, C2-Cι alkenyl, C2- C12 alkynyl, C3-C12 cycloalkyl, C6-C-i2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR8, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)nOR8, -CN, -C(0)R8, -OC(0)R8, -O(CR10R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8, -(CR10R11)nNCR8R9, -C(=NR10)NR8R9, -NR8C(0)NR9R10, -NR8S(0)pR9 and -C(0)NR8R9, and each hydrogen in R6 is optionally substituted by an R17 group; R4 is C1-C12 alkyl, C2-C12 alkenyl, C2-C 2 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR12, -S02NR12R13, -S(0)2OR12, -N02, -NR12R13, -(CR14R15)πOR12, -CN, -(CR14R15)nC(0)R12, -(CR14R15)nC(S)R12, -(CR14R 5)nC(0)NR1 R13, -(CR14R15)nC(S)NR12R13, -OC(0)R12, -0(CR14R15)nR12, -NR12C(0)R13, -(CR14R15)nC(0)OR12, -(CR14R15)nNCR12R13, -C(=NR14)NR12R13, -NR12C(0)NR13R14, -NR12S(0)pR13 or -C(0)NR12R13, and each hydrogen in R4 is optionally substituted by an R17 group; each R8, R9, R 0 and R11 is independently hydrogen, halogen, Cι-Cι2 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C 2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R8, R9, R10 and R11 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R8, R9, R10 and R11 bound to the same carbon atom may be combined to form a C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R8, R9, R10 and R11 is optionally substituted by an R17 group; each R12, R13, R14 and R15 is independently hydrogen, halogen, C Cι2 alkyl, C2-C12 alkenyl, C2- Ci2 alkynyl, C3-C12 cycloalkyl, C6-C 2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R16 or -C(S)R16; or any two of R 2, R13, R14 and R15 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5- 12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R12, R13, R14 and R15 bound to the same carbon atom may be combined to form a C3- C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R12, R13, R14 and R15 is optionally substituted by an R17 group; R16 is hydrogen, halogen, C C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl; and each hydrogen in R16 is optionally substituted by an R 7 group; each R17 is independently halogen, CrC12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -0-C1-Cι2 alkyl, -O- (CH2)πC3-C12 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) or -0-(CH2)π(5- 12 membered heteroaryl); and each hydrogen in R17 is optionally substituted by an R18 group; each R18 is independently halogen, CrC12 alkyl, CrC12 alkoxy, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-CrC12 alkyl, -0-(CH2)nC3-C12 cycloalkyl, -O- (CH2)nC3-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), -0-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R18 is optionally substituted by a group selected from halogen, -OH, -CN, -CM 2 alkyl which may be partially or fully halogenated, -0-CrC1 alkyl which may be partially or fully halogenated, -CO, -SO and -S02; m is O, 1 or 2; n is 0, 1 , 2, 3 or 4; and p is 1 or 2; or a pharmaceutically acceptable salt, solvate or hydrate thereof. In a particular aspect of this embodiment, R4 is C1-C12 alkyl, C2-C12 alkenyl, C2-Cι2 alkynyl, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR14R15)nOR12, -(CR14R15)nC(0)R12, -(CR14R15)nC(S)R12, -(CR14R15)nC(0)NR12R13, -(CR1 R15)nC(S)NR12R13,
-(CR14R15)nC(0)OR12, -(CR14R15)nNR12R13, -C(=NR14)NR12R13, or -C(0)NR12R13, and each hydrogen in R4 is optionally substituted by an R17 group. In a particular aspect of this embodiment, each R17 is independently halogen, CrCι2 alkyl, C2-Cι2 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-C12 aryl, -C(0)R19, -C(0)OR19 -C(0)NR19R2°, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-CrC12 alkyl, -0-(CH2)nC3-Cι2 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) or -0-(CH2)n(5-12 membered heteroaryl), and each hydrogen in R17 is optionally substituted by an R18 group, wherein each R 8 is independently -H, halogen, Cι-C12 alkyl, CrC12 alkoxy, C3-C12 cycloalkyl, C6-C12 aryl,
3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -O-Ci-C^ alkyl, -0-(CH2)nC3-C12 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), or -0-(CH2)n(5-12 membered heteroaryl), and each R18 is optionally substituted by a group selected from halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -0-C1-C12 alkyl which may be partially or fully halogenated, and -S03H; and each R19 and R20, which may be the same or different, is independently selected from -H, halogen, CrCι2 alkyl, C C 2 alkoxy, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R19 and R20 is optionally substituted by a group selected from halogen, -OH, -CN, -Cι.12 alkyl which may be partially or fully halogenated, -0-Cι-Cι2 alkyl which may be partially or fully halogenated, and -S03H; or R19 and R20, taken together with the nitrogen atom to which they are attached, may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R18 groups. In another embodiment, the invention provides a compound formula 5
Figure imgf000015_0001
wherein: X and Y are independently N or CR7; each R1, R2, R3, R5 and R7, which may be the same or different, is independently selected from hydrogen, halogen, CrCι2 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR' -N02, -NR8R9,
-(CR10R11)nOR8 -CN, -C(0)RB, -OC(0)Ra,
Figure imgf000015_0002
-NR C(0)Ra, -(CRl R")nC(0)OR ,
-(CRιυRηι)nNRBRa, -C(=NRlu)NRBRa, -NRBC(0)NRaRlu, and -C(0)NRBRy, and each of Rη, R Rd, W and R7 is optionally substituted by from 1 to 6 R17 groups; each R6, which may be the same or different, is independently selected from halogen, C-ι-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)nOR8, -CN, -C(0)R8, -OC(0)R8,
-O(CR10R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8, -(CR10R11)nNCR8R9, -C(=NR10)NR8R9,
-NR8C(0)NR9R1°, and -C(0)NR8R9, and each R8 is optionally substituted by from 1 to 6 R17 groups; R4 is CrCι2 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C 2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR14R15)nOR12, -(CR14R15)nC(0)R12, -(CR14R15)nC(S)R12, -(CR14R15)πC(0)NR R13, -(CR14R15)nC(S)NR12R13, -(CR14R15)nC(0)OR12, -(CR14R15)nNR12R13, -C(=NR14)NR12R13, and -C(0)NR12R13, and each R4 is optionally substituted by from 1 to 6 R17 groups; each R8, R9, R10 and R11, which may be the same or different, is independently selected from hydrogen, halogen, C Cι2 alkyl, C2-C-i2 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-12 membered heteroaryl; or any two of R8, R9, R10 and R11 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R8, R9, R10 and R11 bound to the same carbon atom may be combined to form a C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered, heteroalicyclic or 5-12 membered heteroaryl group; and each R8, R9, R10 and R11 is optionally substituted by from 1 to 6 R17 groups; each R12, R13, R14 and R15, which may be the same or different, is independently selected from hydrogen, halogen, Cι-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R16 and -C(S)R16; or any two of R12, R13, R14 and R15 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R12, R13, R14 and R15 bound to the same carbon atom may be combined to form a C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each of R12, R13, R 4 and R15 is optionally substituted by from 1 to 6 R17 groups; each R16, which may be the same or different, is selected from hydrogen, halogen, C Cι2 alkyl,
C2-Cι2 alkenyl, C2-Cι2 alkynyl, C3-C-ι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl; and each R18 is optionally substituted by from 1 to 6 R17 groups; each R17, which may be the same or different, is independently selected from halogen, C Cι2 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, -C(0)R19, -C(0)OR19 -C(0)NR19R20, 3- 12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C Cι2 alkyl, -0-(CH2)nC3-Cι2 cycloalkyl, -O-
(CH2)πC6-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) and -0-(CH2)n(5-12 membered heteroaryl), and each R17 is optionally substituted by from 1 to 6 R18 groups; each R18, which may be the same or different, is independently selected from -H, halogen, C C12 alkyl, C1-C12 alkoxy, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-CrC12 alkyl, -0-(CH2)nC3-C12 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)π(3-12 membered heteroalicyclic), and -0-(CH2)π(5-12 membered heteroaryl), and each R18 is optionally substituted by a group selected from halogen, -OH, -CN, -C-M2 alkyl which may be partially or fully halogenated, -0-Cι-C12 alkyl which may be partially or fully halogenated, and -S03H; each R19 and R20, which may be the same or different, is independently selected from -H, halogen, CrCι2 alkyl, CrC12 alkoxy, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R19 and R20 is optionally substituted by a group selected from halogen, -OH, -CN, -Cι.12 alkyl which may be partially or fully halogenated, -0-GrC12 alkyl which may be partially or fully halogenated, and -S03H; or R19 and R20, taken together with the nitrogen atom to which they are attached, may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R18 groups; and n is 0, 1 , 2, 3 or 4; and /" q is 1, 2, 3 or 4; or a pharmaceutically acceptable salt, solvate or hydrate thereof. In a particular aspect of this embodiment, Y is CR7. In another particular aspect of this embodiment, and in combination with any other particular aspect not inconsistent, X is CR7. In another particular aspect of this embodiment, and in combination with any other particular aspect not inconsistent, R4 is selected from -(CR14R15)nC(0)R12, -(CR14R15)πC(S)R12, -(CR14R15)nC(0)NR12R13 and -(CR14R15)nC(S)NR12R13. In another particular aspect of this embodiment, and in combination with any other particular aspect not inconsistent, R4 is -C(0)NR12R13. In another particular aspect of this embodiment, and in combination with any other particular aspect not inconsistent, R4 is -C(S)NR12R13. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, each R7 is H. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, R3 is H. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, R1 and R2 are independently H or halogen. In another embodiment, the invention provides a compound selected from the group consisting of:
Figure imgf000017_0001
Figure imgf000017_0002
and pharmaceutically acceptable salts, solvates and hydrates thereof. ι In another embodiment, the invention provides a compound selected from the group consisting of:
Figure imgf000018_0001
and pharmaceutically acceptable salts, solvates and hydrates thereof. Preferred compounds of the invention include those having c-MET inhibitory activity as defined by any one or more of IC50, Ki, or percent inhibition (%l). One skilled in the art can readily determine if a compound has such activity by carrying out the appropriate assay, and descriptions of such assays are shown in the Examples section herein. In one embodiment, particularly preferred compounds have a c- MET IC50 of less than 10 μM, or less than 5 μM, or less than 3 μM. In another embodiment, particularly preferred compounds have a c-MET Ki of less than 5 μM or less than 2 μM, or less than 1 μM, or less than 500 nM. In another embodiment, particularly preferred compounds have a c-MET inhibition at 1 μM of at least 10% or at least 20% or at least 30% or at least 40% or at least 50% or at least 60% or at least 70% or at least 80% or at least 90%. Methods for measuring c-MET/HGFR activity are described in the Examples herein. In another embodiment, the invention provides a method of treating abnormal cell growth in a mammal, including a human, the method comprising administering to the mammal any of the pharmaceutical compositions of the invention. In a specific embodiment of any of the inventive methods described herein, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis. In another embodiment, the invention provides a method of treating an HGFR mediated disorder in a mammal, including a human, the method comprising administering to the mammal any of the pharmaceutical compositions of the invention. In further specific embodiments of any of the inventive methods described herein, the method further comprises administering to the mammal an amount of one or more substances selected from anti- tumor agents, anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth. Such substances include those disclosed in PCT Publication Nos. WO 00/38715, WO 00/38716, WO 00/38717, WO 00/38718, WO 00/38719, WO 00/38730, WO 00/38665, WO 00/37107 and WO 00/38786, the disclosures of which are incorporated herein by reference in their entireties. Examples of anti-tumor agents include mitotic inhibitors, for example vinca alkaloid derivatives such as vinblastine vinorelbine, vindescine and vincristine; colchines allochochine, halichondrine, N- benzoyltrimethyl-methyl ether colchicinic acid, dolastatin 10, maystansine, rhizoxine, taxanes such as taxol (paclitaxel), docetaxel (Taxotere), 2'-N-[3-(dimethylamino)propyl]glutaramate (taxol derivative), thiocholchicine, trityl cysteine, teniposide, methotrexate, azathioprine, fluorouricil, cytocine arabinoside, 2'2'- difluorodeoxycytidine (gemcitabine), adriamycin and mitamycin. Alkylating agents, for example cis-platin, carboplatin oxiplatin, iproplatin, Ethyl ester of N-acetyl-DL-sarcosyl-L-leucine (Asaley or Asalex), 1,4- cyclohexadiene-1 ,4-dicarbamic acid, 2,5 -bis(1-azirdinyl)-3,6-dioxo-, diethyl ester (diaziquone), 1 ,4- bis(methanesulfonyloxy)butane (bisulfan or leucosulfan) chlorozotocin, clomesone, cyanomorpholinodoxorubicin, cyclodisone, dianhydroglactitol, fluorodopan, hepsulfam, mitomycin C, hycantheonemitomycin C, mitozolamide, 1-(2-chloroethyl)-4-(3-chloropropyl)-piperazine dihydrochloride, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, teroxirone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard, bis(3-mesyloxypropyl)amine hydrochloride, mitomycin, nitrosoureas agents such as cyclohexyl-chloroethylnitrosourea, methylcyclohexyl-chloroet ylnitrosourea 1- (2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitroso-urea, bis(2-chloroethyl)nitrosourea, procarbazine, dacarbazine, nitrogen mustard-related compounds such as mechloroethamine, cyclophosphamide, ifosamide, melphalan, chlorambucil, estramustine sodium phosphate, strptozoin, and temozolamide. DNA anti-metabolites, for example 5-fluorouracil, cytosine arabinoside, hydroxyurea, 2-[(3hydroxy-2- pyrinodinyl)methylene]-hydrazinecarbothioamide, deoxyfluorouridine, 5-hydroxy-2-formylpyridine thiosemicarbazone, alpha-2'-deoxy-6-thioguanosine, aphidicolin glycinate, 5-azadeoxycytidine, beta- thioguanine deoxyriboside, cyclocytidine, guanazole, inosine glycodialdehyde, macbecin II, pyrazolimidazole, cladribine, pentostatin, thioguanine, mercaptopurine, bleomycin, 2-chlorodeoxyadenosine, inhibitors of thymidylate synthase such as raltitrexed and pemetrexed disodium, clofarabine, floxuridine and fludarabine. DNA RNA antimetabolites, for example, L-alanosine, 5-azacytidine, acivicin, aminopterin and derivatives thereof such as N-[2-chloro-5-[[(2, 4-diamino-5-methyl-6-quinazolinyl)methyl]amino]benzoyl]-L- aspartic acid, N-[4-[[(2, 4-diamino-5-ethyl-6-quinazolinyl)methyl]amino]benzoyl]-L-aspartic acid, N -[2-chloro- 4-[[(2, 4-diaminopteridinyl)methyl]amino]benzoyl]-L-aspartic acid, soluble Baker's antifol, dichloroallyl lawsone, brequinar, ftoraf, dihydro-5-azacytidine, methotrexate, N-(phosphonoacetyl)-L-aspartic acid tetrasodium salt, pyrazofuran, trimetrexate, plicamycin, actinomycin D, cryptophycin, and analogs such as cryptophycin-52 or, for example, one of the preferred 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; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; proteins, for example interferon; and anti-hormones, for example anti-estrogens such as NolvadexD (tamoxifen) or, for example anti-androgens such as Casodex™ (4'-cyano-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide). Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Anti-angiogenesis agents include MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix- metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931 ,788 (published July 28, 1999), WO 90/05719 (published May 331 , 1990), WO 99/52910 (published October 21 , 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT/IB98/01113 (filed July 21 , 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), Great Britain patent application number 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed August 12, 1999), United States Patent 5,863,949 (issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which are herein incorporated by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, 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). Examples of MMP inhibitors include AG-3340, RO 32-3555, RS 13-0830, and the following compounds: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]- propionic acid; 3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3- carboxylic acid hydroxyamide; (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3- methyl-piperidine-2-carboxyIic acid hydroxyamide; 4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]- tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1- hydroxycarbamoyl-cyclobutyl)-amino]-propionic acid; 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]- tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]- tetrahydro-pyran-3-carboxylic acid hydroxyamide; (2R, 3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)- benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)- benzehesulfonyl]-(1 -hydroxycarbamoyl-1 -methyl-ethyl)-amino]-propionic acid; 3-[[4-(4-fluoro-phenoxy)- benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic acid; 3-exo-3-[4-(4-chloro- phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1 ]octane-3-carboxylic acid hydroxyamide; 3-endo-3- t4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide; and pharmaceutically acceptable salts, solvates and hydrates thereof. Examples of signal transduction inhibitors include agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTIN™ (Genentech, Inc. of South San Francisco, California, USA). EGFR inhibitors are described in, for example in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998), and United States Patent 5,747,498 (issued May 5, 1998). EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, New York, USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck & Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusetts). VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, California, USA), can also be combined or co-administered with the composition. VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued August 11 , 1998), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22, 1998), all of which are herein incorporated by reference in their entirety. Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland, Washington, USA); anti-VEGF monoclonal antibody bevacizumab (Genentech, Inc. of South San Francisco, California); and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). ErbB2 receptor inhibitors, such as GW -282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), may be administered in combination with the composition. Such erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issued March 2, 1999), each of which is herein incorporated by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also described in United States Provisional Application No. 60/117,341 , filed January 27, 1999, and in United States Provisional Application No. 60/117,346, filed January 27, 1999, both of which are herein incorporated by reference in their entirety. Other antiproliferative agents that may be used include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following United States patent applications: 09/221946 (filed December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed February 9, 2000); 09/539930 (filed March 31, 2000); 09/202796 (filed May 22, 1997); 09/384339 (filed August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds disclosed and claimed in the following United States provisional patent applications: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21 , 2000); 60/168217 (filed November 30, 1999), and 60/200834 (filed May 1 , 2000). Each of the foregoing patent applications and provisional patent applications is herein incorporated by reference in their entirety. Compositions of the invention can also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors. Specific CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application 60/113,647 (filed December 23, 1998) which is herein incorporated by reference in its entirety. Definitions Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below. Variables defined in this section, such as R, X, n and the like, are for reference within this section only, and are not meant to have the save meaning as may be used outside of this definitions section. Further, many of the groups defined herein can be optionally substituted. The listing in this definitions section of typical substituents is exemplary and is not intended to limit the substituents defined elsewhere within this specification and claims. "Alkyl" refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms (i.e. C1-C12 alkyl), more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. "Lower alkyl" refers specifically to an alkyl group with 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, n- butyl, /so-butyl, fert-butyl, pentyl, and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, silyl, amino and -NRxRy, where Rx and Ry are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-member heteroalicyclic ring. "Cycloalkyl" refers to a 3 to 12 member all-carbon monocyclic ring (i.e. Ca-C! 2 cycloalkyl), an all- carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like. A cycloalkyl group may be substituted or unsubstituted. Typical substituent groups include alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O- carboxy, O-carbamyl, N-carbamyl, C-amido, N-amido, nitro, amino and -NRxRy, with Rx and Ry as defined above. Illustrative examples of cycloalkyl are derived from, but not limited to, the following:
Figure imgf000023_0001
and
"Alkenyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond (e.g. C2-Cι2 alkenyl). Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. "Alkynyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond (e.g. C2-Cι2 alkynyl). Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. "Aryl" refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system (i.e. C6-C-ι2 aryl). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and -NRxRy, with R and Ry as defined above. "Heteroaryl" refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, and S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole. The heteroaryl group may be substituted or unsubstituted. Typical substituents include alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, amino and -NRxRy with Rx and Ry as defined above. A pharmaceutically acceptable heteroaryl is one that is sufficiently stable to be attached to a compound of the invention, formulated into a pharmaceutical composition and subsequently administered to a patient in need thereof. Examples of typical monocyclic heteroaryl groups include, but are not limited to:
Figure imgf000025_0001
pyrrole furan thiophene pyrazole imidazole (pyrrolyl) (furanyl) (thiophenyl) (pyrazolyl) (imidazolyl)
Figure imgf000025_0002
i ff N is oxazole isothiazole thiazolyl 1 ,2,3-triazole (isoxazolyl) (oxazolyl) (isothiazolyl) (thiazolyl) (1 ,2,3-triazolyl)
Figure imgf000025_0003
1 ,3,4-triazole 1-oxa-2,3-diazole 1 -oxa-2,4-diazole 1-oxa-2,5-diazole (1 ,3,4-triazolyl) (1-oxa-2,3-diazolyl) (1 -oxa-2,4-diazolyl) (1-oxa-2,5-diazolyl)
Figure imgf000025_0004
1 -oxa-3,4-diazole 1-thia-2,3-diazole 1-thia-2,4-diazole 1-thia-2,5-diazole (1-oxa-3,4-diazolyl) (1-thia-2,3-diazolyl) (1-thia-2,4-diazolyl) (1-thia-2,5-diazolyl)
Figure imgf000025_0005
1-thia-3,4-diazole tetrazole pyridine pyridazine pyrimidine (1-thia-3,4-diazolyl) (tetrazolyl) (pyridinyl) (pyridazinyl) (pyrimidinyl)
Figure imgf000025_0006
pyrazme (pyrazinyl) Examples of suitable fused ring heteroaryl groups include, but are not limited to:
Figure imgf000026_0001
ben2θtria2θle pyrrolo[2,3-b]pyridine pyrrolo[2,3-c]pyridine pyrrolo[3,2-c]pyridine (ben2θtria2θlyl) (pyrrolo[2,3-b]pyridinyl) (pyrrolo[2,3-c]pyridinyl) (pyrrolo[3,2-c]pyridinyl)
Figure imgf000026_0002
pyrrolo[3,2-b]pyridine imida2θ[4,5-b]pyridine imida2θ[4,5-c]pyridine pyra2olo[4,3-d]pyridine (pyrrolo[3,2-b]pyridinyl) (imidazo[4,5-b]pyridinyl) (imidazo[4,5-c]pyridinyl) (pyra2olo[4,3-d]pyidinyl)
Figure imgf000026_0003
pyra2θlo[4,3-c]pyridine pyra2o!o[3,4-c]pyridine pyra2θlo[3,4-b]pyridine isoindole
(pyrazolo[4,3-c]pyidinyl) (pyra2θlo[3,4-c]pyidinyl) (pyra2θIo[3,4-b]pyidinyl) (isoindolyl)
Figure imgf000026_0004
inda∑ole purine indolizine imidazo[1 ,2-a]pyridine imida2o[1 ,5-a]pyridine (inda∑olyl) (purinyl) (indolininyl) (imida20[1 ,2-a]pyridinyl) (imida2o[1 ,5-a]pyridinyl)
Figure imgf000026_0005
pyra2olo[1 ,5-a]pyridine pyrrolo[1 ,2-b]pyrida2ine imida2o[1 ,2-c]pyrimidine (pyra2θlo[1 ,5-a]pyridinyl) (pyrrolo[1-2,b]pyrida2inyl) (imida2o[1 ,2-cJpyrimidinyl)
Figure imgf000027_0001
quinoline soquinoline cinnoline (quinolinyl) (isoquinolinyl) (cinnolinyl) (azaquinazoline)
Figure imgf000027_0002
quinoxaline phthalazine 1 ,6-naphthyridine 1 ,7-naphthyridine (quinoxalinyl) (phthalazinyl) (1 ,6-naphthyridinyl) (1 ,7-naphthyridinyl)
Figure imgf000027_0003
1 ,8-naphthyridine 1 ,5-naphthyridine 2,6-naphthyridine 2,7-naphthyridine (1 ,8-naphthyridinyl) (1 ,5-naphthyridinyl) (2,6-naphthyridinyl) (2,7-naphthyridinyl)
Figure imgf000027_0004
pyrido[3,2-d]pyrimidine pyrido[4,3-d]pyrimidine pyrido[3,4-d]pyrimidine (pyrido[3,2-d]pyrimidinyl) (pyrido[4,3-d]pyrimidinyl) (pyrido[3,4-d]pyrimidinyl)
Figure imgf000027_0005
pyrido[2,3-d]pyrimidine pyrido[2,3-b]pyrazine pyrido[3,4-b]pyrazine (pyrido[2,3-d]pyrimidinyl) (pyrido[2,3-b]pyrazinyl) (pyrido[3,4-b]pyrazinyl)
Figure imgf000027_0006
pyrimido[5,4-d]pyrimidine pyrazino[2,3-b]pyrazine pyrimidot4,5-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl) (pyrazino[2,3-b]pyrazinyl) (pyrimido[4,5-d]pyrimidinyl) "Heteroalicyclic" or "heterocycle" refers to a monocyclic or fused ring group having in the ring(s) of 3 to 12 ring atoms, in which one or two ring atoms are heteroatoms selected from N, O, and S(0)n (where n is 0, 1 or 2), the remaining ring atoms being C. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Examples of suitable saturated heteroalicyclic groups include, but are not limited to: H Δ Δ N D° Ds DN oxirane thiarane aziridine oxetane thiatane azetidine tetrahyd Orofuran (oxiranyl) (thiaranyl) (aziridinyl) (oxetanyl) (thiatanyl) (azetidinyl) (tetrahydrofuranyl)
Figure imgf000028_0001
tetrahyd orothiophene pyrrolidine tetrahy ropyran tetra ydrothiopyran (tetrahydrothiophenyl) (pyrrolidinyl) (tetrahydropyranyl) (tetrahydrothiopyranyl)
Figure imgf000028_0002
piperidine 1 ,4-dioxane 1 ,4-oxathiane morpholine 1 ,4-dithiane (piperidinyl) (1 ,4-dioxanyl) (1 ,4-oxathianyl) (morpholinyl) (1 ,4-dithianyl)
Figure imgf000028_0003
piperazine 1 ,4-azathiane oxepane thiepane azepane (piperazinyl) (1 ,4-azathianyl) (oxepanyl) (thiepanyl) (azepanyl)
Figure imgf000028_0004
1 ,4-dioxepane 1 ,4-oxathiepane 1 ,4-oxaazepane 1 ,4-dithiepane (1 ,4-dioxepanyl) (1 ,4-oxathiepanyl) (1 ,4-oxaazepanyl) (1 ,4-dithiepanyl)
Figure imgf000028_0005
1 ,4-thieazepane 1 ,4-diazepane (1 ,4-thieazepanyl) (1 ,4-diazepanyl) Examples of suitable partially unsaturated heteroalicyclic groups include, but are not limited to:
Figure imgf000029_0001
3,4-dihydro-2H-pyran 5,6-di ydro-2H-pyran 2H-pyran (3,4-dihydro-2H-pyranyl) (5,6-dihydro-2H-pyranyl) (2H-pyranyl)
Figure imgf000029_0002
1 ,2,3,4-tetrahydropyridine 1 ,2,5,6-tetrahydropyridine (1 ,2,3,4-tetrahydropyridinyl) (1 ,2,5,6-tθtrahydropyridinyl) The heterocycle group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, or mono or dialkylamino. "Hydroxy" refers to an -OH group. "Alkoxy" refers to both an -O-(alkyl) or an -0-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "Haloalkoxy" refers to an -O-(haloalkyl) group. Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like. "Aryloxy" refers to an -O-aryl or an -O-heteroaryl group, as defined herein. Representative examples 'include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof. "Mercapto" refers to an -SH group. "Alkylthio" refers to an -S-(alkyl) or an -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. "Arylthio" refers to an -S-aryl or an -S-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like and derivatives thereof. "Acyl" or "carbonyl" refers to a -C(0)R" group, where R" is selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halo and -NRxRy groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substitutents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NRxRy groups and heteroalicyclic (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NRxRy groups. Representative acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like "Aldehyde" refers to an acyl group in which R" is hydrogen. "Thioacyl" or "thiocarbonyl" refers to a -C(S)R" group, with R" as defined above. A "thiocarbonyl" group refers to a -C(S)R" group, with R" as defined above. A "C-carboxy" group refers to a -C(0)OR" group, with R" as defined above. An "O-carboxy" group refers to a -OC(0)R" group, with R" as defined above. "Ester" refers to a -C(0)OR" group with R" as defined herein except that R" cannot be hydrogen. "Acetyl" group refers to a -C(0)CH3 group. "Halo" group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. "Trihalomethyl" group refers to a methyl group having three halo substituents, such as a trifluoromethyl group. , "Cyano" refers to a -C≡N group. A "sulfinyl" group refers to a -S(0)R" group wherein, in addition to being as defined above, R" may also be a hydroxy group. A "sulfonyl" group refers to a -S(0)2R" group wherein, in addition to being as defined above, R" may also be a hydroxy group. "S-sulfonamido" refers to a -S(0)2NRxRy group, with Rx and Ry as defined above. "N-sulfonamido" refers to a -NRxS(0)2Ry group, with Rx and Ry as defined above. "O-carbamyl" group refers to a -OC(0)NR Ry group with Rx and Ry as defined above. "N-carbamyl" refers to an RyOC(0)NRx- group, with Rx and Ry as defined above. "O-thiocarbamyl" refers to a -OC(S)NRxRy group with Rx and Ry as defined above. "N-thiocarbamyl" refers to a RyOC(S)NRx- group, with Ry and Rx as defined above. "Amino" refers to an -NRxRy group, wherein Rx and Ry are both hydrogen. "C-amido" refers to a -C(0)NRxRy group with Rx and Ry as defined above. "N-amido" refers to a RxC(0)NRy- group, with Rx and Ry as defined above. "Nitro" refers to a -N02 group. "Haloalkyl" means an alkyl, preferably lower alkyl, that is substituted with one or more same or different halo atoms, e.g., -CH2CI, -CF3, -CH2CF3, -CH2CCI3, and the like. "Hydroxyalkyl" means an alkyl, preferably lower alkyl, that is substituted with one, two, or three hydroxy groups; e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1 ,2-, 1,3-, or ,3-dihydroxypropyl, and the like. "Aralkyl" means alkyl, preferably lower alkyl, that is substituted with an aryl group as defined above; e.g., -CH2phenyl, -(CH2)2phenyl, -(CH2)3phenyl, CH3CH(CH3)CH2phenyl,and the like and derivatives thereof. "Heteroaralkyl" group means alkyl, preferably lower alkyl, that is substituted with a heteroaryl group; e.g., -CH2pyridinyl, -(CH2)2pyrimidinyl, -(CH2)3imidazolyl, and the like, and derivatives thereof. "Monoalkylamino" means a radical -NHR where R is an alkyl or unsubstituted cycloalkyl group; e.g., methylamino, (1 -methylethyl)amino, cyclohexylamino, and the like. "Dialkylamino" means a radical -NRR where each R is independently an alkyl or unsubstituted cycloalkyl group; dimethylamino, diethylamino, (l-methylethyl)-ethylamino, cyclohexylmethylamino, cyclopentylmethylamino, and the like. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocycle group optionally substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group. A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. As used herein, a "physiologically/pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. A "pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the parent compound. Such salts include: (i) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. "PK" refers to receptor protein tyrosine kinase (RTKs), non-receptor or "cellular" tyrosine kinase (CTKs) and serine-threonine kinases (STKs). "Modulation" or "modulating" refers to the alteration of the catalytic activity of RTKs, CTKs and
STKs. In particular, modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTK, CTK or STK is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs. "Catalytic activity" refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs. "Contacting" refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly, i.e., by interacting with the kinase itself, or indirectly, i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent. Such "contacting" can be accomplished "in vitro," i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a PK related disorder, i.e., the IC50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques. "In vitro" refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium. "In vivo" refers to procedures performed within a living organism such as, without limitation, a mouse, rat or rabbit. "PK related disorder," "PK driven disorder," and "abnormal PK activity" all refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs, (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth. Over-activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases). Under-activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases. "Treat", "treating" and "treatment" refer to a method of alleviating or abrogating a PK mediated cellular disorder and/or its attendant symptoms. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced. "Organism" refers to any living entity comprised of at least one cell. A living organism can be as simple as, for example, a single eukariotic cell or as complex as a mammal, including a human being. "Therapeutically effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has at least one of the following effects: (1 ) reducing the size of the tumor; (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis; (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer. "Monitoring" means observing or detecting the effect of contacting a compound with a cell expressing a particular PK. The observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a natural binding partner. Techniques for observing or detecting such effects are well-known in the art. The effect is selected from a change or an absence of change in a cell phenotype, a change or absence of change in the catalytic activity of said protein kinase or a change or absence of change in the interaction of said protein kinase with a natural binding partner in a final aspect of this invention. "Cell phenotype" refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known in the art. "Natural binding partner" refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role in propagating a signal in a PK-mediated signal transduction process. A change in the interaction of the natural binding partner with the PK can manifest itself as an increased or decreased concentration of the PK/natural binding partner complex and, as a result, in an observable change in the ability of the PK to mediate signal transduction. Detailed Description Compounds of the invention can be prepared according to the following general scheme:
Figure imgf000033_0001
Compounds of formula 10 can be obtained commercially, synthesized according to methods known in the art, or prepared as described in the Examples herein. To prepare compounds of formula 1a, wherein the aryl group of the O-aryl moiety is a phenyl group (i.e., L is CR5 in formula 1 described above), the heteroaryl chloride 10 is reacted with a p-aminophenol to form the corresponding amine 11. The reaction is conveniently carried out in a polar aprotic solvent. An aprotic solvent is any solvent that, under normal reaction conditions, does not donate a proton to a solute. Polar solvents are those which have a non-uniform distribution of charge. Generally they include 1 to 3 heteroatoms such as N, S or O. Examples of polar aprotic solvents that can be used in the process are ethers such as tetrahydrofuran, diethylether, methyl tert-butyl ether; nitrile solvents such as acetonitrile; dimethylsulfoxide (DMSO); and amide solvents such as dimethylformamide. Mixtures of solvents may also be used. Both compounds 10 and the aminophenol are introduced into a reaction vessel together with the solvent. The reactants may be added in any order. A reactant concentration of 0.1 to 0.5 mol/L is typical, although one skilled in the art will appreciate that the reaction may be conducted at different concentrations. The reaction may be conducted at a temperature of 0 °C up to the reflux temperature of the solvent, and may be catalyzed by, for example, palladium, or in situ-formed palladium complex, or uncatalyzed. The progress of the reaction may be monitored by a suitable analytical method, such as HPLC, TLC, LC/MS or NMR. The amine 11 may be separated from the reaction mixture by methods known to those skilled in the art, such as, for example, crystallization, extractive workup and chromatography. The compounds of formula 1a are easily formed from the amine 11 by reacting with the appropriate R4-containing reagent under conditions suitable to replace a hydrogen on the primary amine group in 11 by R4. For example, when R4 is a group of formula -C(0)NR12R13 or -C(S)NR1 R13, the compound of formula 1 a is formed by reacting the compound of formula 11 with the corresponding R4 isocyanate or thiocyanate in a suitable solvent, such as any of the polar aprotic solvents described above. Similarly, when R4 is a group of formula -C(0)R 2R13, the compound of formula 1a is formed by reacting the compound of formula 11 with the corresponding R4 carboxylic acid or acid chloride in a suitable solvent, such as any of the polar aprotic solvents described above. As a further example, when R4 is an alkyl or substituted alkyl, the compound of formula 1a is formed by reacting the compound of formula 11 with the corresponding R4 reagent containing a halogen, or a mesolate, or a tosylate, in a suitable solvent, such as any of the polar aprotic solvents described above. Suitable R4 groups for such alkylation reaction include d.12 alkyl, C3.12 cycloalkyl, -(CR R15)πOR12 (n = 2-4), -(CR14R15)nC(0)R12 (n = 1-4) and - (CR14R15)πC(S)R12 (n = 1-4). As yet a further example, when R4 is a group of formula -S(0)mR12 or - S02NR12R13, the compound of formula 1a is formed by reacting the compound of formula 11 with the corresponding R4 sulfonyl chloride. Preferred polar aprotic solvents include halogenated solvents, such as methylene chloride or chlorobenzene. One skilled in the art can readily determine the appropriate R4- containing reagent and appropriate conditions, based on the structure of R4. To prepare compounds of formula 1b, the reaction first proceeds through the chloropyridine compound 12 by reacting the compound of formula 10 with a 2-chloro-5-hydroxypyridine in a polar aprotic solvent such as those described above. The resulting compound 12 is then converted to the corresponding amine 13 by reaction with the appropriate amine, protected amine, or amine equivalent. The reaction may be conducted at a temperature of from ambient temperature up to the reflux temperature of the solvent, and may be catalyzed by, for example, palladium, or in situ-formed palladium complex, or uncatalyzed. The progress of the reaction may be monitored by a suitable analytical method, such as HPLC, TLC, LC/MS or NMR. the amine 13 may be separated from the reaction mixture by methods known to those skilled in the art, such as, for example, crystallization, extractive workup or chromatography. The compound of formula 1b is readily formed from the compound of formula 13 in the same manner as described above for compound 1a. Further exemplary information for synthesizing compounds of the invention can be found in the Examples herein. Unless indicated otherwise, all references herein to the inventive compounds include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including poiymorphs, stereoisomers, and isotopically labeled versions thereof. Pharmaceutically acceptable salts include acid addition and base salts (including disalts). Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002), the disclosure of which is incorporated herein by reference in its entirety. A pharmaceutically acceptable salt of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when the solvent is water. Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6-DMSO. Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975), the disclosure of which is incorporated herein by reference in its entirety. Also within the scope of the invention are polymorphs, prodrugs, and isomers (including optical, geometric and tautomeric isomers) of the inventive compounds Derivatives of compounds of the invention which may have little or no pharmacological activity themselves but can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties. Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the inventive compounds with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety. Some examples of prodrugs in accordance with the invention include: > (i) where the compound contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (d-CaJalkyl; (ii) where the compound contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (CrCβJalkanoyloxymethyl; and (iii) where the compound contains a primary or secondary amino functionality (-NH2 or -NHR where R ≠ H), an amide thereof, for example, replacement of one or both hydrogens with (Cr C-io)alkanoyl. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references. Finally, certain inventive compounds may themselves act as prodrugs of other of the inventive compounds. Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. A single compound may exhibit more than one type of isomerism. Included within the scope of the invention are ail stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine.
Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New
York, 1994), the disclosure of which is incorporated herein by reference in its entirety. The invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 3N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon-14, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6-DMSO. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. The compounds can be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety. Oral Administration The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano- particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V\_ (6), 981-986 by Liang and
Chen (2001), the disclosure of which is incorporated herein by reference in its entirety. For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from
1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
The final formulation may include one or more layers and may be coated or uncoated; or encapsulated. The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol.
1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma er a/, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties. Parenteral Administration The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres. Topical Administration The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free {e.g. Powderject™, Bioject™, etc.) injection. The disclosures of these references are incorporated herein by reference in their entireties. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Inhaled/lntranasal Administration The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying. Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 μL to 100μL. A typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing a desired mount of the compound of the invention. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.
Rectal/lntravaqinal Administration Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Ocular Administration Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. Other Technologies Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties. Dosage The amount of the active compound administered will be dependent on the subject being 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 typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/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 used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day. Kit-of-Parts Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid.
Examples Materials: If not indicated otherwise, reagents were obtained from commercial suppliers, or synthesized according to synthetic procedures available in the literature. Abbreviations and Acronyms: As used in the Examples herein, 'TEA" is triethylamine; "Et" is ethyl; "Ac" is an acetyl group; "EtOAc" is ethyl acetate; "HOAc" is acetic acid; "THF" is tetrahydrofuran; "DIEA" is N,N- diisopropylethylamine; "DMSO" is dimethylsulfoxide; and "EtOH" is ethyl alcohol. 4-chloro-6.7-dimethoxyguinoline:
Figure imgf000042_0001
was prepared according to the following scheme, described in detail below:
Figure imgf000042_0002
Microvave
Ethyl 4-hvdroxy-6,7-dimethoxyQuinoline-3-carboxylate:
Figure imgf000043_0001
3,4-Dimethoxyaniline (5g, 32 mmol) and diethyl (ethoxymethylene) malonate (10 mL, 50 mmol) were added to a 250 mL round bottom flask and heated in an oil bath. When the temperature of oil bath reached about 135 °C, EtOH was generated and collected with a condenser. The reaction was heated at 150 °C for 40 minutes to give A. The reaction flask was removed from the oil bath. Phenyl ether (about two times volume of the reaction mixture) was added into the flask. The reaction flask was placed in the oil bath, which was preheated to 270 °C. The reaction mixture was stirred and heated to 272 °C for 15 minutes (the temperature of inside the flask was 241 °C). The reaction flask was removed from heating and reaction mixture was slowly poured into Acetone (1 L). The mixture was stirred at room temperature for about one hour. Ethyl 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylate was precipitated and collected by filtration. The compound was washed by acetone (to remove phenyl ether) and dried (2.75g, 31%); 1H NMR (400 MHz, DMSO- 6) δ ppm 1.26 (t, =7.1 Hz, 3 H) 3.83 (s, 3 H) 3.87 (s, 3 H) 4.18 (q, J=7.1 Hz, 2 H) 7.05 (s, 1 H) 7.50 (s, 1 H) 8.43 (s, 1 H) 12.08 (s, 1 H). 6.7-DimethoxyQuinolin-4-ol:
Figure imgf000043_0002
Ethyl 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylate (700 mg, 2.53 mmol) was added into a solution of potassium hydroxide (450 mg, 7.6 mmol) in 20 mL of H20/EtOH (1:1 ; v:v). This mixture was placed in a sealed vessel (XP-500 Plus vessel) and heated by microwave (MARS 5 Microwave System) at 180°C, under 260-280 psi pressure for 50 minutes. The reaction mixture was cooled to room temperature and transferred into a flask. The solution was then acidified with HOAc (about 2 mL) to pH about 6, saturated with NaCI and extracted with THF (3 x 100 mL). The combined oil layers were washed with brine and concentrated to give 6,7-dimethoxyquinolin-4-ol (90% yield); 1H NMR (400 MHz, DMSO-oB) δ ppm 3.81 (s, 3 H) 3.84 (s, 3 H) 5.93 (d, J=7.3 Hz, 1 H) 7.05 (s, 1 H) 7.42 (s, 1 H) 7.76 (d, J=7.3 Hz, 1 H). 4-chloro-6,7-dimethoxyguinoline: 6,7-Dimethoxyquinolin-4-ol (0.64g) was dissolved in net POCI3 (3 mL). The solution was heated to
125°C for 2 h. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was basified with sat. NaHC03 (aq) and then extracted with EtOAc. The organic layer was dried over Na2S0 , filtered, and concentrated. The residue was purified by column chromatography using 10→20% methanol/EtOAc to give 4-chloro-6,7-dimethoxyquinoline (0.38 g, 55% yield); 1H NMR (400 MHz, CHCI3- d) δ ppm 4.04 (s, 3 H) 4.06 (s, 3 H) 7.35 (d, J=5.1 Hz, 1 H) 7.40 (s, 1 H) 7.42 (s, 1 H) 8.57 (d, =4.8 Hz, 1
H). 4-r(6-chloropyridin-3-yl)oxyl-6.7-dimethoχyguinoline:
Figure imgf000044_0001
2-chloro-5-hydroxypyridine (310 mg, 2.3 mmol) and TEA (5 mL, 28.7 mmol) were added sequentially to a stirred solution of 4-chloro-6,7-dimethoxyquinoline (354 mg, 1.58 mmol) in chlorobenzene (3 mL). The resulting solution was heated to 140 °C for 12 h. The reaction mixture was quenched with H20 (100 mL), and EtOAc (2 x 100 mL) was added to extract the aqueous solution. The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eiuting with 0→10% CH3OH in EtOAc) to give 4-[(6-chloropyridin-3- yl)oxy]-6,7-dimethoxyquinoline as a light brown yellow oil (324.2 mg; 1.02 mmol; 64.8% yield); MS (APCI) (M+H)+ 317. 1H NMR (400 MHz, CDCI3) δ ppm 4.00 (s, 3 H) 4.01 (s, 3 H) 6.45 (d, =5.3 Hz, 1 H) 7.44 (m, 4 H) 8.32 (d, J=2.5 Hz, 1 H) 8.51 (d, J=5Λ Hz, 1 H). 5-r(6.7-dimethoxyguinolin-4-yl)oxylpyridin-2-amine:
Figure imgf000044_0002
Lithium hexamethyldisilazide (1.5 mL, 1.5 mmol), tris(dibenzylideneacetone) dipalladium (0) chloroform adduct (54 mg, 0.052 mmol), and 2-(dicyclohexylphosphino) biphenyl (45 mg, 0.12 mmol) were added sequentially to a stirred solution of 4-[(6-chloropyridin-3-yl)oxy]-6,7-dimethoxyquinoline (324.4 mg, 1.02 mmol) in THF (3 mL) under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 12 h and then 2 M HCl (17 mL) was added and the mixture was stirred for an additional 2 h. The reaction mixture was neutralized with Na2C03 and then extracted with THF (2 x 100 mL). The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eiuting with 10→20% CH3OH in EtOAc) to give 5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-amine as a light brown foam (177.4 mg; 0.60 mmol; 59% yield); MS (APCI) (M+H)+ 298. 1H NMR (400 MHz, CDCI3) δ ppm 4.03 (s, 3 H) 4.03 (s, 3 H) 4.74 (s, 2 H) 6.40 (d, J=5.3 Hz, 1 H) 6.59 (d, J=8.8 Hz, 1 H) 7.29 (m, 1 H) 7.43 (s, 1 H) 7.53 (s, 1 H) 7.98 (s, 1 H) 8.46 (d, J=5.1 Hz, 1 H). 7-chlorothienor3.2-άlpyhdine:
Figure imgf000044_0003
7-Chlorothieno[3,2-b]pyridine was prepared and isolated as described in J. Heterocycle Chemistry (1985), 22(5), 1249-1252 (Klemm, L. H. et al.), the disclosure of which is incorporated herein by reference in its entirety. 7-(2-fluoro-4-nitrophenoxy)thienor3,2-ι_>lpyridine:
Figure imgf000045_0001
2-fluoro-4-nitrophenol (710 mg, 4.5 mmol) and DIEA (10 mL, 57 mmol) were added sequentially to a stirred solution of 7-chlorothieno[3,2-_7]pyridine (500 mg, 2.95 mmol) in chlorobenzene (6 mL). The resulting solution was heated to 140 °C for 12 h. The reaction mixture was quenched with H20 (100 mL), and EtOAc (2 x 100 mL) was added to extract the aqueous solution. The combined organic layers were dried over Na2S0 then concentrated under vacuum. The residue was purified by flash chromatography (eiuting with 40-→50% EtOAc in hexanes) to give 7-(2-fluoro-4-nitrophenoxy)thieno[3,2-ό]pyridine as a yellow oil (43.5 mg; 0.15 mmol; 5% yield); MS (APCI) (M+H)+ 291. 1H NMR (400 MHz, CDCI3) δ ppm 6.64 (d, J=5.3 Hz, 1 H) 7.37 (m, 1 H) 7.61 (d, J=5.3 Hz, 1 H) 7.80 (d, J=5.6 Hz, 1 H) 8.f5 (m, 2 H) 8.60 (d, J=5.31 Hz, 1 H). r3-fluoro-4-(thieno[3,2-ά1pyhdin-7-yloxy)phenyllamine:
Figure imgf000045_0002
Procedure A: Palladium (0.02 g, 5% on activated carbon) was added to a stirred solution of 7-(2-fluoro-4- nitrophenoxy)thieno[3,2-/b]pyridine (43.5 mg, 0.15 mmol) in EtOAc (15 mL) at room temperature. The resulting suspension was stirred for 12 h under H atmosphere. The reaction mixture was filtered through a bed of celite and the filtrate was evaporated to give [3-fluoro-4-(thieno[3,2-_}]pyridin-7- yloxy)phenyl]amine as a light brown yellow oil (37.2 mg; 0.143 mmol; 95.3%). This compound was used in Example 2 without further purification. Procedure B: 4-Amino-2-fluorophenol (see below) (152 mg, 1.20 mmol) and cesium carbonate (974 mg, 2.99 mmol) were added sequentially to a stirred solution of 7-chlorothieno[3,2-b]pyridine (169 mg, 0.996 mmol) in DMSO (2 mL). The reaction mixture was microwaved at 150 °C for 30 min using Smithsynthesizer. H20 (20 mL) was poured to the mixture stir and EtOAc (2 x 20 mL) was added to extract the aqueous solution. The combined organic layers were dried (Na2S04), filtered and concentrated to give a tan oil residue. The residue was purified by preparative thin layer chromatography (50% EtOAc in Hexanes) to give afford [3-fluoro-4-(thieno[3,2-ό]pyridin-7-yloxy)phenyl]amine as tan oil (96 mg; 0.369 mmol; 37% yield); MS (APCI) (M+H)+ 261. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.59 (s, 2 H), 6.51 (ddd, J= 8.6, 2.5, 0.8 Hz, 1 H), 6.60 (dd, J= 13.1 , 2.5 Hz, 1 H), 6.64 (d, J= 6.6 Hz, 1 H), 7.16 (t, J= 9.1 Hz, 1 H), 7.64 (d, J = 5.6 Hz, 1 H), 8.20 (d, J= 5.3 Hz, 1 H), 8.56 (d, J = 5.6 Hz, 1 H). 4-(thienor3,2-blpyridin-7-yloxy)phenylamine:
Figure imgf000045_0003
4-Aminophenol hydrochloride (400 mg, 2.7 mmol) and cesium carbonate (2.6 g, 8 mmol) were added sequentially to a stirred solution of 7-chlorothieno[3,2-fr]pyridine (500 mg, 2.95 mmol) in DMSO (3 mL). The reaction mixture was microwaved at 150 °C for 30 min using Smithsynthesizer. The mixture was poured into H20 (100 mL) to stir and EtOAc (2 x 100 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered and concentrated to give a brown oil residue. The residue was purified by flash chromatography (eiuting with 0→10% CH3OH in EtOAc) to give 4- (thieno[3,2-jb]pyridin-7-yloxy)phenylamine as a light brown yellow oil (265.3 mg; 1.1 mmol; 40% yield); 1H NMR (400 MHz, Chloroform-D) δ ppm 3.75 (s, 2 H) 6.50 (d, J=5.6 Hz, 1 H) 6.71 (d, J=8.6 Hz, 2 H) 6.96 (d, =8.8 Hz, 2 H) 7.52 (d, J=5.3 Hz, 1 H) 7.69 (d, J=5.6 Hz, 1 H) 8.44 (d, J=5.3 Hz, 1 H). 7-r(6-chloropyridin-3-yl)oxyl-2-(1-methyl-1 H-imidazol-2-yl)thienor3,2--7lpyridine:
Figure imgf000046_0001
Potassium f-butoxide (1.5 mL, 1.5 mmol) was added to a solution of 2-chloro-5-hydroxypyridine (0.2 g, 1.5 mmol) in THF (2 mL) under a nitrogen atmosphere. A solution of 7-chloro-2-(1 -methyl-1 H- imidazol-2-yl)thieno[3,2-ό]pyridine (0.13 g, 0.5 mmol) in DMSO (1 mL) was then added to this mixture. The resulting reaction mixture was heated to 110 °C for 12 h. The reaction mixture was poured into H20 (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eiuting with 10→20% MeOH in EtOAc) to give 7-[(6-chloropyridin-3-yl)oxy]-2-(1 -methyl-1 H-imidazoi-2-yl)thieno[3,2- d]pyridine (120.4 mg; 0.35 mmol; 70% yield); 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 6.58 (d, =5.3 Hz, 1 H) 7.01 (s, 1 H) 7.12 (d, J=1.0 Hz, 1 H) 7.35 - 7.43 (m, 1 H) 7.49 (dd, =8.7, 2.9 Hz, 1 H) 7.67 (s, 1 H) 8.32 (d, =2.8 Hz, 1 H) 8.50 (d, J=5.3 Hz, 1 H).
5-(r2-(1-methyl-1H-imidazol-2-yl)thienor3,2-blpyridin-7-ylloxy)pyridin-2-amine:
Figure imgf000046_0002
Lithium hexamethyldisilazide (0.5 mL, 0.42 mmol), tris(dibenzylideneacetone) dipalladium (0) chloroform adduct (20 mg, 0.02 mmol), and 2-(dicyclohexylphosphino) biphenyl (15 mg, 0.04 mmol) were added sequentially to a stirred solution of 7-[(6-chloropyridin-3-yl)oxy]-2-(1 -methyl-1 H-imidazol-2- yl)thieno[3,2-b]pyridine (120 mg, 0.35 mmol) in THF (3 mL) under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 12 h and then 2 M HCl (5 mL) was added and the mixture was stirred for an additional 2 h. The reaction mixture was neutralized with Na2C03 and then extracted with THF (2 x 50 mL). The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eiuting with 50% CH3OH in EtOAc) to give 5-{[2-(1 -methyl- 1 H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}pyridin-2-amine (11.4 mg; 0.035 mmol; 10.1% yield); MS (APCI) (M+H)+ 324. 4-amino-2-fluorophenol:
Figure imgf000047_0001
2-fluoro-4-nitrophenol (500 mg, 3.18 mmol), Pd (10% on activated carbon, 31 mg), and EtOH (20 mL) were combined and stirred under atmospheric H2 at room temperature. After 16 h, the solution was diluted with EtOAc (20 mL), filtered through Celite, concentrated, and purified by preparative thin layer chromatography (30% EtOAc in hexanes) to afford 4-amino-2-fluorophenol as a tan solid of sufficient purity for subsequent transformations (152 mg, 1.20 mmol; 38% yield). 4-amino-3-fluorophenol:
Figure imgf000047_0002
3-fluoro-4-nitrophenol (500 mg, 3.18 mmol), Pd (10% on activated carbon, 62 mg), and EtOH (20 mL) were combined and stirred under atmospheric H2 at room temperature. After 16 h, the solution was diluted with EtOAc (20 mL), filtered through Celite, concentrated under vacuum, and purified by preparative thin layer chromatography (30% EtOAc in hexanes) to afford 4-amino-3-fluorophenol as a tan solid of sufficient purity for subsequent transformations (331 mg, 2.60 mmol; 82% yield). 2-fluoro-4-(thienoF3.2-blPyridin-7-yloxy)aniline:
Figure imgf000047_0003
4-Amino-3-fluorophenol (202 mg, 1.59 mmol) and cesium carbonate (1.41 g, 4.33 mmol) were added sequentially to a stirred solution of 7-chlorothieno[3,2-b]pyridine (244 mg, 1.44 mmol) in DMSO (5 mL). The reaction mixture heated to 100 °C and after 16 h, H20 (20 mL) was poured to the mixture stir and EtOAc (3 x 20 mL) was added to extract the aqueous solution. The combined organic layers were washed with brine (20 mL), dried (Na2S04), filtered, and concentrated to give a tan solid. The residue was purified by flash chromatography (eiuting with 10-»100% EtOAc in hexanes) to afford 2-fluoro-4- (thieno[3,2-b]pyridin-7-yloxy)aniline as a tan solid (23 mg; 0.0883 mmol; 6% yield); MS (APCI) (M+H)+ 261.
4-Chloro-6,7-dimethoxyguinazoline:
Figure imgf000047_0004
was prepared and isolated as described in Tetrahedron (2003), 59(9), 1413-1419 (Alexandre, F.- R. et al.), the disclosure of which is incorporated herein by reference in its entirety. 4-r(6-Chloropyridin-3-yl)oxyl-6.7-dimethoxyguinazoline:
Figure imgf000048_0001
Potassium t-butoxide (1 mL, 1 mmol, 1 M in THF) was added to 2-chloro-5-hydroxypyridine (198 mg, 1.5 mmol) under inert atmosphere. The reaction mixture was stirred at room temperature for 15 min, then a solution of 6,7-dimethoxy-4-chloroquinozoline (225 mg, 1 mmol) in DMSO (1 mL) was added. The resulting solution was heated to 75 °C for 2 h. The reaction mixture was quenched with H20 (50 mL) and EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eiuting with 60→70% EtOAc in hexanes) to give 4-[(6-chloropyridin-3-yl)oxy]-6,7-dimethoxyquinazoline (264 mg; 0.83 mmol; 83% yield); MS (APCI) (M+H)+ 318. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.04 (s, 3 H) 4.05 (s, 3 H) 7.42 (d, J=8.6 Hz, 1 H) 7.48 (s, 1 H) 7.63 (dd, J=8.6, 3.0 Hz, 1 H) 8.38 (d, J=2.8 Hz, 1 H) 8.57 (s, 1 H).
5-[(6.7-Dimethoxyquinazolin-4-yl)oxylpyhdin-2-amine: NH2
Figure imgf000048_0002
Lithium hexamethyldisilazide (3 mL, 3 mmol), tris(dibenzylideneacetone) dipalladium (0) chloroform adduct (166 mg, 0.16 mmol), and 2-(dicyclohexylphosphino) biphenyl (135 mg, 0.38 mmol) were added sequentially to a stirred solution of 4-[(6-chloropyridin-3-yl)oxy]-6,7-dimethoxyquinazoline (264 mg, 0.83 mmol) in THF (13 mL) under a nitrogen atmosphere. The reaction mixture was heated at 65 °C for 2 h and then 2 M HCl (17 mL) was added and the mixture was stirred for an additional 2 h. The reaction mixture was neutralized with Na2C03 and then extracted with THF (2 x 50 mL). The combined organic layers were dried over Na2S04 then concentrated under vacuum. The residue was purified by flash chromatography (eiuting with 15→20% CH3OH in EtOAc) to give 5-[(6,7-dimethoxyquinazolin-4- yl)oxy]pyridin-2-amine (88.2 mg; 0.3 mmol; 36% yield); MS (APCI) (M+H)+ 299. H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.05 (s, 3 H) 4.06 (s, 3 H) 4.69 (s, 2 H) 7.32 (s, 1 H) 7.39 (d, J=3.0 Hz, 1 H) 7.41 (d, J=2.Q Hz, 1 H) 7.52 (s, 1 H) 8.01 (d, J=2.5 Hz, 1 H) 8.60 (s, 1 H). Example 1 : Λ/-f({5-r(6,7-dimethoxyguinolin-4-yl)oxylpyridin-2-yl)amino)carbonothioyll-2-phenylacetamide
Figure imgf000048_0003
Ammonium thiocyanate (40 mg, 0.52 mmol) was added to a stirred solution of phenylacetylchloride (0.07 mL, 0.47 mmol) in chlorobenzene (2 mL). The resulting solution was heated to 105 °C for 3 h. 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (153.7 mg, 0.52 mmol) was added and the resulting mixture was stirred at 70 °C for 3 h. Water (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered and evaporated to get a brown yellow oil. The residue was purified by silica gel chromatography (eiuting with 0→5% CH3OH in EtOAc) to give Λ/-[({5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-yl}amino)-carbonothioyl]-2-phenylacetamide as a white foam (57.5 mg; 0.12 mmol; 23.3% yield); MS (APCI) (M+H)+ 475. 1H NMR (400 MHz, CDCI3) δ ppm 3.77 (s, 2 H) 4.05 (s, 3 H) 4.06 (s, 3 H) 6.49 (d, J=5.3 Hz, 1 H) 7.27 (s, 1 H) 7.33 (m, 2 H) 7.40 (m, 3 H) 7.51 (s, 1 H) 7.57 (dd, J=9.0, 2.9 Hz, 1 H) 8.35 (d, J=2.8 Hz, 1 H) 8.53 (d, =5.1 Hz, 1 H) 8.61 (s, 1 H) 8.88 (d, =9.1 Hz, 1 H) 12.92 (s, 1 H). Anal. Calcd for C25H22N4O4S»0.2CHCI3 »0.75 H20 C: 59.13, H: 4.67, N: 10.94. Found C: 59.20, H: 4.42, N: 10.76. Example 2: Λ/-r3-fluoro-4-(thienor3.2-άlpyridin-7-yloxy)phenvn-Λt-(2-phenylcvclopropyl)urea
Figure imgf000049_0001
Trans-2-phenylcyclopropyl isocyanate (0.04 g, 0.22 mmol) was added to a stirred solution of [3- fluoro-4-(thieno[3,2-i)]pyridin-7-yloxy)phenyl]amine (procedure A) (37.2 mg, 0.143 mmol) in CH2CI2 (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 12 h. The solvent was evaporated to give a brown oil residue. The residue was purified by flash chromatography (eiuting with 75→85% EtOAc in hexanes) to give A/-[3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenyl]-/V-(2- phenylcyclopropyl)urea as a white solid (20 mg; 0.048 mmol; 33% yield); MS (APCI) (M+H)+ 420. 1H NMR (400 MHz, CDCI3) δ ppm 1.39 (m, 2 H) 2.20 (m, 1 H) 2.74 (m, 1 H) 6.48 (d, J=5.6 Hz, 1 H) 7.01 (m, 2 H) 7.13 (m, 3 H) 7.25 (m, 2 H) 7.33 (m, 2 H) 7.57 (m, 2 H) 7.74 (d, J=5.6 Hz, 1 H) 8.48 (d, =5.6 Hz, 1 H). Anal. Calcd for C23Hι8FN302S*1.25 H20 C: 62.50, H: 4.67, N: 9.51. Found C: 62.78, H: 4.34, N: 9.25. Example 3: Λ/-(2-phenylcvclopropyl)-Λ/-[4-(thienof3,2-blpyridin-7-yloxy)phenvπurea
Figure imgf000049_0002
Trans-2-phenylcyclopropyl isocyanate (0.09 g, 0.53 mmol) was added to a stirred solution of 4-
(thieno[3,2-b]pyridin-7-yloxy)phenylamine (84 mg, 0.347 mmol) in CH2CI2 (15 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 12 h. The solvent was evaporated to give a brown oil residue. The residue was purified by flash chromatography (eiuting with 0→5% CH3OH in EtOAc) to give -(2-phenylcyclopropyl)-W-[4-(thieno[3,2-Jb]pyridin-7-yloxy)phenyl]urea as a light brown foam (108.6 mg; 0.27 mmol; 78% yield); MS (APCI) (M+H)+ 402. 1H NMR (400 MHz, CDCI3) δ ppm 1.37 (m, 2 H) 2.19 (m, 1 H) 2.76 (m, 1 H) 5.32 (s, 1 H) 6.53 (d, =5.3 Hz, 1 H) 7.05 (s, 1 H) 7.11 (m, 4 H) 7.25 (m, 1 H) 7.33 (t, =7.3 Hz, 2 H) 7.44 (m, 2 H) 7.56 (d, J=5.6 Hz, 1 H) 7.73 (d, J=5.3 Hz, 1 H) 8.47 (d, =5.3 Hz, 1 H). Anal. Calcd for C23H19N3O2S»0.5 H20 C: 67.30, H: 4.91, N: 10.24. Found C: 67.55, H: 4.80, N: 10.11. Example 4: 2-phenyl-Λ/-({[4-(thienor3,2-dlpyridin-7-yloxy)phenyllamino)carbonothioyl)acetamide
Figure imgf000050_0001
Ammonium thiocyanate (60 mg, 0.75 mmol) was added to a stirred solution of phenylacetylchloride (0.1 mL, 0.7 mmol) in chlorobenzene (3 mL). The resulting solution was heated to 105 °C for 3 h. 4-(thieno[3,2-£>]pyridin-7-yloxy)phenylamine (153.7 mg, 0.52 mmol) was added to the reaction mixture and the resulting mixture was stirred at 70 °C for 3 h. Water (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered and evaporated to get a brown yellow oil. The residue was purified by silica gel chromatography (eiuting with 50-→60% EtOAc in hexanes) to give 2-phenyl-Λ/- ({[4-(thieno[3,2-b]pyridin-7-yloxy)phenyl]amino}carbonothioyl)acetamide as a pinkish solid foam (237.3 mg; 0.57 mmol; 76% yield); MS (APCI) (M+H)+ 420. 1H NMR (400 MHz, CDCI3) δ ppm 3.76 (s, 2 H) 6.62 (d, J=5.3 Hz, 1 H) 7.20 (d, J=8.8 Hz, 2 H) 7.32 (m, 2 H) 7.41 (m, 3 H) 7.58 (d, =5.6 Hz, 1 H) 7.74 (m, 3 H) 8.52 (d, J=5.3 Hz, 1 H) 8.74 (s, 1 H) 12.38 (s, 1 H). Anal. Calcd for C22H17N3O2S2 «0.25 H20 C: 62.32, H: 4.16, N: 9.91. Found C: 62.49, H: 4.26, N: 9.65. Example 5: 2-phenyl-Λ/-((r4-(thienof3.2--?lpyridin-7-yloxy)phenyl1aminolcarbonyl)acetamide
Figure imgf000050_0002
Potassium iodate (0.09 g, 0.4 mmol) was added to a stirred solution of 2-phenyl-Λ/-({[4-
(thieno[3,2-_7]pyridin-7-yloxy)phenyl]amino}carbonothioyl)acetamide (Example 4) (108.8 mg, 0.259 mmol) in H20 (15 mL). The reaction was heated to 100 °C for 1 h. Ethyl acetate (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried, filtered and evaporated to get a brown oil. The residue was purified by silica gel chromatography (eiuting with 70-→85% EtOAc in hexanes) to give 2-phenyl-Λ/-({[4-(thieno[3,2-_)]pyridin-7-yloxy)phenyl]amino}carbonyl)acetamide as a brown solid foam (41 mg; 0.1 mmol; 39% yield); MS (APCI) (M+H)+ 404. 1H NMR (400 MHz, CDCI3) δ ppm 3.75 (s, 2 H) 6.55 (m, 1 H) 7.16 (m, 2 H) 7.38 (m, 5 H) 7.57 (m, 3 H) 7.73 (d, J=5.3 Hz, 1 H) 8.49 (d, =5.6 Hz, 1 H) 8.91 (s, 1 H) 10.65 (s, 1 H). Anal. Calcd for C22H17N303S«1.25 H20 C: 62.03, H: 4.61, N: 9.86. Found C: 62.18, H: 4.25, N: 9.59. Example 6: /V-r({5-f(6.7-dimethoxyguinolin-4-yl)oxylpyridin-2-yllamino)carbonyllbenzamide
Figure imgf000050_0003
Benzoyl isocyanate (0.04 g, 0.25 mmol) was added to a solution of 5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-amine (0.04 g, 0.12 mmol) in CH2CI2 (10 mL). The resulting mixture was stirred at room temperature for 12 h under inert atmosphere. The mixture was evaporated and CH3OH (5 mL) was added. The precipitate was filtered and washed with more CH3OH to give Λ/-[({5-[(6,7-dimethoxyquinoIin- 4-yl)oxy]pyridin-2-yl}amino)carbonyl]benzamide as a light yellow solid (39.3 mg; 0.088 mmol; 72% yield); MS (APCI) (M+H)+ 445. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.03 (s, 3 H) 4.03 (s, 3 H) 6.99 (d, J=6.3 Hz, 1 H) 7.44 - 7.64 (m, 3 H) 7.68 (t, J=7.5 Hz, 1 H) 7.76 (s, 1 H) 7.91 - 8.03 (m, 1 H) 8.04 (d, =7.1 Hz, 2 H) 8.26 (d, J=9.1 Hz, 1 H) 8.50 (d, J=2.Q Hz, 1 H) 8.81 (d, =6.6 Hz, 1 H) 11.32 (s, 1 H) 11.46 (s, 1 H). Anal. Calcd for C24H20N4O5*1 CH2CI2 »0.75 H20 C: 55.31 , H: 4.36, N: 10.32. Found C: 55.72, H: 4.60, N: 9.89. Example 7: Λ/-r((5-[(6,7-dimethoxyguinolin-4-yl)oxylpyridin-2- yl)amino)carbonothiovπbenzamide
Figure imgf000051_0001
Benzoyl isothiocyanate (0.05 g, 0.3 mmol) was added to a solution of 5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-amine (0.067 g, 0.23 mmol) in CH2CI2 (10 mL). The resulting mixture was stirred at room temperature for 12 h under inert atmosphere. The mixture was evaporated and the oil residue was purified by flash chromatography (eiuting with 0→3% CH3OH in EtOAc) to give Λ/-[({5-[(6,7- dimethoxyquinolin-4-yl)oxy]pyridin-2- yl}amino)carbonothioyl]benzamide as a white foam (74 mg; 0.16 mmol; 71.3% yield); MS (APCI) (M+H)+ 461. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.94 (s, 3 H) 3.95 (s, 3 H) 6.60 (d, J=5.3 Hz, 1 H) 7.42 (s, 1 H) 7.51 - 7.54 (m, 1 H) 7.56 (t, J=7.7 Hz, 2 H) 7.67 (t, J=7.5 Hz, 1 H) 7.92 (dd, J=9.0 Hz, 2.91 Hz, 1 H) 7.96 - 8.03 (m, 2 H) 8.47 - 8.54 (m, 2 H) 8.91 (s, 1 H) 11.80 (s, 1 H) 13.39 (s, 1 H). Anal. Calcd for C24H20N4O4»0.5 H20 C: 61.64, H: 4.51 , N: 11.93. Found C: 61.60, H: 4.57, N: 11.56. Example 8: Λ/-r((5-r(6,7-dimethoxyquinolin-4-yl)oxylpyridin-2-yl)amino)carbonyl1-2,6-difluorobenzamide
Figure imgf000051_0002
2,6-Difluorobenzoyl isocyanate (0.05 g, 0.3 mmol) was added to a solution of 5-[(6,7- dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (0.065 g, 0.22 mmol) in CH2CI2 (10 mL). The resulting mixture was stirred at room temperature for 12 h under inert atmosphere. The mixture was evaporated and the oil residue was purified by flash chromatography (eiuting with 1→3% CH3OH in EtOAc) to give Λ/-[({5-[(6,7- dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]-2,6-difluorobenzamide as a white solid (73 mg; 0.15 mmol; 69.4% yield); MS (APCI) (M+H)+ 481. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.93 (s, 3 H) 3.94 (s, 3 H) 6.54 (d,
Figure imgf000051_0003
2.91 Hz, 1 H) 8.10 (d, J=9.09 Hz, 1 H) 8.39 (d, =2.78 Hz, 1 H) 8.49 (d, J=5.31 Hz, 1 H) 10.74 (s, 1 H) 11.68 (s, 1 H). Anal. Calcd for C24H18F2N4O5 »0.25 CH2CI2 C: 58.06, H: 3.72, N: 11.17. Found C: 58.25, H: 3.82, N: 10.88.
Example 9: 2.6-dif luoro-Λ/-f [(5-(r2-(1 -methyl-1 H-imidazol-2-yl)thienor3.2-frlpyridin-7-yl1oxylpyridin-2- vPaminolcarbonvUbenzamide
Figure imgf000052_0001
2,6-Difluorobenzoyl isocyanate (12 mg, 0.05 mmol) was added to a solution of 5-{[2-(1 -methyl-1 H- imidazoI-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}pyridin-2-amine (11.4 mg, 0.035 mmol) in CH2CI2 (4 mL). The resulting mixture was stirred at room temperature for 12 h under inert atmosphere. The mixture was evaporated and the oil residue was purified by flash chromatography (eiuting with 10→15% CH3OH in EtOAc) to give 2,6-difluoro-Λ/-{[(5-{[2-(1 -methyl-1 H-imidazol-2-yl)thieno[3,2-φyridin-7-yl]oxy}pyridin-2- yl)amino]carbonyl}benzamide as an oil (10 mg; 0.02 mmol; 57.1% yield); MS (APCI) (M+H)+ 507. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.99 (s, 3 H) 6.76 (d, J=5.31 Hz, 1 H) 7.05 (s, 1 H) 7.26 (t, J=8.2 Hz, 1 H) 7.41 (s, 1 H) 7.57 - 7.69 (m, 1 H) 7.88 (d, J=2.8 Hz, 1 H) 7.90 (s, 1 H) 8.11 (d, J=8.8 Hz, 1 H) 8.43 (d, J=2.8 Hz, 1 H) 8.54 (d, =5.6 Hz, 1 H) 10.51 - 11.02 (m, 1 H) 11.69 (s, 1 H). Example 10: Λ/-r(f5-r(6,7-dimethoxyguinazolin-4-yl)oxylpyridin-2-yl amino)carbonvn-2.6-difluorobenzamide
Figure imgf000052_0002
2,6-Difluorobenzoyl isocyanate (0.05 g, 0.2 mmol) was added to a solution of 5-[(6,7- dimethoxyquinazolin-4-yl)oxy]pyridin-2-amine (0.04 g, 0.13 mmol) in CH2CI2 (10 mL). The resulting mixture was stirred at room temperature for 12 h under inert atmosphere. The mixture was evaporated and the oil residue was purified by flash chromatography (eiuting with 100% EtOAc) to give Λ/-[({5-[(6,7- dimethoxyquinazolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]-2,6-difluorobenzamide as a white solid (58.7 mg; 0.122 mmol; 92.4% yield); MS (APCI) (M+H)+ 482. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.98 (s, 3 H) 3.99 (s, 3 H) 7.27 (t, J=8.2 Hz, 2 H) 7.41 (s, 1 H) 7.59 (s, 1 H) 7.60 - 7.69 (m, 1 H) 7.90 (dd, J=9.1 , 2.8 Hz, 1 H) 8.09 (d, J=8.8 Hz, 1 H) 8.40 (d, =2.8 Hz, 1 H) 8.57 (s, 1 H) 10.71 (s, 1 H) 11.67 (s, 1 H). Anal. Calcd for C23Hι7F2N5O5»0.5 H20 C: 56.33, H: 3.70, N: 14.28. Found C: 56.49, H: 3.53, N: 14.28.
Example 11 : N-(fr3-fluoro-4-(thienor3,2-blpyridin-7-yloxy)phenvπaminolcarbonothioyl)-2-phenylacetamide
Figure imgf000052_0003
Ammonium thiocyanate (28 mg, 0.369 mmol) was added to a stirred solution of phenylacetylchloride (51 mg, 0.332 mmol) in chlorobenzene (2 mL) and CH2CI2 (2 mL). The resulting solution was heated to 105 °C and after 3 h, [3-fluoro-4-(thieno[3,2-_)]pyridin-7-yloxy)phenyl]amine
(procedure B) (96 mg, 0.369 mmol) was added to the reaction mixture and the resulting mixture was stirred at 70 °C. After 16 h, water (20 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 20 mL) was added to extract the aqueous solution. The combined organic layers were dried (Na2S04), filtered and evaporated to get a tan oil. The residue was purified by preparative thin layer chromatography (eiuting 50% EtOAc in hexanes) to give afford N-({[3-fluoro-4-(thieno[3,2-b]pyridin-7- yloxy)phenyl]amino}carbonothioyl)-2-phenylacetamide as a white solid (66 mg; 0.151 mmol; 41% yield); MS (APCI) (M+H)+ 438. 1H NMR (400 MHz, DMSO-cfe). δ ppm 3.90 (s, 2H), 6.73 (d, J = 5.3 Hz, 1 H), 7.34 - 7.38 (m, 1 H), 7.41 - 7.42 (m, 4 H), 7.56 - 7.63 (m, 2 H), 7.68 (d, J = 5.6 Hz, 1 H), 8.09 (d, J= 13.4 Hz, 1 H), 8.25 (d, J= 5.3 Hz, 1 H), 8.61 (d, J= 5.6 Hz, 1 H), 11.89 (s, 1 H), 12.57 (s, 1 H). Example 12: N-((r2-fluoro-4-(thieno[3.2-b1pyridin-7-yloxy)phenyllaminolcarbonothioyl)-2-phenylacetamide
Figure imgf000053_0001
Ammonium thiocyanate (9 mg, 0.115 mmol) was added to a stirred solution of phenylacetylchloride (16 mg, 0.104 mmol) in chlorobenzene (1 mL) and CH2CI2 (1 mL). The resulting solution was heated to 105 °C and after 3 h, 2-fiuoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (30 mg, 0.115 mmol) was added to the reaction mixture and the resulting mixture was stirred at 70 °C. After 16 h, water
(20 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 20 mL) was added to extract the aqueous solution. The combined organic layers were dried (Na2S04), filtered and evaporated to get a tan oil. The residue was purified by preparative thin layer chromatography (eiuting 50% EtOAc in hexanes) to give N-({[2-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenyl]amino}carbonothioyl)-2- phenylacetamide as a white solid (5 mg; 0.0114 mmol; 10% yield); MS (APCI) (M+H)+ 438. 1H NMR (400
MHz, DMSO-cfe) δ ppm 3.85 (s, 2 H), 6.89 (d, J= 6.3 Hz, 1 H), 7.05 - 7.11 (m, 2 H), 7.33 - 7.44 (m, 5 H),
8.11 - 8.14 (m, 2 H), 8.52 (t, J= 8.8 Hz, 1 H), 8.70 (d, J= 6.3 Hz, 1 H), 9.21 (s, 1 H), 12.55 (s, 1H). Example 13: -l5-r(6,7-dimethoxyguinolin-4-yl)oxylpyridin-2-yl)acetamide
Figure imgf000053_0002
To a solution of 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (971 mg, 3.27 mmol) in acetic acid (30 mL) was added potassium cyanate (795 mg, 9.80 mmol). The mixture was then heated to 80°C for 16 hours and allowed to cool to ambient temperature. Toluene was added and the solution concentrated to dryness. The crude product was dissolved in MeOH and EtOAc and passed through a silica plug and then the plug was washed with EtOAc. The solution was then purified by flash chromatography (Biotage Horizon 100%EtOAc) to afford 628 mg of product as a tan solid. 1H NMR (400 MHz, DMSO-cfe) δ ppm 2.12 (s, 3 H) 3.94 (d, =4.04 Hz, 6 H) 6.51 (d, J=5.31 Hz, 1 H) 7.41 (s, 1 H) 7.53 (s, 1 H) 7.77 (dd, =9.09, 3.03 Hz, 1 H) 8.22 (d, =9.09 Hz, 1 H) 8.34 (d, J=2.78 Hz, 1 H) 8.48 (d, J=5.31 Hz, 1 H) 10.67 (s, 1 H). OAMS (APCI) supporting ion at: 340.20 (M+1).
Example 14: Λ/-r2-(2.6-dichlorophenyl)ethyll-Λ/'-f5-r(6.7-dimethoxyguinolin-4-yl)oxy1pyridin-2-yl)urea: ϊ ό
To a solution of 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (100 mg, 0.336mmol) in dichloromethane (2 mL) was added 1 ,3-dichloro-2-(2-isocyanatoethyl)benzene (80 mg, 0.370 mmol). The mixture was then stirred at ambient temperature for 16 hours and then the mixture was concentrated. The crude product was purified by flash chromatography (Biotage Horizon 3%MeOH/CH2CI2) to afford 47mg of product as a white solid (27%). Anal. Calcd for C25H22CI2N404 »0.5H2O C 57.48, H 4.44, N 10.73. Found:C 57.77, H 4.30, N 10.33. 1H NMR (400 MHz, DMSO-cfe) δ ppm 3.12 (t, J=7.07 Hz, 2 H) 3.44 (q, J=6.57 Hz, 2 H) 3.93 (d, J=2.53 Hz, 6 H) 6.47 (d, =5.31 Hz, 1 H) 7.25 - 7.31 (m, 1 H) 7.39 (s, 1 H) 7.44 (s, 1 H) 7.46 (s, 1 H) 7.51 (s, 1 H) 7.58 (d, J=9.09 Hz, 1 H) 7.69 (dd, J=9.09, 2.78 Hz, 1 H) 7.90 (s, 1 H) 8.14 (d, J=2.78 Hz, 1 H) 8.47 (d, J=5.31 Hz, 1 H) 9.30 (s, 1 H). OAMS (APCI) supporting ion at: 514.10 and 516.10 (M+1).
Figure imgf000054_0001
To a solution of 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (100 mg, 0.336mmol) in dichloromethane (2 mL) was added (2-isocyanatoethyl)benzene (64mg, 0.437mmol). The mixture was then heated to 75°C for 16 hours and allowed to cool to ambient temperature. The mixture was concentrated to dryness and the crude product was purified by flash chromatography (Biotage Horizon 3%MeOH/CH2CI2) to afford 85mg of product as a white solid (57%). Anal. Calcd for C25H24N404 »0.25H2O C 66.88, H 5.50, N 12.48. Found:C 67.27, H 5.56, N 12.01. 1H NMR (400 MHz, DMSO-cfe) δ ppm 2.79 (t, J=7.07 Hz, 2 H) 3.43 (q, J=6.82 Hz, 2 H) 3.94 (d, J=2.27 Hz, 6 H) 6.47 (d, J=5.31 Hz, 1 H) 7.21 (t, J=7.07 Hz, 1 H) 7.25 - 7.34 (m, 4 H) 7.40 (s, 1 H) 7.52 (s, 1 H) 7.57 (d, J=8.84 Hz, 1 H) 7.70 (dd, J=9.09, 2.78 Hz, 1 H) 7.88 (s, 1 H) 8.14 (d, =2.78 Hz, 1 H) 8.48 (d, J=5.05 Hz, 1 H) 9.36 (s, 1 H). OAMS (APCI) supporting ion at: 445.20 (M+1). Example 16: Λ/-benzyl-ΛH5-[(6.7-dimethoxyguinolin-4-yl)oxylpyridin-2-yl)urea:
Figure imgf000054_0002
To a solution of 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (100 mg, 0.336mmol) in dichloromethane (2 mL) was added (isocyanatomethyl)benzene (67mg, 0.505mmol). The mixture was then heated to 75°C for 16 hours and allowed to cool to ambient temperature. The mixture was concentrated to dryness and the crude product was purified by flash chromatography (Biotage Horizon 3%MeOH/CH2CI2) to afford 137mg of product as a white solid (95%). Elemental Analysis: Calculatedd for C24H22N404 «0.5H2O: C 65.59, H 5.28, N 12.75. Found: C 65.43, H 5.32, N 12.60. 1H NMR (400 MHz, DMSO-cfe) δ ppm 3.94 (d, J=2.78 Hz, 6 H) 4.41 (d, J=6.06 Hz, 2 H) 6.49 (d, J=5.31 Hz, 1 H) 7.22 - 7.29 (m, 1 H) 7.30 - 7.37 (m, 4 H) 7.40 (s, 1 H) 7.52 (s, 1 H) 7.62 - 7.67 (m, 1 H) 7.69 - 7.75 (m, 1 H) 8.15 - 8.25 (m, 2 H) 8.47 (d, J=5.31 Hz, 1 H) 9.43 (s, 1 H). OAMS (APCI) supporting ion at: 431.20 (M+1). Example 17: Λ/-{5-f(6.7-dimethoxyquinolin-4-yl)oxylpyridin-2-yl)-2-pyridin-2-ylacetamide
Figure imgf000055_0001
Diisopropylamine (0.2 mL, 1 mmol) and 1 ,1'-carbonyldiimidazole (200 mg, 1.2 mmol) were added to a solution of 2-pyridylacetic acid hydrochloride in 2 mL of dichloroethanne. The mixture was stirred at room temperature for 30 min under inert atmosphere. A solution of 5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-amine (150 mg, 0.5 mmol) in 2 mL of dichloroethane was added. The mixture was heated at 80°C for 12 h then cool to ambient temperature. Water (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried (Na2S04), filtered and evaporated to get a tan oil. The residue was purified by silica gel chromatography (eiuting 10% CH3OH in DCM) to afford Λ/-{5-[(6,7-dimethoxyquinolin-4- yl)oxy]pyridin-2-yl}-2-pyridin-2-ylacetamideas a yellow solid (70 mg; 0.168 mmol; 33.6% yield); MS (APCI) (M+H)+ 417. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.01 (s, 1 H) 4.02 (s, 3 H) 4.03 (s, 3 H) 4.07 (s, 1 H) 6.97 (d, J=6.32 Hz, 1 H) 7.42 - 7.50 (m, 1 H) 7.53 - 7.59 (m, 2 H) 7.74 (s, 1 H) 7.91 (t, =9.1 , 3.0 Hz, 1 H) 7.96 (t, J=7.2 Hz, 1 H) 8.26 (d, J=9.1 Hz, 1 H) 8.48 (d, J=3.0 Hz, 1 H) 8.61 (d, J=4.3 Hz, 1 H) 8.75 - 8.84 (m, =6.3 Hz, 1 H) 11.10 (s, 1 H). Anal. Calcd for C23H20N4O4 «2.5CF3COOH »0.5H2O: C, 47.33; H, 3.33; N, 7.89. Found: C, 47.14, H, 3.36, N, 8.07.
Example 18: 2-chloro-Λ/-[({5-[(6,7-dimethoxyquinolin-4-yl)oxylpyridin-2-yl|amino)carbonyll-acetamide
Figure imgf000055_0002
Chloroacetylisocyanate (114 mg, 0.95 mmol) was added to a solution of 5-[(6,7- dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (300 mg, 1 mmol) in 5 mL of DCM under inert atmosphere. After stirring at room temperature for 12 h, precipitate formed in the reaction mixture. This precipitate was filtered and washed with DCM to give 2-chloro-Λ/-[({5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2- yl}amino)carbonyl]acetamide as off white solid (270.5 mg; 0.65 mmol; 68.4% yield); MS (APCI) (M+H)+ 417. 1 H NMR (400 MHz, DMSO-D6) δ ppm 3.93 (s, 3 H) 3.94 (s, 3 H) 4.43 (s, 2 H) 6.54 (d, J=5.05 Hz, 1 H) 7.41 (s, 1 H) 7.52 (s, 1 H) 7.84 (dd, J=9.09, 2.78 Hz, 1 H) 8.09 (d, =9.09 Hz, 1 H) 8.37 (d, J=3.03 Hz, 1 H) 8.49 (d, =5.05 Hz, 1 H). Example 19: Λ/-f((5-r(6,7-dimethoxyquinolin-4-yl)oxylpyridin-2-yl)amino)carbonvπ-2-piperidin-1- ylacetamide
Figure imgf000056_0001
Piperidine (40 mg, 0.4 mmol) and DIEA (0.2 mL, 1 mmol) were added sequentially to a solution of 2-chloro-Λ/-[({5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]acetamide (80 mg, 0.19 mmol) in 3 mL of DMF. The mixture was heated at 60°C for 12 h then cool to ambient temperature.
Water (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried (Na2S04), filtered and evaporated to get a tan oil. The residue was purified by silica gel chromatography (eiuting 85 →90% EtOAc in hexanes) to afford Λ/-[({5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]-2- piperidin-1-ylacetamide as a white solid (72 mg; 0.16 mmol; 80.7% yield); MS (APCI) (M+H)+ 466. 1 H
NMR (400 MHz, MeOD) δ ppm 1.43 (d, J=3.8 Hz, 2 H) 1.57 - 1.65 (m, 4 H) 2.44 - 2.53 (m, 4 H) 3.12 (s, 2
H) 3.93 (s, 3 H) 3.94 (s, 3 H) 6.47 (d, J=5.3 Hz, 1 H) 7.22 (s, 1 H) 7.47 (s, 1 H) 7.63 (dd, =9.1, 2.8 Hz, 1
H) 8.08 (d, J=7.3 Hz, 1 H) 8.18 (d, J=2.8 Hz, 1 H) 8.35 (d, J=5.3 Hz, 1 H). Anal. Calcd for C24H27N502 »0.5H2O: C, 60.75; H, 5.95; N, 14.76. Found: C, 60.95, H, 5.80, N, 14.80.
Example 20: Λ/-r((5-[(6.7-dimethoxyguinolin-4-yl)oxylpyridin-2-yl)amino)carbonyl1-2-pyrrolidin-1 -ylacetamide
Figure imgf000056_0002
Pyrrolidine (35 mg, 0.4 mmol) and DIEA (0.2 mL, 1 mmol) were added sequentially to a solution of 2-chioro-Λ/-[({5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]acetamide (80 mg, 0.19 mmol) in 3 mL of DMF. The mixture was heated at 60°C for 12 h then cool to ambient temperature. Water (50 mL) was added to the reaction mixture to quench the reaction. EtOAc (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried (Na2S0 ), filtered and evaporated to get a tan oil. The residue was purified by silica gel chromatography (eiuting 0 →5% MeOH in EtOAc) to afford Λ/-[({5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]-2-pyrrolidin-1- ylacetamide as a white solid (43 mg; 0.09 mmol; 49.5% yield); MS (APCI) (M+H)+ 452. 1 H NMR (400 MHz, MeOD) δ ppm 1.82 - 1.89 (m, 4 H) 2.68 (t, J=5.6 Hz, 4 H) 3.39 (s, 2 H) 3.97 (s, 3 H) 3.98 (s, 3 H) 6.53 (d, J=5.3 Hz, 1 H) 7.30 (s, 1 H) 7.56 (s, 1 H) 7.69 (dd, J=9.1 , 3.0 Hz, 1 H) 8.15 (d, J=7.3 Hz, 1 H) 8.24 (d, J=2.5 Hz, 1 H) 8.40 (d, J=5.6 Hz, 1 H). Anal. Calcd for C23H25N505 «0.5H2O: C, 59.99; H, 5.69; N, 15.21. Found: C, 59.76, H, 5.44, N, 15.25. Example 21 : Ethyl Λ/-r(f5-r(6.7-dimethoxyquinolin-4-yl)oxylPyridin-2-yllamino)carbonyllglvcinate
Figure imgf000057_0001
A reaction solution of 5-(6,7-Dimethoxy-quinolin-4-yloxy)-pyridin-2-ylamine (297.31 mg, 1.0 mmol.) and Ethyl isocyanatoacetate (0.12ml, l.lmmol.) in 8.0ml of CH2CI2 was stirred at room temperature for 12 hours. The reaction is completed by LCMS. The reaction mixture of yellow solution was partitioned between CH2CI2 (150ml) and sat.NaHC03 solution (50ml) and brine (50ml). The organic layer was dried (Na2S04) and then concentrated by vacuum. The residue was purified by Biotage system [25M, CH2CI2 (450ml), CH2CI2 /MeOH 100% to 90% (1000ml)] to collect desired fraction to afford 400mg as yellowish solid (94% yield). Elemental Analysis: Calculated for C21H22N4O6x0.26hexane: C 59.51 , H 5.70, N 12.25. Found: C 59.57, H 5.47, N 11.90. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.26 - 1.33 (m, 3 H) 4.07 (d, J=4.80 Hz, 6 H) 4.15 - 4.21 (m, 2 H) 4.23 (d, J=7.07 Hz, 2 H) 6.48 (d, =5.56 Hz, 1 H) 7.03 (d, =9.09 Hz, 1 H) 7.49 (dd, J=8.84, 2.78 Hz, 1 H) 7.55 (s, 1 H) 7.61 (s, 1 H) 8.17 (d, J=2.78 Hz, 1 H) 8.52 (d, =5.56 Hz, 1 H) 8.56 (s, 1 H) 9.46 (s, 1 H). Example 22: Λ-cvclohexyl-Λf-(5-[(6,7-dimethoxyguinolin-4-yl)oxylPyridin-2-yl)υrea
Figure imgf000057_0002
A reaction solution of 5-(6,7-Dimethoxy-quinolin-4-yloxy)-pyridin-2-ylamine (119mg, 0.4 mmol.) and Cyclohexyl isocyanate (1.0ml, δ.Ommol.) in 4.0ml of CH2CI2 was stirred at room temperature for 12 hours. The reaction is completed by LCMS. The reaction mixture of yellow solution was partitioned between CH2CI2 (150ml) and sat.NaHC03 solution (50ml) and brine (50ml). The organic layer was dried (Na2S04) and then concentrated by vacuum. The residue was purified by Biotage system [25M, CH2CI2 (450ml), CH2CI2 /MeOH 100% to 90% (1000ml)] to collect desired fraction to afford 148 mg as yellowish solid (88% yield). Elemental Analysis: Calculated for C23H26N4O4x0.28hexane: C 65.69, H 6.70, N 12.38; Found: C 65.63, H 6.92, N 12.05. 1 H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.18 - 1.45 (m, 3 H) 1.58 (s, 2 H) 1.71 (s, 2 H) 1.85 - 2.22 (m, 3 H) 3.82 (s, 1 H) 4.05 (s, 6 H) 6.43 (d, J=5.31 Hz, 1 H) 7.04 (d, J=9.09 Hz, 1 H) 7.42 - 7.50 (m, 2 H) 7.54 (s, 1 H) 8.12 (d, J=2.53 Hz, 1 H) 8.50 (d, J=5.05 Hz, 1 H) 8.91 (s, 1 H) 8.95 - 9.07 (m, 1 H).
Example 23: Λ/-{5-r(6,7-dimethoxyquinolin-4-yl)oxylPyridin-2-yl)-Λ/-(2-oxo-2-pyrrolidin-1-ylethyl)urea
Figure imgf000058_0001
To a reaction solution of /V-[({5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl] glycine (100mg, 0.25 mmol.) with Diisopropylethylamine (90ul, O.δmmol.) in 1.0 ml of DMF was added HATU (95mg, 0.25mmol). After stirred at room temperature for 30min, another chemical of corresponding amine (1.1 eq. mmol.) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction is completed by LCMS. The reaction mixture was partitioned between EtOAc (150ml) and sat. NaHC03 solution (75ml) and brine (75ml). The organic layer was dried (Na2S04), then concentrated by vacuum. The residue of yellow grease was treated was MeOH (5ml). The precipitated solid was filtered off and washed well with MeOH. The solid was dried under vacuum to give 30mg as white solid (27% yield). Elemental Analysis: Calculated for C23H25N5O5x0.36MeOH: C 60.60, H 5.76, N 15.13; Found: C 60.34, H 5.61 , N 15.09. 1 H NMR (400 MHz, DMSO-D6) δ ppm 1.71 - 1.83 (m, 2 H) 1.84 - 1.95 (m, 2 H) 3.32 - 3.36 (m, 2 H) 3.41 (t, J=6.82 Hz, 2 H) 3.94 (d, =2.27 Hz, 6 H) 3.98 (d, J=4.80 Hz, 2 H) 6.48 (d, J=5.31 Hz, 1 H) 7.39 (s, 1 H) 7.52 (s, 1 H) 7.62 - 7.67 (m, 1 H) 7.66 - 7.78 (m, 1 H) 7.97 (s, 1 H) 8.21 (d, J=2.78 Hz, 1 H) 8.47 (d, J=5.31 Hz, 1 H) 9.56 (s, 1 H) Example 24: Λ/-(5-[(6,7-dimethoxyguinolin-4-yl)oxylpyridin-2-yl)-Λ/-(2-oxo-2-pipehdin-1-ylethyl)-urea
Figure imgf000058_0002
The reaction was carried out by same method as Example 23. When reaction was completed, the reaction mixture was partitioned between EtOAc (150ml) and sat. NaHC03 solution (75ml) and brine (75ml). The organic layer was dried (Na2S04), then concentrated by vacuum. The residue yellow grease was purified by Dionex system (5% to 90% MeCN:H20 w 0.1%HOAc) to collect desired fractions to afford 20 mg as white solid (18% yield). Elemental Analysis: Calculated for C24H27N505x1.42H2Ox0.26HOAc: C 58.12, H 6.14, N 13.82; Found: C 58.01, H 5.73, N 13.70. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 - 1.63 (m, 6 H) 3.40 - 3.50 (m, 4 H) 3.95 (d, =2.78 Hz, 6 H) 4.05 (d, J=4.55 Hz, 2 H) 6.58 (s, 1 H) 7.42 (s, 1 H) 7.52 - 7.59 (m, 1 H) 7.63 - 7.70 (m, 1 H) 7.70 - 7.77 (m, 1 H) 7.96 (d, =11.87 Hz, 1 H) 8.18 - 8.28 (m, 1 H) 8.54 (d, J=5.05 Hz, 1 H) 9.59 (s, 1 H). Example 25: /vg-[((5-[(6,7-dimethoxyquinolin-4-yl)oxylpyridin-2-yl}amino)carbonyl1-Λ/ ,Λ1-dimethyl- glvcinamide
Figure imgf000059_0001
The reaction was carried out by same method as Example 23 to afford 18 mg as white solid (17% yield). Elemental Analysis: Calculated for C21H23N505x2.26H2Ox1.15HOAc: C 52.29, H 6.05, N 13.08; Found: C 52.01 , H 5.82, N 12.71. 1 H NMR (400 MHz, DMSO-D6) δ ppm 2.85 (s, 3 H) 2.96 (s, 3 H) 3.87 - 4.00 (m, 6 H) 4.04 (d, J=4.80 Hz, 2 H) 6.56 (d, J=5.31 Hz, 1 H) 7.41 (s, 1 H) 7.56 (s, 1 H) 7.61 - 7.69 (m, 1 H) 7.69 - 7.77 (m, 1 H) 7.88 - 8.03 (m, 1 H) 8.23 (d, =2.78 Hz, 1 H) 8.52 (d, J=5.56 Hz, 1 H) 9.58 (s, 1 H). Biological Examples It will be appreciated that, in any given series of compounds, a range of biological activities will be observed. In its presently preferred aspects, this invention relates to novel compounds capable of modulating, regulating and/or inhibiting protein kinase activity. The following assays may be employed to select those compounds demonstrating the optimal degree of the desired activity. Assay Procedures The following in vitro assay may be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed along the same lines for any PK using techniques well known in the art. A literature reference is provided (Technikova-Dobrova Z, Sardanelli AM, Papa S FEBS Lett. 1991 Nov 4; 292: 69-72). The general procedure is as follows: compounds and kinase assay reagents are introduced into test wells. The assay is initiated by addition of the kinase enzyme. Enzyme inhibitors reduce the measured activity of the enzyme. In the continuous-coupled spectrophotometric assay the time-dependent production of ADP by the kinase is determined by analysis of the rate of consumption of NADH by measurement of the decrease in absorbance at 340 nm. As the PK produces ADP it is re-converted to ATP by reaction with phosphoenol pyruvate and pyruvate kinase. Pyruvate is also produced in this reaction. Pyruvate is subsequently converted to lactate by reaction with lactate dehydrogenase, which simultaneously converts NADH to NAD. NADH has a measurable absorbance at 340 nm whereas NAD does not. The presently preferred protocol for conducting the continuous-coupled spectrophotometric experiments for specific PKs is provided below. However, adaptation of this protocol for determining the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art. HGFR Continuous-coupled Spectrophotometric Assay This assay analyzes the tyrosine kinase activity of HGFR on the Met-2 substrate peptide, a peptide derived from the activation loop of the HGFR. Materials and Reagents: 1. HGFR enzyme from Upstate (Met, active) Cat. # 14-526 2. Met-2 Peptide (HGFR Activation Loop) Ac-ARDMYDKEYYSVHNK (MW = 1960). Dissolve up in 200 mM HEPES, pH 7.5 at 10 mM stock. 3. 1 M PEP (phospho-enol-pyruvate) in 200 mM HEPES, pH 7.5 4. 100 mM NADH (B-Nicotinamide Adenine Dinucleotide, Reduced Form) in 200mM HEPES, pH 7.5 5. 4 M MgCI2 (Magnesium Chloride) in ddH20 6. 1 M DTT (Dithiothreitol) in 200 mM HEPES, pH 7.5 7. 15 Units/mL LDH (Lactic Dehydrogenase) 8. 15 Units/mL PK (Pyruvate Kinase) 9. 5M NaCI dissolved in ddH20 10. Tween-20 (Protein Grade) 10% Solution 11. 1 M HEPES buffer: (N-[2-Hydroxethyl]piperazine-N-[2-ethanesulfonic acid]) Sodium Salt. Dissolve in ddH20, adjust pH to 7.5, bring volume to 1 L. Filter at 0.1 μm. 12. HPLC Grade Water; Burdick and Jackson #365-4, 1 X 4 liters (or equivalent) 13. 100% DMSO (SIGMA) 14. Costar # 3880 - black clear flat bottom half area plates for K| determination and % inhibition 15. Costar # 3359 - 96 well polypropylene plates, round bottom for serial dilutions 16. Costar # 3635 - UV-plate clear flat bottom plates for % inhibition 17. Beckman DU-650 w/ micro cell holders 18. Beckman 4-position micro cell cuvette
Procedure: Prep Dilution Buffer (DB) for Enzyme (For 30 mL prep) 1.DB final concentration is 2 mM DTT, 25 mM NaCI2, 5 mM MgCI2, 0.01% Tween-20, and 50 mM HEPES buffer, pH 7.5. 2.Make up 50 mM HEPES by adding 1.5 mL 1 M HEPES into 28.1 mL of ddH20. Add rest of the reagents. Into 50 mL conical vial, add 60 μL of 1 M DTT, 150 μL 5M NaCI2, 150 μL 1 M MgCI2, and 30 μL of 10% Tween-20 to give total volume of 30 mL. 3. Vortex for 5-10 seconds. 4.Aliquot out DB at 1 mL/tube and label tubes as "DB HGFR" 5. Note: This can be prepared and stored ahead of time. 6. Freeze un-used aliquots in microcentrifuge tubes at -20°C freezer. Prep Compounds 1. For compound dilution plate, add 4 μL of 10 mM stock into column 1 of plate, and bring volume to 100 μL with 100% DMSO. 2. Set up the Precision 2000 dilution method. A final concentration of 200 μM compound in 50% DMSO, 100 mM HEPES (1 :2 serial dilution). Prep Coupled Enzymatic Buffer: 1. Final concentration in assay: Reagent (Stock Cone.) Final Cone. In Assay a. PEP (1 M) 1 mM b. NADH (100 mM) 300 μM c. MgCI2 (4 M) 20 mM d. DTT (1 M) 2 mM e. ATP (500 mM) 300 μM f. HEPES 200 mM (pH 7.5) 100 mM g. Pyruvate Kinase (PK) 15 units/mL h. Lactic Dehydrogenase (LDH) 15 units/mL i. Met-2 peptide (10 mM) 0.500 mM j. HGFR 50 nM 2. For a 10 mL reaction buffer add 10 μL of 1M PEP, 33 μL of 100 mM NADH, 50 μL of 4M MgCI2, 20 μL of 1M DTT, 6 μL of 500 mM ATP, and 500 μL of 10 mM Met-2 peptide into 100 mM HEPES buffer pH 7.5 and vortex/mix. 3. Add coupling enzymes, LDH and PK, into reaction mix. Mix by gentle inversion. Running samples 1. Spectrophotometer settings: i. Absorbance wavelength (λ): 340 nm ii. Incubation time: 10 min iii. Run time: 10 min iv. Temperature: 37°C 2. Add 85 μL of CE reaction mix into each well of assay plate. 3. Add 5 μL of diluted compound into a well of the assay plate. 4. Add 5 μL of 50% DMSO for negative control into last column of assay plate. 5. Mix with multi-channel pipettor or orbital shaker. 6. Pre-incubate for 10 minutes at 37°C. 7. Add 10 μL of 500 nM HGFR to each well of assay plate; the final HGFR concentration is 50 nM in a total final volume of 100 μL. 8. Measure activity for 10 minutes at λ = 340 nm and 37°C. The following in vitro assays may be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed along the same lines for any PK using techniques well known in the art. Several of the assays described herein are performed in an ELISA (Enzyme-Linked Immunosorbent Sandwich Assay) format (Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay," Manual of Clinical Immunology, 2d ed., Rose and Friedman, Am. Soc. Of Microbiology, Washington, D.C., pp. 359-371). General procedure is as follows: a compound is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand known to activate the receptor is added. The cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody recognizing the substrate of the enzymatic phosphorylation reaction. Non-substrate components of the cell lysate are washed away and the amount of phosphorylation on the substrate is detected with an antibody specifically recognizing phosphotyrosine compared with control cells that were not contacted with a test compound. The presently preferred protocols for conducting the ELISA experiments for specific PKs is provided below. However, adaptation of these protocols for determining the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art. Other assays described herein measure the amount of DNA made in response to activation of a test kinase, which is a general measure of a proliferative response. General procedure for this assay is as follows: a compound is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand known to activate the receptor is added. After incubation at least overnight, a DNA labeling reagent such as 5- bromodeoxyuridine (BrdU) or H3-thymidine is added. The amount of labeled DNA is detected with either an anti-BrdU antibody or by measuring radioactivity and is compared to control cells not contacted with a test compound. MET Transphosphorylation Assay This assay is used to measure phosphotyrosine levels on a poly(glutamic acid: tyrosine, 4:1) substrate as a means for identifying agonists/antagonists of met transphosphorylation of the substrate. Materials and Reagents: I . Corning 96-well ELISA plates, Corning Catalog # 25805-96. 2. Poly(glu-tyr), 4:1 , Sigma, Cat. No; P 0275. 3. PBS, Gibco Catalog # 450-1300EB 4. 50 mM HEPES 5. Blocking Buffer: Dissolve 25 g Bovine Serum Albumin, Sigma Cat. No A-7888, in 500 mL PBS, filter through a 4 μm filter. 6. Purified GST fusion protein containing the Met kinase domain, SUGEN, Inc. 7. TBST Buffer. 8. 10% aqueous (MilliQue H20) DMSO. 9. 10 mM aqueous (dH20) Adenosine-5'-triphosphate, Sigma Cat. No. A-5394. 10. 2X Kinase Dilution Buffer: for 100 mL, mix 10 mL 1M HEPES at pH 7.5 with 0.4 mL 5% BSA/PBS, 0.2 mL 0.1 M sodium orthovanadate and 1 mL 5M sodium chloride in 88.4 mL dH20. II. 4X ATP Reaction Mixture: for 10 mL, mix 0.4 mL 1 M manganese chloride and 0.02 mL 0.1 M ATP in 9.56 mL dHaO. 12. 4X Negative Controls Mixture: for 10 mL, mix 0.4 mL 1 M manganese chloride in 9.6 mL dH20. 13. NUNC 96-well V bottom polypropylene plates, Applied Scientific Catalog # S-72092 14. 500 mM EDTA. 15. Antibody Dilution Buffer: for 100 mL, mix 10 mL 5% BSA/PBS, 0.5 mL 5% Carnation® Instant Milk in PBS and 0.1 mL 0.1 M sodium orthovanadate in 88.4 mL TBST. 16. Rabbit polyclonal antophosphotyrosine antibody, SUGEN, Inc. 17. Goat anti-rabbit horseradish peroxidase conjugated antibody, Biosource, Inc. 18. ABTS Solution: for 1 L, mix 19.21 g citric acid, 35.49 g Na2HP04 and 500 mg ABTS with sufficient dH20 to make 1 L. 19. ABTS/H202: mix 15 mL ABST solution with 2μL H202 five minutes before use. 20. 0.2 M HCl Procedure: 1. Coat ELISA plates with 2 μg Poly(Glu-Tyr) in 100 μL PBS, hold overnight at 4°C. 2. Block plate with 150 μL of 5% BSA/PBS for 60 min. 3. Wash plate twice with PBS then once with 50 mM Hepes buffer pH 7.4. 4. Add 50 μL of the diluted kinase to all wells. (Purified kinase is diluted with Kinase Dilution Buffer. Final concentration should be 10 ng/well.) 5. Add 25 μL of the test compound (in 4% DMSO) or DMSO alone (4% in dH20) for controls to plate. 6. Incubate the kinase/compound mixture for 15 minutes. 7. Add 25 μL of 40 mM MnCI2 to the negative control wells. 8. Add 25 μL ATP/ MnCI2 mixture to the all other wells (except the negative controls). Incubate for 5 min. 9. Add 25 μL 500 mM EDTA to stop reaction. 10. Wash plate 3x with TBST. 11. Add 100 μL rabbit polyclonal anti-Ptyr diluted 1 :10,000 in Antibody Dilution Buffer to each well. Incubate, with shaking, at room temperature for one hour. 12. Wash plate 3x with TBST. 13. Dilute Biosource HRP conjugated anti-rabbit antibody 1 : 6,000 in Antibody Dilution buffer.
Add 100 μL per well and incubate at room temperature, with shaking, for one hour. 14. Wash plate 1X with PBS. - 15. Add 100 μl of ABTS/H202 solution to each well. 16. If necessary, stop the development reaction with the addition of 100 μL of 0.2M HCl per well. 17. Read plate on Dynatech MR7000 ELISA reader with the test filter at 410 nM and the reference filter at 630 nM.
BrdU INCORPORATION ASSAYS The following assays use cells engineered to express a selected receptor and then evaluate the effect of a compound of interest on the activity of ligand-induced DNA synthesis by determining BrdU incorporation into the DNA. The following materials, reagents and procedure are general to each of the following BrdU incorporation assays. Variances in specific assays are noted. General Materials and Reagents: 1. The appropriate ligand. 2. The appropriate engineered cells. 3. BrdU Labeling Reagent: 10 mM, in PBS, pH7.4(Roche Molecular Biochemicals, Indianapolis, IN). 4. FixDenat: fixation solution (Roche Molecular Biochemicals, Indianapolis, IN). 5. Anti-BrdU-POD: mouse monoclonal antibody conjugated with peroxidase (Chemicon,
Temecula, CA). 6. TMB Substrate Solution: tetramethylbenzidine (TMB, ready to use, Roche Molecular Biochemicals, Indianapolis, IN). 7. PBS Washing Solution : 1 X PBS, pH 7.4. 8. Albumin, Bovine (BSA), fraction V powder (Sigma Chemical Co., USA).
General Procedure: 1. Cells are seeded at 8000 cells/well in 10% CS, 2mM Gin in DMEM, in a 96 well plate.
Cells are incubated overnight at 37°C in 5% CO2. 2. After 24 hours, the cells are washed with PBS, and then are serum-starved in serum free medium (0%CS DMEM with 0.1% BSA) for 24 hours. 3. On day 3, the appropriate ligand and the test compound are added to the cells simultaneously. The negative control wells receive serum free DMEM with 0.1% BSA only; the positive control cells receive the ligand but no test compound. Test compounds are prepared in serum free DMEM with ligand in a 96 well plate, and serially diluted for 7 test concentrations. 4. After 18 hours of ligand activation, diluted BrdU labeling reagent (1:100 in DMEM, 0.1% BSA) is added and the cells are incubated with BrdU (final concentration is 10 μM) for 1.5 hours. 5. After incubation with labeling reagent, the medium is removed by decanting and tapping the inverted plate on a paper towel. FixDenat solution is added (50 μl/well) and the plates are incubated at room temperature for 45 minutes on a plate shaker. 6. The FixDenat solution is removed by decanting and tapping the inverted plate on a paper towel. Milk is added (5% dehydrated milk in PBS, 200 μL/well) as a blocking solution and the plate is incubated for 30 minutes at room temperature on a plate shaker. 7. The blocking solution is removed by decanting and the wells are washed once with PBS. Anti-BrdU-POD solution is added (1 :200 dilution in PBS, 1% BSA, 50 μUwell) and the plate is incubated for 90 minutes at room temperature on a plate shaker. 8. The antibody conjugate is removed by decanting and rinsing the wells 5 times with PBS, and the plate is dried by inverting and tapping on a paper towel. 9. TMB substrate solution is added (100 μl/well) and incubated for 20 minutes at room temperature on a plate shaker until color development is sufficient for photometric detection. 10. The absorbance of the samples are measured at 410 nm (in "dual wavelength" mode with a filter reading at 490 nm, as a reference wavelength) on a Dynatech ELISA plate reader. HGF-lnduced BrdU Incorporation Assay Materials and Reagents: 1. Recombinant human HGF (Cat. No. 249-HG, R&D Systems, Inc. USA). 2. BxPC-3 cells (ATCC CRL-1687). Remaining Materials and Reagents, as above. Procedure: 1. Cells are seeded at 9000 cells/well in RPMI 10% FBS in a 96 well plate. Cells are incubated overnight at 37°C in 5% C02. 2. After 24 hours, the cells are washed with PBS, and then are serum starved in 100 μL serum-free medium (RPMI with 0.1% BSA) for 24 hours. 3. on day 3, 25 μL containing ligand (prepared at 1 μg/mL in RPMI with 0.1% BSA; final
HGF cone, is 200 ng/mL) and test compounds are added to the cells. The negative control wells receive 25 μL serum-free RPMI with 0.1% BSA only; the positive control cells receive the ligand (HGF) but no test compound. Test compounds are prepared at 5 times their final concentration in serum-free RPMI with ligand in a 96 well plate, and serially diluted to give 7 test concentrations. Typically, the highest final 5 concentration of test compound is 100 μM, and 1:3 dilutions are used (i.e. final test compound concentration range is 0.137-100 μM). 4. After 18 hours of ligand activation, 12.5 μL of diluted BrdU labeling reagent (1 :100 in RPMI, 0.1% BSA) is added to each well and the cells are incubated with BrdU (final concentration is 10 μM) for 1 hour. ° 5. Same as General Procedure. 6. Same as General Procedure. 7. The blocking solution is removed by decanting and the wells are washed once with PBS. Anti-BrdU-POD solution (1 :100 dilution in PBS, 1% BSA) is added (100 μlJwell) and the plate is incubated for 90 minutes at room temperature on a plate shaker.5 8. Same as General Procedure. 9. Same as General Procedure. 10. Same as General Procedure. Cellular HGFR Autophosphorylation Assay A549 cells (ATCC) were used in this assay. Cells were seeded in the growth media (RPMI +0 10%FBS) into 96 well plates and cultured overnight at 37 °C for attachment. Cells were exposed to the starvation media (RPMI + 0.05% BSA). Dilutions of the inhibitors were added to the plates and incubated at 37 °C for 1 hour. Cells were then stimulated by adding 40 ng/mL HGF for 15 minutes. Cells were washed once with 1mM Na3V04 in HBSS and then lysed. The lysates were diluted with 1mM Na3V04 in HBSS and transferred to a 96 well goat ant-rabbit coated plate (Pierce) which was pre-coated with anti-5 HGFR antibody (Zymed Laboratories). The plates were incubated overnight at 4 °C and washed with 1% Tween 20 in PBS for seven times. HRP-PY20 (Santa Cruz) was diluted and added to the plates for 30 minutes incubation. Plates were then washed again and TMB peroxidase substrate (Kirkegaard & Perry) was added and incubated for 10 minutes. The reaction was then stopped by adding 0.09N H2S04. Plates were measured at OD-450 nm using a spectrophotometer. IC50 values were calculated by curve fitting0 using a four-parameter analysis. Compounds of the invention were measured for HGFR inhibition activity; the data are shown in Tables 1 and 2. Ki data were obtained using the HGFR Continuous-Coupled Spectrophotometric Assay, and 1C50 data were obtained using the Cellular HGFR Autophosphorylation Assay, both of which are described above.
Table 1
Figure imgf000066_0001
Table 2

Claims

Claims
We claim: 1. A compound of compounds of formula 1
Figure imgf000068_0001
wherein: L is selected from N and CR5; when L is N, A represents a fused 5 or 6-membered aryl or heteroaryl group, and when L is CR5, A represents a fused 5-membered heteroaryl group; and A is optionally substituted by from 1-4 R6 groups; X and Y are independently selected from N and CR7; R1 , R2, R3, R5 and R7, which may be the same or different, are each independently selected from hydrogen, halogen, C-ι-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)nOR8, -CN, -C(0)R8, -OC(0)R8, -O(CR10R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8,
-(CRlϋR11)nNRBR'',
Figure imgf000068_0002
R , Rd, Rs and R7 is optionally substituted by from 1 to 6 R 7 groups; R6 is selected from halogen, Cι-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9,
-(CR10R11)nOR8, -CN, -C(0)R8, -OC(0)R8, -O(CR10R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8,
-(CR10R11)nNR8R9 ; -C(=NR10)NR8R9, -NR8C(0)NR9R10, and -C(0)NR8R9, wherein each R6 is optionally substituted by from 1 to 6 R 51"7 . groups; R4 is selected from -H, Cι-C-|2 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR14R15)nOR12, -(CR14R15)nC(0)R12, -(CR14R15)nC(S)R12, -(CR14R15)nC(0)NR12R13, -(CR14R15)nC(S)NR12R13, -(CR14R15)nC(0)OR12, -(CR14R15)nNR12R13, -C(=NR14)NR12R13, and -C(0)NR12R13, and each R4 is optionally substituted by from 1 to 6 R17 groups; each R8, R9, R10 and R11, which may be the same or different, is independently selected from hydrogen, halogen, C-ι-Cι2 alkyl, C2-Cι2 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-12 membered heteroaryl; or any two of R8, R9, R10 and R11 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl ring optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R8, R9, R10 and R11 bound to the same carbon atom may be combined to form a C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring; and each of R8, R9, R10 and R11 is optionally substituted by from 1 to 6 R17 groups; each R12, R13, R14 and R15, which may be the same or different, is independently selected from hydrogen, halogen, CrC12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R16, and -C(S)R16; or any two of R12, R13, R14 and R15 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl ring optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R12, R13, R14 and R15 bound to the same carbon atom may be combined to form a C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring; and each of R12, R 3, R14 and R15 is optionally substituted by from 1 to 6 R17 groups; R16 is selected from hydrogen, halogen, C C12 alkyl, C2-C12 alkenyl, C2-Cι2 alkynyl, C3-Cι2 cycloalkyl, Cβ-C-|2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R18, and - C(0)NR19R2°; and each R16 is optionally substituted by from 1 to 6 R17 groups; each R17, which may be the same or different, is independently selected from halogen, C C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, -C(0)R19, -C(0)OR19 -C(0)NR19R2°, 3- 12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C C12 alkyl, -0-(CH2)nC3-Cι2 cycloalkyl, -O- (CH2)nC6-C12 aryl, -0-(CH2)π(3-12 membered heteroalicyclic) and -0-(CH2)n(5-12 membered heteroaryl), and each R17 is optionally substituted by from 1 to 6 R18 groups; each R18, which may be the same or different, is independently selected from -H, halogen, Cι-C1 alkyl, Cι-Cι2 alkoxy, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-CrC12 alkyl, -0-(CH2)πC3-C12 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), and -0-(CH2)π(5-12 membered heteroaryl), and each R18 is optionally substituted by a group selected from halogen, -OH, -CN, -C1.12 alkyl which may be partially or fully halogenated, -0-Cι-Cι2 alkyl which may be partially or fully halogenated, and -S03H; each R19 and R20, which may be the same or different, is independently selected from -H, halogen, CrCι2 alkyl, C C12 alkoxy, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R19 and R20 is optionally substituted by a group selected from halogen, -OH, -CN, -Cι.12 alkyl which may be partially or fully halogenated, -0-Cι-Cι2 alkyl which may be partially or fully halogenated, and -S03H; or R19 and R20 taken together with the nitrogen atom to which they are attached may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R18 groups; and n is 0, 1 , 2, 3 or 4; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
2. The compound of claim 1 , wherein L is CR5, X is CR7 and Y is CR7.
3. The compound of claim 1 , wherein L is N and Y is CR7.
4. A compound of formula 4
Figure imgf000070_0001
wherein: X and Y are independently N or CR7; each of R1, R2, R3 and R7, which may be the same or different, is independently selected from hydrogen, halogen, CrC12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9,
-(CR10R11)nOR8 -CN, -C(0)R8, -OC(0)R8 -O(CR10R11)nR8, -NRBC(0)Rs -(CR10R11)nC(O)OR8, ,1C l 1 10 -(CR^R1 ')πNRBRa, -C(=NRιυ)NR°Ra, -NRBC(0)NRaRlu, and -C(0)NRBRa, and each of R1, R2, R3 and R7 is optionally substituted by from 1-6 R17 groups; each R6, which may be the same or different, is independently selected from halogen, C C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)nOR8, -CN, -C(0)R8, -OC(0)R8,
-O(CR 0R11)nR8, -NR8C(0)R9, -(CR10R11)nC(O)OR8, 1C\ -(CRluR")nNRBRa -C(=NRιυ)NR -)8BRπ9a -,9r,10
-NRBC(0)NRaR , and -C(0)NRBRa, and each R is optionally substituted by from 1 to 6 R1' groups; R4 is Cι-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C-|2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR14R15)πOR12, -(CR 4R15)nC(0)R12, -(CR14R15)nC(S)R12, "(CR14R15)nC(0)NR12R13, -(CR14R15)nC(S)NR12R13, -(CR14R15)nC(0)OR12, -(CR14R15)πNR12R13, -C(=NR14)NR12R13, or -C(0)NR12R13, and R4 is optionally substituted by from 1 to 6 R17 groups; each of R8, R9, R10 and R11, which may be the same or different, is independently selected from hydrogen, halogen, C C-i2 alkyl, C2-C-|2 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, and 5-12 membered heteroaryl; or any two of R8, R9, R10 and R11 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl ring optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R8, R9, R10 and R11 bound to the same carbon atom may be combined to form a C3-C12 cycloalkyl, C6-C-ι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring; and each of R8, R9, R10 and R11 is optionally substituted by from 1-6 R17 groups; each R12, R13, R14 and R15 is independently hydrogen, halogen, CrC12 alkyl, C2-C12 alkenyl, C2- C12 alkynyl, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R16, and -C(S)R16; or any two of R12, R13, R14 and R15 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl ring optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R12, R13, R14 and R15 bound to the same carbon atom may be combined to form a C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring; and each hydrogen in R 2, R13, R14 and R15 is optionally substituted by from 1 to 6 R17 group; each R16, which may be the same or different, is selected from hydrogen, halogen, C C12 alkyl,
C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-12 membered heteroaryl; and each R16 is optionally substituted by from 1 to 6 R17 groups; each R17, which may be the same or different, is independently selected from halogen, C C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, -C(0)R19, -C(0)OR19 -C(0)NR19R20, 3- 12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C1-C12 alkyl, -0-(CH2)πC3-Cι2 cycloalkyl, -O-
(CH2)nC6-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) and -0-(CH2)n(5-12 membered heteroaryl), and each R17 is optionally substituted by from 1 to 6 R18 groups; each R18, which may be the same or different, is independently selected from -H, halogen, Cι-C 2 alkyl, CrC12 alkoxy, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C C12 alkyl, -0-(CH2)nC3-C12 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), and -0-(CH2)„(5-12 membered heteroaryl), and each R18 is optionally substituted by a group selected from halogen, -OH, -CN, -C -12 alkyl which may be partially or fully halogenated, -0-CrC12 alkyl which may be partially or fully halogenated, and -S03H; each R19 and R20, which may be the same or different, is independently selected from -H, halogen, CrC12 alkyl, C-|-C12 alkoxy, C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R19 and R20 is optionally substituted by a group selected from halogen, -OH, -CN, -C-|.12 alkyl which may be partially or fully halogenated, -0-Cι-C12 alkyl which may be partially or fully halogenated, and -S03H; or R19 and R20 taken together with the nitrogen atom to which they are attached may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R18 groups; and n is O, 1 , 2, 3 or 4; and q is 1 , 2, 3 or 4; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
5. A compound of formula 5
Figure imgf000072_0001
wherein: X and Y are independently N or CR7; each R1, R2, R3, R5 and R7, which may be the same or different, is independently selected from hydrogen, halogen, Cι-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, Ce-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S02NR8R9, -S(0)2OR8, -N02, -NR8R9, -(CR10R11)nOR8 -CN, -C(0)R°, -OC(0)R°, -O(CR10R11)nR8 -NR8C(0)R9 (CR10R11)nC(O)OR8 -(CR10R11)πNR8R9, -C(=NR10)NR8R9, -NR8C(0)NR9R10, and -C(0)NR8R9, and each of R1, R2, R3, R5 and R7 is optionally substituted by from 1 to 6 R17 groups; each R6, which may be the same or different, is independently selected from halogen, CrC12 alkyl, C2-Cι2 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 -8r>9 membered heteroaryl, -S02NR°Ra, -S(0)2OR°, -N02, -NRBRa, -(CRluR")nORB, -CN, -C(0)RB, -OC(0)RB 10r,11 r-)9
-0(CRπuR")nR -NR°C(0)Ra, -(CRluR11)nC(0)ORl -(CR10R11)nNCR8R9 C(=NRlu)NR 8BRa NR°C(0)NRaR ,10 , and -C(0)NRBRa, and each R° is optionally substituted by from 1 to 6 R1' groups; R4 is CrC12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -(CR14R15)nOR12, -(CR14R15)πC(0)R 12 -(CR14R15)πC(S)R12,
Figure imgf000072_0002
-(CR D1' rR-1'5°)- nC(S)NR 1"2irR-13 -(CR14R15)πC(0)OR12, -(CR14R15)nNR12R13,
-C(=NR14)NR12R13, and -C(0)NR12R13, and each R4 is optionally substituted by from 1 to 6 R17 groups; each R8, R9, R10 and R11, which may be the same or different, is independently selected from hydrogen, halogen, Cι-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, and 5-1 membered heteroaryl; or any two of R8, R9, R10 and R11 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R8, R9, R10 and R11 bound to the same carbon atom may be combined to form a C3-Cι2 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each R8, R9, R10 and R11 is optionally substituted by from 1 to 6 R17 groups; each R12, R13, R14 and R15, which may be the same or different, is independently selected from hydrogen, halogen, C C12 alkyl, C2-C12 alkenyl, C2-Cι2 alkynyl, C3-C 2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -C(0)R16 and -C(S)R16; or any two of R12, R13, R14 and R15 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R12, R13, R14 and R15 bound to the same carbon atom may be combined to form a C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each of R12, R13, R14 and R15 is optionally substituted by from 1 to 6 R17 groups; each R16, which may be the same or different, is selected from hydrogen, halogen, C C12 alkyl,
C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl; and each R16 is optionally substituted by from 1 to 6 R17 groups; each R17, which may be the same or different, is independently selected from halogen, C Cι2 alkyl, C2-Cι2 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, -C(0)R19, -C(0)OR19 -C(0)NR19R20, 3- 12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C C12 alkyl, -0-(CH2)nC3-C12 cycloalkyl, -O-
(CH2)nC6-Cι2 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) and -0-(CH2)n(5-12 membered heteroaryl), and each R17 is optionally substituted by from 1 to 6 R18 groups; each R18, which may be the same or different, is independently selected from -H, halogen, CrCι2 alkyl, C1-C12 alkoxy, C3-C12 cycloalkyl, C6-Cι2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-CrC12 alkyl, -0-(CH2)nC3-C12 cycloalkyl, -0-(CH2)nC6-C12 aryl, -0-(CH2)π(3-12 membered heteroalicyclic), and -0-(CH2)n(5-12 membered heteroaryl), and each R18 is optionally substituted by a group selected from halogen, -OH, -CN, -C-M2 alkyl which may be partially or fully halogenated, -0-C1-C12 alkyl which may be partially or fully halogenated, and -S03H; each R19 and R20, which may be the same or different, is independently selected from -H, halogen, C-|-C12 alkyl, CrC12 alkoxy, C3-Cι2 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5- 12 membered heteroaryl, and each R19 and R20 is optionally substituted by a group selected from halogen, -OH, -CN, -C^2 alkyl which may be partially or fully halogenated, -0-CrC12 alkyl which may be partially or fully halogenated, and -S03H; or R19 and R20 taken together with the nitrogen atom to which they are attached may form a 3-12 membered heteroalicyclic ring optionally substituted by from 1 to 6 R18 groups; and n is O, 1 , 2, 3 or 4; and q is 1, 2, 3 or 4; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
6. The compound according to any of the preceding claims, wherein Y is CR7.
7. The compound according to any of the preceding claims, wherein X is CR7.
8. The compound according to any of the preceding claims, wherein R6 is 5-12 membered heteroaryl or -(CR10R11)πOR8.
9. The compound according to any of the preceding claims, wherein at least one R6 group is - (CR10R11)nOR8.
10. The compound according to any of the preceding claims, wherein R4 is -(CR14R15)nC(0)R12, -(CR14R15)nC(S)R12, -(CR14R15)nC(0)NR12R13 or -(CR14R15)nC(S)NR12R13.
11. A compound selected from the group consisting of:
Figure imgf000074_0001
and pharmaceutically acceptable salts, solvates and hydrates thereof.
12. A compound selected from the group consisting of:
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000075_0003
and pharmaceutically acceptable salts, solvates and hydrates thereof.
13. A pharmaceutical composition comprising the compound according to any of the preceding claims and a pharmaceutically acceptable carrier.
14. A method of treating abnormal cell growth in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound according to any of claims 1-12.
15. A method of treating an HGFR related disorder in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound according to any of claims 1-12.
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