WO2009079767A1 - Indazolyl, benzimidazolyl, benzotriazolyl substituted indolinone derivatives as kinase inhibitors useful in the treatment of cancer - Google Patents

Indazolyl, benzimidazolyl, benzotriazolyl substituted indolinone derivatives as kinase inhibitors useful in the treatment of cancer Download PDF

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WO2009079767A1
WO2009079767A1 PCT/CA2008/002227 CA2008002227W WO2009079767A1 WO 2009079767 A1 WO2009079767 A1 WO 2009079767A1 CA 2008002227 W CA2008002227 W CA 2008002227W WO 2009079767 A1 WO2009079767 A1 WO 2009079767A1
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alkyl
group
optionally substituted
phenyl
independently
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PCT/CA2008/002227
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French (fr)
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WO2009079767A9 (en
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Heinz W. Pauls
Bryan T. Forrest
Radoslaw Laufer
Miklos Feher
Peter Brent Sampson
Guohua Pan
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University Health Network
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Priority to CA2709536A priority Critical patent/CA2709536C/en
Priority to JP2010538297A priority patent/JP2011506494A/en
Priority to EP08865534A priority patent/EP2235004A4/en
Priority to US12/808,961 priority patent/US8765748B2/en
Priority to CN2008801272472A priority patent/CN101970426A/en
Priority to AU2008340991A priority patent/AU2008340991B2/en
Publication of WO2009079767A1 publication Critical patent/WO2009079767A1/en
Publication of WO2009079767A9 publication Critical patent/WO2009079767A9/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Protein kinases have been the subject of extensive study in the search for new therapeutic agents in various diseases, for example, cancer. Protein kinases are known to mediate intracellular signal transduction by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell.
  • the polo-like kinase (PLK) family of serine/threonine kinases comprises at least four known members: PLKl, PLK2 (also known as Snk), PLK3 (also known as Fnk or Prk) and PLK4 (also known as Sak).
  • PLK4 is the least understood and most divergent member of the PLK family.
  • the N-terminal catalytic domain of PLK4 has a different substrate specificity from that of PLK1-3.
  • PLK4 also has a divergent C- terminus comprising only a single polo-box sequence, not the tandem PB sequences in PLK 1-3, that appears to act as a homodimerization domain rather than a localization domain (Lowery et al, (2005) Oncogene 24: 248-259).
  • PLK4 is known to be involved in the control of mitotic entry and exit, and a regulator of centrosome duplication (Habedanck et al. Nature Cell Biology 7: 1140- 1146, 2005). PLK4 transcripts increase from S through M phase, and the protein is ubiquitylated and destroyed by the anaphase promoting complex (APC) (Hudson et al. Curr. Biol. 11: 441- 446, 2001; Fode etal MoI. Cell. Biol. 16: 4665 ⁇ 672, 1996). PLK4 is required for late mitotic progression (Fode et al. PNAS. 91 : 6388- 6392, 1994; Hudson et al. Curr. Biol.
  • API anaphase promoting complex
  • PLK4 knockout mice are embryonic lethal (E7.5), with a marked increase in mitotic and apoptotic cells (Hudson et al. Curr. Biol. 11: 441-446, 2001).
  • PLK4 is transcriptionally repressed by p53 (Li et al. Neoplasia 7: 312-323, 2005). This repression is likely mediated through the recruitment of histone deacetylase (HDAC) repressors and repression appears to contribute to p53-induced apoptosis (Li et al.
  • HDAC histone deacetylase
  • PLK4 has been reported to be overexpressed in colorectal tumors with expression reported as low in adjacent normal intestinal mucosa (Macmillian et al. Ann. Surg. Oncol. 8: 729-740, 2001).
  • PLK4 mRNA has been reported to be overexpressed in some tumor cell lines (Hitoshi, et al., U.S. Patent Application No. US 2003/0027756).
  • agents which inhibit a protein kinase have the potential to treat cancer.
  • agents which inhibit a protein kinase have the potential to treat cancer.
  • agents which can act as protein kinase inhibitors in particular PLK4 inhibitors.
  • indolinone compounds are potent kinase inhibitors, such as polo-like kinases (PLK) (see Example B). Applicants have also now discovered that these indolinone compounds have potent anticancer activity (see Example C). Based on these discoveries, indolinone compounds, pharmaceutical compositions thereof, and methods of treating cancer with the indolinone compounds are disclosed herein.
  • PLK polo-like kinases
  • the present invention is directed to a compound represented by Structural Formula (A):
  • Ring A is an optionally substituted 5- or 6-membered aromatic ring.
  • Ring B is an optionally substituted phenyl ring.
  • Ring C is a 5-membered heteroaromatic ring wherein one of X1-X3 is N, one of X1-X3 is NR 5 , and one of X1-X3 is N or CR 6 .
  • R 3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl.
  • each of R 4 and R 5 independently is -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O) 2 (Cl-Co alkyl) or -S(O) 2 (phenyl), wherein each said alkyl in the groups represented by R 4 and R 5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and C1-C6 haloalkoxy, and wherein each said phenyl in the groups represented
  • R 6 is hydrogen, halogen, nitro, cyano, R', -OR, -SR, -N(R) 2 , -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R) 2 , -OC(O)N(R) 2 , -NRC(O)R, -NRC(O)OR, -SOR', -SO 2 R', -SO 3 R', -SO 2 N(R) 2 , -NRS(O)R', -NRSO 2 R', -NRC(O)N(R) 2 , -NRC(O)ON(R) 2 , or -NRSO 2 N(R) 2 .
  • each R independently is hydrogen, C 1-10 aliphatic, phenyl or 5-6 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and wherein each of the phenyl and heteroaryl groups represented by R, and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or
  • each R independently is Ci -10 aliphatic, phenyl or 5-14 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C ⁇ alkylamino, C 1-6 dialkylamino, -C(O)(C1-C6 alkyl), -C(O)(C1-C6 haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(C 1-C6 alkyl), -C(O)O(C 1-C6 haloalkyl),-C(O)O(phenyl), -OC(O)(Cl-Co alkyl), -OC(O)(C1
  • each of the phenyl and heteroaryl groups represented by R 1 , and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R 1 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, non-aromatic heterocyclic group, C 1-6 alkylamino, C 1-6 dialkylamino, -C(O)(C 1-C6 alkyl), -C(O)(C 1-C6 haloalkyl), -C(O)(
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention also includes a method of treating a subject having cancer comprising administering a therapeutically effective amount of a compound of the invention disclosed herein or a pharmaceutically acceptable salt thereof.
  • the present invention also includes a method of inhibiting Aurora B and/or PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4, comprising administering a therapeutically effective amount of a compound of the invention disclosed herein or a pharmaceutically acceptable salt thereof. Also, use of a compound of the invention disclosed herein or a pharmaceutically acceptable salt thereof in therapy is included in the present invention.
  • the therapy is for treating a subject with cancer. In another embodiment, the therapy is for inhibiting Aurora B and/or PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4.
  • Also included in the present invention is the use of a compound of the invention disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a subject with cancer.
  • Also included in the present invention is the use of a compound of the invention disclosed herein or a pharamceutically acceptable salt thereof for the manufacture of a medicament for inhibiting Aurora B and/or PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4.
  • the figure is a bar graph showing the inhibition of HUV-EC-C Cell Tube Formation by compound Example A57.
  • the present invention is directed to an indolinone compound represented by Structural Formula (A).
  • Structural Formula (A) A first set of values and specific values for the variables in Structural Formula (A) are provided in the following paragraphs:
  • Ring A is an optionally substituted 5- or 6-membered aromatic ring.
  • ring A is optionally subsituted benzene ring.
  • ring A is optionally substituted pyridine ring.
  • ring A is optionally substituted pyrrole ring.
  • ring A is optionally substituted thiophene ring.
  • ring A is optionally substituted thiozole ring.
  • ring A is optionally substituted with one or more substituents Q a
  • phenyl ring B is optionally substituted with one or more substituents Q b
  • each of Q a and Q b independently is selected from the group consisting of halogen, -X-R 1 , -NO 2 , -CN, -NCS, Ak 1 , Ar 1 , (C 1-10 alkylene ⁇ Ar 1 , (C 2-10 alkenylene ⁇ Ar 1 , -O-[CH 2 ] P -O-, -S-[CH 2 ] P -S- and -[CH 2 ] q -.
  • one of Q a and Q b is halogen, -NO 2 , -CN, Ak 1 , Ar 1 , (Ci -10 alkylene)-Ar 1 , (C 2-10 alkenylene ⁇ Ar 1 or -X-R 1 ; and the other of Q a and Q b is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
  • one of Q a and Q b is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(Cl-CO alkyl), -C(O)NH 2 , -C(O)NH(Cl- C6 alkyl), -C(O)N(Cl-CO alkyl) 2 , -SO 2 NH 2 , -SO 2 NH(Cl-Co alkyl), -SO 2 N(C1-C6 alkyl) 2 , -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -SH, -S(Cl-Co alkyl), -S(Cl- C6 haloalkyl), -NH 2 , -NH(Cl-Co alkyl), -N(Cl-Co alkyl) 2 , , -NH
  • one of Q a and Q b is halogen, hydroxy, cyano, nitro, Ph, -CH 2 Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(Cl-Co alkyl)(Ph), -SO 2 NH(Ph), -SO 2 N(Cl-CO alkyl)(Ph), -O(Ph), -S(Ph), -NH(Ph), -N(Cl-Co alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(Cl-CO alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(Cl-Co alkyl)(Ph), -NHSO 2 NH(Ph), -NHSO 2 N(Cl-Co alkyl)(
  • both of Q a and Q b are independently halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
  • Q a is halogen, cyano, -NR 1 R 2 , -NR 2 C(O)R 1 , -C(O)OR 1 , -OC(O)R 1 , -N(R ⁇ C(O)NR 1 R 2 , -OR 1 , Ci -6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -SH, -0(C 1-6 alkyl), -S(Ci -6 alkyl) and C 1-6 haloalkoxy; and Q b is halogen, C 1-3 alkyl, Ci -3 haloalkyl, Ci -3 alkoxy, or Cj -3 haloalkoxy.
  • Q a is -OH, Ci -6 alkoxy or C 1-6 haloalkoxy
  • Q b is halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C] -3 haloalkoxy.
  • X is -C(O)O-, -C(O)-, -C(S)-, -OC(O)-, -C(O)N(R 2 )-, -C(S)N(R 2 )-, -OC(O)N(R 2 )-, -S(O)-, -S(O) 2 -, -SO 3 -, -SO 2 NR 2 -, -0-, -S-, -NR 2 -, -NR 2 C(O)-, -NR 2 S(O)-, -NR 2 C(O)O-, -NR 2 C(O)ONR 2 -, -N(R 2 )C(O)NR 2 -, -NR 2 SO 2 NR 2 - or -NR 2 SO 2 -.
  • X is -C(O)-, -C(S)-, -C(O)N(R 2 )-, -OC(O)N(R 2 )-, -SO 2 NR 2 -, -0-, -S-, -NR 2 -, -NR 2 C(O)-, -NR 2 C(O)O-, -NR 2 C(O)ONR 2 -, -N(R 2 )C(O)NR 2 -, -NR 2 SO 2 NR 2 - or -NR 2 SO 2 -.
  • Each R 1 independently is: i) hydrogen; ii) an optionally substituted C 6-14 aryl group or an optionally substituted 5-14 membered heteroaryl group; or iii) an optionally substituted C 1-I0 aliphatic group, provided that R 1 is other than hydrogen when X is -S(O)-, -S(O) 2 -, -SO 3 -, -NR 2 S(O)- or -NR 2 SO 2 -.
  • each R 1 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted C 1-10 alkyl, provided that R 1 is other than hydrogen when X is -S(O)-, -S(O) 2 -, -SO 3 -, -NR 2 S(O)- or -NR 2 SO 2 -.
  • each of the aryl and heteroaryl groups represented by R 1 is independently and optionally substituted with one or more substitutents selected from the group consisting of halogen, -N0 2> -CN, -NCS, Ak 10 , (Ci -I0 alkylene)-Ar 10 , (C 2-I0 alkenylene)-Ar 10 , -C(O)OR 10 , -C(O)R 10 , -C(S)R 10 , -OC(O)R 10 , -C(O)N(R 1 ⁇ , -C(S)N(R 1 ⁇ -OC(O)N(R 11 ) 2 , -S(O)R 12 , -S(O) 2 R 12 , -SO 3 R 12 , -SO 2 N(R 11 ⁇ , -OR 10 , -SR 10 , -N(R 11 J 2 , -NR 11 C(O)R 10 , -NR 11 S
  • each of the aryl and heteroaryl groups represented by R 1 is independently and optionally substituted with one or more substitutents selected from the group consisting of halogen, nitro, cyano, Ak 10 , (CM O alkylene)-Ar 10 , (C 2-I0 alkenylene)-Ar 10 , -OR 10 , -SR 10 , -OC(O)N(R 11 J 2 , -N(R 1 ⁇ -C(O)NR 11 , -NR 11 C(O)R 10 , -N(R 1 ⁇ C(O)N(R 11 J 2 , -NR 11 SO 2 N(R 1 ') 2 , -NR 11 SO 2 R 12 , -SO 2 N(R n ) 2 , -OC(O)R 10 -C(O)OR 10 and -C(O)R 10 .
  • the aliphatic group, including alkyl group, represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of halogen, -NO 2, -CN, -NCS, Ar 10 , -C(O)OR 10 , -C(O)R 10 , -C(S)R 10 , -OC(O)R 10 , -C(0)N(R n ) 2 , -C(S)N(R ⁇ ) 2 , -OC(O)N(R 1 %, -S(O)R 12 , -S(O) 2 R 12 , -SO 3 R 12 , -SO 2 N(R ⁇ ) 2 , -OR 10 , -SR 10 , -N(R n ) 2 , -NR 11 C(O)R 10 , -NR 11 S(O)R 12 , -NR 11 C(O)OR 12 , -N(R n )
  • the aliphatic group, including alkyl group, represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ar 10 , -OR 10 , -SR 10 , -N(R U ) 2 , -OC(O)R 10 , -C(O)OR 10 and -C(O)R 10 .
  • R 1 is -H- or Ci -6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SH, -0(C 1-3 alkyl), -S(C 1-3 alkyl) and C 1-6 haloalkoxy.
  • Each R 2 independently is R 1 , -CO 2 R 1 , -SO 2 R 1 or -C(O)R 1 , or, taken together with NR 1 , forms an optionally substituted non-aromatic heterocyclic group represented by NR 1 R 2 .
  • each R 2 is -H or C1-C6 alkyl.
  • R 2 is -H- or Cj -6 alkyl, wherein the Ci -6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SH, -0(Ci -3 alkyl), -S(Ci -3 alkyl) and Ci -6 haloalkoxy.
  • R 4 is H or Cl-C6 alkyl, then ring A is not phenyl or phenyl substituted with halogen or trifluoromethyl.
  • Z N-, then
  • R 3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In one embodiment, R 3 is -H or C1-C6 alkyl. In another embodiment, R 3 is -H, halogen, C1-C6 alkyl or Cl-
  • Each of R 4 and R 5 independently is -H, C1-C6 alkyl, phenyl, -C(O)(C1-C6 alkyl), -C(O)(phenyl), -C(O)O(C 1-C6 alkyl), -C(O)O(phenyl), -S(O) 2 (Cl-Co alkyl) or -S(0) 2 (phenyl).
  • each alkyl in the groups represented by R 4 and R 5 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and C1-C6 haloalkoxy.
  • each phenyl in the groups represented by R 4 and R 5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy.
  • R 4 and R 5 are both -H.
  • R 6 is hydrogen, halogen, nitro, cyano, R 1 , -OR, -SR, -N(R) 2 , -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R) 2 , -OC(O)N(R) 2 , -NRC(O)R, -NRC(O)OR, -SOR 1 , -SO 2 R 1 , -SO 3 R', -SO 2 N(R) 2 , -NRS(O)R', -NRSO 2 R', -NRC(O)N(R) 2 , -NRC(O)ON(R) 2 or -NRSO 2 N(R) 2 .
  • R 6 is hydrogen, halogen, nitro, cyano, R 1 , -OR, -SR or -N(R) 2 .
  • R 6 is hydrogen, halogen, nitro, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, Cl- C6 haloalkoxy, -S(C1-C6 alkyl), -S(Cl-Co haloalkyl), amino, C1-C6 alkylamino, C1-C6 dialkylamino, phenoxy or phenyl, wherein each of said alkyl and said alkoxy in the groups respresented by R 6 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, C1-C3 alkoxy and C1-C3 haloalkoxy, and
  • R 6 is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.
  • R 6 is an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl.
  • the phenyl and 5-6 membered heteroaryl represented by R 6 are independently and optionally substituted with one or more substitutents selected from the group consisting of: halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and Cl- C6 haloalkoxy.
  • R 6 is an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrrolyl group, an optionally substituted pyrazolyl, an optionally substituted thiazolyl, an optionally substituted pyrimidyl, or an optionally substituted thienyl.
  • Each R 10 independently is: i) hydrogen; ii) an optionally substitued C 6- I 4 aryl group or an optionally substituted 5-14 membered heteroaryl group; or iii) an optionally substituted C 1-1O aIlCyI group. In one embodiment, each R 10 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted C 1-6 alkyl group.
  • each of the aryl, including phenyl, and heteroaryl groups represented by R 10 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-I0 alkyl, C 1- !0 haloalkyl, (C 1-10 haloalkoxy)C 1- i 0 alkyl, (Ci -10 alkoxy)Ci -10 alkyl, Ci -I0 hydroxyalkyl, C 1-10 aminoalkyl, (Ci -I0 alkylamino)Ci-i 0 alkyl, (Ci-io dialkylamino)Ci.
  • substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-I0 alkyl, C 1- !0 haloalkyl, (C 1-10 haloalkoxy)C 1- i 0 alkyl, (Ci -10 alkoxy)Ci -10 alky
  • each of the aryl, including phenyl, and heteroaryl groups represented by R 10 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci -6 alkyl, Ci -6 haloalkyl, (Ci -6 haloalkoxy)C I-6 alkyl, (Ci .
  • each of the aryl, including phenyl, and heteroaryl groups represented by R 10 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy.
  • the alkyl group represented by R 10 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci -I0 haloalkyl, C] -10 alkoxy, C 1-10 haloalkoxy, amino, Ci -10 alkylamino, C 1-10 dialkylamino, C 1-10 alkylcarbonyloxy, C 1- 10 alkoxycarbonyl, Ci -10 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
  • substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci -I0 haloalkyl, C] -10 alk
  • the alkyl group represented by R 10 is optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, Q -6 haloalkyl, Ci -6 alkoxy, C 1-6 haloalkoxy, amino, Ci-e alkylamino, C 1-6 dialkylamino, C ⁇ alkylcarbonyloxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl and phenyl.
  • substituents selected from the group consisting halogen, nitro, cyano, hydroxy, Q -6 haloalkyl, Ci -6 alkoxy, C 1-6 haloalkoxy, amino, Ci-e alkylamino, C 1-6 dialkylamino, C ⁇ alkylcarbonyloxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl and phenyl.
  • the alkyl group represented by R 10 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloaloxy and phenyl.
  • Each R 11 independently is R 10 , -CO 2 R 10 , -SO 2 R 10 or -C(O)R 10 , or -N(R 1 ' ) 2 taken together is an optionally substituted non-aromatic heterocyclic group.
  • Each R 12 independently is: i) an optionally substitued C 6 .H aryl group or an optionally substituted 5-14 membered heteroaryl group; or ii) an optionally substituted Ci -I0 alkyl group. Alternativrly, each R 12 independently is i) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or ii) an optionally substituted Ci -6 alkyl group.
  • each of the aryl, including phenyl, and heteroaryl groups represented by R 12 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci -10 alkyl, Cj.io haloalkyl, (Ci -I0 haloalkoxy)Ci.io alkyl, (Ci -I0 alkoxy)Ci.i 0 alkyl, Ci -I0 hydroxyalkyl, CM 0 aminoalkyl, (Ci -I0 alkylamino)Ci -10 alkyl, (Ci -I0 dialkylamino)Ci.i 0 alkyl, (phenyl)Ci.io alkyl, (5-6 membered heteroaryl)Ci.i 0 alkyl, amino, Ci -I0 alkylamino, C 1-10 dialkylamino, C 1-10 alkoxy, Ci-jo halo
  • each of the aryl, including phenyl, and heteroaryl groups represented by R 12 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci -6 alkyl, Cj -6 haloalkyl, (C 1-6 haloalkoxy)d ⁇ alkyl, (Ci -6 alkoxy)C! ⁇ alkyl, C 1-6 hydroxyalkyl, (Ci-6aminoalkyl, (C 1-6 alkylaminoX ⁇ alkyl, (C 1-6 dialkylamino)C 1-6 alkyl, amino, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkoxy, Ci -6 haloalkoxy, C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyl and C 1-6 alkylcarbonyl.
  • each of the aryl, including phenyl, and heteroaryl groups represented by R 12 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and Cl- C3 haloaloxy.
  • the alkyl group represented by R 12 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-10 haloalkyl, Ci -10 alkoxy, C 1-I0 haloalkoxy, amino, C 1-10 alkylamino, C 1-10 dialkylamino, C 1-I0 alkylcarbonyloxy, C 1-10 alkoxycarbonyl, C 1-I0 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
  • substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-10 haloalkyl, Ci -10 alkoxy, C
  • the alkyl group represented by R 12 is optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, CJ -6 haloalkyl, Ci -6 alkoxy, C 1 ⁇ haloalkoxy, amino, C 1-6 alkylamino, Ci -6 dialkylamino, C I-6 alkylcarbonyloxy, Ci -6 alkoxycarbonyl, C 1-6 alkylcarbonyl and phenyl.
  • substituents selected from the group consisting halogen, nitro, cyano, hydroxy, CJ -6 haloalkyl, Ci -6 alkoxy, C 1 ⁇ haloalkoxy, amino, C 1-6 alkylamino, Ci -6 dialkylamino, C I-6 alkylcarbonyloxy, Ci -6 alkoxycarbonyl, C 1-6 alkylcarbonyl and phenyl.
  • the alkyl group represented by R 12 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloaloxy and phenyl.
  • Each R 21 independently is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted phenyl or optionally substitued 5-6 membered heteroaryl, or N(R 21 ) 2 forms an optionally substituted non-aromatic heterocyclic group.
  • each R 21 independently is hydrogen, optionally substituted Ci -6 alkyl or optionally substituted phenyl.
  • each of the phenyl and heteroaryl groups represented by R 21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
  • the alkyl group represented by R 21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkoxy, C1-C3 haloalkoxy and phenyl.
  • Each R 22 independently is optionally substituted C 1-6 alkyl, optionally substituted phenyl or optionally substitued 5-6 membered heteroaryl.
  • each R 22 independently is optionally substituted C 1-6 alkyl or optionally substituted phenyl.
  • each of the phenyl and heteroaryl groups represented by R 22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
  • the alkyl group represented by R 22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkoxy, C1-C3 haloalkoxy and phenyl.
  • Each R independently is hydrogen, optionally substituted C 1-10 aliphatic, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl.
  • N(R) 2 forms an optionally substituted non-aromatic heterocyclic group.
  • the aliphatic group represented by R is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and C1-C6 haloalkoxy, wherein each of the phenyl and the 5-6 membered heteroaryl groups are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy.
  • each of the phenyl and the heteroaryl groups represented by R is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and Cl- C6 haloalkoxy.
  • Each R' independently is optionally substituted CMO aliphatic, optionally substituted phenyl or optionally substituted 5-14 membered heteroaryl.
  • the aliphatic group represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and C1-C6 haloalkoxy, Ci -6 alkylamino, C w dialkylamino, -C(O)(C 1 -C6 alkyl), -C(O)(C 1 -C6 haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(C 1-C6 alkyl), -C(O)O(C 1-C6 haloalkyl),-C(O)O(phenyl), -OC(O)(C 1-C6 alkyl), -OC(O)(C 1-C6 haloalkyl), -OC(O)(phenyl),
  • each of the phenyl and the heteroaryl groups represented by R' is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, non-aromatic heterocyclic group, C 1-6 alkylamino, C 1-6 dialkylamino, -C(O)(C 1 -C6 alkyl), -C(O)(C 1 -C6 haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(Cl-Co alkyl), -C(O)O(Cl-Co haloalkyl),-C(O)O(phenyl), -OC(O)(C 1-C6 alkyl),
  • each Ak 1 independently is an optionally substituted C 1-10 alkyl group.
  • each Ak 1 independently is an optionally substituted C 1-6 alkyl group.
  • each of the aliphatic and alkyl groups represented by Ak' is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -N(R 21 ) 2 , -C(O)N(R 21 ) 2 , -C(O)N(R 21 ) 2 , -NR 21 C(O)R 21 , -SO 2 R 22 , -SO 2 N(R 21 ) 2 , -NR 21 SO 2 R 22 , -NR 21 C(O)OR 21 , -OC(O)N(R 2I ) 2 , -NR 21 C(O)N(R 21 ) 2 , -NRC(O)ON(R) 2 , -NR 2I SO 2 N(R 21 ) 2 , -OR
  • each of the aliphatic and alkyl groups represented by Ak 1 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloaloxy and phenyl.
  • Each Ak 10 independently is an optionally substituted C 1-10 alkyl group.
  • each Ak 1 independently is an optionally substituted C 1-6 alkyl group.
  • the alkyl group represented by Ak 10 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci -6 alkyl), -S(Ci -6 alkyl), Ci -6 haloalkoxy, amino, Ci -6 alkylamino, Ci -6 dialkylamino, Ci -6 alky lcarbonyloxy, Q- ⁇ alkoxycarbonyl and Ci -6 alkylcarbonyl.
  • the alkyl group represented by Ak 10 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloaloxy and phenyl.
  • Each Ar 1 independently is an optionally substituted C 6-14 aryl group or an optionally substituted 5-14 membered heteroaryl group.
  • each Ar 1 independently is an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group.
  • suitable substituents for each of the aryl and heteroaryl groups represented by Ar 1 independently include halogen, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, (Ci -6 haloalkoxy)Ci-6alkyl, (C 1-6 ⁇ alkyl, (C M dialkylamino)Ci -6 alkyl, -NR 21 2 , -C(O)NR 21 2 , -C(O)NR 21 2 , -NR 21 C(O)R 21 , -S(O) 2 R 22 , -SO 2 NR 21 2 , -NR 21 SO 2 R 22 , -NR 21 C(O)NR 2 ⁇ 5 -NR 21 SO 2 NR 21 2 , -OR 21 , -SR 21 , Q -6 haloalkoxy, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 and benzyl.
  • substituents include a phenyl group and a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
  • each of the phenyl and heteroaryl groups represented by Ar 1 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci -6 alkyl, Q -6 haloalkyl, (Ci -6 haloalkoxy)C I-6 alkyl, (Ci -6 aminoalkyl, (Ci -6 alkylamino)Ci ⁇ alkyl, (Ci -6 dialkylamino)Ci -6 alkyl, -NR 21 2 , -C(O)NR 21 2 , -C(O)NR 21 2 , -NR 21 C(O)R 21 , -S(O) 2 R 22 , -SO 2 NR 21 2 , -NR 21 SO 2 R 22 , -NR 21 C(O)NR 22 2 , -NR 21 SO 2 NR 21 2 , -OR 21 , -SR 21 , Q -6 haloalk
  • each of the phenyl and heteroaryl groups represented by Ar 1 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci -6 alkyl), -S(Ci -6 alkyl), Ci -6 alkyl, Ci -6 haloalkyl, (C 1-6 haloalkoxy)C I-6 alkyl, (Ci -6 alkoxy)C I-6 alkyl, Ci- ⁇ hydroxyalkyl, (Ci -6 aminoalkyl, (Ci -6 alkylamino)Ci ⁇ alkyl, (Ci -6 dialkylamino)Ci -6 alkyl, (phenyl)C ⁇ alkyl, (5-6 membered heteroary I)C I-6 alkyl, amino, Ci -6 alkylamino, Ci -6 dialkylamino, Ci -6 haloalkoxy, Ci ⁇ alkylcarbonyl
  • each of the phenyl and heteroaryl groups represented by Ar 1 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy.
  • Each Ar 10 independently is an optionally substituted C 6-14 aryl group or an optionally substituted 5-14 membered heteroaryl group. Alternatively, each Ar 10 independently is an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group.
  • suitable substituents for each of the aryl and heteroaryl groups represented by Ar 10 include halogen, nitro, cyano, -OH, -SH, -0(C 1-10 alkyl), -S(CM 0 alkyl), CM 0 alkyl, CM 0 haloalkyl, (C 1-10 haloalkoxy)C 1-10 alkyl, (C 1-10 alkoxy)C M0 alkyl, C 1-10 hydroxyalkyl, (C 1-10 aminoalkyl, (C 1-10 alkylamino)C 1-10 alkyl, (C 1-1 O dialkylamino)C M0 alkyl, (phenyl)C 1-10 alkyl, (5-6 membered heteroaryl)C M O alkyl, amino, C 1-10 alkylamino, Ci-iodialkylamino, CM 0 haloalkoxy, CM 0 alky lcarbonyloxy, C 1-10 alkoxycarbonyl and CM
  • each of the phenyl and heteroaryl groups represented by Ar 10 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy.
  • Each p independently is 1, 2 or 3.
  • Each q independently is 2, 3, 4 or 5.
  • heteroaryl groups including 5-14 membered heteroaryl groups or 5-6 membered heteroaryl groups, referred to in the definitions of the variables for Structural Formual (A) are as described later.
  • Typical examples of the 5-6 membered heteroaryl groups referred to in the definitions of variables for Structural Formual (A) include a furanyl group, an imidazolyl group, an isoxazolyl group, an oxadiazolyl group, an oxazolyl, a pyrazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thiazolyl group, a triazolyl group, a tetrazolyl group, a thienyl group, a pyrimidinyl group, a pyridinyl group or a pyridazinyl group.
  • Typical 5-14 membered heteroaryl groups referred to in the definitions of variables for Structural Formual (A) include an indolyl group, a quinolinyl group, a furanyl group, an imidazolyl group, an isoxazolyl group, an oxadiazolyl group, an oxazolyl, a pyrazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thiazolyl group, a triazolyl group, a tetrazolyl group, a thienyl group, a pyrimidinyl group, a pyridinyl group or a pyridazinyl group.
  • the compound of the present invention is represented by Structural Formula (B), (C), (D), (E), (F), (G), (H), (Y), (J) or (K):
  • Each OfY 1 , Y 2 , Y 3 and Y 4 in Strucutral Formula (B) is independently -N or
  • Ring A and ring B of Structural Formulas (B)-(K) are optionally substituted. Values and specific values for the remainder of the variables are as described above for Structural Formula (A).
  • the compound of the present invention is represented by Structural Formula (I):
  • R 3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, provided when R 3 is halogen, then
  • R 3 is H, C 1 -C6 alkyl or C 1 -C6 haloalky.
  • the compound of the present invention is represented by Structural Formula (I), wherein a first set of values for the variables of Structural Formula (I) is provided in the following paragraphs:
  • R 3 is -H, C1-C6 alkyl or C1-C6 haloalkyl.
  • each R' independently is Cj.io aliphatic, phenyl or 5-6 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and wherein each of the phenyl and heteroaryl groups represented by R 1 , and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R' independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C
  • X is -C(O)-, -C(S)-, -C(O)N(R 2 )-, -OC(O)N(R 2 )-, -SO 2 NR 2 -, -O-, -S-, -NR 2 -, -NR 2 C(O)-, -NR 2 C(O)O-, -NR 2 C(O)ONR 2 -, -N(R 2 )C(O)NR 2 -, -NR 2 SO 2 NR 2 - or -NR 2 SO 2 -.
  • Each R 1 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted Ci -I0 alkyl group.
  • Suitable substitutents for each of the alkyl, phenyl and heteroaryl groups represented by R 1 independently are as described above for the first set of values.
  • Each Ak 1 independently is an optionally substituted C 1-I0 alkyl group. Suitable substitutents for the alkyl group represented by Ak 1 are as described above for the first set of values.
  • Each Ar 1 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, (Ci -6 (C 1- 6 aminoalkyl, (C i .
  • Each Ak 10 independently is an optionally substituted C 1-6 alkyl group. Suitable substitutents for the alkyl group represented by Ak 10 are as described above for the first set of values.
  • Each Ar 10 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Q -6 alkyl, Ci -6 haloalkyl, (C 1-6 haloalkoxy)Ci -6 alkyl, (Ci -6 alkoxy)C I-6 alkyl, Ci -6 hydroxyalkyl, Ci -6 aminoalkyl, (C 1-6 alkylamino)Ci ⁇ alkyl, (Ci -6 dialkylamino)Ci ⁇ alkyl, benzyl, phenyl, Ci ⁇ alkoxy, Ci -6 haloalkoxy, amino, Ci -6 alkylamino, Ci ⁇ dialkylamino, Ci -6 alkylcarbonyloxy, Ci -6 alkoxycarbonyl and Ci -6 alkylcarbonyl.
  • Each R 10 independently is: i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally susbstituted Ci -6 alkyl group.
  • Each of the phenyl and heteroaryl groups represented by R 10 is optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-6 alkyl, C I-6 haloalkyl, (C 1-6 haloalkoxy)C 1-6 alkyl, (Q -6 alkoxy)C 1-6 alkyl, Cj -6 hydroxyalkyl, (C 1-6 aminoalkyl, (Ci -6 alkylamino)C I-6 alkyl, alkyl, amino, C 1-6 alkylamino, C 1-6 dialkylamino, Ci -6 alkoxy, Ci -6 haloalkoxy, C 1-6 alkylcarbonyloxy, C 1-6 alkoxycarbonyl and C 1 ⁇ alkylcarbonyl.
  • substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-6 alkyl, C I-6 haloalkyl,
  • the alkyl group represented by R 10 is optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, C 1-6 haloalkyl, Ci -6 alkoxy, C 1 . 6 haloalkoxy, amino, Q -6 alkylamino, Ci -6 dialkylamino, Cj -6 alkylcarbonyloxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl and phenyl.
  • Each R 1 ' independently is R 10 , -CO 2 R 10 , -SO 2 R 10 or -C(O)R 10 , or
  • Each R 12 independently is: i) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or ii) an optionally susbstituted C 1-6 alkyl group.
  • Each of the phenyl and heteroaryl groups represented by R 12 is optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, (Ci -6 haloalkoxy)C 1-6 alkyl, (Ci -6 alkoxy)C 1-6 alkyl, C 1-6 hydroxyalkyl, (Ci.
  • the alkyl group represented by R 12 is optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, Ci -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, Ci -6 alkylamino, Ci -6 dialkylamino, Ci -6 alkylcarbonyloxy, Ci -6 alkoxycarbonyl, Ci -6 alkylcarbonyl and phenyl.
  • substituents selected from the group consisting halogen, nitro, cyano, hydroxy, Ci -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, Ci -6 alkylamino, Ci -6 dialkylamino, Ci -6 alkylcarbonyloxy, Ci -6 alkoxycarbonyl, Ci -6 alkylcarbonyl and phenyl.
  • Each R 21 independently is hydrogen, Ci -6 alkyl or optionally substituted phenyl. Suitable substitutents for the phenyl group represented by R 21 are as described above for the first set of values.
  • Each R 22 independently is Ci -6 alkyl or optionally substituted phenyl.
  • Suitable substitutents for the phenyl group represented by R 22 are as described above for the first set of values. Values and specific values for X, R 1 , Ak 1 and Ar 1 are each independently as described above in the second set of values of the second embodiment.
  • Each R 1 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted Ci -10 alkyl group.
  • Each of the phenyl and heteroaryl groups represented by R 1 is optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ak 10 , (Ci -10 alkylene)-Ar 10 , (C 2-10 alkenylene)-Ar 10 , -OR 10 , -SR 10 , -OC(O)N(R 11 ⁇ , -N(R 11 ⁇ , -C(O)NR 11 , -NR 11 C(O)R 10 , -N(R u )C(0)N(R ⁇ ) 2 , -NR 11 SO 2 N(R 1 ⁇ 2 , -NR 11 SO 2 R 12 , -SO 2 N(R 1
  • the alkyl group represented by R 1 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ar 10 , -OR 10 , -SR 10 , -N(R 11 ⁇ , -OC(O)R 10 , -C(O)OR 10 and -C(O)R 10 .
  • Each Ak 1 independently is a C 1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C 1-O aIlCyI), -S(C I-6 alkyl), amino, Ci- 6 alkylamino, C] -6 dialkylamino, C 1-6 alky lcarbonyloxy, Ci -6 alkoxycarbonyl and C 1-6 alkylcarbonyl.
  • Each Ar 1 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C 1-6 alkyl), -S(C 1-6 alkyl), Ci -6 alkyl, (Ci -6 haloalkoxy)C I-6 alkyl, (Ci -6 alkoxy)C I-6 alkyl, (Ci -6 aminoalkyl, (Ci -6 alky lamino)C I-6 alkyl, (Ci -6 dialkylamino)C I-6 alkyl, (phenyl)C I-6 alkyl, (5-6 membered heteroaryl)Ci_ 5 alkyl, amino, Cj -6 alkylamino, Ci -6 dialkylamino, Ci -6 haloalkoxy, Ci -6 alkylcarbonyloxy, Ci -6 alkoxycarbony
  • Each R 10 independently is i) hydrogen, ii) a phenyl group group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy, or iii) a C 1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C 1 -C3 alkoxy, C 1 -C3 haloaloxy and phenyl.
  • Each R 12 independently i) a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy, or ii) a C 1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, Cl- C3 haloaloxy and phenyl.
  • Each Ar 10 independently is a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy.
  • Values and specific values for X, R 1 , R 11 , R 21 , R 22 , Ak 1 , Ak 10 and Ar 1 are each independently as described above in the fourth set of values of the second embodiment. Values and specific values for the remainder of the variables of Structural
  • Formula (I) are each independently as described above in the first set of values of the second embodiment.
  • the compound of the invention is represented by Structural Formula (II) or a pharmaceutically acceptable salt thereof:
  • Each of n and m is independently 0, 1 or 2.
  • Each R 2 is -H or C1-C6 alkyl.
  • Each of R 4 and R 5 is independently -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(C 1 -C6 alkyl), -C(O)O(phenyl), -S(O) 2 (C 1 -C6 alkyl) or -S(O) 2 (phenyl), wherein each said phenyl in the groups represented by R 4 and R 5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, and wherein each said alkyl in the groups represented by by R 4 and R 5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen,
  • each of n and m is independently 0, 1 or 2; and values and specific values for the remaining variables of Structural Formula (II) are each independently as described in the first set, the second set, the third set, the fourth set or the fifth set of values for the variables of Structural Formula (I) in the second specific embodiment.
  • the compound of the invention is represented by Structural Formula (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof:
  • Q a and Q b is halogen, -NO 2 , -CN, Ak 1 , Ar 1 , (C 1-10 alkylene)-Ar ⁇ (C 2- io alkenylene ⁇ Ar 1 or -X-R 1 ; and the other of Q a and Q b is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
  • n and m independently is 0, 1 or 2.
  • Each R 2 is -H or C1-C6 alkyl.
  • R 3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl.
  • Each of R 4 and R 5 independently is -H, C 1 -C6 alkyl, phenyl, -C(O)(C 1 -C6 alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O) 2 (Cl-Co alkyl) or -S(O) 2 (phenyl), wherein each said phenyl in the groups represented by R 4 and R 5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C 1 -C6 alkoxy and C 1 -C6 haloalkoxy, and wherein each said alkyl in
  • R 6 is hydrogen, halogen, nitro, cyano, R 1 , -OR, -SR, -N(R) 2 , -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R) 2 , -OC(O)N(R) 2 , -NRC(O)R, -NRC(O)OR, -SOR', -SO 2 R 1 , -SO 3 R', -SO 2 N(R) 2 , -NRS(O)R', -NRSO 2 R', -NRC(O)N(R) 2 , -NRC(O)ON(R) 2 or -NRSO 2 N(R) 2 .
  • Each R 7 independently is -H, F, Cl or
  • Each of R 4 and R 5 independently is -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O) 2 (Cl-Co alkyl) or -S(O) 2 ( ⁇ henyl).
  • n, m, Q a and Q b , R 2 , R 6 and R 7 are each independently as described above in the first set of values for Structural Formulas (III) - (VII).
  • Both of Q a and Q b are independently halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
  • n, m, R 2 , R 2 , R 4 , R 5 , R 6 and R 7 are each independently as described above in the second set of values for Structural Formulas (IH) - (VII).
  • One of Q a and Q b is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(Cl-CO alkyl), -C(O)NH 2 , -C(O)NH(Cl-Co alkyl), -C(O)N(Cl-Co alkyl) 2 , -SO 2 NH 2 , -SO 2 NH(Cl-Co alkyl), -SO 2 N(Cl-Co alkyl) 2 , -OH, -0(Cl-C6 alkyl), -O(C1-C6 haloalkyl), -SH, -S(Cl-Co alkyl), -S(Cl-CO haloalkyl), -NH 2 , -NH(Cl-Co alkyl), -N(Cl-CO alkyl), -SH, -S(Cl-Co alky
  • one of Q a and Q b is halogen, hydroxy, cyano, nitro, Ph, -CH 2 Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(Cl-CO alkyl)(Ph), -SO 2 NH(Ph), -SO 2 N(Cl-Co alkyl)(Ph), -0(Ph), -S(Ph), -NH(Ph), -N(Cl-Co alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(Cl-Co alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(C 1 -C6 alkyl)(Ph), -NHSO 2 NH(Ph),
  • each Ph independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; and the other of Q a and Q b is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
  • each of n and m independently is O, 1 or 2; and values and specific values for the remaining variables of each Structural Formula (III) - (VII) are independently as described in the first set, the second set, the third set, the fourth set or the fifth set of values for the variables of Structural Formula (I) in the second embodiment.
  • each Structural Formula (III) - (VII) values and specific values for the remaining variables of each Structural Formula (III) - (VII) are independently as described in the first set of values for the variables of Structural Formula (II) in the third embodiment.
  • the compound of the invention is represented by a structural formula selected from Structural Formulas (VIII) - (XXXV) or a pharmaceutically acceptable salt thereof:
  • (XVII), (XXI), (XXII), (XXIII), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI) and (XXXII) independently is halogen, -NO 2 , -CN, Ak 1 , Ar 1 , (C] -10 alkylene)-Ar 1 , (C 2-10 alkenylene)-Ar 1 or -X-R 1 .
  • Each Q b in Structural Formulas (IX), (XI), (XIV), (XVIII), (XIX), (XX), (XXIV), (XXV), (XXVI), (XXXIII), (XXXIV) and (XXXV) independently is halogen, -NO 2 , -CN, Ak 1 , Ar 1 , (C 1-10 alkylene ⁇ Ar 1 , (C 2-10 alkenylene ⁇ Ar 1 or -X-R 1 .
  • n and m in Strcutrual Formulas (VIII), (IX), (XV), (XVI), (XVII), (XVIII), (XIX) and (XX) independently is 0, 1 or 2.
  • Each R 2 is -H or C1-C6 alkyl.
  • R 3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl.
  • Each R 7 in Structural Formulas (VIII) - (XII) and (XV) - (XXIX) independently is -H, F, Cl or methyl.
  • Each Q a in Structural Formulas (VIII), (X), (XII), (XIII), (XV), (XVI), (XVII), (XXI), (XXII), (XXIII), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI) and (XXXII) independently is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C 1-C6 alkyl), -C(O)NH 2 , -C(O)NH(C 1-C6 alkyl), -C(O)N(Cl-Co alkyl) 2 , -SO 2 NH 2 , -SO 2 NH(Cl-Co alkyl), -SO 2 N(Cl-Co alkyl) 2 , -OH, -O(C1-C6 alkyl), -O(C1
  • each Q a in Structural Formulas (VIII), (X), (XII), (XIII), (XV), (XVI), (XVII), (XXI), (XXII), (XXIII), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI) and (XXXII) independently is halogen, hydroxy, cyano, nitro, Ph, -CH 2 Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(Cl-Co alkyl)(Ph), -SO 2 NH(Ph), -SO 2 N(Cl-Co alkyl)(Ph), -O(Ph), -S(Ph), -NH(Ph), -N(Cl-CO alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)O(
  • Each Q b in Structural Formulas (IX), (XI), (XIV), (XVIII), (XIX), (XX), (XXIV), (XXV), (XXVI), (XXXIII), (XXXIV) and (XXXV) independently is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(Cl-Co alkyl), -C(O)NH 2 , -C(O)NH(Cl-Co alkyl), -C(O)N(Cl-Co alkyl) 2 , -SO 2 NH 2 , -SO 2 NH(Cl- C6 alkyl), -SO 2 N(Cl-Co alkyl) 2 , -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -SH, -S(Cl-
  • each Q b in Structural Formulas (IX), (XI), (XIV), (XVIII), (XIX), (XX), (XXIV), (XXV), (XXVI), (XXXIII), (XXXIV) and (XXXV) independently is halogen, hydroxy, cyano, nitro, Ph, -CH 2 Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(Cl-Co alkyl)(Ph), -SO 2 NH(Ph), -SO 2 N(C 1 -C6 alkyl)(Ph), -O(Ph), -S(Ph), -NH(Ph), -N(C 1 -C6 alkyl)(Ph), -NHC(O)(Ph), -NHC(O)(Ph), -NHC(O)(Ph), -NHC(O)(Ph), -NHC(O
  • each of n and m independently is 0, 1 or 2; and values and preferred values of the remaining variables of Structural Formulas (VIII) - (XXXV) are each independently as described above for the first set, second set, third set, fourth set or the fifth set of values for the variables of Structural Formula (I) of the second embodiment.
  • the compound of the present invention is represented by Structural Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (C1)-(C4), (Dl)-(DS), (El)-(ES), (Fl)-(FS), (Gl)-(GS), (Hl)-(HS), (1'I)-(PS), (Jl)- (JSX (Kl)-(KS):
  • R 6 for Strucutral Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ik), (II), (Cl), (C2), (Dl), (D2), (D5), (D6), (El), (E2), (E5), (E6), (Fl), (F2), (F5), (F6), (Gl), (G2), (G5), (G6), (Hl), (H2), (H5), (H6), (I'l), (I'2), (F5), (I'6), (Jl), (J2), (J5), (J6), (Kl), (K2), (K5) and (K6) is optionally substituted phenyl, optionally substituted 5-12 membered heteroaryl, -CH 2 -(optionally substituted phenyl), -CH 2 - (optionally substituted 5-12 membered heteroaryl), -CH 2 -CH 2 -
  • R 6 can also be -C ⁇ C-(optionally substituted phenyl), -C ⁇ C-(optionally substituted 5-12 membered heteroaryl), -C ⁇ C- C(O)O(optionally substitutued Ci -6 alkyl), or -C ⁇ €-OC(O)(optionally substitutued
  • R 7 of Structural Formulas (Ig), (Ih), (Ii) and (Ij) is -H, -F, -Cl or methyl and n in Structural Formulas (Ii), (Ij), (Ik) and (II) is 0 or 1.
  • Values and specific values for the remainder of the variables of Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), and (II) are as describe above for Structural Formula (I) in the first embodiment.
  • Values and specific values for the remainder of the variables of Structural Formulas (C1)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (ri)-(I'8), (J1)-(J8) and (K1)-(K8) are as described above for Structural Formula (A).
  • ring A is not phenyl or phenyl substituted with halogen or trifluoromethyl.
  • R 5 and R 6 are not both -H.
  • R 3 is-H, C 1 -C6 alkyl or C 1 -C6 haloalkyl.
  • R 4 and R 5 of Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If),(Cl)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I' 1)-(I'8), (J1)-(J8), and (K1)-(K8) are each independently -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O) 2 (Cl-Co alkyl) or -S(O) 2 (phenyl), wherein each phenyl in the group represented by R 4 and R 5 is optionally substituted with one or more substituents independently selected from the group consist
  • R 6 can also be -C ⁇ C-(optionally substituted phenyl), -C ⁇ C-(optionally substituted 5-12 membered heteroaryl), -C ⁇ C-C(O)O(optionally substitutued C 1 ⁇ alkyl), or -C ⁇ C-OC(O)(optionally substitutued C 1-6 alkyl).
  • the 5-12 membered heteroaryl in the group represented by R 6 is selected from the group consisting of pyridyl, thiazolyl, pyrazinyl, thiophenyl, indolyl, quinolinyl, pyrrolyl, pyrazolyl, and pyrimidyl, each of which is optionally substituted. Values and specific values for the remainder of the variables are as described above in the sixth embodiment.
  • values for the variables in Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (C1)-(C4), (Dl)-(DS), (El)- (E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (ri)-(I'8), (J1)-(J8) and (K1)-(K8) are provided in the following paragraphs:
  • Ring A in Structural Formulas (C1)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I' 1)-(I'8), (J1)-(J8) and (K1)-(K8) are optionally substituted with one or more Q a and ring B in Structural Formulas (C1)-(C4), (D1)-(D8), (El)- (E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I'1)-(I'8), (J1)-(J8) and (K1)-(K8) are optionally substituted with one or more Q b .
  • Q a and Q b are each independently halogen, cyano, -NR 1 R 2 , -NR 2 C(O)R 1 , -C(O)OR 1 , -OC(O)R 1 , -C(O)NR 1 R 2 , -NR 2 C(O)OR 1 , -N(R ⁇ C(O)NR 1 R 2 , -OR 1 , -SO 2 NR 1 R 2 , -NR 2 SO 2 R 1 , Ci -6 alkyl, phenyl or 5-12 membered heteroaryl, wherein the C i- 6 alkyl represented by Q a and Q b is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C 1-6 alkyl), -S(Ci -6 alkyl), Cj -6 haloalkoxy, amino, Ci -6 alky lamino, C 1-6 dialky
  • R 1 and R 2 are each independently -H- or Ci -6 alkyl, wherein the Ci -6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SH, -0(Ci -3 alkyl), -S(Ci -3 alkyl) and Ci -6 haloalkoxy; the phenyl or the 5-12 membered heteroaryl in the group represented by R 6 for Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Cl), (C2), (Dl), (D2), (D5), (D6), (El), (E2), (E5), (E6), (Fl), (F2), (F5), (F6), (Gl), (G2), (G5), (G6), (Hl), (H2), (H5)
  • -(CH 2 ) 0-3 -A/-piperidinyl, -(CH 2 )o -3 -N-morpholinyl, -(CH 2 ) 0-3 -N- pyrrolidinyl and -(CH 2 ) 0-3 -N-piperazinyl are additional permissible substituents for the phenyl or the 5-12 membered heteroaryl in the group represented by R 6 ; and the C 1-6 alkyl in the group represented by R 6 for Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Cl), (C2), (Dl), (D2), (D5), (D6), (El), (E2),
  • values for the variables in Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (C1)-(C4), (D1)-(D8), (El)- (E8), (F1)-(F8), (Gl)-(GS), (H1)-(H8), (I'1)-(I'8), (Jl)-(JS) and (K1)-(K8) are provided in the following paragraphs:
  • Q a is halogen, cyano, -NR 1 R 2 , -NR 2 C(O)R 1 , -C(O)OR 1 , -OC(O)R 1 , -N(R 2 )C(O)NR'R 2 , -OR 1 , C 1-6 alkyl, wherein the Cj -6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -SH, -0(Ci -6 alkyl), -S(Ci -6 alkyl) and Q -6 haloalkoxy;
  • Q b is halogen, Ci -3 alkyl, Ci -3 haloalkyl, Ci -3 alkoxy, or Ci -3 haloalkoxy; and the phenyl, the 5-12 membered heteroaryl and the Ci -6 alkyl in the group represented by R 6 is optionally substituted with one or more substituents selected from the group consisting of
  • Ring A in Structural Formulas (C1)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I' I)-(I' 8), (J1)-(J8) and (K1)-(K8) are optionally substituted with one or more Q a and ring B in Structural Formulas (C1)-(C4), (D1)-(D8), (E I)- (E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (ri)-(F8), (J1)-(J8) and (K1)-(K8) are optionally substituted with one or more Q b .
  • Q a is -OH, Ci -6 alkoxy or Ci -6 haloalkoxy
  • Q b is halogen, Ci -3 alkyl, Ci -3 haloalkyl, C 1 . 3 alkoxy, or Ci -3 haloalkoxy and the phenyl, the 5-12 membered heteroaryl and the Ci -6 alkyl in the group represented by R 6 are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, methyl, methoxy and trifluoromethyl.
  • the compound of the present invention is represented by a structural formula selected from (II) and (12):
  • Q a is -H, halogen, -NH 2 , (C 1-6 alkyl)amine or C 1-6 alkoxy;
  • each heteroaryl in the group represented by R ⁇ is pyridinyl, pyrimidinyl or pyrazinyl and each is optionally substituted halogen, C 1-6 alkyl, Ci ⁇ haloalkyl, (Ci -6 aminoalkyl), alkyl, (Ci -6 dialkylamino)C I-6 alkyl, (phenyl)C 1-6 alkyl, amino, dialkylamino, -(CH 2 )o -3 -JV-piperidinyl, -(CH 2 ) 0- 3 -N-morpholinyl, -(CH 2 ) 0-3 -JV-pyrrolidinyl and -(CH 2 ) 0-3 -JV-piperazinyl, wherein the JV-piperazinyl is optionally JV '-substituted with Q -6 alkyl or C] -6 acyl.
  • a specific moiety in the group represented by a variable refers to the moiety represented by the variable or the moiety in a group represented by the variable.
  • Specific examples of the compounds of the invention include compounds exemplified in the examples below, stereoisomers thereof, and pharmaceutically acceptable salts thereof.
  • Tautomeric forms exist when a compound is a mixture of two or more structurally distinct compounds that are in rapid equilibrium.
  • Certain compounds of the invention exist as tautomeric forms.
  • the following compound represented by Structural Formula (A), wherein two of X1-X3 are N, one of X1-X3 is NH or compound represented by Structural Formula (I), wherein two of X1-X3 are N, one of X1-X3 is NH include at least the following tautomers forms:
  • the compounds of the invention may contain one or more chiral center and/or double bond and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, and/or diastereomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, and/or diastereomers.
  • stereomerically pure forms e.g., geometrically pure, enantiomerically pure, or diastereomerically pure
  • stereoisomeric mixtures are encompassed.
  • compounds represented by Structural Formulas (A) or (I) have E and Z geometric isomers shown below:
  • the compounds of the invention depicted by Structural Formula (A) or (I) include the pure E geometric isomer isomer, the pure Z geometric isomer, and mixtures thereof.
  • the invention encompasses all geometrically-pure forms and geometrically- enriched (i.e.greater than 50% of either E or Z isomer) mixtures, of the compounds disclosed herein.
  • Mixtures include 1:20, 1:10, 20:80, 30:70, 40:60 and 50:50 E:Z and Z:E ratios by mole.
  • a racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer relative to all chiral centers in the molecule.
  • the invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds of the invention which have chiral center(s).
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral- phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers.
  • the depicted or named stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure.
  • Percent purity by weight is the ratio of the weight of the named stereoisomer over the weight of the named stereoisomer plus the weight of its stereoisomers.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p- toluenesulfonic, and tartaric acids).
  • inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids
  • organic acids such as, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic,
  • Compounds of the invention with acidic groups such as carboxylic acids can form pharamceutically acceptable salts with pharmaceutically acceptable base(s).
  • suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
  • Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.
  • salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid.
  • halo as used herein means halogen and includes chloro, fluoro, bromo and iodo.
  • An "aliphatic group” is non-aromatic, consists solely of carbon and hydrogen and may optionally contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched or cyclic. When straight chained or branched, an aliphatic group typically contains between about one and about twenty carbon atoms, typically between about one and about ten carbon atoms, more typically between about one and about six carbon atoms. When cyclic, an aliphatic group typically contains between about three and about ten carbon atoms, more typically between about three and about seven carbon atoms.
  • a “substituted aliphatic group” is substituted at any one or more "substitutable carbon atom".
  • a “substitutable carbon atom” in an aliphatic group is a carbon in an aliphatic group that is bonded to one or more hydrogen atoms.
  • One or more hydrogen atoms can be optionally replaced with a suitable substituent group.
  • a “haloaliphatic group” is an aliphatic group, as defined above, substituted with one or more halogen atoms. Suitable substituents on a substitutable carbon atom of an aliphatic group are the same as those for an alkyl group.
  • alkyl used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, “arylalkyl”, “alkylamine”, “cycloalkyl”, “dialkyamine”, “alkylamino”, “dialkyamino” “alkylcarbonyl”, “alkoxycarbonyl” and the like, includes as used herein means saturated straight-chain, cyclic or branched aliphatic group.
  • a C1-C6 alkyl group is referred to "lower alkyl.”
  • the terms “lower alkoxy”, “lower haloalkyl”, “lower arylalkyl”, “lower alkylamine”, “lower cycloalkylalkyl”, “lower dialkyamine”, “lower alkylamino”, “lower dialkyamino” “lower alkylcarbonyl”, “lower alkoxycarbonyl” include straight and branched, saturated chains containing one to six carbon atoms, and cyclic saturated chains containing three to six carbon atoms.
  • alkoxy means -O-alkyl
  • hydroxyalkyl means alkyl substituted with hydroxy
  • aralkyl means alkyl substituted with an aryl group
  • alkoxyalkyl mean alkyl substituted with an alkoxy group
  • alkylamine means amine substituted with an alkyl group
  • cycloalkylalkyl means alkyl substituted with cycloalkyl
  • dialkylamine means amine substituted with two alkyl groups
  • alkylcarbonyl means -C(O)-R, wherein R is alkyl
  • alkoxycarbonyl means -C(O)-OR, wherein R is alkyl; and where alkyl is as defined above.
  • haloalkyl and haloalkoxy means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • halogen means F, Cl, Br or I.
  • the halogen in a haloalkyl or haloalkoxy is F.
  • acyl group means -C(O)R, wherein R is an optionally substituted alkyl group or aryl group (e.g., optionally substituted phenyl). R is preferably an unsubstituted alkyl group or phenyl.
  • alkylene group is represented by -[CH 2 ] Z -, wherein z is a positive integer, preferably from one to eight, more preferably from one to four.
  • alkynylene group is an alkylene in which at least a pair of adjacent methylenes are replaced with -C ⁇ C-.
  • aryl group used alone or as part of a larger moiety as in
  • aralkyl means carbocyclic aromatic rings.
  • the term “carbocyclic aromatic group” may be used interchangeably with the terms “aryl”, “aryl ring” “carbocyclic aromatic ring”, “aryl group” and “carbocyclic aromatic group”.
  • An aryl group typically has six - fourteen ring atoms.
  • a "substituted aryl group” is substituted at any one or more substitutable ring atom.
  • C 6-H aIyI as used herein means a monocyclic, bicyclic or tricyclic carbocyclic ring system containing from 6 to 14 carbon atoms and includes phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like.
  • heteroaryl refers to aromatic ring groups having five to fourteen ring atoms selected from carbon and at least one (typically 1 -4, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen or sulfur). They include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other carbocyclic aromatic or heteroaromatic rings.
  • 5-14 membered heteroaryl as used herein means a monocyclic, bicyclic or tricyclic ring system containing one or two aromatic rings and from 5 to 14 atoms of which, unless otherwise specified, one, two, three, four or five are heteroatoms independently selected from N, NH, N(Ci -6 alkyl), O and S and includes thienyl, furyl, pyrrolyl, pyrididyl, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
  • Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl ( e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5 -oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5- oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1 -pyrrolyl, 2- pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyrid
  • polycyclic aromatic heteroaryl groups examples include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.
  • aryl and heteroaryl groups include:
  • rings A1-Z7 is optionally substituted. It is noted that, as shown above, rings O1-Z7 can be attached to their designated atom through any ring carbon of the rings which is not at a position bridging two aryl groups. For example,
  • aryl and heteroaryl groups include:
  • each of rings Al-Nl is optionally substituted. More specific values for the aryl and heteroaryl groups include:
  • each of rings Al-Cl is optionally substituted.
  • An optionally substituted ring Al is the most common specific value for each of the aryl group, including the C 6-14 aryl group.
  • non-aromatic heterocyclic group means a monocyclic (typically having 3- to 10-members) or a polycyclic (typically having 7- to 20-members) heterocyclic ring system which is an unsaturated non-aromatic ring.
  • a 3- to 10-membered heterocycle can contain up to 5 heteroatoms; and a 7- to 20- membered heterocycle can contain up to 7 heteroatoms.
  • a heterocycle has at least one carbon atom ring member.
  • Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the heterocycle may be attached via any heteroatom or carbon atom.
  • Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • the aryl group, and the aromatic and non-aromatic heteroaryl groups can be optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-20 alkyl, C 2- 20 alkenyl, C 2-20 alkynyl, amino, Ci -20 alky lamino, Ci -20 dialkylamino, C 1-20 alkoxy, (Ci.ioalkoxy)Ci -2 o alkyl, Ci -20 haloalkoxy, (Ci -I0 haloalkoxy)Ci -20 alkyl and Ci -20 haloalkyl.
  • substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C 1-20 alkyl, C 2- 20 alkenyl, C 2-20 alkynyl, amino, Ci -20 alky lamino, Ci -20 dialkylamino, C 1-20 alkoxy, (Ci.ioalkoxy)C
  • Typical substituents include halogen, nitro, cyano, hydroxy, CMO alkyl, C 2-I0 alkenyl, C 2-I0 alkynyl, amino, Cj -I0 alkylamino, Ci -I0 dialkylamino, CMO alkoxy, (Ci. 6 alkoxy)Ci-io alkyl, Cuiohaloalkoxy, (Ci -6 haloalkoxy)Ci.i 0 alkyl and Ci -I0 haloalkyl. More typical substituents include CMO alkyl, -OH, CMO alkoxy, Ci-io haloalkyl, halogen, CMO haloalkoxy,amino, nitro and cyano.
  • the compounds of the invention can be prepared by processes analogous to those established in the art.
  • a secondary amine such as piperidine
  • a protic solvent such as ethanol
  • this reaction can be carried out under a variety of alternative conditions including secondary amines in aprotic solvents such as DMSO or DMF; solventless with KF/A1 2 O 3 ; acidic conditions (p- TsOH) in toluene or a strong base (e.g. LDA) in THF.
  • the ketone Bl is first converted to an enamine B2 (wherein Y and Z are proton or small alkyl) by reaction with a secondary amine (wherein R* and R** are small alkyl or together form five or six membered ring such as pyrrolidine or piperidine).
  • a secondary amine wherein R* and R** are small alkyl or together form five or six membered ring such as pyrrolidine or piperidine.
  • R* and R** are small alkyl or together form five or six membered ring
  • a refluxing organic solvent such as toluene
  • the present invention includes radiolabeled forms of the compounds of the invention, for example, compounds of the invention labeled by incorporation within the structure of 3 H, 11 C or 14 C or a radioactive halogen such as 125 I and 18 F.
  • a radiolabeled compound of the invention may be prepared using standard methods known in the art.
  • tritium may be incorporated into a compound of the invention using standard techniques, for example by hydrogenation of a suitable precursor to a compound of the invention using tritium gas and a catalyst.
  • a compound of the invention containing radioactive iodine may be prepared from the corresponding trialkyltin (suitably trimethyltin) derivative using standard iodination conditions, such as [ 125 I] sodium iodide in the presence of chloramine-T in a suitable solvent, such as dimethylformamide.
  • standard iodination conditions such as [ 125 I] sodium iodide in the presence of chloramine-T in a suitable solvent, such as dimethylformamide.
  • the trialkyltin compound may be prepared from the corresponding non-radioactive halo-, suitably iodo-, compound using standard palladium-catalyzed stannylation conditions, for example hexamethylditin in the presence of tetrakis(triphenylphosphine) palladium (0) in an inert solvent, such as dioxane, and at elevated temperatures, suitably 50- 100°C.
  • a compound of the invention containing a radioactive fluorine may be prepared, for example, by reaction of K[ 18 F]/K222 with a suitable precursor compound, such as a compound of Formula I comprising a suitable leaving group, for example a tosyl group, that may be displaced with the 18 F anion.
  • a suitable precursor compound such as a compound of Formula I comprising a suitable leaving group, for example a tosyl group, that may be displaced with the 18 F anion.
  • the chemistries outlined above may have to be modified, for instance by use of protective groups, to prevent side reactions due to reactive groups, such as reactive groups attached as substituents. This may be achieved by means of conventional protecting groups, for example as described in "Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973 and in Greene, T. W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd
  • Indolinone compounds of the invention can inhibit various kinases, including the PLK4, PLKl, PLK2, Aurora A, Aurora B and FLT-3 ⁇ see Examples B, C, D, E, F, and H).
  • the indolinone compounds of the invention are useful in the treatment of diseases or conditions associated with such kinases.
  • PLK4, PLKl, Aurora A and Aurora B are believed to be involved in cellular miotic progression.
  • small molecule inhibitors of these enzymes can be potential antitumor agents.
  • the compounds of the invention are PLK, Aurora
  • the compounds of the invention are PLK inhibitors and are useful for treating diseases associated with PLK, such as cancer.
  • the PLK is PLK4, PLK2 and PLK 1.
  • the PLK is PLKl and PLK4.
  • the PLK is PLK4.
  • the compounds of the invention are Aurora A and/or B inhibitors and are useful in inhibiting Aurora A and/or B activity for the treatment of various conditions such as cancers.
  • the compounds of the invention are FLT-3 inhibitors and are useful in inhibiting FLT-3 activity for the treatment of various conditions such as cancers.
  • the compounds of the invention inhibit the growth of a tumor.
  • the compounds of the invention inhibit the growth of a tumor that overexpresses at least one of PLK, Aurora A, Aurora B, and FLT-3. More specifically, the compounds of the invention inhibit the growth of a tumor that overexpresses PLK, for example, PLKl, PLK2 and/or PLK4. Even more specifically, the compounds of the invention inhibit the growth of a tumor that overexpresses PLK4.
  • the compounds of the invention inhibit the growth of the tumor by inducing apoptosis of the tumor cells or by inhibiting proliferation of the tumor cells.
  • Cancers that can be treated or prevented by the methods of the present invention include lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform, ovarian cancer, lymphoma, leukemia, melanoma, sarcoma, paraneoplasia, osteosarcoma, germinoma, glioma and mesothelioma.
  • the cancer is lung cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma mutiform or ovarian cancer.
  • the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform or ovarian cancer.
  • the cancer is a breast cancer.
  • the cancer is a basal sub-type breast cancer or a luminal B sub-type breast cancer.
  • the cancer is a soft tissue cancer.
  • a "soft tissue cancer” is an art-recognized term that encompasses tumors derived from any soft tissue of the body.
  • soft tissue connects, supports, or surrounds various structures and organs of the body, including, but not limited to, smooth muscle, skeletal muscle, tendons, fibrous tissues, fatty tissue, blood and lymph vessels, perivascular tissue, nerves, mesenchymal cells and synovial tissues.
  • soft tissue cancers can be of fat tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymph vessels, and fibrous tissues.
  • Soft tissue cancers can be benign or malignant. Generally, malignant soft tissue cancers are referred to as sarcomas, or soft tissue sarcomas.
  • soft tissue tumors including lipoma, lipoblastoma, hibernoma, liposarcoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma, schwannoma (neurilemoma), neuroma, malignant schwannoma, neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovial sarcoma, hemangioma, glomus tumor, hemangiopericytoma, hemangioendothelioma, angiosarcoma, Kaposi sarcoma, lymphangioma, fibroma, elastofibroma, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP), malignant fibrous hist
  • the soft tissue cancer is a sarcoma selected from the group consisting of a fibrosarcoma, a gastrointestinal sarcoma, a leiomyosarcoma, a dedifferentiated liposarcoma, a pleomorphic liposarcoma, a malignant fibrous histiocytoma, a round cell sarcoma, and a synovial sarcoma.
  • the invention further relates to a method of treating a subject with tumor cells, comprising administering to the subject, an amount of a compound disclosed herein that is effective to reduce effectively PLK activity, such as PLK 2 or PLK4 activity, in the subject.
  • PLK is PLK4.
  • the invention further relates to a method of inhibiting Aurora B and/or PLK- 4 in a subject in need of inhibition of Aurora B and/or PLK-4.
  • a subject in need of inhibition of Aurora B and/or PLK-4" means the subject has a disease(s) or condition(s) associated with overexpression of Aurora B and/or PLK-4, or a disease(s) or condition(s) on which inhibition of Aurora B and/or PLK-4 have a beneficial effect(s).
  • a “therapeutically effective amount”, “effective amount” or a “sufficient amount” of a compound of the present invention is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results.
  • a “therapeutically effective amount” of a compound of the invention is an amount which prevents, inhibits, suppresses or reduces the cancer (e.g., as determined by clinical symptoms or the amount of cancer cells) in a subject as compared to a control.
  • treating a subject with a cancer includes achieving, partially or substantially, one or more of the following: arresting the growth or spread of a cancer, reducing the extent of a cancer (e.g., reducing size of a tumor or reducing the number of affected sites), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components).
  • a therapeutically effective amount amount of a compound of the invention varies depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • a therapeutically effective amount of a compound of the present invention may be readily determined by one of ordinary skill by routine methods known in the art.
  • a therapeutically effective amount of a compound of the invention ranges from about 0.1 to about 15 mg/kg body weight, suitably about 1 to about 5 mg/kg body weight, and more suitably, from about 2 to about 3 mg/kg body weight.
  • factors may influence the dosage required to effectively treat a subject suffering from cancer and these factors include, but are not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject and other diseases present.
  • a "treatment" regime of a subject with a therapeutically effective amount of the compound of the present invention may consist of a single administration, or alternatively comprise a series of applications.
  • the compound of the present invention may be administered at least once a week.
  • the compound may be administered to the subject from about one time per week to once daily for a given treatment.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration and the activity of the compounds of the present invention, or a combination thereof.
  • the effective dosage of the compound used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • subject or “patient” or synonym thereto, as used herein includes all members of the animal kingdom, especially mammals, including human.
  • the subject or patient is suitably a human.
  • the method of the present invention is a mono-therapy where the pharmaceutical compositions of the invention are administered alone. Accordingly, in this embodiment, the compound of the invention is the only pharmaceutically active ingredient in the pharmaceutical compositions or the only pharmaceutically active ingredient administered to the subject.
  • the method of the invention is a co-therapy with one or more of other therapeutically active drugs or therapies known in the art for treating the desired diseases or indications.
  • one or more other antiproliferative or anticancer therapies are combined with the compounds of the invention.
  • the compounds disclosed herein are co-administered with one or more of other anticancer drugs known in the art.
  • Anticancer therapies that may be used in combination with the compound of the invention include surgery, radiotherapy (including, but not limited to, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes) and endocrine therapy.
  • Anticancer agents that may be used in combination with the the compounds of the invention include biologic response modifiers (including, but not limited to, interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs (e.g. taxol and analogs thereof).
  • biologic response modifiers including, but not limited to, interferons, interleukins, and tumor necrosis factor (TNF)
  • hyperthermia and cryotherapy agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs (e.g. taxol and analogs thereof).
  • administered contemporaneously means that two substances are administered to a subject such that they are both biologically active in the subject at the same time.
  • the exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering one substance within a period of time of one another, e.g., 24 hours of administration of the other, if the pharmacokinetics are suitable. Designs of suitable dosing regimens are routine for one skilled in the art.
  • two substances will be administered substantially simultaneously, i.e. within minutes of each other, or in a single composition that comprises both substances.
  • the two agents can be administered separately, such that only one is biologically active in the subject at the same time.
  • the compounds of the invention can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.
  • the compounds of the invention can be suitably formulated into pharmaceutical compositions for administration to a subject.
  • the pharmaceutical compositions of the invention optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose.
  • Other excipients such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes.
  • a compound of the invention may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • solutions of a compound of the invention can generally be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • sterile aqueous solutions or dispersion of, and sterile powders of, a compound of the invention for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the compounds of the invention can be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • the compounds of the invention can be formulated with with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine, as tablets, lozenges or pastilles.
  • the compounds of the invention can be formulated in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • a pharmaceutical composition of the invention comprises a pharmaceutically acceptable carrier or diluent, a compound disclosed herein or a pharmacuetically acceptable salt thereof and another anti-cancer agent, for example, but not limited to a glucose metabolism inhibitor or taxol. Meanings for the abbreviations used herein are provided below:
  • HPLC high pressure liquid chromatography prep-HPLC preparative scale high pressure liquid chromatography prepTLC preparative scale thin layer chromatography calcd calculated mL, L, uL milliliters, liters, microliters mmol, mol millimoles, moles milligrams, grams
  • Initiator microwave reactor Reaction progress was generally monitored by TLC using Merck silica gel plates with visualization by UV at 254 nm, by analytical HPLC or by LCMS (Bruker Exquire 4000). Work-up means drying over sodium or magnesium sulfate, filtering, and concentrating in vacuo. Flash column chromatographic purification of intermediates or final products was performed using 230-400 mesh silica gel 60 from EMD chemicals. Final products were sometimes purified by preparative reverse-phase HPLC.
  • Precipitated formed was collected by suction filtration, rinsed thoroughly with H 2 O (100 mL x 2), 2 M HCl (100 mL x 2), H 2 O (100 mL x 2), 0.5 M Na 2 CO 3 (100 mL x 2), H 2 O (100 mL x 2), dried in air for 1 h and under high vacuum for 2 days to give 6- bromo-lH-indazole (30.05 g, 76%) as a light yellow solid.
  • the reaction mixture was sealed and heated with stirring under microwave irradiation at 100 0 C for 99 min. Later the reaction was cooled to rt and treated with degassed H 2 O (0.25 mL). The mixture was reheated under microwave irradiation at 110 0 C for 1 h. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using MeOH (0 to 6 %) in DCM as the eluent to provide the title compound as a pale yellow solid (100 mg, 80 %). %).
  • the reaction mixture was cooled to 0 0 C and slowly acidified with 2M HCl until pH 5. During this addition, a copious amount of precipitate was formed. After stirring for 2 min at this temperture, sat NaHCO 3 was added slowly until pH 8 and the mixture was stirred for an additional 2 min. Water was added until the total volume reached 600 mL. After stirring for 10 min, the resulting precipitate was collected by suction filtration and rinsed thoroughly with water, then dried under high vacuum to give the title compound (3.30 g, 67%) as a beige solid.
  • the compound was synthesized according to the method described for Example A6 except reacting N-methyl-2-oxoindoline-5-sulfonamide (14 mg, 0.0618 mmol) with lH-benzo[d][l,2,3]triazole-5-carbaldehyde (10 mg, 0.0680 mmol) to obtain 5.6 mg, 12 % of the title compound as a mixture of (E) and (Z) isomers (69:21 by NMR).
  • the title compound was synthesized according to the method described for N- methyl-2-oxoindoline-5-carboxamide from 2-oxoindoline-6-carboxylic acid (89 mg, 0.500 mmol) and aniline (0.14 mL, 1.50 mmol) to obtain 45 mg, 36 %.
  • Example A (E)-N-(3-(( 1 H-benzofdi f 1.2.31triazol-5-vnmethyleneV2-oxoindolin- 6-yl)acetamide
  • Example A20 According to the method of Example A20, except substituting N-(2- oxoindolin-5-yl)methanesulfonamide (12 mg, 0.053 mmol) and IH- benzo[d][l,2,3]triazole-5-carbaldehyde (9 mg, 0.058 mmol), the title compound was obtained as an orange solid (8 mg, 42%).
  • Example A26 (EVl-G -(H H-indazol-6-vnmethyleneV2-oxoindolin-5-yl)-3- isopropvlurea - I l l -
  • Example A27 (EV 1 -(3-(T 1 H-benzofdi ⁇ 1.2.31triazol-5-yr)methylene)-2-oxoindolin- 5-yl)-3-isopropylurea
  • Example A20 According to the method of Example A20, except substituting l-isopropyl-3- (2-oxoindolin-5-yl)urea (23 mg, 0.099 mmol) and lH-benzo[d][l,2,3]triazole-5- carbaldehyde (15 mg, 0.11 mmol), the title compound was obtained as an orange solid (6 mg, 16%).
  • Example A 19 utilizing 6-(pyridin-3-yl)indolin- 2-one (25 mg, 0.12 mmol) and lH-indazole-5-carbaldehyde (17.4 mg, 0.12 mmol), the title compound was obtained as an orange solid (7 mg, 17 %).
  • the title compound was synthesized according to the method described for Example AI lB except substituting 5-bromooxindole (40 mg, 0.189 mmol) and IH- indazole-5-carbaldehyde (30 mg, 0.208 mmol) to obtain the title compound (6.8 mg, 4.0 %) as a yellow solid.
  • Example Al IB except substituting l-methylindolin-2-one (18 mg, 0.124 mmol) and lH-benzo[d][l,2,3]triazole-6-carbaldehyde (20 mg, 0.136 mmol) and then purified by preparatory HPLC to obtain 3.4 mg, 10 % of a yellow solid.
  • the desired product was synthesized according to the method described for Example Al IB, except substituting l-methylindolin-2-one (37 mg, 0.249 mmol) and lH-indazole-6-carbaldehyde (40 mg, 0.274 mmol) and then purified by preparatory HPLC to obtain the title compound (12 mg, 17 %) as a yellow solid.
  • Example Al except substituting 5-bromooxindole (40 mg, 0.189 mmol) and IH- indazole-6-carbaldehyde (30 mg, 0.208 mmol) to obtain 1.0 mg (1.6 %) of a yellow solid.
  • the title compound was synthesized from 3-iodo-lH-indazole-6- carbaldehyde (15 mg, 0.0551 mmol) and oxindole (8 mg, 0.0616 mmol) according to the method described for Example AI lB and purified by column chromatography (silica gel, CH 2 Cl 2 /Me0H, 98:2 to 96:4) to obtain 6.9 mg, 33 % of a yellow solid.
  • Example A41 (E and Z>3-(G-((E>2- ⁇ yridin-2-vnvinylHH-indazol-6- vDmethyleneMndolin-2-one
  • the solid was titurated 2X with 5:1 hexanes/Et 2 O while decanting off the solvent to give the orange solid (10 mg, 71 %).
  • the compound was a 3:1 mixture of (E)Z(Z) isomers by analysis of the proton NMR.
  • Example A53a (E)-3-((4-bromo-lH-indazol-6-yl)methyleneMndolin-2-one and A53b: (Z)-3-((4-bromo-lH-indazol-6-yDmethyleneMndolin-2-one
  • oxindole (15 mg, 0.11 mmol) was reacted with 4-bromo-lH-indazole-6-carbaldehyde (25 mg, 0.11 mmol) to give the title compound as an orange solid.
  • the E and Z stereoisomers were separated by HPLC.
  • Example A54a (E)-3-((4-(pyridin-4-yl)-lH-indazol-6-v ⁇ methylene)indolin-2-one and A54b: (E)-3-((4-(pyridin-4-yl)-lH-indazol-6-yl)methyleneMndolin-2-one
  • Example A60 fEV3-((3-((EV2-chlorostyryl)-lH-indazol-6-yl)methyleneMndolin-2- one
  • Example A68 (EV3-((lH-indazol-5-vnmethyleneVlH-pyrrolor2.3-bl ⁇ yridin-2f3HV one
  • the title compound (50mg, 95 %) was synthesized as an orange solid according to the method described for Example A67 using lH-pyrrolo[2,3- b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and lH-indazole-5-carbaldehyde (29.2 mg, 0.2 mmol).
  • Example A69 (E and ZV3-((lH-indazol-6-v ⁇ methyleneV5-bromo-lH-pyrrolor2.3- blpyridin-2(3HVone
  • Example A70 fEV3-(6-((EV(2-oxoindolin-3-ylidene)methylVlH-indazol-3- vDacrylic acid
  • Example A72 fEV3-f(3-((EV2-fpyridin-2-yl)vinvn-lH-indazol-6-vnmethylene)- lH-Dyrrolo[23-blpyridin-2(3H)-one
  • Example A84 (EV5-chloro-3-((3-((EV2-(pyridin-4-vnvinvn-lH-indazol-6- yl)methylene)indolin-2-one
  • the reaction mixture was sealed and heated with stirring under microwave irradiation at 125 0 C for 60 min.
  • the crude reaction mixture was concentrated under reduced pressure.
  • the residue was purified by flash chromatography on silica gel using EtOAc (2 %) in DCM as the eluent to provide a pale yellow solid (39 mg, 71 %).
  • the solid was dissolved in THF (8 mL) and treated with IM TBAF (0.44 mL, 0.44 mmol); the resulting reaction mixture was heated under reflux for 16 h.
  • the crude reaction mixture was concentrated under reduced pressure. Ethyl acetate (5 mL) was added and the solution was washed with brine (2 x 10 mL), dried over MgSO 4 , filtered and concentrated.
  • Example A 102 (EV3 -((3 -cvclopropyl- 1 H-indazol-6-yr)methylene * )indolin-2-one

Abstract

The present invention is directed to a compound is represented by Structural Formula (A):or a pharmaceutically acceptable salt therof. The present invention is also directed to a pharmaceutical composition comprising a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. Also disclosed is a method of treating a subject having cancer, wherein the method comprises administering a therapeutically effective amount of a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof.

Description

KINASE INHIBITORS AND METHOD OF TREATING CANCER
WITH SAME
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Serial No. 61/131,717, filed June 11, 2008 and U.S. Provisional Application No.
61/008,865, filed December 21, 2007. The entire teachings of these two applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
Protein kinases have been the subject of extensive study in the search for new therapeutic agents in various diseases, for example, cancer. Protein kinases are known to mediate intracellular signal transduction by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. The polo-like kinase (PLK) family of serine/threonine kinases comprises at least four known members: PLKl, PLK2 (also known as Snk), PLK3 (also known as Fnk or Prk) and PLK4 (also known as Sak). PLK4 is the least understood and most divergent member of the PLK family. The N-terminal catalytic domain of PLK4 has a different substrate specificity from that of PLK1-3. PLK4 also has a divergent C- terminus comprising only a single polo-box sequence, not the tandem PB sequences in PLK 1-3, that appears to act as a homodimerization domain rather than a localization domain (Lowery et al, (2005) Oncogene 24: 248-259).
PLK4 is known to be involved in the control of mitotic entry and exit, and a regulator of centrosome duplication (Habedanck et al. Nature Cell Biology 7: 1140- 1146, 2005). PLK4 transcripts increase from S through M phase, and the protein is ubiquitylated and destroyed by the anaphase promoting complex (APC) (Hudson et al. Curr. Biol. 11: 441- 446, 2001; Fode etal MoI. Cell. Biol. 16: 4665^672, 1996). PLK4 is required for late mitotic progression (Fode et al. PNAS. 91 : 6388- 6392, 1994; Hudson et al. Curr. Biol. 11 : 441^46, 2001), cell survival and postgastrulation embryonic development (Hudson et al . Curr. Biol. 11: 441-446, 2001). PLK4 knockout mice are embryonic lethal (E7.5), with a marked increase in mitotic and apoptotic cells (Hudson et al. Curr. Biol. 11: 441-446, 2001). PLK4 is transcriptionally repressed by p53 (Li et al. Neoplasia 7: 312-323, 2005). This repression is likely mediated through the recruitment of histone deacetylase (HDAC) repressors and repression appears to contribute to p53-induced apoptosis (Li et al. Neoplasia 7: 312-323, 2005). PLK4 has been reported to be overexpressed in colorectal tumors with expression reported as low in adjacent normal intestinal mucosa (Macmillian et al. Ann. Surg. Oncol. 8: 729-740, 2001). In addition, PLK4 mRNA has been reported to be overexpressed in some tumor cell lines (Hitoshi, et al., U.S. Patent Application No. US 2003/0027756). In addition, Applicants described overexpression of PLK4 in basal-like tumors in a co-pending U.S. Provisional Application No. 61 ,003,825, filed on November 20, 2007 (the entire teachings of which are incorporated herein by reference).
Therefore, agents which inhibit a protein kinase, in particular PLK4, have the potential to treat cancer. There is a need for additional agents which can act as protein kinase inhibitors, in particular PLK4 inhibitors.
SUMMARY OF THE INVENTION
Applicants have now discovered that certain indolinone compounds are potent kinase inhibitors, such as polo-like kinases (PLK) (see Example B). Applicants have also now discovered that these indolinone compounds have potent anticancer activity (see Example C). Based on these discoveries, indolinone compounds, pharmaceutical compositions thereof, and methods of treating cancer with the indolinone compounds are disclosed herein.
In one embodiment, the present invention is directed to a compound represented by Structural Formula (A):
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof.
Ring A is an optionally substituted 5- or 6-membered aromatic ring. Ring B is an optionally substituted phenyl ring.
Ring C is a 5-membered heteroaromatic ring wherein one of X1-X3 is N, one of X1-X3 is NR5, and one of X1-X3 is N or CR6.
Z is =N- or =CR3-. R3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl. each of R4 and R5 independently is -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O)2(Cl-Co alkyl) or -S(O)2(phenyl), wherein each said alkyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and C1-C6 haloalkoxy, and wherein each said phenyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C 1 -C6 haloalkoxy.
R6 is hydrogen, halogen, nitro, cyano, R', -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)OR, -SOR', -SO2R', -SO3R', -SO2N(R)2, -NRS(O)R', -NRSO2R', -NRC(O)N(R)2, -NRC(O)ON(R)2, or -NRSO2N(R)2. each R independently is hydrogen, C1-10 aliphatic, phenyl or 5-6 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and wherein each of the phenyl and heteroaryl groups represented by R, and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or
N(R)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of =0, =S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C^hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6aminoalkyl, (Cϊ-6 alkylamino^i-ό alkyl, (Cj-6 dialkylamino)C1-6alkyl, (phenyl)C1-6alkyl, (5-6 membered heteroaryl)C1-6alkyl, Cj-6 alkoxy, C1-6 haloalkoxy, C1-6 alky lcarbonyloxy, Ci-6alkoxycarbonyl, Ci^ alkylcarbonyl, phenyl and 5-6 membered heteroaryl. each R independently is Ci-10 aliphatic, phenyl or 5-14 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, C^alkylamino, C1-6 dialkylamino, -C(O)(C1-C6 alkyl), -C(O)(C1-C6 haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(C 1-C6 alkyl), -C(O)O(C 1-C6 haloalkyl),-C(O)O(phenyl), -OC(O)(Cl-Co alkyl), -OC(O)(C1-C6 haloalkyl),
-OC(O)(phenyl), -S(O)2(C1-C6 alkyl), -S(O)2(C1-C6 haloalkyl) and -S(O)2(phenyl), and wherein each of the phenyl and heteroaryl groups represented by R1, and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R1 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, non-aromatic heterocyclic group, C1-6alkylamino, C1-6 dialkylamino, -C(O)(C 1-C6 alkyl), -C(O)(C 1-C6 haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(C 1-C6 alkyl), -C(O)O(C1-C6 haloalkyl),-C(O)O(phenyl), -OC(O)(C1-C6 alkyl), -OC(O)(Cl-Co haloalkyl), -OC(O)(phenyl), -S(O)2(Cl-CO alkyl), -S(O)2(Cl-Co haloalkyl), and -S(O)2(phenyl).
In another embodiment, the present invention is directed to a pharmaceutical composition comprising a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
The present invention also includes a method of treating a subject having cancer comprising administering a therapeutically effective amount of a compound of the invention disclosed herein or a pharmaceutically acceptable salt thereof.
The present invention also includes a method of inhibiting Aurora B and/or PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4, comprising administering a therapeutically effective amount of a compound of the invention disclosed herein or a pharmaceutically acceptable salt thereof. Also, use of a compound of the invention disclosed herein or a pharmaceutically acceptable salt thereof in therapy is included in the present invention. In one embodiment, the therapy is for treating a subject with cancer. In another embodiment, the therapy is for inhibiting Aurora B and/or PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4.
Also included in the present invention is the use of a compound of the invention disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a subject with cancer.
Also included in the present invention is the use of a compound of the invention disclosed herein or a pharamceutically acceptable salt thereof for the manufacture of a medicament for inhibiting Aurora B and/or PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4.
BRIEF DESCRIPTION OF THE DRAWINGS
The figure is a bar graph showing the inhibition of HUV-EC-C Cell Tube Formation by compound Example A57.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention is directed to an indolinone compound represented by Structural Formula (A). A first set of values and specific values for the variables in Structural Formula (A) are provided in the following paragraphs: Ring A is an optionally substituted 5- or 6-membered aromatic ring. In one embodiment, ring A is optionally subsituted benzene ring. In another embodiment, ring A is optionally substituted pyridine ring. In another embodiment, ring A is optionally substituted pyrrole ring. In another embodiment, ring A is optionally substituted thiophene ring. In another embodiment, ring A is optionally substituted thiozole ring.
In one embodiment, ring A is optionally substituted with one or more substituents Qa, and phenyl ring B is optionally substituted with one or more substituents Qb. Typically, each of Qa and Qb independently is selected from the group consisting of halogen, -X-R1, -NO2, -CN, -NCS, Ak1, Ar1, (C1-10 alkylene^Ar1, (C2-10 alkenylene^Ar1, -O-[CH2]P-O-, -S-[CH2]P-S- and -[CH2]q-. In one embodiment, one of Qa and Qb is halogen, -NO2, -CN, Ak1, Ar1, (Ci-10 alkylene)-Ar1, (C2-10 alkenylene^Ar1 or -X-R1; and the other of Qa and Qb is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy. In another embodiment, one of Qa and Qb is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(Cl-CO alkyl), -C(O)NH2, -C(O)NH(Cl- C6 alkyl), -C(O)N(Cl-CO alkyl)2, -SO2NH2, -SO2NH(Cl-Co alkyl), -SO2N(C1-C6 alkyl)2, -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -SH, -S(Cl-Co alkyl), -S(Cl- C6 haloalkyl), -NH2, -NH(Cl-Co alkyl), -N(Cl-Co alkyl)2, , -NHC(O)(Cl-CO alkyl), -NHC(O)O(Cl-Co alkyl), -NHC(O)NH2, -NHC(O)NH(C 1-C6 alkyl), -NHC(O)N(Cl-Co alkyl)2, -NHC(O)ONH2, -NHC(O)ONH(Cl-CO alkyl), -NHC(O)ON(C 1 -C6 alkyl)2, -NHSO2NH2, -NHSO2NH(C 1 -C6 alkyl),
-NHSO2N(Cl-Co alkyl)2 or -NHSO2(Cl-Co alkyl); and the other Qa and Qb is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy. In yet another embodiment, one of Qa and Qb is halogen, hydroxy, cyano, nitro, Ph, -CH2Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(Cl-Co alkyl)(Ph), -SO2NH(Ph), -SO2N(Cl-CO alkyl)(Ph), -O(Ph), -S(Ph), -NH(Ph), -N(Cl-Co alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(Cl-CO alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(Cl-Co alkyl)(Ph), -NHSO2NH(Ph), -NHSO2N(Cl-Co alkyl)(Ph) or -NHSO2(Ph), wherein each Ph is a phenyl group independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; and the other Qa and Qb is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy. In yet another example, both of Qa and Qb are independently halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy. In another embodiment, Qa is halogen, cyano, -NR1R2, -NR2C(O)R1, -C(O)OR1, -OC(O)R1, -N(R^C(O)NR1R2, -OR1, Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -SH, -0(C1-6 alkyl), -S(Ci-6 alkyl) and C1-6 haloalkoxy; and Qb is halogen, C1-3 alkyl, Ci-3 haloalkyl, Ci-3 alkoxy, or Cj-3 haloalkoxy. In another embodiment, Qa is -OH, Ci-6 alkoxy or C1-6 haloalkoxy; and Qb is halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C]-3 haloalkoxy. X is -C(O)O-, -C(O)-, -C(S)-, -OC(O)-, -C(O)N(R2)-, -C(S)N(R2)-, -OC(O)N(R2)-, -S(O)-, -S(O)2-, -SO3-, -SO2NR2-, -0-, -S-, -NR2-, -NR2C(O)-, -NR2S(O)-, -NR2C(O)O-, -NR2C(O)ONR2-, -N(R2)C(O)NR2-, -NR2SO2NR2- or -NR2SO2-. Alternatively, X is -C(O)-, -C(S)-, -C(O)N(R2)-, -OC(O)N(R2)-, -SO2NR2-, -0-, -S-, -NR2-, -NR2C(O)-, -NR2C(O)O-, -NR2C(O)ONR2-, -N(R2)C(O)NR2-, -NR2SO2NR2- or -NR2SO2-.
Each R1 independently is: i) hydrogen; ii) an optionally substituted C6-14 aryl group or an optionally substituted 5-14 membered heteroaryl group; or iii) an optionally substituted C1-I0 aliphatic group, provided that R1 is other than hydrogen when X is -S(O)-, -S(O)2-, -SO3-, -NR2S(O)- or -NR2SO2-. In one embodiment, each R1 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted C1-10 alkyl, provided that R1 is other than hydrogen when X is -S(O)-, -S(O)2-, -SO3-, -NR2S(O)- or -NR2SO2-. Typically, each of the aryl and heteroaryl groups represented by R1 is independently and optionally substituted with one or more substitutents selected from the group consisting of halogen, -N02> -CN, -NCS, Ak10, (Ci-I0 alkylene)-Ar10, (C2-I0 alkenylene)-Ar10, -C(O)OR10, -C(O)R10, -C(S)R10, -OC(O)R10, -C(O)N(R1 \, -C(S)N(R1 \ -OC(O)N(R11)2, -S(O)R12, -S(O)2R12, -SO3R12, -SO2N(R11^, -OR10, -SR10, -N(R11J2, -NR11C(O)R10, -NR11S(O)R12, - NR11C(O)OR12, -N(R11XXO)N(R11J2, -NR11SO2N(R1^2 and -NR11SO2R12. In one embodiment, each of the aryl and heteroaryl groups represented by R1 is independently and optionally substituted with one or more substitutents selected from the group consisting of halogen, nitro, cyano, Ak10, (CMO alkylene)-Ar10, (C2-I0 alkenylene)-Ar10, -OR10, -SR10, -OC(O)N(R11J2, -N(R1 \ -C(O)NR11, -NR11C(O)R10, -N(R1 ^C(O)N(R11J2, -NR11 SO2N(R1 ')2, -NR11SO2R12, -SO2N(Rn)2, -OC(O)R10 -C(O)OR10 and -C(O)R10. Typically, the aliphatic group, including alkyl group, represented by R1 is optionally substituted with one or more substituents selected from the group consisting of halogen, -NO2, -CN, -NCS, Ar10, -C(O)OR10, -C(O)R10, -C(S)R10, -OC(O)R10, -C(0)N(Rn)2, -C(S)N(Rπ)2, -OC(O)N(R1 %, -S(O)R12, -S(O)2R12, -SO3R12, -SO2N(Rπ)2, -OR10, -SR10, -N(Rn)2, -NR11C(O)R10, -NR11S(O)R12, -NR11C(O)OR12, -N(Rn)C(0)N(Rπ)2, -NR11 SO2N(R1 ^2 and - NR11SO2R12. In one embodiment, the aliphatic group, including alkyl group, represented by R1 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ar10, -OR10, -SR10, -N(RU)2, -OC(O)R10, -C(O)OR10 and -C(O)R10. In another embodiment, R1 is -H- or Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SH, -0(C1-3 alkyl), -S(C1-3 alkyl) and C1-6haloalkoxy.
Each R2 independently is R1, -CO2R1, -SO2R1 or -C(O)R1, or, taken together with NR1, forms an optionally substituted non-aromatic heterocyclic group represented by NR1R2. In one embodiment, each R2 is -H or C1-C6 alkyl. Typically, the non-aromatic heterocyclic group represented by NR1R2 is optionally substituted with one or more substituents selected from the group consisting of =0, =S, halogen, nitro, cyano, hydroxy, C1^ alkyl, Ci-βhaloalkyl, C1-6 hydroxyalkyl, amino, Ci-6 alky lamino, Q-6 dialkylamino, Ci-6 aminoalkyl, (Ci-6 alky IaInUiO)Ci-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (pheny I)C1-6 alkyl, (5-6 membered heteroary I)C1- 6 alkyl, C1-6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkylcarbonyloxy, Cj-6 alkoxycarbonyl, Ci-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl. In one embodiment, the non- aromatic heterocyclic group represented by NR1R2 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, =0, C1-C3 alky, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and amino. In another embodiment, R2 is -H- or Cj-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SH, -0(Ci-3 alkyl), -S(Ci-3 alkyl) and Ci-6 haloalkoxy.
Z is =N- or =CR3-. In one embodiment, when Z is =N-,
Figure imgf000009_0001
, R4 is H or Cl-C6 alkyl, then ring A is not phenyl or phenyl substituted with halogen or trifluoromethyl. In another embodiment, when Z is =N-, then
Figure imgf000010_0001
Figure imgf000010_0002
R3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In one embodiment, R3 is -H or C1-C6 alkyl. In another embodiment, R3 is -H, halogen, C1-C6 alkyl or Cl-
C6 haloalkyl, wherein when R3 is halogen, then
Figure imgf000010_0003
is not
Figure imgf000010_0004
Each of R4 and R5 independently is -H, C1-C6 alkyl, phenyl, -C(O)(C1-C6 alkyl), -C(O)(phenyl), -C(O)O(C 1-C6 alkyl), -C(O)O(phenyl), -S(O)2(Cl-Co alkyl) or -S(0)2(phenyl). Typically, each alkyl in the groups represented by R4 and R5 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and C1-C6 haloalkoxy. Typically, each phenyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy. In one embodiment, R4 and R5 are both -H.
R6 is hydrogen, halogen, nitro, cyano, R1, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)OR, -SOR1, -SO2R1, -SO3R', -SO2N(R)2, -NRS(O)R', -NRSO2R', -NRC(O)N(R)2, -NRC(O)ON(R)2 or -NRSO2N(R)2. In one embodiment, R6 is hydrogen, halogen, nitro, cyano, R1, -OR, -SR or -N(R)2. In another embodiment, R6 is hydrogen, halogen, nitro, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, Cl- C6 haloalkoxy, -S(C1-C6 alkyl), -S(Cl-Co haloalkyl), amino, C1-C6 alkylamino, C1-C6 dialkylamino, phenoxy or phenyl, wherein each of said alkyl and said alkoxy in the groups respresented by R6 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, C1-C3 alkoxy and C1-C3 haloalkoxy, and wherein each said phenyl in the groups respresented by R6 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy. In another embodiment, R6 is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In another embodiment, R6 is optionally substituted phenyl, optionally substituted 5-12 membered heteroaryl, -CH2-(optionally substituted phenyl), -CH2-(optionally substituted 5-12 membered heteroaryl), -CH2- CH2-(optionally substituted phenyl), -CH2-CH2-(optionally substituted 5-12 membered heteroaryl), -CH=CH-(optionally substituted phenyl), -CH=CH- (optionally substituted 5-12 membered heteroaryl), -CH=CH-C(O)O(optionally substituted C1-6 alkyl), or -CH=CH-OC(O)(optionally substitutued C1-6 alkyl). In another embodiment, R6 is an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl. In another embodiment, the phenyl and 5-6 membered heteroaryl represented by R6 are independently and optionally substituted with one or more substitutents selected from the group consisting of: halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and Cl- C6 haloalkoxy. In yet another embodiment, R6 is an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrrolyl group, an optionally substituted pyrazolyl, an optionally substituted thiazolyl, an optionally substituted pyrimidyl, or an optionally substituted thienyl. In yet another embodiment, R6 is an -CH=CH-(optionally substituted phenyl) -CH=CH-(optionally substituted 5-12 membered heteroaryl), -C≡C-(optionally substituted phenyl) or -C≡C-(optionally substituted 5-12 membered heteroaryl), wherein the heteroaryl is an optionally substituted pyridyl group, an optionally substituted pyrrolyl group, an optionally substituted pyrazolyl, an optionally substituted thiazolyl, an optionally substituted pyrimidyl, or an optionally substituted thienyl.
Each R10 independently is: i) hydrogen; ii) an optionally substitued C6-I4 aryl group or an optionally substituted 5-14 membered heteroaryl group; or iii) an optionally substituted C1-1OaIlCyI group. In one embodiment, each R10 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted C1-6alkyl group. Typically, each of the aryl, including phenyl, and heteroaryl groups represented by R10 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-I0 alkyl, C1- !0 haloalkyl, (C1-10 haloalkoxy)C1-i0 alkyl, (Ci-10 alkoxy)Ci-10 alkyl, Ci-I0 hydroxyalkyl, C1-10 aminoalkyl, (Ci-I0 alkylamino)Ci-i0 alkyl, (Ci-io dialkylamino)Ci. io alkyl, (phenyl)Ci.io alkyl, (5-6 membered heteroaryl)Ci-io alkyl, amino, Ci-I0 alkylamino, C1-1O dialkylamino, Q.io alkoxy, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, CM0 alkoxycarbonyl and Ci-I0 alkylcarbonyl. In one embodiment, each of the aryl, including phenyl, and heteroaryl groups represented by R10 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 haloalkoxy)C I-6 alkyl, (Ci .6 alkoxy)C I-6 alkyl, Ci-6 hydroxyalkyl, (Ci- 6 aminoalkyl, (Ci-6 alkylamino)Ci.6 alkyl, (Ci-6 dialkylamino)Ci-6 alkyl, amino, Ci-6 alkylamino, Ci^ dialkylamino, Q-6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkylcarbonyloxy, Cj-6 alkoxycarbonyl and Ci-6 alkylcarbonyl. In another embodiment, each of the aryl, including phenyl, and heteroaryl groups represented by R10 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy. Typically, the alkyl group represented by R10 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci-I0 haloalkyl, C]-10 alkoxy, C1-10 haloalkoxy, amino, Ci-10 alkylamino, C1-10 dialkylamino, C1-10 alkylcarbonyloxy, C1- 10 alkoxycarbonyl, Ci-10 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy. In one embodiment, the alkyl group represented by R10 is optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, Q-6 haloalkyl, Ci-6 alkoxy, C1-6 haloalkoxy, amino, Ci-e alkylamino, C1-6dialkylamino, C^alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl and phenyl. In another embodiment, the alkyl group represented by R10 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloaloxy and phenyl.
Each R11 independently is R10, -CO2R10, -SO2R10 or -C(O)R10, or -N(R1 ' )2 taken together is an optionally substituted non-aromatic heterocyclic group. Typically, the non-aromatic heterocyclic group represented by N(R1 *)2 is optionally substituted with one or more substituents selected from the group consisting of =0, =S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C I-6 haloalkyl, C^hydroxyalkyl, amino, C1-6alkylamino, C1-6dialkylamino, C1^ aminoalkyl, (Ci-6 alkylamino)C I-6 alkyl, (Ci-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)Ci. β alkyl, Ci-6 alkoxy, C1-6 haloalkoxy, C1-6 alky lcarbonyloxy, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl. In one example, the non- aromatic heterocyclic group represented by N(R1 % is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, =0, C 1 -C3 alky, C 1 -C3 haloalkyl, C 1 -C3 alkoxy, C 1 -C3 haloalkoxy and amino.
Each R12 independently is: i) an optionally substitued C6.H aryl group or an optionally substituted 5-14 membered heteroaryl group; or ii) an optionally substituted Ci-I0 alkyl group. Alternativrly, each R12 independently is i) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or ii) an optionally substituted Ci-6 alkyl group. Typically, each of the aryl, including phenyl, and heteroaryl groups represented by R12 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci-10 alkyl, Cj.io haloalkyl, (Ci-I0 haloalkoxy)Ci.io alkyl, (Ci-I0 alkoxy)Ci.i0 alkyl, Ci-I0 hydroxyalkyl, CM0 aminoalkyl, (Ci-I0 alkylamino)Ci-10 alkyl, (Ci-I0 dialkylamino)Ci.i0 alkyl, (phenyl)Ci.io alkyl, (5-6 membered heteroaryl)Ci.i0 alkyl, amino, Ci-I0 alkylamino, C1-10 dialkylamino, C1-10 alkoxy, Ci-jo haloalkoxy, C1-10 alkylcarbonyloxy, Ci-10 alkoxycarbonyl and C^o alkylcarbonyl. In one example, each of the aryl, including phenyl, and heteroaryl groups represented by R12 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci-6 alkyl, Cj-6 haloalkyl, (C1-6 haloalkoxy)d^ alkyl, (Ci-6 alkoxy)C!^ alkyl, C1-6 hydroxyalkyl, (Ci-6aminoalkyl, (C1-6 alkylaminoX^ alkyl, (C1-6 dialkylamino)C1-6 alkyl, amino, C1-6alkylamino, C1-6 dialkylamino, C1-6 alkoxy, Ci-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and C1-6 alkylcarbonyl. In another example, each of the aryl, including phenyl, and heteroaryl groups represented by R12 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and Cl- C3 haloaloxy. Typically, the alkyl group represented by R12 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 haloalkyl, Ci-10alkoxy, C1-I0 haloalkoxy, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-I0 alkylcarbonyloxy, C1-10 alkoxycarbonyl, C1-I0 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy. In one example, the alkyl group represented by R12 is optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, CJ-6 haloalkyl, Ci-6 alkoxy, C1^ haloalkoxy, amino, C1-6 alkylamino, Ci-6 dialkylamino, C I-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl, C1-6 alkylcarbonyl and phenyl. In another example, the alkyl group represented by R12 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloaloxy and phenyl.
Each R21 independently is hydrogen, optionally substituted C1-6 alkyl, optionally substituted phenyl or optionally substitued 5-6 membered heteroaryl, or N(R21)2 forms an optionally substituted non-aromatic heterocyclic group. Alternatively, each R21 independently is hydrogen, optionally substituted Ci-6 alkyl or optionally substituted phenyl. Typically, each of the phenyl and heteroaryl groups represented by R21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy. Typically, the alkyl group represented by R21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkoxy, C1-C3 haloalkoxy and phenyl. Typically, the non- aromatic heterocyclic represented by N(R21)2 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, =0, C1-C3 alky, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and amino. Each R22 independently is optionally substituted C1-6 alkyl, optionally substituted phenyl or optionally substitued 5-6 membered heteroaryl. Alternatively, each R22 independently is optionally substituted C1-6 alkyl or optionally substituted phenyl. Typically, each of the phenyl and heteroaryl groups represented by R22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy. Typically, the alkyl group represented by R22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkoxy, C1-C3 haloalkoxy and phenyl. Each R independently is hydrogen, optionally substituted C1-10 aliphatic, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl. Alternatively, N(R)2 forms an optionally substituted non-aromatic heterocyclic group. Typically, the aliphatic group represented by R is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and C1-C6 haloalkoxy, wherein each of the phenyl and the 5-6 membered heteroaryl groups are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy. Typically, each of the phenyl and the heteroaryl groups represented by R is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and Cl- C6 haloalkoxy. Typically, the non-aromatic heterocyclic group represented by N(R)2 is optionally substituted with one or more substituents selected from the group consisting of =0, =S, halogen, nitro, cyano, hydroxy, Q-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, amino, Ci-6alkylamino, Ci-όdialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (Ci-6 dialkylamino)Ci.6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C1-6 alky lcarbonyloxy, C1-6alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl. In one example, the non-aromatic heterocyclic group represented by N(R)2 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, =0, C 1 -C3 alky, C 1 -C3 haloalkyl, Cl- C3 alkoxy, C1-C3 haloalkoxy and amino.
Each R' independently is optionally substituted CMO aliphatic, optionally substituted phenyl or optionally substituted 5-14 membered heteroaryl. Alternatively, each R' independently is -CH2-(optionally-substituted phenyl), -CH2(optionally-substituted 5-6 membered heteroaryl), -CH2-CH2-(optionally- substituted phenyl), -CH2-CH2-(optionally-substituted 5-6 membered heteroaryl), CH=CH-(optionally-substituted phenyl) or -CH=CH2-(optionally-substituted 5-6 membered heteroaryl). Alternatively, each R' independently is -CH2-(optionally- substituted phenyl), -CH2-(optionally-substituted pyridyl), -CH2-CH2-(optionally- substituted phenyl), -CH2-CH2-(optionally-substituted pyridyl), CH=CH-(optionally- substituted phenyl) or -CH=CH2-(optionally-substituted pyridyl). Typically, the aliphatic group represented by R1 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and C1-C6 haloalkoxy, Ci-6 alkylamino, C w dialkylamino, -C(O)(C 1 -C6 alkyl), -C(O)(C 1 -C6 haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(C 1-C6 alkyl), -C(O)O(C 1-C6 haloalkyl),-C(O)O(phenyl), -OC(O)(C 1-C6 alkyl), -OC(O)(C 1-C6 haloalkyl), -OC(O)(phenyl), -S(O)2(Cl-Co alkyl), -S(O)2(Cl-CO haloalkyl) and -S(0)2(phenyl), wherein each of the phenyl and the 5-6 membered heteroaryl groups are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy. Typically, each of the phenyl and the heteroaryl groups represented by R' is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, non-aromatic heterocyclic group, C1-6 alkylamino, C1-6 dialkylamino, -C(O)(C 1 -C6 alkyl), -C(O)(C 1 -C6 haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(Cl-Co alkyl), -C(O)O(Cl-Co haloalkyl),-C(O)O(phenyl), -OC(O)(C 1-C6 alkyl), -OC(O)(Cl-Co haloalkyl), -OC(OXphenyl), -S(O)2(Cl-Co alkyl), -S(O)2(Cl-CO haloalkyl), and -S(O)2(phenyl). Each Ak1 independently is an optionally substituted CMO aliphatic group.
Alternatively, each Ak1 independently is an optionally substituted C1-10 alkyl group. Alternatively, each Ak1 independently is an optionally substituted C1-6 alkyl group. Typically, each of the aliphatic and alkyl groups represented by Ak' is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -N(R21)2, -C(O)N(R21)2, -C(O)N(R21)2, -NR21C(O)R21, -SO2R22, -SO2N(R21)2, -NR21SO2R22, -NR21C(O)OR21, -OC(O)N(R2I)2, -NR21C(O)N(R21)2, -NRC(O)ON(R)2, -NR2ISO2N(R21)2, -OR21, -SR21, C1-10 haloalkoxy, -C(O)R21, -C(O)OR21 and -OC(O)R21. In one example, each of the aliphatic and alkyl groups represented by Ak1 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloaloxy and phenyl.
Each Ak10 independently is an optionally substituted C1-10 alkyl group. Alternatively, each Ak1 independently is an optionally substituted C1-6 alkyl group. Typically, the alkyl group represented by Ak10 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(Ci-6 alkyl), Ci-6 haloalkoxy, amino, Ci-6 alkylamino, Ci-6 dialkylamino, Ci-6 alky lcarbonyloxy, Q-όalkoxycarbonyl and Ci-6 alkylcarbonyl. In one example, the alkyl group represented by Ak10 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloaloxy and phenyl. Each Ar1 independently is an optionally substituted C6-14 aryl group or an optionally substituted 5-14 membered heteroaryl group. Alternatively, each Ar1 independently is an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group. Typically, suitable substituents for each of the aryl and heteroaryl groups represented by Ar1 independently include halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6haloalkyl, (Ci-6 haloalkoxy)Ci-6alkyl, (C1-6
Figure imgf000018_0001
^ alkyl, (CM dialkylamino)Ci-6 alkyl, -NR21 2, -C(O)NR21 2, -C(O)NR21 2, -NR21C(O)R21, -S(O)2R22, -SO2NR21 2, -NR21SO2R22, -NR21C(O)NR2^5 -NR21SO2NR21 2, -OR21, -SR21, Q-6 haloalkoxy, -C(O)R21, -C(O)OR21, -OC(O)R21 and benzyl. Additional suitable substituents include a phenyl group and a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy. In one example, each of the phenyl and heteroaryl groups represented by Ar1 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci-6 alkyl, Q-6 haloalkyl, (Ci-6 haloalkoxy)C I-6 alkyl,
Figure imgf000018_0002
(Ci-6 aminoalkyl, (Ci-6 alkylamino)Ci^ alkyl, (Ci-6 dialkylamino)Ci-6 alkyl, -NR21 2, -C(O)NR21 2, -C(O)NR21 2, -NR21C(O)R21 , -S(O)2R22, -SO2NR21 2, -NR21 SO2R22, -NR21C(O)NR22 2, -NR21SO2NR21 2, -OR21, -SR21, Q-6 haloalkoxy, -C(O)R21, -C(O)OR21, -OC(O)R21, phenyl, benzyl and 5-6 membered heteroaryl. In another example, each of the phenyl and heteroaryl groups represented by Ar1 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(Ci-6 alkyl), Ci-6 alkyl, Ci-6 haloalkyl, (C1-6 haloalkoxy)C I-6 alkyl, (Ci-6 alkoxy)C I-6 alkyl, Ci-δhydroxyalkyl, (Ci-6 aminoalkyl, (Ci-6 alkylamino)Ci^ alkyl, (Ci-6 dialkylamino)Ci-6 alkyl, (phenyl)C^ alkyl, (5-6 membered heteroary I)C I-6 alkyl, amino, Ci-6 alkylamino, Ci-6 dialkylamino, Ci-6 haloalkoxy, Ci^alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Cj-6 alkylcarbonyl. In yet another example, each of the phenyl and heteroaryl groups represented by Ar1 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy.
Each Ar10 independently is an optionally substituted C6-14 aryl group or an optionally substituted 5-14 membered heteroaryl group. Alternatively, each Ar10 independently is an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group. Typically, suitable substituents for each of the aryl and heteroaryl groups represented by Ar10 include halogen, nitro, cyano, -OH, -SH, -0(C1-10 alkyl), -S(CM0 alkyl), CM0 alkyl, CM0 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C M0 alkyl, C1-10 hydroxyalkyl, (C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-1O dialkylamino)CM0 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C MO alkyl, amino, C1-10 alkylamino, Ci-iodialkylamino, CM0 haloalkoxy, CM0 alky lcarbonyloxy, C1-10 alkoxycarbonyl and CM0 alkylcarbonyl. In one example, each of the phenyl and heteroaryl groups represented by Ar10 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy.
Each p independently is 1, 2 or 3.
Each q independently is 2, 3, 4 or 5.
Examples of the heteroaryl groups, including 5-14 membered heteroaryl groups or 5-6 membered heteroaryl groups, referred to in the definitions of the variables for Structural Formual (A) are as described later. Typical examples of the 5-6 membered heteroaryl groups referred to in the definitions of variables for Structural Formual (A) include a furanyl group, an imidazolyl group, an isoxazolyl group, an oxadiazolyl group, an oxazolyl, a pyrazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thiazolyl group, a triazolyl group, a tetrazolyl group, a thienyl group, a pyrimidinyl group, a pyridinyl group or a pyridazinyl group. Typical 5-14 membered heteroaryl groups referred to in the definitions of variables for Structural Formual (A) include an indolyl group, a quinolinyl group, a furanyl group, an imidazolyl group, an isoxazolyl group, an oxadiazolyl group, an oxazolyl, a pyrazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thiazolyl group, a triazolyl group, a tetrazolyl group, a thienyl group, a pyrimidinyl group, a pyridinyl group or a pyridazinyl group.
In one embodiment, the compound of the present invention is represented by Structural Formula (B), (C), (D), (E), (F), (G), (H), (Y), (J) or (K):
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof. Each OfY1, Y2, Y3 and Y4 in Strucutral Formula (B) is independently -N or
-CH.
Ring A and ring B of Structural Formulas (B)-(K) are optionally substituted. Values and specific values for the remainder of the variables are as described above for Structural Formula (A). In a first embodiment, the compound of the present invention is represented by Structural Formula (I):
Figure imgf000022_0002
or a pharmaceutically acceptable salt thereof. Value and specific values are as described above for Structural Formula (A). In a more specific embodiment, R3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, provided when R3 is halogen, then
Figure imgf000023_0001
then more specific embodiment, R3 is H, C 1 -C6 alkyl or C 1 -C6 haloalky.
In a second embodiment, the compound of the present invention is represented by Structural Formula (I), wherein a first set of values for the variables of Structural Formula (I) is provided in the following paragraphs:
R3 is -H, C1-C6 alkyl or C1-C6 haloalkyl. each R' independently is Cj.io aliphatic, phenyl or 5-6 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and wherein each of the phenyl and heteroaryl groups represented by R1, and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R' independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.
Values and specific values for the remainder of the variables are as described above for Structural Formula (A).
A second set of values for the variables in Structural Formula (I) is provided in the following paragraphs:
X is -C(O)-, -C(S)-, -C(O)N(R2)-, -OC(O)N(R2)-, -SO2NR2-, -O-, -S-, -NR2-, -NR2C(O)-, -NR2C(O)O-, -NR2C(O)ONR2-, -N(R2)C(O)NR2-, -NR2SO2NR2- or -NR2SO2-.
Each R1 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted Ci-I0 alkyl group. Suitable substitutents for each of the alkyl, phenyl and heteroaryl groups represented by R1 independently are as described above for the first set of values.
Each Ak1 independently is an optionally substituted C1-I0 alkyl group. Suitable substitutents for the alkyl group represented by Ak1 are as described above for the first set of values.
Each Ar1 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, (Ci-6
Figure imgf000024_0001
(C1- 6 aminoalkyl, (C i .6 alkylamino)C \ ^ alkyl, (C i ^ dialkylamino)C i ^ alkyl, -NR21 2, -C(O)NR21 2, -C(O)NR21 2, -NR21C(O)R21, -S(O)2R22, -SO2NR21 2, -NR21SO2R22, -NR21C(O)NR22 2, -NR21SO2NR21 2, -OR21, -SR21, Ci-6 haloalkoxy, -C(O)R21, -C(O)OR21, -OC(O)R21, phenyl, benzyl and 5-6 membered heteroaryl.
Values and specific values for the remainder of the variables of Structural Formula (I) are each independently as described above in first set of values of the second embodiment.
A third set of values for the variables in Structural Formula (I) is provided in the following paragraphs
Each Ak10 independently is an optionally substituted C1-6 alkyl group. Suitable substitutents for the alkyl group represented by Ak10 are as described above for the first set of values.
Each Ar10 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Q-6 alkyl, Ci-6 haloalkyl, (C1-6 haloalkoxy)Ci-6 alkyl, (Ci-6 alkoxy)C I-6 alkyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, (C1-6 alkylamino)Ci ^ alkyl, (Ci-6 dialkylamino)Ci^ alkyl, benzyl, phenyl, Ci^ alkoxy, Ci-6 haloalkoxy, amino, Ci-6alkylamino, Ci^dialkylamino, Ci-6 alkylcarbonyloxy, Ci-6alkoxycarbonyl and Ci-6 alkylcarbonyl.
Each R10 independently is: i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally susbstituted Ci-6 alkyl group. Each of the phenyl and heteroaryl groups represented by R10 is optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-6alkyl, C I-6 haloalkyl, (C1-6 haloalkoxy)C1-6alkyl, (Q-6 alkoxy)C1-6 alkyl, Cj-6 hydroxyalkyl, (C1-6 aminoalkyl, (Ci-6 alkylamino)C I-6 alkyl,
Figure imgf000025_0001
alkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, Ci-6 alkoxy, Ci-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and C1^ alkylcarbonyl. The alkyl group represented by R10 is optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, C1-6 haloalkyl, Ci-6 alkoxy, C1.6 haloalkoxy, amino, Q-6 alkylamino, Ci-6 dialkylamino, Cj-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl and phenyl. Each R1 ' independently is R10, -CO2R10, -SO2R10 or -C(O)R10, or
-N(R1 !)2 taken together is a 5-6 membered non-aromatic heterocyclic group optionally substituted with halogen, hydroxy, nitro, cyano, =0, C1-C3 alky, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and amino.
Each R12 independently is: i) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or ii) an optionally susbstituted C1-6 alkyl group. Each of the phenyl and heteroaryl groups represented by R12 is optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, (Ci-6 haloalkoxy)C1-6alkyl, (Ci-6 alkoxy)C1-6 alkyl, C1-6 hydroxyalkyl, (Ci. 6 aminoalkyl, (Ci-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, Ci-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl. The alkyl group represented by R12 is optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, Ci-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, Ci-6 alkylamino, Ci-6 dialkylamino, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonyl and phenyl.
Each R21 independently is hydrogen, Ci-6 alkyl or optionally substituted phenyl. Suitable substitutents for the phenyl group represented by R21 are as described above for the first set of values. Each R22 independently is Ci-6 alkyl or optionally substituted phenyl.
Suitable substitutents for the phenyl group represented by R22 are as described above for the first set of values. Values and specific values for X, R1, Ak1 and Ar1 are each independently as described above in the second set of values of the second embodiment.
Values and specific values for the remainder of the variables of Structural Formula (I) are each independently as described above in the first set of values of the second embodiment.
A fourth set of values for the variables in Structural Formula (I) is provided in the following paragraphs:
Each R1 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted Ci-10 alkyl group. Each of the phenyl and heteroaryl groups represented by R1 is optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ak10, (Ci-10 alkylene)-Ar10, (C2-10 alkenylene)-Ar10, -OR10, -SR10, -OC(O)N(R11^, -N(R11^, -C(O)NR11, -NR11C(O)R10, -N(Ru)C(0)N(Rπ)2, -NR11SO2N(R1^2, -NR11SO2R12, -SO2N(R1 ^2, -OC(O)R10 , -C(O)OR10 and -C(O)R10. The alkyl group represented by R1 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ar10, -OR10, -SR10, -N(R11^, -OC(O)R10, -C(O)OR10 and -C(O)R10.
Each Ak1 independently is a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C1-OaIlCyI), -S(C I-6 alkyl),
Figure imgf000026_0001
amino, Ci-6 alkylamino, C]-6 dialkylamino, C1-6 alky lcarbonyloxy, Ci-6alkoxycarbonyl and C1-6 alkylcarbonyl.
Each Ar1 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C1-6 alkyl), -S(C1-6 alkyl), Ci-6 alkyl,
Figure imgf000026_0002
(Ci-6 haloalkoxy)C I-6 alkyl, (Ci-6 alkoxy)C I-6 alkyl,
Figure imgf000026_0003
(Ci-6 aminoalkyl, (Ci-6 alky lamino)C I-6 alkyl, (Ci-6 dialkylamino)C I-6 alkyl, (phenyl)C I-6 alkyl, (5-6 membered heteroaryl)Ci_5 alkyl, amino, Cj-6 alkylamino, Ci-6 dialkylamino, Ci-6 haloalkoxy, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Cj-6 alkylcarbonyl. Values and specific values for X, R10, R11, R12, R21, R22, Ak10 and Ar10 are each independently as described above in the third set of values of the second embodiment.
Values and specific values for the remainder of the variables of Structural Formula (I) are each independently as described above in the first set of values of the second embodiment.
A fifth set of values for the variables in Structural Formula (I) is provided in the following paragraphs:
Each R10 independently is i) hydrogen, ii) a phenyl group group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy, or iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C 1 -C3 alkoxy, C 1 -C3 haloaloxy and phenyl.
Each R12 independently i) a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy, or ii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, Cl- C3 haloaloxy and phenyl.
Each Ar10 independently is a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloaloxy.
Values and specific values for X, R1, R11, R21, R22, Ak1, Ak10 and Ar1 are each independently as described above in the fourth set of values of the second embodiment. Values and specific values for the remainder of the variables of Structural
Formula (I) are each independently as described above in the first set of values of the second embodiment. In a third embodiment, the compound of the invention is represented by Structural Formula (II) or a pharmaceutically acceptable salt thereof:
Figure imgf000028_0001
wherein values and specific values for the variables of Structural Formula (II) are provided in the following paragraphs:
Each of n and m is independently 0, 1 or 2. Each R2 is -H or C1-C6 alkyl.
Each of R4 and R5 is independently -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(C 1 -C6 alkyl), -C(O)O(phenyl), -S(O)2(C 1 -C6 alkyl) or -S(O)2(phenyl), wherein each said phenyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, and wherein each said alkyl in the groups represented by by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkoxy, C1-C6 haloalkoxy and phenyl. R7 is -H, F, Cl or methyl.
Values and specific values for the remainder of the variables of Structural Formula (II) are each independently as described above in the second embodiment for the variables of Structural Formula (I).
Alternatively, each of n and m is independently 0, 1 or 2; and values and specific values for the remaining variables of Structural Formula (II) are each independently as described in the first set, the second set, the third set, the fourth set or the fifth set of values for the variables of Structural Formula (I) in the second specific embodiment. In a fourth embodiment, the compound of the invention is represented by Structural Formula (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof:
Figure imgf000029_0001
Figure imgf000030_0001
wherein a first set of values and specific values for the variables of Structural Formulas (III) - (VII) is provided in the following paragraphs:
One of Qa and Qb is halogen, -NO2, -CN, Ak1, Ar1, (C1-10 alkylene)-Ar\ (C2- io alkenylene^Ar1 or -X-R1; and the other of Qa and Qb is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
Each of n and m independently is 0, 1 or 2.
Each R2 is -H or C1-C6 alkyl.
R3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl. Each of R4 and R5 independently is -H, C 1 -C6 alkyl, phenyl, -C(O)(C 1 -C6 alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O)2(Cl-Co alkyl) or -S(O)2(phenyl), wherein each said phenyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C 1 -C6 alkoxy and C 1 -C6 haloalkoxy, and wherein each said alkyl in the groups represented by by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkoxy, C1-C6 haloalkoxy and phenyl.
R6 is hydrogen, halogen, nitro, cyano, R1, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)OR, -SOR', -SO2R1, -SO3R', -SO2N(R)2, -NRS(O)R', -NRSO2R', -NRC(O)N(R)2, -NRC(O)ON(R)2 or -NRSO2N(R)2. Alternatively, each R6 is hydrogen, halogen, nitro, cyano, R', -OR, -SR or -N(R)2; and each R independently is hydrogen, optionally substituted Cj-6 alkyl, optionally substituted C2-6alkenyl, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl, or N(R)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, =0, C1-C3 alky, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and amino; and each R1 independently is optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl. Each R7 independently is -H, F, Cl or methyl.
Values and specific values for the remainder of the variables of Structural Formulas (III) - (VII) are each independently as described above in the first set of values for the variables of Structural Formula (I).
A second set of values and specific values for the variables of Structural Formulas (III) - (VII) is provided in the following paragraphs:
Each of R4 and R5 independently is -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O)2(Cl-Co alkyl) or -S(O)2(ρhenyl).
Values and specific values for n, m, Qa and Qb, R2, R6 and R7 are each independently as described above in the first set of values for Structural Formulas (III) - (VII).
Values and specific values for the remainder of the variables of Structural Formulas (III) - (VII) are each independently as described above in the first set of values for the variables of Structural Formula (I). A third set of values and specifc values for the variables of Structural
Formulas (III) - (VII) is provided in the following paragraphs:
Both of Qa and Qb are independently halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
Values and specific values for n, m, R2, R2, R4, R5, R6 and R7 are each independently as described above in the second set of values for Structural Formulas (IH) - (VII).
Values and specific values for the remainder of the variables of Structural Formulas (III) - (VII) are each independently as described above in the first set of values for the variables of Structural Formula (I). A fourth set of values and specifc values for the variables of Structural
Formulas (III) - (VII) is provided in the following paragraphs: One of Qa and Qb is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(Cl-CO alkyl), -C(O)NH2, -C(O)NH(Cl-Co alkyl), -C(O)N(Cl-Co alkyl)2, -SO2NH2, -SO2NH(Cl-Co alkyl), -SO2N(Cl-Co alkyl)2, -OH, -0(Cl-C6 alkyl), -O(C1-C6 haloalkyl), -SH, -S(Cl-Co alkyl), -S(Cl-CO haloalkyl), -NH2, -NH(Cl-Co alkyl), -N(Cl-CO alkyl)2, , -NHC(O)(Cl-Co alkyl), -NHC(O)O(Cl-Co alkyl), -NHC(O)NH2, -NHC(O)NH(Cl-Co alkyl), -NHC(O)N(Cl-Co alkyl)2, -NHC(O)ONH2, -NHC(O)ONH(Cl-Co alkyl), -NHC(O)ON(Cl-CO alkyl)2, -NHSO2NH2, -NHSO2NH(Cl-Co alkyl), -NHSO2N(Cl-Co alkyl)2 or -NHSO2(Cl- C6 alkyl); and the other of Qa and Qb is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
Alternatively, one of Qa and Qb is halogen, hydroxy, cyano, nitro, Ph, -CH2Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(Cl-CO alkyl)(Ph), -SO2NH(Ph), -SO2N(Cl-Co alkyl)(Ph), -0(Ph), -S(Ph), -NH(Ph), -N(Cl-Co alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(Cl-Co alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(C 1 -C6 alkyl)(Ph), -NHSO2NH(Ph),
-NHSO2N(Cl-Co alkyl)(Ph) or -NHSO2(Ph), wherein each Ph independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; and the other of Qa and Qb is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
Values and specific values for the remainder of the variables of Structural Formulas (III) - (VII) are each independently as described above in the first set of values for the variables of Structural Formula (I) in second embodiment.
In a fifth set, each of n and m independently is O, 1 or 2; and values and specific values for the remaining variables of each Structural Formula (III) - (VII) are independently as described in the first set, the second set, the third set, the fourth set or the fifth set of values for the variables of Structural Formula (I) in the second embodiment.
In a sixth set, values and specific values for the remaining variables of each Structural Formula (III) - (VII) are independently as described in the first set of values for the variables of Structural Formula (II) in the third embodiment. In a fifth embodiment, the compound of the invention is represented by a structural formula selected from Structural Formulas (VIII) - (XXXV) or a pharmaceutically acceptable salt thereof:
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
wherein a first set of values and preferred values for the variables of Structural Formulas (VIII) - (XXXV) is provided in the following paragraphs: Each Qa in Structural Formulas (VIII), (X), (XII), (XIII), (XV), (XVI),
(XVII), (XXI), (XXII), (XXIII), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI) and (XXXII) independently is halogen, -NO2, -CN, Ak1, Ar1, (C]-10 alkylene)-Ar1, (C2-10 alkenylene)-Ar1 or -X-R1. Each Qb in Structural Formulas (IX), (XI), (XIV), (XVIII), (XIX), (XX), (XXIV), (XXV), (XXVI), (XXXIII), (XXXIV) and (XXXV) independently is halogen, -NO2, -CN, Ak1, Ar1, (C1-10 alkylene^Ar1, (C2-10 alkenylene^Ar1 or -X-R1.
Each of n and m in Strcutrual Formulas (VIII), (IX), (XV), (XVI), (XVII), (XVIII), (XIX) and (XX) independently is 0, 1 or 2.
Each R2 is -H or C1-C6 alkyl. R3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl.
Each R7 in Structural Formulas (VIII) - (XII) and (XV) - (XXIX) independently is -H, F, Cl or methyl.
Values and specific values for the remainder of the variables of Structural Formulas (VIII) - (XXXV) are each independently as described above in the first set of values for the variables of Structural Formula (I).
A second set of values and specific values for the variables of Structural Formulas (VIII) - (XXXV) is provided in the following paragraphs:
Each Qa in Structural Formulas (VIII), (X), (XII), (XIII), (XV), (XVI), (XVII), (XXI), (XXII), (XXIII), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI) and (XXXII) independently is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C 1-C6 alkyl), -C(O)NH2, -C(O)NH(C 1-C6 alkyl), -C(O)N(Cl-Co alkyl)2, -SO2NH2, -SO2NH(Cl-Co alkyl), -SO2N(Cl-Co alkyl)2, -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -SH, -S(Cl-Co alkyl), -S(C1-C6 haloalkyl), -NH2, -NH(Cl-Co alkyl), -N(C1-C6 alkyl)2, , -NHC(O)(Cl-Co alkyl), -NHC(O)O(Cl-Co alkyl), -NHC(O)NH2, -NHC(O)NH(Cl-Co alkyl), -NHC(O)N(Cl-Co alkyl)2, -NHC(O)ONH2, -NHC(O)ONH(Cl-Co alkyl), -NHC(O)ON(Cl-Co alkyl)2, -NHSO2NH2, -NHSO2NH(Cl-Co alkyl), -NHSO2N(Cl-Co alkyl)2 or -NHSO2(Cl- C6 alkyl). Alternatively, each Qa in Structural Formulas (VIII), (X), (XII), (XIII), (XV), (XVI), (XVII), (XXI), (XXII), (XXIII), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI) and (XXXII) independently is halogen, hydroxy, cyano, nitro, Ph, -CH2Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(Cl-Co alkyl)(Ph), -SO2NH(Ph), -SO2N(Cl-Co alkyl)(Ph), -O(Ph), -S(Ph), -NH(Ph), -N(Cl-CO alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(Cl-Co alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(Cl-Co alkyl)(Ph), -NHSO2NH(Ph), -NHSO2N(Cl-Co alkyl)(Ph) or -NHSO2(Ph), wherein each Ph is a phenyl group independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
Each Qb in Structural Formulas (IX), (XI), (XIV), (XVIII), (XIX), (XX), (XXIV), (XXV), (XXVI), (XXXIII), (XXXIV) and (XXXV) independently is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(Cl-Co alkyl), -C(O)NH2, -C(O)NH(Cl-Co alkyl), -C(O)N(Cl-Co alkyl)2, -SO2NH2, -SO2NH(Cl- C6 alkyl), -SO2N(Cl-Co alkyl)2, -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -SH, -S(Cl-CO alkyl), -S(Cl-CO haloalkyl), -NH2, -NH(Cl-CO alkyl), -N(Cl-Co alkyl)2, , -NHC(O)(Cl-Co alkyl), -NHC(O)O(Cl-Co alkyl), -NHC(O)NH2, -NHC(O)NH(Cl- C6 alkyl), -NHC(O)N(Cl-Co alkyl)2, -NHC(O)ONH2, -NHC(O)ONH(Cl-Co alkyl), -NHC(O)ON(C 1 -C6 alkyl)2, -NHSO2NH2, -NHSO2NH(C 1 -C6 alkyl),
-NHSO2N(Cl-Co alkyl)2 or -NHSO2(C1-C6 alkyl). Alternatively, each Qb in Structural Formulas (IX), (XI), (XIV), (XVIII), (XIX), (XX), (XXIV), (XXV), (XXVI), (XXXIII), (XXXIV) and (XXXV) independently is halogen, hydroxy, cyano, nitro, Ph, -CH2Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(Cl-Co alkyl)(Ph), -SO2NH(Ph), -SO2N(C 1 -C6 alkyl)(Ph), -O(Ph), -S(Ph), -NH(Ph), -N(C 1 -C6 alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(Cl-Co alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(C 1-C6 alkyl)(Ph), -NHSO2NH(Ph), -NHSO2N(Cl-Co alkyl)(Ph) or -NHSO2(Ph), wherein each Ph is a phenyl group independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy. Values and specific values for R3, R7, n and m are each independently as described above in the first set of values for the variables of Structural Formulas (VIII) - (XXXV).
In a third set, each of n and m independently is 0, 1 or 2; and values and preferred values of the remaining variables of Structural Formulas (VIII) - (XXXV) are each independently as described above for the first set, second set, third set, fourth set or the fifth set of values for the variables of Structural Formula (I) of the second embodiment.
In a fourth set, values and specific values for the remaining variables of each Structural Formulas (VIII) - (XXXV) are each independently as described in the first set of values for the variables of Structural Formula (II).
In a sixth embodiment, the compound of the present invention is represented by Structural Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (C1)-(C4), (Dl)-(DS), (El)-(ES), (Fl)-(FS), (Gl)-(GS), (Hl)-(HS), (1'I)-(PS), (Jl)- (JSX (Kl)-(KS):
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
or a pharmaceutically acceptable salt thereof, wherein:
R6 for Strucutral Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ik), (II), (Cl), (C2), (Dl), (D2), (D5), (D6), (El), (E2), (E5), (E6), (Fl), (F2), (F5), (F6), (Gl), (G2), (G5), (G6), (Hl), (H2), (H5), (H6), (I'l), (I'2), (F5), (I'6), (Jl), (J2), (J5), (J6), (Kl), (K2), (K5) and (K6) is optionally substituted phenyl, optionally substituted 5-12 membered heteroaryl, -CH2-(optionally substituted phenyl), -CH2- (optionally substituted 5-12 membered heteroaryl), -CH2-CH2-(optionally substituted phenyl), -CH2-CH2-(optionally substituted 5-12 membered heteroaryl), -CH=CH-(optionally substituted phenyl), -CH=CH-(optionally substituted 5-12 membered heteroaryl), -CH=CH-C(O)O(optionally substitutued Ci-6 alkyl), or -CH=CH-OC(O)(optionally substitutued C1-6 alkyl). R6 can also be -C≡C-(optionally substituted phenyl), -C≡C-(optionally substituted 5-12 membered heteroaryl), -C≡C- C(O)O(optionally substitutued Ci-6 alkyl), or -C≡€-OC(O)(optionally substitutued
Ci-6 alkyl);
R7 of Structural Formulas (Ig), (Ih), (Ii) and (Ij) is -H, -F, -Cl or methyl and n in Structural Formulas (Ii), (Ij), (Ik) and (II) is 0 or 1.
Values and specific values for the remainder of the variables of Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), and (II) are as describe above for Structural Formula (I) in the first embodiment. Values and specific values for the remainder of the variables of Structural Formulas (C1)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (ri)-(I'8), (J1)-(J8) and (K1)-(K8) are as described above for Structural Formula (A). In one embodiment, for Structural Formula (Cl), when R6 is -H, R5 is H and R4 is H or C1-C6 alkyl, then ring A is not phenyl or phenyl substituted with halogen or trifluoromethyl. In another embodiment, for Structural Formula (Cl), R5 and R6 are not both -H. In one embodiment for Structural Formulas (Ia) and (Ib), R3 is-H, C 1 -C6 alkyl or C 1 -C6 haloalkyl.
In a seventh embodiment, R4 and R5 of Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If),(Cl)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I' 1)-(I'8), (J1)-(J8), and (K1)-(K8) are each independently -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O)2(Cl-Co alkyl) or -S(O)2(phenyl), wherein each phenyl in the group represented by R4 and R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, -0(C1-6 alkyl), C1-6 haloalkyl, C1-6 haloalkoxy, cyano and nitro. Values and specific values for the remainder of the variables are as described above in the sixth embodiment. In an eighth embodiment, R4 and R5 of Structural Formulas (Ia), (Ib), (Ic),
(Id), (Ie) (If), (C1)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I'1)-(F8), (J1)-(J8) and (K1)-(K8) are as described above in the seventh embodiment and R6 for Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Cl), (C2), (Dl), (D2), (D5), (D6), (El), (E2), (E5), (E6), (Fl), (F2), (F5), (F6), (Gl), (G2), (G5), (G6), (Hl), (H2), (H5), (H6), (Fl), (I'2), (I'5), (I'6), (Jl), (J2), (J5), (J6), (Kl), (K2), (K5) and (K6) is optionally substituted phenyl, optionally substituted 5-12 membered heteroaryl, -CH2-(optionally substituted phenyl), -CH2-(optionally substituted 5-12 membered heteroaryl), -CH2- CH2-(optionally substituted phenyl), -CH2-CH2-(optionally substituted 5-12 membered heteroaryl), -CH=CH-(optionally substituted phenyl), -CH=CH-
(optionally substituted 5-12 membered heteroaryl), -CH=CH-C(O)O(optionally substitutued C1-6 alkyl), or -CH=CH-OC(O)(optionally substitutued C1-6 alkyl). Alternatively, R6 can also be -C≡C-(optionally substituted phenyl), -C≡C-(optionally substituted 5-12 membered heteroaryl), -C≡C-C(O)O(optionally substitutued C1^ alkyl), or -C≡C-OC(O)(optionally substitutued C1-6 alkyl). The 5-12 membered heteroaryl in the group represented by R6 is selected from the group consisting of pyridyl, thiazolyl, pyrazinyl, thiophenyl, indolyl, quinolinyl, pyrrolyl, pyrazolyl, and pyrimidyl, each of which is optionally substituted. Values and specific values for the remainder of the variables are as described above in the sixth embodiment.
In a ninth embodiment, values for the variables in Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (C1)-(C4), (Dl)-(DS), (El)- (E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (ri)-(I'8), (J1)-(J8) and (K1)-(K8) are provided in the following paragraphs:
Ring A in Structural Formulas (C1)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I' 1)-(I'8), (J1)-(J8) and (K1)-(K8) are optionally substituted with one or more Qa and ring B in Structural Formulas (C1)-(C4), (D1)-(D8), (El)- (E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I'1)-(I'8), (J1)-(J8) and (K1)-(K8) are optionally substituted with one or more Qb.
Qa and Qb are each independently halogen, cyano, -NR1R2, -NR2C(O)R1, -C(O)OR1, -OC(O)R1, -C(O)NR1R2, -NR2C(O)OR1, -N(R^C(O)NR1R2, -OR1, -SO2NR1R2, -NR2SO2R1, Ci-6 alkyl, phenyl or 5-12 membered heteroaryl, wherein the C i-6 alkyl represented by Qa and Qb is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C1-6 alkyl), -S(Ci-6 alkyl), Cj-6 haloalkoxy, amino, Ci-6 alky lamino, C1-6 dialkylamino, Ci-βalkylcarbonyloxy, Ci-6 alkoxycarbonyl and C1-6 alky lcarbonyl; and the phenyl or the 5-12 membered heteroaryl represented by Q3 and Qb is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C I-6 alkyl), -S(C1-6 alkyl), Ci-6 alkyl, C1-6haloalkyl, (Ci-6 haloalkoxy)Ci-6 alkyl, (Ci-6 alkoxy)C I-6 alkyl, Ci-6 hydroxyalkyl, (C1-6 aminoalkyl, (Ci-6 alky IaTnUiO)C1.6 alkyl, (Ci-6 dialkylamino)Ci-6 alkyl, (phenyl)C I-6 alkyl, (5-6 membered heteroaryl)C I-6 alkyl, amino, Ci-6 alkylamino, Ci-6 dialkylamino, Ci-6 haloalkoxy, C1-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl;
R1 and R2 are each independently -H- or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SH, -0(Ci-3 alkyl), -S(Ci-3 alkyl) and Ci-6 haloalkoxy; the phenyl or the 5-12 membered heteroaryl in the group represented by R6 for Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Cl), (C2), (Dl), (D2), (D5), (D6), (El), (E2), (E5), (E6), (Fl), (F2), (F5), (F6), (Gl), (G2), (G5), (G6), (Hl), (H2), (H5), (H6), (F l), (I'2), (I'5), (I'6), (Jl), (J2), (J5), (J6), (Kl), (K2), (K5) and (K6) is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C1-6 alkyl), -S(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, (C1-6 haloalkoxy)C1-6 alkyl, (C1-6 8IkOXy)C1-6 alkyl, C1-6hydroxyalkyl, (C1-6 aminoalkyl, (Ci-6 alky IaInUiO)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (pheny I)C I-6 alkyl, (5-6 membered heteroaryl)Ci-6 alkyl, amino, C1-6 alkylamino, C1-6dialkylamino, C1-6 haloalkoxy, C1- 6 alkylcarbonyloxy, C1-6alkoxycarbonyl and C1-6 alkylcarbonyl. In another embodiment, -(CH2)0-3-A/-piperidinyl, -(CH2)o-3-N-morpholinyl, -(CH2)0-3-N- pyrrolidinyl and -(CH2)0-3-N-piperazinyl, wherein the N-piperaziinyl is optionally N -substituted with C1-6 alkyl or Ci-6 acyl are additional permissible substituents for the phenyl or the 5-12 membered heteroaryl in the group represented by R6; and the C1-6 alkyl in the group represented by R6 for Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Cl), (C2), (Dl), (D2), (D5), (D6), (El), (E2), (E5), (E6), (Fl), (F2), (F5), (F6), (Gl), (G2), (G5), (G6), (Hl), (H2), (H5), (H6), (Fl), (F2), (I'5), (I'6), (Jl), (J2), (J5), (J6), (Kl), (K2), (K5) and (K6) is optionally substituted one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C1-6 alkyl), -S(C1-6 alkyl), Ci-6 haloalkoxy, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and Ci-6 alkylcarbonyl.
Values and specific values for the remainder of the variables are as described above in the sixth, seventh or eighth embodiments.
In a tenth embodiment, values for the variables in Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (C1)-(C4), (D1)-(D8), (El)- (E8), (F1)-(F8), (Gl)-(GS), (H1)-(H8), (I'1)-(I'8), (Jl)-(JS) and (K1)-(K8) are provided in the following paragraphs:
Ring A in Structural Formulas (C1)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I' 1)-(I'8), (J1)-(J8) and (K1)-(K8) are optionally substituted with one or more Qa and ring B in Structural Formulas (C 1 )-(C4), (D 1 )-(D8), (E 1 )- (E8), (Fl)-(FS), (Gl)-(GS), (Hl)-(HS), (T1KT8), (Jl)-(JS) and (Kl)-(KS) are optionally substituted with one or more Qb. Qa is halogen, cyano, -NR1R2, -NR2C(O)R1, -C(O)OR1, -OC(O)R1, -N(R2)C(O)NR'R2, -OR1, C1-6 alkyl, wherein the Cj-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -SH, -0(Ci-6 alkyl), -S(Ci-6 alkyl) and Q-6 haloalkoxy; Qb is halogen, Ci-3 alkyl, Ci-3 haloalkyl, Ci-3 alkoxy, or Ci-3 haloalkoxy; and the phenyl, the 5-12 membered heteroaryl and the Ci-6 alkyl in the group represented by R6 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -0(Ci-6 alkyl), Ci-6 alkyl, Ci-6 haloalkyl and C1-6 haloalkoxy. Values and specific values for the remainder of the variables are as described above in the sixth, seventh, eighth or ninth embodiments.
In a eleventh embodiment, values for the variables in Structural Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (1I)5(Cl )-(C4), (Dl)-(DS), (El)- (E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (ri)-(I'8), (J1)-(J8) and (Kl)-(K8)are provided in the following paragraphs:
Ring A in Structural Formulas (C1)-(C4), (D1)-(D8), (E1)-(E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (I' I)-(I' 8), (J1)-(J8) and (K1)-(K8) are optionally substituted with one or more Qa and ring B in Structural Formulas (C1)-(C4), (D1)-(D8), (E I)- (E8), (F1)-(F8), (G1)-(G8), (H1)-(H8), (ri)-(F8), (J1)-(J8) and (K1)-(K8) are optionally substituted with one or more Qb.
Qa is -OH, Ci-6 alkoxy or Ci-6 haloalkoxy;
Qb is halogen, Ci-3 alkyl, Ci-3 haloalkyl, C1.3 alkoxy, or Ci-3 haloalkoxy and the phenyl, the 5-12 membered heteroaryl and the Ci-6 alkyl in the group represented by R6 are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, methyl, methoxy and trifluoromethyl.
In a twelvth embodiment, the compound of the present invention is represented by a structural formula selected from (II) and (12):
Figure imgf000062_0001
or a pharmaceutically acceptable salt thereof, wherein: Qa is -H, halogen, -NH2, (C1-6alkyl)amine or C1-6 alkoxy; R6 is phenyl, 5-6 membered heteroaryl, -CH=CH-( phenyl), -CH=CH-(5-6 membered heteroaryl), -C≡C -(phenyl), -C≡C-(5-6 membered heteroaryl) wherein each phenyl and heteroaryl in the group represented by R6 is optionally substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C1-6 aminoalkyl), (C1-6 alkylamino)C1-6 alkyl, (Ci-6 dialkylamino)Ci^ alkyl, (phenyl)Ci .6 alkyl, amino, Ci^alkylamino, Ci-6 dialkylamino, -(CH2)0-3-N-piperidinyl, -(CH2)0-3-N-morpholinyl, -(CH2)0-3-N- pyrrolidinyl and -(CH2)o-3-N-piperazinyl, wherein the N-piperazinyl is optionally JV'- substituted with Ci-6 alkyl or Ci-6 acyl. Alternatively for Structural Formulas (II) and (12), each heteroaryl in the group represented by Rθ is pyridinyl, pyrimidinyl or pyrazinyl and each is optionally substituted halogen, C1-6 alkyl, Ci^ haloalkyl, (Ci-6 aminoalkyl), alkyl, (Ci-6 dialkylamino)C I-6 alkyl, (phenyl)C1-6 alkyl, amino,
Figure imgf000062_0002
dialkylamino, -(CH2)o-3-JV-piperidinyl, -(CH2)0- 3-N-morpholinyl, -(CH2)0-3-JV-pyrrolidinyl and -(CH2)0-3-JV-piperazinyl, wherein the JV-piperazinyl is optionally JV '-substituted with Q-6 alkyl or C]-6 acyl. Values and specific values for the remainder of the variables are as described above in the the sixth, seventh, eighth, ninth or tenth embodiments.
As used herein, the phenyl, the 5-12 membered heteroaryl and the Ci-6 alkyl in the group represented by R6 refers to the phenyl, the 5-12 membered heteroaryl and the C1-6 alkyl represented by R6 as well as the phenyl, the 5-12 membered heteroaryl and the C1-6 alkyl in the groups represented by R6, for example, -CH2- (optionally substituted phenyl), -CH2-(optionally substituted 5-12 membered heteroaryl), -CH2-CH2-(optionally substituted phenyl), -CH2-CH2-(optionally substituted 5-12 membered heteroaryl), -CH=CH-(optionally substituted phenyl), -CH=CH-(optionally substituted 5-12 membered heteroaryl), -CH=CH- C(O)O(optionally substitutued C1-6 alkyl), and -CH=CH-OC(O)(optionally substitutued C1-6 alkyl) represented by R6. Similarly, the language "a specific moiety in the group represented by a variable" refers to the moiety represented by the variable or the moiety in a group represented by the variable. Specific examples of the compounds of the invention include compounds exemplified in the examples below, stereoisomers thereof, and pharmaceutically acceptable salts thereof.
In Structural Formulas described herein, when a hydrogen atom(s) is depicted at a particular position(s) of the aromatic ring(s) of the structual formula(s), no substitution is permitted at that (those) particular position(s).
Tautomeric forms exist when a compound is a mixture of two or more structurally distinct compounds that are in rapid equilibrium. Certain compounds of the invention exist as tautomeric forms. For example, the following compound represented by Structural Formula (A), wherein two of X1-X3 are N, one of X1-X3 is NH or compound represented by Structural Formula (I), wherein two of X1-X3 are N, one of X1-X3 is NH, include at least the following tautomers forms:
Figure imgf000063_0001
Figure imgf000064_0001
(ketone form) and
Figure imgf000064_0003
Figure imgf000064_0002
(ketone form) (enol form)
It is to be understoond that when one tautomeric form of a compound is depicted by name or structure, all tautomeric forms of the compound are included.
The compounds of the invention may contain one or more chiral center and/or double bond and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, and/or diastereomers. When compounds of the invention are depicted or named without indicating the stereochemistry, it is to be understood that both stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and stereoisomeric mixtures are encompassed. For example, compounds represented by Structural Formulas (A) or (I) have E and Z geometric isomers shown below:
Figure imgf000065_0001
(Z)
Figure imgf000065_0002
Accordingly, the compounds of the invention depicted by Structural Formula (A) or (I) include the pure E geometric isomer isomer, the pure Z geometric isomer, and mixtures thereof.
The invention encompasses all geometrically-pure forms and geometrically- enriched (i.e.greater than 50% of either E or Z isomer) mixtures, of the compounds disclosed herein. Mixtures include 1:20, 1:10, 20:80, 30:70, 40:60 and 50:50 E:Z and Z:E ratios by mole.
As used herein, a racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer relative to all chiral centers in the molecule. The invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds of the invention which have chiral center(s). Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral- phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single stereoisomer is named or depicted by structure, the depicted or named stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure. Percent purity by weight is the ratio of the weight of the named stereoisomer over the weight of the named stereoisomer plus the weight of its stereoisomers.
Included in the invention are pharmaceutically acceptable salts of the compounds disclosed herein. The disclosed compounds have basic amine groups and therefore can form pharamceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p- toluenesulfonic, and tartaric acids). Compounds of the invention with acidic groups such as carboxylic acids can form pharamceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid.
The term "halo" as used herein means halogen and includes chloro, fluoro, bromo and iodo.
An "aliphatic group" is non-aromatic, consists solely of carbon and hydrogen and may optionally contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic. When straight chained or branched, an aliphatic group typically contains between about one and about twenty carbon atoms, typically between about one and about ten carbon atoms, more typically between about one and about six carbon atoms. When cyclic, an aliphatic group typically contains between about three and about ten carbon atoms, more typically between about three and about seven carbon atoms. A "substituted aliphatic group" is substituted at any one or more "substitutable carbon atom". A "substitutable carbon atom" in an aliphatic group is a carbon in an aliphatic group that is bonded to one or more hydrogen atoms. One or more hydrogen atoms can be optionally replaced with a suitable substituent group. A "haloaliphatic group" is an aliphatic group, as defined above, substituted with one or more halogen atoms. Suitable substituents on a substitutable carbon atom of an aliphatic group are the same as those for an alkyl group.
The term "alkyl" used alone or as part of a larger moiety, such as "alkoxy", "haloalkyl", "arylalkyl", "alkylamine", "cycloalkyl", "dialkyamine", "alkylamino", "dialkyamino" "alkylcarbonyl", "alkoxycarbonyl" and the like, includes as used herein means saturated straight-chain, cyclic or branched aliphatic group. As used herein, a C1-C6 alkyl group is referred to "lower alkyl." Similarly, the terms "lower alkoxy", "lower haloalkyl", "lower arylalkyl", "lower alkylamine", "lower cycloalkylalkyl", "lower dialkyamine", "lower alkylamino", "lower dialkyamino" "lower alkylcarbonyl", "lower alkoxycarbonyl" include straight and branched, saturated chains containing one to six carbon atoms, and cyclic saturated chains containing three to six carbon atoms. The term "alkoxy" means -O-alkyl; "hydroxyalkyl" means alkyl substituted with hydroxy; "aralkyl" means alkyl substituted with an aryl group; "alkoxyalkyl" mean alkyl substituted with an alkoxy group; "alkylamine" means amine substituted with an alkyl group; "cycloalkylalkyl" means alkyl substituted with cycloalkyl; "dialkylamine" means amine substituted with two alkyl groups; "alkylcarbonyl" means -C(O)-R, wherein R is alkyl; "alkoxycarbonyl" means -C(O)-OR, wherein R is alkyl; and where alkyl is as defined above.
The terms "haloalkyl" and "haloalkoxy" means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br or I. Preferably the halogen in a haloalkyl or haloalkoxy is F.
The term "acyl group" means -C(O)R, wherein R is an optionally substituted alkyl group or aryl group (e.g., optionally substituted phenyl). R is preferably an unsubstituted alkyl group or phenyl.
An "alkylene group" is represented by -[CH2]Z-, wherein z is a positive integer, preferably from one to eight, more preferably from one to four.
An "alkenylene group" is an alkylene in which at least a pair of adjacent methylenes are replaced with -CH=CH-.
An "alkynylene group" is an alkylene in which at least a pair of adjacent methylenes are replaced with -C≡C-. The term "aryl group" used alone or as part of a larger moiety as in
"aralkyl", "aralkoxy", or "aryloxyalkyl", means carbocyclic aromatic rings. The term "carbocyclic aromatic group" may be used interchangeably with the terms "aryl", "aryl ring" "carbocyclic aromatic ring", "aryl group" and "carbocyclic aromatic group". An aryl group typically has six - fourteen ring atoms. A "substituted aryl group" is substituted at any one or more substitutable ring atom. The term "C6-HaIyI" as used herein means a monocyclic, bicyclic or tricyclic carbocyclic ring system containing from 6 to 14 carbon atoms and includes phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like. The term "heteroaryl", "heteroaromatic", "heteroaryl ring", "heteroaryl group" and "heteroaromatic group", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to aromatic ring groups having five to fourteen ring atoms selected from carbon and at least one (typically 1 -4, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen or sulfur). They include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other carbocyclic aromatic or heteroaromatic rings. The term "5-14 membered heteroaryl" as used herein means a monocyclic, bicyclic or tricyclic ring system containing one or two aromatic rings and from 5 to 14 atoms of which, unless otherwise specified, one, two, three, four or five are heteroatoms independently selected from N, NH, N(Ci-6alkyl), O and S and includes thienyl, furyl, pyrrolyl, pyrididyl, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl ( e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5 -oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5- oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1 -pyrrolyl, 2- pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5- triazolyl), tetrazolyl (e.g., tetrazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.
Other examples for the aryl and heteroaryl groups include:
Figure imgf000069_0001
Figure imgf000070_0001
wherein each of rings A1-Z7 is optionally substituted. It is noted that, as shown above, rings O1-Z7 can be attached to their designated atom through any ring carbon of the rings which is not at a position bridging two aryl groups. For example,
Figure imgf000070_0002
means that the group is attached to its designated atom through either ring Ql or ring Rl. Yet other examples for the aryl and heteroaryl groups include:
Figure imgf000070_0003
wherein each of rings Al-Nl is optionally substituted. More specific values for the aryl and heteroaryl groups include:
Figure imgf000071_0001
wherein each of rings Al-El is optionally substituted. Even more specific values for the aryl and heteroaryl groups include:
Figure imgf000071_0002
wherein each of rings Al-Cl is optionally substituted. An optionally substituted ring Al is the most common specific value for each of the aryl group, including the C6-14 aryl group.
As used herein, the term "non-aromatic heterocyclic group" means a monocyclic (typically having 3- to 10-members) or a polycyclic (typically having 7- to 20-members) heterocyclic ring system which is an unsaturated non-aromatic ring. A 3- to 10-membered heterocycle can contain up to 5 heteroatoms; and a 7- to 20- membered heterocycle can contain up to 7 heteroatoms. Typically, a heterocycle has at least one carbon atom ring member. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The heterocycle may be attached via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
The aryl group, and the aromatic and non-aromatic heteroaryl groups, unless otherwise indicated, can be optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-20 alkyl, C2- 20alkenyl, C2-20 alkynyl, amino, Ci-20 alky lamino, Ci-20dialkylamino, C1-20 alkoxy, (Ci.ioalkoxy)Ci-2o alkyl, Ci-20haloalkoxy, (Ci-I0 haloalkoxy)Ci-20 alkyl and Ci-20 haloalkyl. Typical substituents include halogen, nitro, cyano, hydroxy, CMO alkyl, C2-I0 alkenyl, C2-I0 alkynyl, amino, Cj-I0 alkylamino, Ci-I0 dialkylamino, CMO alkoxy, (Ci.6alkoxy)Ci-io alkyl, Cuiohaloalkoxy, (Ci-6 haloalkoxy)Ci.i0 alkyl and Ci-I0 haloalkyl. More typical substituents include CMO alkyl, -OH, CMO alkoxy, Ci-io haloalkyl, halogen, CMO haloalkoxy,amino, nitro and cyano.
In accordance with another aspect of the present invention, the compounds of the invention can be prepared by processes analogous to those established in the art. By way of illustration, compounds of Structural Formula (A) (wherein Z is =CR3-) or (I), wherein Rings A, B and C are as defined herein may be prepared by the methods outlined in Scheme 1. Reaction of an appropriately substituted Al or indolin-2-one A2 wherein ring A is as defined herein is reacted with a suitable aldehyde (R3 = H) or a ketone (R3 is not H) in the presence of a secondary amine (such as piperidine) in a protic solvent (such as ethanol) at the reflux temperature of the solvent (generally about 60 0C to 120 0C). In addition this reaction can be carried out under a variety of alternative conditions including secondary amines in aprotic solvents such as DMSO or DMF; solventless with KF/A12O3; acidic conditions (p- TsOH) in toluene or a strong base (e.g. LDA) in THF.
Scheme 1
Figure imgf000072_0001
(E and Z)
Figure imgf000073_0001
(E and Z)
In another aspect of the invention (Scheme 2) in which R3 of compound Bl is not H, the ketone Bl is first converted to an enamine B2 (wherein Y and Z are proton or small alkyl) by reaction with a secondary amine (wherein R* and R** are small alkyl or together form five or six membered ring such as pyrrolidine or piperidine). Subsequent reaction of the enamine B2 with the indolin-2-one A2 in a refluxing organic solvent (such as toluene) yields compounds of Structural Formula (I) (wherein Z is =CR3-).
Scheme 2.
Figure imgf000073_0002
(E and Z)
Compounds of Structural Formula (A) (wherein Z is =N-) or compounds of Structural Formula (C) (wherein Z is =N-), wherein Rings A, B and C are as defined herein may be prepared by the methods outlined in Scheme 3.
Scheme 3
Figure imgf000074_0001
(E and Z)
Figure imgf000074_0002
(E and Z)
The present invention includes radiolabeled forms of the compounds of the invention, for example, compounds of the invention labeled by incorporation within the structure of 3H, 11C or 14C or a radioactive halogen such as 125I and 18F. A radiolabeled compound of the invention may be prepared using standard methods known in the art. For example, tritium may be incorporated into a compound of the invention using standard techniques, for example by hydrogenation of a suitable precursor to a compound of the invention using tritium gas and a catalyst. Alternatively, a compound of the invention containing radioactive iodine may be prepared from the corresponding trialkyltin (suitably trimethyltin) derivative using standard iodination conditions, such as [125I] sodium iodide in the presence of chloramine-T in a suitable solvent, such as dimethylformamide. The trialkyltin compound may be prepared from the corresponding non-radioactive halo-, suitably iodo-, compound using standard palladium-catalyzed stannylation conditions, for example hexamethylditin in the presence of tetrakis(triphenylphosphine) palladium (0) in an inert solvent, such as dioxane, and at elevated temperatures, suitably 50- 100°C. Further, a compound of the invention containing a radioactive fluorine may be prepared, for example, by reaction of K[18F]/K222 with a suitable precursor compound, such as a compound of Formula I comprising a suitable leaving group, for example a tosyl group, that may be displaced with the 18F anion. In some cases the chemistries outlined above may have to be modified, for instance by use of protective groups, to prevent side reactions due to reactive groups, such as reactive groups attached as substituents. This may be achieved by means of conventional protecting groups, for example as described in "Protective Groups in Organic Chemistry" McOmie, J.F.W. Ed., Plenum Press, 1973 and in Greene, T. W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd Edition, 1999.
Indolinone compounds of the invention can inhibit various kinases, including the PLK4, PLKl, PLK2, Aurora A, Aurora B and FLT-3 {see Examples B, C, D, E, F, and H). Thus, generally, the indolinone compounds of the invention are useful in the treatment of diseases or conditions associated with such kinases. For example, PLK4, PLKl, Aurora A and Aurora B are believed to be involved in cellular miotic progression. Thus, small molecule inhibitors of these enzymes can be potential antitumor agents. In a specific embodment, the compounds of the invention are PLK, Aurora
A, Aurora B and/or FLT-3 inhibitors, and are useful for treating diseases, such as cancer, associated with such a kinase(s). In another specific embodment, the compounds of the invention are PLK inhibitors and are useful for treating diseases associated with PLK, such as cancer. Typically, the PLK is PLK4, PLK2 and PLK 1. In one example, the PLK is PLKl and PLK4. In another example, the PLK is PLK4. In another specific embodment, the compounds of the invention are Aurora A and/or B inhibitors and are useful in inhibiting Aurora A and/or B activity for the treatment of various conditions such as cancers. In yet another specific embodiment, the compounds of the invention are FLT-3 inhibitors and are useful in inhibiting FLT-3 activity for the treatment of various conditions such as cancers.
Another aspect of the invention relates to a method of treating cancer comprising administering an effective amount of a compound of the invention disclosed herein. In one embodiment, the compounds of the invention inhibit the growth of a tumor. Specifically, the compounds of the invention inhibit the growth of a tumor that overexpresses at least one of PLK, Aurora A, Aurora B, and FLT-3. More specifically, the compounds of the invention inhibit the growth of a tumor that overexpresses PLK, for example, PLKl, PLK2 and/or PLK4. Even more specifically, the compounds of the invention inhibit the growth of a tumor that overexpresses PLK4. In another embodiment, the compounds of the invention inhibit the growth of the tumor by inducing apoptosis of the tumor cells or by inhibiting proliferation of the tumor cells. Cancers that can be treated or prevented by the methods of the present invention include lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform, ovarian cancer, lymphoma, leukemia, melanoma, sarcoma, paraneoplasia, osteosarcoma, germinoma, glioma and mesothelioma. In one specific embodiment, the cancer is lung cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma mutiform or ovarian cancer. In another specific embodiment, the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform or ovarian cancer. In yet another specific embodiment, the cancer is a breast cancer. In yet another specific embodiment, the cancer is a basal sub-type breast cancer or a luminal B sub-type breast cancer. In yet another specific embodiment, the cancer is a soft tissue cancer. A "soft tissue cancer" is an art-recognized term that encompasses tumors derived from any soft tissue of the body. Such soft tissue connects, supports, or surrounds various structures and organs of the body, including, but not limited to, smooth muscle, skeletal muscle, tendons, fibrous tissues, fatty tissue, blood and lymph vessels, perivascular tissue, nerves, mesenchymal cells and synovial tissues. Thus, soft tissue cancers can be of fat tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymph vessels, and fibrous tissues. Soft tissue cancers can be benign or malignant. Generally, malignant soft tissue cancers are referred to as sarcomas, or soft tissue sarcomas. There are many types of soft tissue tumors, including lipoma, lipoblastoma, hibernoma, liposarcoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma, schwannoma (neurilemoma), neuroma, malignant schwannoma, neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovial sarcoma, hemangioma, glomus tumor, hemangiopericytoma, hemangioendothelioma, angiosarcoma, Kaposi sarcoma, lymphangioma, fibroma, elastofibroma, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor, malignant mesenchymomas, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, and desmoplastic small cell tumor. In a particular embodiment, the soft tissue cancer is a sarcoma selected from the group consisting of a fibrosarcoma, a gastrointestinal sarcoma, a leiomyosarcoma, a dedifferentiated liposarcoma, a pleomorphic liposarcoma, a malignant fibrous histiocytoma, a round cell sarcoma, and a synovial sarcoma.
The invention further relates to a method of treating a subject with tumor cells, comprising administering to the subject, an amount of a compound disclosed herein that is effective to reduce effectively PLK activity, such as PLK 2 or PLK4 activity, in the subject. In a specific embodiment, the PLK is PLK4.
The invention further relates to a method of inhibiting Aurora B and/or PLK- 4 in a subject in need of inhibition of Aurora B and/or PLK-4. As used herein, a "subject in need of inhibition of Aurora B and/or PLK-4" means the subject has a disease(s) or condition(s) associated with overexpression of Aurora B and/or PLK-4, or a disease(s) or condition(s) on which inhibition of Aurora B and/or PLK-4 have a beneficial effect(s).
The term a "therapeutically effective amount", "effective amount" or a "sufficient amount" of a compound of the present invention is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results. A "therapeutically effective amount" of a compound of the invention is an amount which prevents, inhibits, suppresses or reduces the cancer (e.g., as determined by clinical symptoms or the amount of cancer cells) in a subject as compared to a control. Specifically, "treating a subject with a cancer" includes achieving, partially or substantially, one or more of the following: arresting the growth or spread of a cancer, reducing the extent of a cancer (e.g., reducing size of a tumor or reducing the number of affected sites), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components). Generally, a therapeutically effective amount amount of a compound of the invention varies depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. As defined herein, a therapeutically effective amount of a compound of the present invention may be readily determined by one of ordinary skill by routine methods known in the art.
In an embodiment, a therapeutically effective amount of a compound of the invention ranges from about 0.1 to about 15 mg/kg body weight, suitably about 1 to about 5 mg/kg body weight, and more suitably, from about 2 to about 3 mg/kg body weight. The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject suffering from cancer and these factors include, but are not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject and other diseases present.
Moreover, a "treatment" regime of a subject with a therapeutically effective amount of the compound of the present invention may consist of a single administration, or alternatively comprise a series of applications. For example, the compound of the present invention may be administered at least once a week. However, in another embodiment, the compound may be administered to the subject from about one time per week to once daily for a given treatment. The length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration and the activity of the compounds of the present invention, or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
As used herein, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.
The term "subject" or "patient" or synonym thereto, as used herein includes all members of the animal kingdom, especially mammals, including human. The subject or patient is suitably a human.
In one embodiment, the method of the present invention is a mono-therapy where the pharmaceutical compositions of the invention are administered alone. Accordingly, in this embodiment, the compound of the invention is the only pharmaceutically active ingredient in the pharmaceutical compositions or the only pharmaceutically active ingredient administered to the subject.
In another embodiment, the method of the invention is a co-therapy with one or more of other therapeutically active drugs or therapies known in the art for treating the desired diseases or indications. In one example, one or more other antiproliferative or anticancer therapies are combined with the compounds of the invention. In another example, the compounds disclosed herein are co-administered with one or more of other anticancer drugs known in the art. Anticancer therapies that may be used in combination with the compound of the invention include surgery, radiotherapy (including, but not limited to, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes) and endocrine therapy. Anticancer agents that may be used in combination with the the compounds of the invention include biologic response modifiers (including, but not limited to, interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs (e.g. taxol and analogs thereof).
When the compounds of the invention are combined with other anticancer drugs, they can be administered contemperaneously. As used herein, "administered contemporaneously" means that two substances are administered to a subject such that they are both biologically active in the subject at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering one substance within a period of time of one another, e.g., 24 hours of administration of the other, if the pharmacokinetics are suitable. Designs of suitable dosing regimens are routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e. within minutes of each other, or in a single composition that comprises both substances. Alternatively, the two agents can be administered separately, such that only one is biologically active in the subject at the same time.
The compounds of the invention can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.
The compounds of the invention can be suitably formulated into pharmaceutical compositions for administration to a subject. The pharmaceutical compositions of the invention optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and/or excipients are "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof. Typically, for oral therapeutic administration, a compound of the invention may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
Typically for parenteral administration, solutions of a compound of the invention can generally be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Typically, for injectable use, sterile aqueous solutions or dispersion of, and sterile powders of, a compound of the invention for the extemporaneous preparation of sterile injectable solutions or dispersions.
For nasal administration, the compounds of the invention can be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. For buccal or sublingual administration, the compounds of the invention can be formulated with with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine, as tablets, lozenges or pastilles.
For rectal administration, the compounds of the invention can be formulated in the form of suppositories containing a conventional suppository base such as cocoa butter.
The compounds of the invention, can be formulated alone or for contemporaneous adminstration with other agents for treating cancer. Therefore, in another aspect, a pharmaceutical composition of the invention comprises a pharmaceutically acceptable carrier or diluent, a compound disclosed herein or a pharmacuetically acceptable salt thereof and another anti-cancer agent, for example, but not limited to a glucose metabolism inhibitor or taxol. Meanings for the abbreviations used herein are provided below:
Chemicals :
THF tetrahydrofuran
EtOAc ethyl acetate
Et20 diethyl ether
PDC pyridinium dichromate
MeOH methanol
DMSO dimethylsulfoxide
DMF N,N-dimethylformamide
H2NMe methyl amine
AcOH, HOAc acetic acid
DMAP dimethylaminopyridine dba dibenzylidineacetone n-BuOH n-butanol
DCM dichloromethane
DI-H2O distilled or deionized water
'BuOK potassium tert-butoxide
Et3N triethylamine
EtOH ethanol
TBTU ... uranium**
HOBt 1 -hydroxy-benzotriazole
DIPEA diisopropylethylamine (Hunig's base)
TFA trifluoroacetic acid
MeCN acetonitrile
OAc acetate (e.g. Pd(OAc)2) o-Tol ortho-toluenyl** o-tolyl ortho-toluenyl**
0-MeC6H4 ortho-toluenyl**
EDC **
Hex hexane
TBAB tetrabutylammonium bromide
SEMCl (2-(Chloromethoxy)ethyl)trimethylsilane mCPBA meta-cloroperoxybenzoic acid
DME dimethoxyethane
TBAF tetrabutylammonium fluoride
PPh3 triphenylphosphine
PhMe toluene n-BuLi n-butyllithium Other:
NMR nuclear magnetic resonance s, d, t, q, br. s, m singlet, doublet, triplet, quartet, broad singlet, multiplet
MS ESI mass spectroscopy, electrospray ionization
LC-MS liquid chromatography coupled to mass spectroscopy
HPLC high pressure liquid chromatography prep-HPLC preparative scale high pressure liquid chromatography prepTLC preparative scale thin layer chromatography calcd calculated mL, L, uL milliliters, liters, microliters mmol, mol millimoles, moles milligrams, grams
MHz megaHertz
M molar
N normal rt room temperature
0C degrees Celsius min minutes hrs, h hour(s) d day(s) sep. separatory
Wt. % percent by weight atm atmospheres of pressure temp. temperature sat., sat saturated
O/N overnight quant quantitative
XS. excess anh, anh. anhydrous aq aqueous
SSPPEE solid phase extraction
The invention is illustrated by the following examples which are not intended to be limiting in any way.
EXEMPLIFICATION A. Syntheses of Compounds of the Invention
General Experimental Methods
All starting materials, reagents, and solvents were used as received from commercial sources. In general, anhydrous reactions were performed under an inert atmosphere such as nitrogen or argon. Microwave reactions were performed with a Biotage
Initiator microwave reactor. Reaction progress was generally monitored by TLC using Merck silica gel plates with visualization by UV at 254 nm, by analytical HPLC or by LCMS (Bruker Exquire 4000). Work-up means drying over sodium or magnesium sulfate, filtering, and concentrating in vacuo. Flash column chromatographic purification of intermediates or final products was performed using 230-400 mesh silica gel 60 from EMD chemicals. Final products were sometimes purified by preparative reverse-phase HPLC. Purification was performed on a Varian PrepStar model SD-I HPLC system with a Varian Monochrom 1Ou C- 18 reverse-phase column using a gradient of about 5-30% acetonitrile/ 0.05% TFA water to 70-100% acetonitrile/0.05% TFA water over a 20-40-min period at a flow rate of 30-50 mL/min. Fractions containing the desired material were concentrated and lyophilized to obtain the final products. Proton NMRs were recorded on a Bruker Avance III 400 MHz spectrometer, and mass spectra were obtained using a Bruker Esquire 4000 spectrometer.
Preparation of Starting Materials
Synthesis of lH-benzordiπ,2,31triazole-5-carbaldehvde
Figure imgf000084_0001
A. Synthesis of (lH-benzo[d] [1 ,2,3]triazol-5-yl)methanol Under a nitrogen atmosphere a dry round-bottom flask was charged with
LiAlH4 (0.316 g, 7.90 mmol) and THF (15 mL). Methyl lH-benzo[d][l,2,3]triazole- 5-carboxylate (1.0 g, 5.64 mmol) was then added portion-wise over lOmin at room temperature and reaction allowed to stir for 4 hours at which time the reaction was quenched with EtOAc (5 mL), and the mixture poured into ice-water. The mixture was acidified to pH = 3 with 10% H2SO4 and extracted 4X with EtOAc. The combined organics were washed with brine, dried (MgSO4) and the solvent removed. The resulting brown solid was boiled in Et2O and the solids filtered and dried to give the title compound as a light brown solid (678 mg, 81 %). 1H NMR (400 MHz, CD3OD) δ 7.85 (m, 2H), 7.47 (d, J= 8.4 Hz, IH), 4.79 (s, 2H); MS ESI 150.0 [M + H]+, calcd for [C7H7N3O + H]+ 150.16. B. lH-benzo[d][l, 2, 3]triazole-5-carbaldehyde
A suspension of (lH-benzo[tfl[l,2,3]triazol-5-yl)methanol (0.860 g, 5.77 mmol) in acetone (25 mL) was purged with Ar, by bubbling through solution, then PDC (2.60 g, 6.92 mmol) was added portion-wise over 20 min. The reaction was stirred overnight (18 hrs). The acetone was removed in vacuo, the solids dissolved in MeOH and silica gel was added. The MeOH was then removed and the silica dry-loaded onto a silica gel column, and the product eluted with 1 : 1 Ηexanes/EtOAc to give 444 mg, 52 % of a white solid. 1H NMR (400 MHz, CD3OD) δ 10.14 (s, IH), 8.55 (s, IH), 8.04 (d, J = 8.8 Hz, IH), 7.96 (d, J = 8.4 Hz, IH); MS ESI 148.0
[M + H]+, calcd for [C7H5N3O + H]+ 148.14.
Synthesis of lH-indazole-6-carbaldehvde
Figure imgf000085_0001
A. 6-bromo-lH-indazole
To a vigorously stirred solution of 5-bromo-2-fluorobenzaldehyde (40.6 g, 0.2 mol) in DMSO (80 mL) was added N2H4-xH2O (40 mL, 0.8 mol) dropwise over 15 min (slow addition to keep the reaction not too hot). The resulting yellow slurry was heated at 120 0C (oil temp.) for 21 h. The whole mixture was transferred to a 1 L flask and cooled for 10 min in air before quenching with ice (300 mL) and ice- cold H2O (100 mL). The resulting mixture was stirred for 30 min at it. Precipitated formed was collected by suction filtration, rinsed thoroughly with H2O (100 mL x 2), 2 M HCl (100 mL x 2), H2O (100 mL x 2), 0.5 M Na2CO3 (100 mL x 2), H2O (100 mL x 2), dried in air for 1 h and under high vacuum for 2 days to give 6- bromo-lH-indazole (30.05 g, 76%) as a light yellow solid. MS ESI 196.9 [M + H]+, calcd for [C7H5BrN2 + H]+ 197.0.
B. lH-indazole-6-carbaldehyde
To a suspension of 60 % NaH (10.0 g, 0.24 mol) in THF (240 mL) was added a suspension of 6-bromo-lH-indazole (39.4 g, 0.2 mol) in THF (280 mL) dropwise over 45 min. After addition, the resulting mixture was stirred for 1 h at rt to give a dark red clear solution which was cooled to -78 0C.5-BuLi (1.4 M in hexane, 300 mL, 0.42 mol) was added dropwsie over 1 h. During this addition, additional THF (130 mL) was added to keep the mixture stirring. After the addition, the resulting mixture was stirred for 75 min at -78 0C; DMF (90 mL) was added dropwise (note: reaction solidified upon addition of DMF, occasional warming was needed to keep the mixture stirring). The resulting mixture was stirred at it overnight and cooled to 0 0C. Solid NH4Cl and saturated NH4Cl were added to quench the reaction and bring the pH to about 7. The product was extracted with EtOAc (800 mL + 200 mL +300 mL, 1.3 L in total) and the combined extracts were washed with H2O (300 mL x 3) and dried (Na2SO4). Evaporation of the solvent gave a dark red solid which was triturated by EtOAc (4 times, the last filtrate was purified by flash chromatography) to give the title compound (16.96 g in total, 58%) as yellow brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.62 (s, IH, NH), 10.12 (s, IH, CHO), 8.23 (s, IH), 8.17 (s, IH), 7.93 (d, J = 8.4 Hz, IH), 7.59 (d, J = 8.4 Hz, IH); MS ESI 147.0 [M + H]+, calcd for [C8H6N2O+ H]+ 147.0.
Synthesis of 3-iodo-lH-indazole-6-carbaldehvde
Figure imgf000086_0001
To a solution of lH-Indazole-6-carbaldehyde (2.00 g, 13.7 mmol), K2CO3 (3.79 g, 27.4 mmol) in DMF (15 mL) was added dropwise a solution of I2 (5.91 g, 23.3 mmol) in DMF (15 mL) and the reaction allowed to stir for two hours. An aqueous solution consisting Of Na2S2O4 (3.30 g) / K2CO3 (0.20 g) / H2O (30 mL) was then added and the solution stirred for one hour. The product was then precipitated by pouring the solution over ice-water (300 mL) and collected by vacuum filtration to give after drying 3.02 g, 81 % of a beige powder. 1H NMR (400 MHz, CD3OD) δ 10.11 (s, IH), 8.11 (s, IH), 7.74 (d, J= 8.34 Hz, IH), 7.62 (d, J= 8.34 Hz, IH); MS ESI 272.9 [M + H]+, calcd for [C8H5IN2O + H]+ 272.95.
Synthesis of 3 -iodo- 1 -((2-(trimethylsilyl)ethoxy)methylV 1 H-indazole-6- carbaldehyde and 3-iodo-2-(T2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-6- carbaldehyde
Figure imgf000087_0001
To a suspension of S-iodo-lH-indazole-β-carbaldehyde (3.01 g, 11.1 mmol) in CH2Cl2 (70 mL) and 50 % aq. KOH (20 mL) was added tetrabutylammonium bromide (36 mg, 0.111 mmol) and the solution cooled to 0 0C. (2- (Chloromethoxy)ethyl)trimethylsilane (2.3 mL, 13.3 mmol) was then added dropwise and the reaction stirred at 0 0C for 3 hours. The solution was then transferred to a sep. funnel containing CH2Cl2 (200 mL) and the organic layer was washed with brine (2 X 100 mL), dried (MgSO4) and the solvent removed in vacuo. The resulting residue was purified by column chromatography (100 % CH2Cl2) to give 2.88 g, 65 % of the N-I isomer (higher eluting spot) and 757 mg, 17 % of the N-2 isomer (lower eluting spot). N-I isomer: 1H NMR (400 MHz, CDCl3) δ 10.18 (s, IH), 8.11 (s, IH), 7.81 (d, J= 8.4 Hz, IH), 7.65 (d, J= 8.4 Hz, IH), 5.82 (s, 2H), 3.60 (m, 2H), 0.91 (m, 2H), -0.042 (s, 9H); MS ESI 425.0 [M + Na]+, calcd for [Ci4H19IN2O2Si + Na]+ 425.02. N-2 isomer : 1H NMR (400 MHz, CD3OD) 10.09 (s, IH), 8.31 (s, IH), 7.62 (m, 2H), 5.91 (s, 2H), 3.71 (m, 2H), 0.92 (m, 2H), -0.039 (s, 9H); MS ESI 425.0 [M + Na]+, calcd for [C14H19IN2O2Si + Na]+ 425.02
Synthesis of N-methyl-2-oxoindoline-5-sulfonamide
Figure imgf000087_0002
A dry round-bottom flask was charged with 1 mL of a 2.0 M solution of H2NMe in
THF. 2-oxoindoline-5-sulfonyl chloride (100 mg, 0.432 mmol) was then added and the reaction stirred overnight. The solvents were removed and the residue purified by column chromatography (silica gel, 93:7 CH2Cl2ZMeOH) to give 73 mg, 74 % of a brown solid. 1U NMR (400 MHz, CD3OD) δ 7.73 (d, J = 8.8 Hz, IH), 7.72 (s, IH), 7.03 (d, J = 8.0 Hz, IH), 3.35 (s, 2H), 2.52 (s, 3H); MS ESI 226.9 [M + H]+, calcd for [C9H10N2O3S + H]+ 227.05.
Synthesis of 6-aminoindolin-2-one
Figure imgf000088_0001
A solution of 2-(2,4-dinitrophenyl)acetic acid (1.0 g, 4.42 mmol), AcOH (10 mL), and MeOH (5 mL) was purged with Ar for 15 minutes at which time 10wt. % Pd/C (lOOmg) was added. The mixture was then purged briefly with H2 and then stirred under latm of H2 overnight. The mixture was filtered through a pad of celite, the solvent removed in vacuo, and the residue purified by column chromatography (silica gel, 90:10 CH2Cl2/Me0H) to give 462 mg, 71 % of a brown solid. 1H NMR (400 MHz, CD3OD) δ 6.95 (d, J = 7.7 Hz, IH), 6.37 (d, J = 7.8 Hz, IH), 6.34 (s, IH), 3.38 (s, 2H); MS ESI 149.0 [M + H]+, calcd for [C8H8N2O + H]+ 149.07.
Synthesis of N-(2-oxoindolin-6-v0acetamide
Figure imgf000088_0002
To 6-aminoindolin-2-one (30 mg, 0.202 mmol) in THF (1 mL) was added acetic anhydride (19 uL, 0.202 mmol). After 2 hrs the product was precipitated with ether, filtered and dried to give 25 mg, 66% of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.41 (s, IH), 7.16 (d, J = 7.0 Hz, IH), 7.00 (d, J = 8.0 Hz, IH), 3.49 (s, 2H), 2.12 (s, 3H); MS ESI 191.0 [M + H]+, calcd for [C10H10N2O2 + H]+ 191.08.
Synthesis of N-(2-oxoindolin-5 -vDacetamide
Figure imgf000088_0003
According to procedure for the synthesis of N-(2-oxoindolin-6-yl)acetamide, except substituting 5-aminoindolin-2-one (50 mg, 0.34 mmol), the title compound was prepared as a beige solid (46 mg,71%). 1H NMR (400 MHz, CDCl3) δ 7.49 (s, IH), 7.31 (d, J = 7.0 Hz, IH), 6.83 (d, J = 8.0 Hz, IH), 3.52 (s, 2H), 2.10 (s, 3H).
Synthesis of NJV-dimethyl-N'-(2-oxo-2.3-dihvdro-lH-mdol-5-vπsulfamide
Figure imgf000089_0001
To 5-aminoindolin-2-one (100 mg, 0.68 mmol) in ethyl acetate/DMF 1:1 (2 mL) was added dimethylsulfamoyl chloride (290 mg, 2.04 mmol) and DMAP (1 mg). After 72 h the product was precipitated with ether, filtered and dried to give 56 mg, 32% of a white solid. 1H ΝMR (400 MHz, CD3OD) δ 7.21 (s, IH), 7.16 (d, J = 7.0 Hz, IH), 7.00 (d, J = 8.0 Hz, IH), 3.53 (s, 2H), 2.77 (s, 6H).
Synthesis of l-isopropyl-3-(2-oxoindolin-5-vl)urea
Figure imgf000089_0002
To 5-aminoindolin-2-one (50 mg, 0.34 mmol) in ethyl acetate (1 mL) was added isopropylisocyanate (0.04 mL, 0.4 mmol). The solution was stirred at rt for 16h and the product was precipitated with ether, filtered and dried to give 46 mg, 58% of a yellow solid. 1H ΝMR (400 MHz, CD3OD) δ 7.31 (s, IH), 7.13 (d, J = 8.3 Hz, IH), 6.80 (d, J = 8.3 Hz, IH), 3.90-3.83 (m, IH), 3.51 (s, 2H), 1.77 (d, J = 7.3 Hz, 6H).
Synthesis of Ν-(2-oxoindolin-5-vDmethanesulfonamide
Figure imgf000089_0003
To 5-aminoindolin-2-one (50 mg, 0.34 mmol) in DMF (1 mL) was added methanesulfonyl chloride (51 mg, 0.51 mmol) and DMAP (1 mg). The solution was stirred at rt for 16h and the product was precipitated with ether, filtered and dried to give 10 mg, 13% of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.22 (s, IH), 7.13 (d, J = 8.3 Hz, IH), 6.87 (d, J = 7.6 Hz, IH), 3.55 (s, 2H), 2.91 (s, 3H). Svnthesis of 6-(Pyridin-3-vDindolin-2-one
Figure imgf000090_0001
A mixture 6-chloroindolin-2-one (100 mg, 0.60 mmol), 3-(3,3,4,4- tetramethylborolan-l-yl)pyridine (184 mg, 0.90 mmol), Pd2dba3 (5.4 mg, 0.0060 mmol) and powdered K3PO4 (252 mg, 1.2 mmol) in w-BuOH (2 mL) was degassed by evacuation and refilling with Ar. Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2- yl)phosphine (11.4 mg, 0.024 mmol) was added under the atmosphere of Ar. The reaction mixture was sealed and heated with stirring under microwave irradiation at 100 0C for 99 min. Later the reaction was cooled to rt and treated with degassed H2O (0.25 mL). The mixture was reheated under microwave irradiation at 110 0C for 1 h. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using MeOH (0 to 6 %) in DCM as the eluent to provide the title compound as a pale yellow solid (100 mg, 80 %). %). 1H NMR (400 MHz, CD3OD) δ ppm 8.77 (d, J=I.52 Hz, 1 H), 8.52 (dd, J=4.80, 1.52 Hz, 1 H), 8.05 - 8.10 (m, 1 H), 7.52 (dd, J=7.33, 4.80 Hz, 1 H), 7.39 (d, J= 7.6 Hz, 1 H), 7.30 (dd, J=7.71, 1.39 Hz, 1 H), 7.17 (s,l H), 3.59 (s, 2 H); MS ESI 211.0 (100) [M + H]+, calcd for [C13H10N2O + H]+ 211.2.
Synthesis of 3-formyl-lH-indazole-6-carbonitrile
Figure imgf000090_0002
To a solution OfNaNO2 (11.04g, 160 mmol) in DI-H2O (200 mL) was added 6-cyanoindole (5.68 g, 40 mmol) in one portion slowly. The resulting suspension was stirred for 5 min at rt. 6N HCl (32 mL, 192 mmol) was added dropwise via a dropping funnel over 30 min and the pH was about 1. The resulting suspension was stirred for 4.5 h at rt before 400 mL of EtOAc was added. After stirring for additional 10 min to dissolve the precipitate, the two layers were separated and the aqueous layer was extracted with EtOAc (150 mL). Combined extracts were dried over Na2SO4. Removal of solvents afforded 6.864 g (100%) of title compound as brown (coffee color) solid. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, IH, NH), 10.22 (s, IH, CHO), 8.38 (s, IH), 8.28 (d, J = 8.4 Hz, IH), 7.69 (d, J = 8.4 Hz, IH). MS ESI 172.0 [M + H]+, calcd for [C9H5N3O + H]+ 172.0.
Synthesis of (E)-3-(2-(pyridin-4-yl)vinyl)- 1 H-indazole-6-carbaldehyde
Figure imgf000091_0001
a) (E)-3-(2-(pyridin-4-yl)vinyl)-lH-indazole-6-carbonitrile To a suspension of 4-chloropyridine hydrochloride (3.28 g, 20 mmol) in benzene (50 mL) was added 40% NaOH (1.35 mL). The resulting mixture was sonicated for 10 min and filtered. The residue was treated with additional benzene (15 mL), sonicated and filtered. The combined benzene layers were dried (Na2SO4) to give a solution of 4-chloropyridine which was used without further characterization (yida infra). A solution of diethyl phosphate (3.03 g, 22 mmol) in benzene (35 mL) was treated with freshly cut Na (510 mg, 22 mmol). The resulting mixture was refluxed for 30 min (oil temp. 90 0C), cooled to 0 0C, then treated added dropwise over 10 min. with the solution of 4-chloropyridine in benzene (prepared as described above). After addition, the resulting mixture was refluxed for 3 h (oil temp. 1000C) under argon then cooled to rt. The insoluble white precipitate was removed by filtration and rinsed with benzene (20 mL). The combined filtrate was concentrated and dried under high vacuum to give 3.5 g of diethyl pyridin-4- ylmethylphosphonate as a colorless liquid.
Diethyl pyridin-4-ylmethylphosphonate was redissolved in DMF (25 mL) and cooled to 0 0C. 'BuOK (3.36 g, 30 mmol) was added portion wise over 2 min and the reaction mixture turned dark brown red. After stirring for 2 min at 0 0C, a solution of 3-formyl-lH-indazole-6-carbonitrile (1.71 g, 10 mmol) in DMF (15 mL) was added dropwise by pipette over 5 min. The resulting mixture was stirred for 40 min at 0 0C before quenching with ice, 2N HCl (20 mL) and H2O (20 mL). After stirring for 10 min at rt, the reaction mixture was carefully basified with sat. NaHCO3 to pH about 8 and copious amounts of yellow precipitate formed. The solid was collected by suction filtration and rinsed with H2O. After dying under high vacuum, 2.016 g (82%) of title compound was obtained as beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, IH, NH), 8.60-8.54 (m, 2H), 8.43 (d, J = 8.0 Hz, IH), 8.20 (s, IH), 7.93 (d, J = 16.0 Hz, IH), 7.70 (d, J = 4.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, IH, partially overlapping with the doublet at 7.55 ppm), 7.55 (d, J = 16.0 Hz, IH, partially overlapping with the doublet at 7.58 ppm); MS ESI 250.0 [M + H]+, calcd for [Ci5H11N3O + H]+ 250.1. b) (E)-3-(2-(pyridin-4-yl)vinyl)-lH-indazole-6-carbaldehyde
To a solution of (E)-3-(2-(pyridin-4-yl)vinyl)-lH-indazole-6-carbonitrile (246 mg, 1 mmol) in HOAc/pyridine (3 mL/6 mL) was added a solution of sodium hypophosphite (352 mg, 4 mmol) in H2O (3 mL), followed by Raney-Nickel 2400 (slurry in H2O, 0.2 mL). The resulting mixture was heated at 55 0C (oil temp.) for 1 h then cooled to rt. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined extracts were washed with H2O (20 mL x 3), brine (10 mL) and dried (Na2SO4). Removal of solvent gave a yellow solution containing pyridine. H2O (60 mL) was added with swirling and large amounts of yellow precipitate formed which was collected by suction filtration and rinsed with H2O. After dying under high vacuum, the title compound (75 mg, 30 %) was obtained as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, IH, NH), 10.14 (s, IH, CHO), 8.57 (d, J = 5.6 Hz, 2H), 8.40 (d, J = 8.4 Hz, IH), 8.20 (s, IH), 7.89 (d, J = 16.8 Hz, IH), 7.73-7.69 (m, 3H), 7.55 (d, J = 16.4 Hz, IH). MS ESI 247.0 [M + H]+, calcd for [C15HnN3O + H]+ 247.1.
Synthesis of (TEV3-(2-(pyridin-3-yl)vinv0-lH-indazole-6-carbaldehyde
Figure imgf000092_0001
a) (E)-3-(2-(pyridin-3-yl)vinyl)-lH-indazole-6-carbonitrile To a suspension of 3-chloropyridine hydrochloride (6.54 g, 40 mmol) in benzene (75 mL) was added 40% NaOH (2.7 mL). The resulting mixture was sonicated for 10 min and filtered. The residue was treated with additional benzene (25 ml), sonicated and filtered. The combined benzene layers were dried (Na2SO4) to give a solution of 4-chloropyridine in benzene.
To a solution of diethyl phosphate (6.06 g, 44 mmol) in benzene (50 mL) was added freshly cut Na (1.02 g, 44 mmol). The resulting mixture was refluxed (oil temp. 95 0C) for 30 min then cooled to 0 0C. The solution of 4-chloropyridine in benzene obtained above was added dropwise to this solution via dropping funnel over 15 min. After addition, the resulting mixture was refluxed for 2 h (oil temp. 100 0C) and LC-MS indicated the completion of reaction. After cooling to rt, the insoluble white precipitate (NaCl) was filtered off and rinsed with benzene (50 mL). The filtrate was concentrated and dried under high vacuum to give 6.30 g of diethyl pyridin-3-ylmethylphosphonate as a light yellow liquid.
Diethyl pyridin-3-ylmethylphosphonate was redissolved in DMF (50 mL), cooled to 0 0C and treated with 'BuOK (6.72 g, 60 mmol) portion wise over 3 min; the reaction turned a dark reddish brown. After stirring for 3 min at 0 0C, a solution of 3-formyl-lH-indazole-6-carbonitrile (3.42 g, 20 mmol) in DMF (25 mL) was added dropwise by pipette over 5 min. After addition, the resulting mixture was stirred for 1 h at 0 0C before quenching with ice (100 mL). The reaction mixture was cooled to 0 0C and slowly acidified with 2M HCl until pH 5. During this addition, a copious amount of precipitate was formed. After stirring for 2 min at this temperture, sat NaHCO3 was added slowly until pH 8 and the mixture was stirred for an additional 2 min. Water was added until the total volume reached 600 mL. After stirring for 10 min, the resulting precipitate was collected by suction filtration and rinsed thoroughly with water, then dried under high vacuum to give the title compound (3.30 g, 67%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, IH, NH), 8.89 (s, IH), 8.48 (d, J = 4.4 Hz, IH), 4.42 (d, J = 8.4 Hz, IH), 8.22- 8.17 (m, 2H), 7.74 (d, J = 16.8 Hz, IH), 7.59 (d, J = 18.0 Hz, IH, partially overlapping with the doublet at 7.55 ppm), 7.55 (d, J = 10.0 Hz, IH, partially overlapping with the doublet at 7.59 ppm), 7.43 (dd, J = 8.0 Hz, 5.6 Hz, IH); MS ESI 247.0 [M + H]+, calcd for [Ci5H10N4 + H]+ 247.1. b) (E)-3-(2-(pyridin-3-yl)vinyl)-lH-indazole-6-carbaldehyde
To a suspension of (E)-3-(2-(pyridin-4-yl)vinyl)-lH-indazole-6-carbonitrile (984 mg, 3 mmol) in pyridine (30 mL) was added HOAc (8 mL), followed by DMF (30 mL). The resulting mixture was heated and sonicated to make a clear solution. After cooling to 0 0C, a solution of sodium hypophosphite (1.408 g, 16 mmol) in H2O (8 mL) was added, followed by Raney-Nickel 2400 (slurry in H2O, 0.8 mL). The resulting mixture was heated at 60 0C (oil temp.) for 1 h before cooling to it. H2O (50 mL) was added and the mixture was extracted with EtOAc (100 mL + 50 mL x 2). The combined extracts were dried (Na2SO4). Removal of low boiling point solvents gave a yellow solution in DMF (about 30 mL); H2O (500 mL) was added with swirling and a yellow precipitate formed. After standing 10 min, the resulting precipitate was collected by suction filtration, rinsed with H2O and dried under high vacuum to give the title compound (500 mg, 50 %) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.79 (s, IH, NH), 10.14 (s, IH, CHO), 8.90 (s, IH), 8.48 (d, J = 4.8 Hz, IH), 8.39 (d, J = 8.0 Hz, IH), 8.19 (d, J = 9.2 Hz, IH, partially overlapping with the singlet at 8.18 ppm), 8.18 (s, IH, partially overlapping with the doublet at 8.19 ppm), 7.75 (d, J = 16.4 Hz, IH), 7.69 (d, J = 8.4 Hz, IH), 7.59 (d, J = 16.8 Hz, IH), 7.43 (dd, J = 8.0 Hz, 5.2 Hz, IH); MS ESI 250.0 [M + H]+, calcd for [C15H11N3O + H]+ 250.1.
Synthesis of (EVethyl 3-(6-formyl-lH-indazol-3-yltecrylate
Figure imgf000094_0001
A) (E)-ethyl 3-(6-cyano-lH-indazol-3-yl)acrylate
To a mixture of triethyl phosphonoacetate (125 mg, 0.55 mmol) and LiOH (26.4 mg, 1.1 mmol) in DMF (3 mL) at rt was added 3-formyl-lH-indazole-6- carbonitrile (85.5 mg, 0.5 mmol) in one portion. The resulting mixture was stirred at rt O/N. It was quenched with ice, followed by 2 M HCl (6 mL). After stirring for 5 min, the resulting precipitate was collected by suction filtration, washed with H2O, hexane, dried to give the title compound (75 mg, 62%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 14.18 (s, IH, NH), 8.35 (d, J = 8.8 Hz, IH), 8.25 (s, IH), 7.92 (d, J = 16.0 Hz, IH), 7.55 (d, J= 8.4 Hz, IH), 6.82 (d, J = 16.4 Hz, IH), 4.22 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H); MS ESI 242.0 [M + H]+, calcd for [C13H11N2O3 + H]+ 242.1. B) ((E)-ethyl 3-(6-formyl-lH-indazol-3-yl)acrγlate
To a solution of (E)-ethyl 3-(6-cyano-lH-indazol-3-yl)acrylate (723 mg, 3 mmol) in pyridine (10 mL) was added acetic acid (3 mL), followed by a solution of NaH2PO2 (1.056 g, 12 mmol) in H2O (3 mL). The resulting mixture was stirred for 0.5 min at it before Raney-Nickel 2400 (slurry in H2O, 0.6 mL) was added in one portion. The resulting mixture was heated at 55 0C (oil temp.) for 1 h before cooling to rt. H2O (30 mL) was added and the mixture was extracted with EtOAc (50 mL x 2). Combined extracts were washed with H2O (20 mL), 2 M HCl (20 mL), H2O (20 mL x 2), brine (15 mL) and dried (Na2SO4). Removal of solvent gave an orange red oil which solidified upon standing O/N under high vacuum. It was then triturated with H2O (30 mL) and suction filtered, rinsed with H2O, dried to give the title compound (476 mg, 65%) as an orange red solid. 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, IH, NH), 10.14 (s, IH, CHO), 8.30 (d, J = 8.8 Hz, IH), 8.22 (s, IH), 7.92 (d, J = 16.4 Hz, IH), 7.71 (d, J= 7.6 Hz, IH), 6.82 (d, J = 8.4 Hz, IH), 4.22 (q, J = 6.8 Hz, 2H), 1.28 (t, J = 6.8 Hz, 3H); MS ESI 245.0 [M + H]+, calcd for [Cj3H12N2O3 + H]+ 245.1.
Synthesis of (EVmethyl 4-(2-(6-formyl-lH-indazol-3-vDvinyl)benzoate
Figure imgf000095_0001
A mixture of .methyl 4-(bromomethyl)benzoate (4.58 g, 20 mmol) and trimethyl phosphite (3.54 mL, 30 mmol) was refluxed (oil temp. 125 0C) for 1 h under argon. After cooling to rt, the reaction mixture was diluted with DMF (50 mL) and cooled to 0 0C using ice bath. 'BuOK (3.92 g, 35 mmol) was added slowly. After addtion, the resulting dark brown solution was stirred for 5 min at 0 0C before a solution of 3-formyl-lH-indazole-6-carbonitrile (2.0 g, 11.7 mmol) in DMF (15 mL) was added dropwise via a pasteur pipette over 5 min. The reaction mixture was then stirred for 90 min at 0 0C; 2N HCl (25 mL) was added slowly over 2 min, followed by H2O (100 mL). The resulting suspension was stirred for 5 min at 0 0C. The precipiates collected by suction filtration were rinsed well with H2O and dried to give crude (E)-methyl 4-(2-(6-cyano-lH-indazol-3-yl)vinyl)benzoate (3.70 g) as an orange solid. Trituration with 50 mL of ether, followed by sonication and suction filtration gave pure (E)-methyl 4-(2-(6-cyano-lH-indazol-3-yl)vinyl)benzoate (2.56 g, 72 %) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 13.83 (s, IH), 8.43 (d, J = 8.8 Hz, IH), 8.18 (s, IH), 7.97 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 16.4 Hz, IH), 7.63 (d, J = 16.8 Hz, IH), 7.55 (d, J = 8.4 Hz, IH), 3.86 (s, 3H); MS ESI 304.1 [M + H]+, calcd for [C18H)3N3O2 + H]+ 304.1.
To a mixture of (E)-methyl 4-(2-(6-cyano-lH-indazol-3-yl)vinyl)benzoate (606 mg, 2 mmol) in HOAc/pyridine/DMF (4 mL/8 mL/6 mL) was added a solution of NaH2PO2 (704 mg, 8 mmol) in H2O (4 mL), followed by Raney-Nickel 2400 (slurry in H2O, 0.4 mL). The resulting mixture was heated for 1 h at 55 0C (oil temp.). After cooling to rt, it was diluted with EtOAc (80 mL) and washed with H2O (30 mL). Aqueous layer was extracted with EtOAc (50 mL). Combined organic layers were washed with 2 N HCl (20 mL), H2O (20 mL) and dried (Na2SO4). Evaporation of solvent gave crude title compound as an orange solid which was triturated with EtOAc (10 mL), followed by suction filtration to give the title compound (240 mg, 39 %) as light beige solid. The filtrate was concentrated, triturated with H2O, sonicated and the resulting precipitates were collected by suction filtration and rinsed with H2O, dried to give additional title compound (151 mg, 25%) as orange solid. 1H NMR (400 MHz, DMSO-d6) δ 13.82 (s, IH), 10.14 (s, IH), 8.40 (d, J = 8.8 Hz, IH), 8.18 (s, IH), 7.97 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 7.6 Hz, 2H), 7.77 (d, J = 16.8 Hz, IH), 7.79 (d, J = 8.4 Hz, IH), 7.64 (d, J = 15.6 Hz, IH), 3.86 (s, 3H); MS ESI 307.0 [M + H]+, calcd for [Ci8H14N2O3 + H]+ 307.1.
Synthesis of (E)-4-(2-(6-formvl-lH-indazol-3-yl)viny0benzoic acid
Figure imgf000096_0001
To a round bottom flash containing (E)-methyl 4-(2-(6-cyano-lH-indazol-3- yl)vinyl)benzoate (606 mg, 2 mmol) was added 2 M NaOH (20 mL, 40 mmol), followed by THF (10 mL) and MeOH (10 mL). The resulting mxiture was stirred O/N at rt. After removal of THF and MeOH via rotavap, the residue was cooled to 0 0C and treated with 2 M HCl (25 mL) and stirred for 2 min at that temp. The precipitates collected by suction filtration were rinsed with H2O to give crude (E)-4- (2-(6-cyano-lH-indazol-3-yl)vinyl)benzoic acid as a brown red solid. It was redissolved in HOAc/pyridine/DMF (4 mL/8 mL/6 mL) and a solution OfNaH2PO2 (704 mg, 8 mmol) in H2O (4 mL) was added, followed by Raney-Nickel 2400 (slurry in H2O, 0.4 mL). The resulting mixture was heated for 1 h at 55 0C (oil temp.). Usual aqueous workup, followed by trituration with H2O gave the title compound (332 mg, 54%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.81 (s, IH), 12.90 (s, br, IH), 10.14 (s, IH), 8.39 (d, J = 8.0 Hz, IH), 8.19 (s, IH), 7.96 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 16.8 Hz, IH), 7.79 (d, J = 8.4 Hz, IH), 7.64 (d, J = 16.4 Hz, IH); MS ESI 293.0 [M + H]+, calcd for [C17H12N2O3 + H]+ 293.1.
Synthesis of 3-(pyridin-3-ylethvnvD-lH-indazole-6-carbaldehvde
Figure imgf000097_0001
To a solution of S-iodo-lH-indazole-ό-carbaldehyde (136 mg, 0.5 mmol),
Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol) in DMF (3 mL) was added Et3N (5 mL), followed by 3-ethynylρyridine (77 mg, 0.75 mmol). The resulting mixture was heated at 100 0C (oil temp.) for 45 min. After removal of Et3N, the residue was loaded directly onto a silical gel column. Flash chromatography (eluent: hex to ethyl acetate), followed by trituration with water and suction filtration gave the title compound (112 mg, 91%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, IH), 10.16 (s, IH), 8.90 (s, IH), 6.64 (d, J = 4.0 Hz, IH), 8.26 (s, IH), 8.12 (d, J = 8.0 Hz, IH), 8.07 (d, J = 8.4 Hz, IH), 7.74 (d, J = 8.4 Hz, IH), 7.52 (dd, J = 8.0 Hz, J = 5.2 Hz, IH); MS ESI 248.0 [M + H]+, calcd for [C15H9N3O + H]+ 248.1.
Preparation of Compounds of the Invention
Example Al. fEVS-rdH-benzordiπ^.Sltriazol-S-vπmethyleneMndolin^-one
Figure imgf000098_0001
A scintillation vial was charged with indolin-2-one (101 mg, 0.760 mmol), lH-benzo[d][l,2,3]triazole-5-carbaldehyde (123 mg, 0.836 mmol), piperidine (7.5 uL, 0.076 mmol) and EtOH (4 mL). The reaction was then heated to 9O0C for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more EtOH (5 mL). The yellow solid was then filtered and washed with EtOH (20 mL) giving 149 mg, 75 % of the title compound. 1H NMR (400 MHz, (I6-DMSO) δ 15.94 (s, IH), 10.65 (s, IH), 8.27 (bs, IH), 8.05 (bs, IH), 7.80 (s, IH), 7.77 (bs, IH), 7.51 (d, J = 7.6 Hz, IH), 7.24 (t, J = 7.6 Hz, IH), 6.88 (d, J = 7.6 Hz, IH), 6.84 (d, J = 7.6 Hz, IH); MS ESI 263.0 [M + H]+, calcd for [C15Hi0N4O + H]+ 263.09.
Example A2. (E)-3-(πH-benzordiri.2.3]triazol-5-vDmethylene)-5-aminoindolin-2- one
Figure imgf000098_0002
A scintillation vial was charged with 5-aminoindolin-2-one (37 mg, 0.247 mmol), lH-benzo[d][l,2,3]triazole-5-carbaldehyde (40 mg, 0.272 mmol), piperidine (2.5 uL, 0.025 mmol) and EtOH (2 mL). The reaction was then heated to 9O0C for 2 hrs. The EtOH was removed in vacuo and the residue loaded onto a silica gel column eluting with 92:8 CH2Cl2MeOH to give 14 mg, 20 % of a red solid. 1H NMR (400 MHz, d6-DMSO) δ 15.96 (bs, IH), 10.15 (s, IH), 8.21 (bs, IH), 8.02 (bs, IH), 7.73 (bs, IH), 7.67 (s, IH), 6.87 (s, IH), 6.59-6.47 (m, 2H), 4.65 (bs, 2H); MS ESI 278.0 [M + H]+, calcd for [C15HnN5O + H]+ 278.10.
Example A3. (EV 3-(( 1 H-benzo[d] F 1.231triazol-5-vBmethyleneV5-bromoindolin-2- one
Figure imgf000099_0001
The title compound was synthesized according to the method described for Example Al, except reacting 5-bromooxindole (39 mg, 0.185 mmol) with IH- benzo[d][l,2,3]triazole-5-carbaldehyde (30 mg, 0.204 mmol) to obtain 32 mg, 51 %. 1H NMR (400 MHz, de-DMSO) δ 15.97 (s, IH), 10.85 (s, IH), 9.27 (s, IH), 8.37 (d, J = 9.2 Hz, IH), 8.16 (s, IH), 8.02 (s, IH), 7.95 (d, J = 8.4 Hz, IH), 7.39 (d, J = 8.2 Hz, IH), 6.80 (d, J = 8.3 Hz, IH); MS ESI 341.0 [M + H]+, calcd for [C15H9BrN4O + H]+ 341.00.
Example A4. (E)-3-(( 1 H-benzofdi F 1.2.31triazol-5-vπmethyleneV6-chloroindolin-2- one
Figure imgf000099_0002
The title compound was synthesized according to the method described for Example Al except reacting 6-chlorooxindole (36 mg, 0.216 mmol) with IH- benzo[d][l,2,3]triazole-5-carbaldehyde (35 mg, 0.238 mmol) to obtain 32 mg, 51 %. 1K NMR (400 MHz, (J6-DMSO) δ 15.95 (s, IH), 10.81 (s, IH), 8.27 (bs, IH), 8.04 (bs, IH), 7.85 (s, IH), 7.76 (bs, IH), 7.49 (d, J = 8.8 Hz, IH), 6.91 (bs, 2H); MS ESI 297.0 [M + H]+, calcd for [C15H9ClN4O + H]+ 297.05.
Example A5. (Ey3-((lH-indazol-6-vDmethylene)indolin-2-one
Figure imgf000100_0001
The title compound was synthesized according to the method described for Example Al except reacting oxindole (67 mg, 0.216 mmol) with lH-indazole-6- carbaldehyde (73 mg, 0.238 mmol) to obtain 32 mg, 51 0Zc1H NMR (400 MHz, CD3OD) δ 8.14 (s, IH), 7.91 (d, J = 8.5 Hz, IH), 7.89 (s, 2H), 7.65 (d, J = 7.6 Hz, IH), 7.47 (d, J = 8.4 Hz, IH), 7.25 (t, J = 7.7 Hz, IH), 6.93 (d, J = 7.8 Hz, IH), 6.87 (t, J = 7.6 Hz, IH); MS ESI 262.0 [M + H]+, calcd for [C16HnN3O + H]+ 262.10.
Example A6. fEV3-((lH-indazol-5-yl)methylene)indolin-2-one
Figure imgf000100_0002
A scintillation vial was charged with indolin-2-one (67 mg, 0.500 mmol), lH-indazole-5-carbaldehyde (73 mg, 0.550 mmol), piperidine (5.0 uL, 0.076 mmol) and EtOH (2 mL). The reaction was then heated to 9O0C for 2 hrs. The EtOH was removed and the product purified by preparatory reverse-phase HPLC to give 10 mg, 7.6 % of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.20-8.18 (m, 2H), 7.89 (s, IH), 7.76 (d, J = 7.9 Hz, IH), 7.71-7.67 (m, 2H), 7.24 (t, J = 7.4 Hz, IH), 6.93 (d, J = 7.7 Hz, IH), 6.90 (t, J = 7.5 Hz, IH); MS ESI 262.0 [M + H]+, calcd for [C16HnN3O + H]+ 262.10.
Example A7. 3-(αH-benzordπi.231triazol-5-yl)methylene)-N-methyl-2- oxoindoline-5-sulfonamide
Figure imgf000101_0001
The compound was synthesized according to the method described for Example A6 except reacting N-methyl-2-oxoindoline-5-sulfonamide (14 mg, 0.0618 mmol) with lH-benzo[d][l,2,3]triazole-5-carbaldehyde (10 mg, 0.0680 mmol) to obtain 5.6 mg, 12 % of the title compound as a mixture of (E) and (Z) isomers (69:21 by NMR). 1H NMR (400 MHz, d6-DMSO) δ 16.02, 16.00 (bs, IH), 11.10, 11.15 (s, IH), 8.55-8.10 (m, 2H), 7.95-7.80 (m, 3H), 7.77-7.60 (m, IH), 7.27, 7.21 (q, J = 5.2 Hz, IH), 7.07, 7.03 (d, J = 8.3 Hz, IH), 2.44, 2.36 (s, 3H); MS ESI 356.1 [M + H]+, calcd for [C16H13N5O3S + H]+ 356.08.
Example A8. (E)-3-((lH-indazol-6-yltoeΦylene)-N-methyl-2-oxoindoline-5- carboxamide
Figure imgf000101_0002
A. N-methyl-l-oxoindolineS-carboxamide An oven-dried round-bottom flask was charged with 2-oxoindoline-5- carboxylic acid (89 mg, 0.500 mmol), TBTU (193 mg, 0.600 mmol), HOBt hydrate (81 mg, 0.600 mmol), DIPEA (0.13 mL, 0.750 mmol) and DMF (3.0 mL) and stirred for 5 minutes. Methyl amine (0.75 mL of a 2.0 M solution in THF) was then added and reaction was stirred for 4 hours at which time NaHCO3(Sat ) (2mL) was added. Solvents were removed in vacuo and the residue was purified by column chromatography (silica gel, 92:8 CH2Cl2ZMeOH) to give the title compound (11 mg, 12 %). IH NMR (400 MHz, CD3OD) δ ppm 7.69 - 7.75 (m, 2 H), 6.94 (d, J=8.1 Hz, 1 H), 3.58 (s, 2 H), 2.97 (s, 3 H); MS ESI 191.0 [M + H]+, calcd for [C10H10N2O2 + H]+ 191.08.
B. (E)-3-((lH-indazol-6-yl)methylene)-N-methyl-2-oxoindoline-5- carboxamide The title compound was synthesized from N-methyl-2-oxoindoline-5- carboxamide (11 mg, 0.0578 mmol) and lH-indazole-6-carbaldehyde (10 mg, 0.0636 mmol) according to the method described for Example Al to obtain 3.0 mg, 17 %. 1K NMR (400 MHz, de-DMSO) δ 13.33 (s, IH), 10.88 (s, IH), 8.24-8.22 (m, IH), 8.18 (s, 2H), 7.93-7.88 (m, 2H), 7.84 (s, IH), 7.72 (d, J = 7.9 Hz, IH), 7.46 (d, J = 8.0 Hz, IH), 6.91 (d, J = 8.0 Hz, IH), 2.68 (d, J = 4.0 Hz, 3H); MS ESI 319.1 [M + H]+, calcd for [C18Hi4N4O2 + H]+ 319.12.
Example A9. (E and Z)-3-((lH-indazol-6-vπmethylene)-N-methyl-2-oxoindoline-5- sulfonamide
Figure imgf000102_0001
According to the method described for Example Al the title compound was prepared from N-methyl-2-oxoindoline-5-sulfonamide (41 mg, 0.181 mmol) and lH-indazole-6-carbaldehyde (29 mg, 0.199 mmol) as a mixture of geometric isomers (24 mg, 38 %). (E) and (Z) isomers: 55:45 by NMR. 1H NMR (400 MHz, (I6-DMSO) δ 13.43, 13.38 (s, IH), 11.13, 11.11 (s, IH), 9.03, 8.23 (s, IH), 8.20-7.82 (m, 5H), 7.65, 7.47 (d, J = 8.4 Hz, IH), 7.25, 7.20 (m, IH), 7.06, 7.01 (d, J = 8.4 Hz, IH), 2.45, 2.32 (s, 3H); MS ESI 355.1 [M + H]+, calcd for [C17H14N4O3S + H]+ 355.09. Example AlO. (E and Zy(3-((lH-indazol-6-yr)methylene)-N-methyl-2-oxoindoline- 6-carboxamide
Figure imgf000103_0001
A. Η-methyl-2-oxoindoline-6-carboxamide
The compound was synthesized according to the method described for N- methyl-2-oxoindoline-5-carboxamide except substituting 2-oxoindoline-6- carboxylic acid (89 mg, 0.500 mmol), to obtain the title compound (18 mg, 19 %). 1H NMR (400 MHz, CD3OD) δ 7.52 (d, J = 7.6 Hz, IH), 7.15 (d, J = 8.0 Hz, IH), 6.40 (d, J = 7.6 Hz, IH), 3.33 (s, 2H), 2.87 (s, 3H); MS ESI 191.0 [M + H]+, calcd for [CiOH10N2O2 + H]+ 191.08.
B. (3-((lH-indazol-6-yl)methylene)-N-methyl-2-oxoindoline-6-carboxamide According to the method described for Example A6, the title compound (2.8 mg, 9.3 %) was obtained from N-methyl^-oxoindoline-δ-carboxamide (18 mg, 0.0950 mmol) as a mixture of (E) and (Z) isomers (70:30 by NMR). 1H NMR (400 MHz, CD3OD) δ 8.99, 8.16 (s, IH), 8.10-7.69 (m, 4H), 7.52-7.36 (m, IH), 7.37-7.28 (m, 2H), 2.94, 2.91 (s, 3H); MS ESI 319.1 [M + H]+, calcd for [C18H14N4O2 + H]+ 319.12.
Example Al 1. (EV3-((lH-indazol-6-vDmethylene)-2-oxo-N-phenylindoline-5- carboxamide
Figure imgf000103_0002
A. 2-oxo-N-phenylindoline-5-carboxamide
The title compound was synthesized according to the method described for N- methyl-2-oxoindoline-5-carboxamide from 2-oxoindoline-6-carboxylic acid (89 mg, 0.500 mmol) and aniline (0.14 mL, 1.50 mmol) to obtain 45 mg, 36 %. 1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 8.4 Hz, IH), 7.87 (s, IH), 7.67 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.15 (t, J = 7.4 Hz, IH), 7.00 (d, J = 8.0 Hz, IH), 3.34 (s, 2H); MS ESI 253.0 [M + H]+, calcd for [Ci5H12N2O2 + H]+ 253.10.
B. β)-3-((lH-indazol-6-yl)methylene)-2-oxo-N-phenylindoline-5- carboxamide
A scintillation vial was charged with 2-oxo-N-phenylindoline-5-carboxamide (22 mg, 0.087 mmol), lH-indazole-6-carbaldehyde (14 mg, 0.096 mmol), piperidine (1 uL, 0.008 mmol) and MeOH (2 mL). The reaction was then heated to 6O0C for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more MeOH (2 mL). The yellow solid was then filtered and washed with MeOH (10 mL) to give 8.0 mg, 24 % of the title compound. 1H NMR (400 MHz, de-DMSO) δ 13.42 (s, IH), 11.02 (s, IH), 10.16 (s, IH), 9.01 (s, IH), 8.39 (s, IH), 8.14 (s, 2H), 8.03 (d, J = 7.3 Hz, IH), 7.89-7.82 (m, 2H), 7.79 (d, J = 6.5 Hz, 2H), 7.36 (t, J = 6.6 Hz, 2H), 7.11-7.09 (m, IH), 6.96 (d, J = 6.9 Hz, IH); MS ESI 381.1 [M + H]+, calcd for [C23Hi6N4O2 + H]+ 381.14.
Example A 12. (EVtert-butyl S-rπH-indazol-ό-vDmethyleney∑-oxoindolin-S- ylcarbamate
Figure imgf000104_0001
A. tert-butyl 2-oxoindolin-5-ylcarbamate
A THF (20 mL) solution of 5-aminoindolin-2-one (200 mg, 1.3 mmol) and di-t-butyl dicarbonate (300 mg, 1.4 mmol) at rt under N2, was treated with Et3N (0.37 mL, 2.7 mmol). The stirring was continued at rt overnight; the reaction mixture was concentrated under reduced pressure, taken into DCM and washed (H2O 2x, brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Trituration with hexanes provided the title compound as a white solid (260 mg, 77 %). 1H NMR (400 MHz, CDCl3) δ ppm 7.43 (br. s., 2 H), 7.07 (dd, J=8.84, 1.26 Hz, 1 H), 6.77 (d, J=8.59 Hz, 1 H), 6.39 (br. s., 1 H), 3.52 (s, 2 H), 1.52 (s, 9 H); MS ESI 249.0 (80) [M + H]+, calcd for [C13H16N2O3 + H]+ 249.3.
B. (E)-tert-butyl 3-((lH-indazol-6-yl)methylene)-2-oxoindolin-5-ylcarbamate The title compound was synthesized according to the method described for Example AI lB from tert-butyl 2-oxoindolin-5-ylcarbamate (100 mg, 0.403 mmol) and precipitation with CH2Cl2 to obtain the title compound (70 mg, 46 %). 1H NMR (400 MHz, CD3OD) δ 8.92 (s, IH), 8.09 (s, IH), 7.89-7.80 (m, 4H), 7.18 (d, J = 7.0 Hz, IH), 6.80 (d, J = 8.3 Hz, IH), 1.56 (s, 9H); MS ESI 377.3 [M + H]+, calcd for [C21H20N4O3 + H]+ 377.16.
Example A 13. (EVN-(3-(( 1 H-indazol-6-yl)methylene)-2-oxoindolin-6-yl)acetamide
Figure imgf000105_0001
The title compound was synthesized according to the method described for Example AI lB except substituting N-(2-oxoindolin-6-yl)acetamide (25 mg, 0.131 mmol), to obtain 12 mg, 29 %. 1H NMR (400 MHz, (I6-DMSO) δ 13.25 (s, IH), 10.59 (s, IH), 10.08 (s, IH), 8.15 (s, IH), 7.88 (s, 2H), 7.62 (s, IH), 7.54 (d, J = 6.9 Hz, IH), 7.50 (s, IH), 7.41 (d, J = 7.9 Hz, IH), 6.87 (d, J = 7.0 Hz, IH), 2.04 (s, 3H); MS ESI 319.1 [M + H]+, calcd for [C18H14N4O2+ H]+ 319.12.
Example A14. (E)-3-(αH-benzord1fl.2.31triazol-5-vnmethyleneV5-
(trifluoromethoxy)indolin-2-one
Figure imgf000106_0001
A scintillation vial was charged with 5-(trifluoromethoxy)indolin-2-one (27 mg, 0.124 mmol), lH-benzo[d][l,2,3]triazole-5-carbaldehyde (20 mg, 0.136 mmol), piperidine (2 uL, 0.012 mmol) and MeOH (2 mL). The reaction was then heated to 6O0C for 2 hrs. The MeOH was removed in vacuo and the residue purified by column chromatography (silica gel, 95:4:1, CH2Cl2/Me0H/Ac0H) to give the title compound as a yellow solid (10 mg, 23 %). 1H NMR (400 MHz, CD3OD) δ 8.23 (s, IH), 8.04 (d, J = 4.5 Hz, IH), 8.02 (s, IH), 7.77 (d, J = 9.3 Hz, IH), 7.42 (s, IH), 7.21-7.18 (m, IH), 6.99 (s, IH); MS ESI 347.0 [M + H]+, calcd for [C16H9F3N4O2 + H]+ 347.08.
Example A15. (E>3-((lH-indazol-6-y0meΦyleneV2-oxoindolin-5-aminium 2.2.2- trifluoroacetate
Figure imgf000106_0002
To (E)-tert-butyl 3-((lH-indazol-6-yl)methylene)-2-oxoindolin-5- ylcarbamate (15 mg, 0.040 mmol) in CH2Cl2 (2 mL) was added TFA (0.1 mL). After 1.5 hrs the solvent was removed and the product precipitated with ether and filtered washing with ether to give 9 mg, 56 % of the title compound as a brown solid. 1H NMR (400 MHz, Cl6-DMSO) δ 13.41 (s, IH), 10.79 (s, IH), 9.25-8.90 (bs, 3H), 9.01 (s, IH), 8.14 (s, IH), 8.00-7.96 (m, 2H), 7.82 (d, J = 8.5 Hz, IH), 7.56 (s, IH), 7.09-7.07 (m, IH), 6.86 (d, J = 8.1 Hz, IH); MS ESI 277.0 [M]+, calcd for [C16H13N4O]+ 277.11. Example Alβ. fEVB-αiH-indazol-ό-vπmethyleneVS-fluoroindolin^-one
Figure imgf000107_0001
A scintillation vial was charged with 5-fluoroindolin-2-one (40 mg, 0.265 mmol), lH-indazole-6-carbaldehyde (43 mg, 0.292 mmol), piperidine (3 uL, 0.027 mmol) and MeOH (2 mL). The reaction was then heated to 6O0C for 2 hrs. LC-MS analysis of the filtered yellow solid indicated a 9: 1 mixture of geometric isomers. The mixture was resolved through prep-HPLC purification to give 11 mg, 15 % of the major isomer (E) as the title compound. The minor fraction was also isolated; see Example A32. 1H NMR (400 MHz, de-DMSO) δ 13.31 (s, IH), 10.66 (s, IH), 8.18 (s, IH), 7.92 (d, J = 8.7 Hz, IH), 7.91 (s, IH), 7.86 (s, IH), 7.42 (d, J = 8.5 Hz, IH), 7.29 (d, J = 9.5 Hz, IH), 7.10 (t, J = 6.8 Hz, IH), 6.88 (dd, Jl = 8.8 Hz, J2 = 4.7, IH); MS ESI 280.0 [M + H]+, calcd for [Ci6H10FN3O + H]+ 280.09.
Example A 17. (E)-N-(3-(( 1 H-benzofdi f 1.2.31triazol-5-vnmethyleneV2-oxoindolin- 6-yl)acetamide
Figure imgf000107_0002
The title compound was synthesized according to the method described for Example AIlB except substituting N-(2-oxoindolin-6-yl)acetamide (30 mg, 0.158 mmol) and lH-benzo[d][l,2,3]triazole-6-carbaldehyde (26 mg, 0.174 mmol) to obtain 22 mg, 44 %. 1H NMR (400 MHz, dό-DMSO) δ -16 (s, IH), 10.60 (s, IH), 10.10 (s, IH), 8.23 (s, IH), 8.01 (s, IH), 7.73 (d, J = 8.0 Hz, IH), 7.64 (s, IH), 7.51 (s, IH), 7.47 (d, J = 8.0 Hz, IH), 6.86 (d, J = 7.4 Hz, IH), 2.02 (s, 3H); MS ESI 320.1 [M + H]+, calcd for [C17Hi3N5O2+ H]+ 320.11. Example Al 8. ((EVN-O-(T lH-indazol-5-vDmethyleneV2-oxoindolin-6-vπacetamide
Figure imgf000108_0001
The title compound was synthesized according to the method described for Example AIlB except substituting N-(2-oxoindolin-6-yl)acetamide (40mg, 0.210 mmol) and lH-indazole-5-carbaldehyde (34 mg, 0.231 mmol) to obtain 41 mg, 61
%. 1H NMR (400 MHz, de-DMSO) δ 13.31 (s, IH), 10.55 (s, IH), 10.07 (s, IH),
8.19 (s, IH), 8.15 (s, IH), 7.71-7.64 (m, 2H), 7.61 (s, IH), 7.57 (d, J = 8.4 Hz, IH),
7.48 (s, IH), 6.89 (d, J = 8.3 Hz, IH), 2.04 (s, 3H); MS ESI 319.1 [M + H]+, calcd for [C18H14N4O2+ H]+ 319.12.
Example A19 (EV3-((lH-benzord1imidazol-5-vπmethylene)indolin-2-one
Figure imgf000108_0002
Indolin-2-one (80 mg, 0.60 mmol), lH-benzo[<f]imidazole-5-carbaldehyde (97 mg, 0.66 mmol) and piperidine (2 drops) in EtOH (2 mL) were heated with stirring in a sealed tube under microwave irradiation at 900C for 15 min. A yellow precipitate was filtered and rinsed with EtOH. Recrystallization from EtOH afforded the title compound as a yellow powder (15.5 mg, 10 %). 1H NMR (400
MHz,
Figure imgf000108_0003
δ ppm 12.71 (br. s., 1 H), 10.59 (s, 1 H), 8.35 (s, 1 H), 7.99 (s, 1 H), 7.78 (s, 1 H), 7.65-7.75 (m, 2 H), 7.59 (d, J=8.34 Hz, 1 H), 7.22 (t, J=7.58 Hz, 1
H), 6.82 - 6.91 (m, 2 H); MS ESI [M + H]+ 262.0, calcd for [C16H11N3O+ H]+
262.3. Example A20, iV-[(3£)-3-(lH-indazol-6-ylmethylideneV2-oxo-2.3-dihvdro-lH- indol-5-yll-iVjV-dimethylsulfamide
Figure imgf000109_0001
To a solution of ΛyV-dimethyl-iV-(2-oxo-2,3-dihydro-lH-indol-5- yl)sulfamide (28 mg, 0.11 mmol) was added lΗ-indazole-6-carbaldehyde (18 mg,
0.12 mmol), piperidine (2 uL, 0.012 mmol) and MeOH (2 mL). The reaction was then heated to 850C for 30 min. The MeOH was removed in vacuo and the residue purified by column chromatography (silica gel, 95:5, CH2Cl2MeOH) to give 14 mg,
33 % of the title compound as an orange solid. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, IH), 7.91 (s, IH), 7.84 (s, IH), 7.64 (s, IH), 7.45 (d, J = 8.3 Hz, IH), 7.07 (d, J =
8.1 Hz, IH), 6.86 (d, J = 8.3 Hz, IH), 2.59 (s, 6H); MS ESI 384.1 [M + H]+, calcd for [C18H17N5O3S + H]+ 384.1.
Example A21. N'-[(3E)-3-(lH-benzotriazol-5-ylmethylideneV2-oxo-2.3-dihvdro- lH-indol-5-yll-NJV-dimethylsulfamide
Figure imgf000109_0002
According to the method described in example A20, except substituting 1Η- benzo[d][l,2,3]triazole-5-carbaldehyde (18 mg, 0.12 mmol), the title compound was obtained as an orange solid (16 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 8.20 (s, IH), 8.02 (d, J = 8.3 Hz, IH), 7.92 (s, IH), 7.78 (d, J = 8.3 Hz, IH), 7.59 (s, IH), 7.09 (d, J = 8.1 Hz, IH), 6.87 (d, J = 8.6 Hz, IH), 2.61 (s, 6H); MS ESI 385.1 [M + H]+, calcd for [C17H16N6O3S + H]+ 385.1.
Example A22. (EVN-(3-(flH-indazol-6-yl)methylene)-2-oxoindolin-5-yl)acetamide
Figure imgf000110_0001
To a solution of N-(2-oxoindolin-5-yl)acetamide (19 mg, 0.1 mmol) was added lH-indazole-6-carbaldehyde (16 mg, 0.12 mmol), piperidine (2 uL, 0.011 mmol) and MeOH (2 mL). The reaction was then heated to 850C for 30 min. The MeOH was removed in vacuo and the solid triturated with ether to give 11 mg, 34 % of the title compound as an orange solid. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, IH), 8.06 (s, IH), 7.92-7.88 (m, 2H), 7.84 (s, IH), 7.49 (d, J = 8.6 Hz, IH), 7.35 (d, IH), 6.88 (d, J = 8.3 Hz, IH), 2.04 (s, 3H); MS ESI 319.1 [M + H]+, calcd for [C18H17N5O3S + H]+ 319.11.
Example A23. (EVN-G -(( 1 H-benzoFdl [ 1.2.31triazol-5-vDmethyleneV2-oxoindolin- 5-yDacetamide
Figure imgf000110_0002
According to the method of Example A22, except substituting substituting lH-benzo[d][l,2,3]triazole-5-carbaldehyde (16 mg, 0.12 mmol), the title compound was obtained as an orange solid (7 mg, 22%). 1H NMR (400 MHz, DMSO-de) δ 10.54 (s, IH), 9.73 (s, IH), 8.32-8.22 (m, IH), 8.05-7.75 (m, 2H), 7.92 (s, IH), 7.80- 7.7 (m, 2H), 7.47 (d, IH), 6.82 (d, J = 8.3 Hz, IH), 1.92 (s, 3H); MS ESI 320.0 [M + H]+, calcd for [C17H13N5O2 + H]+ 320.1.
Example A24. (EVN-(3-((lH-benzordiri.2.31triazol-5-yl)methylene)-2-oxoindolin- 5-vDmethanesulfonamide
Figure imgf000111_0001
According to the method of Example A20, except substituting N-(2- oxoindolin-5-yl)methanesulfonamide (12 mg, 0.053 mmol) and IH- benzo[d][l,2,3]triazole-5-carbaldehyde (9 mg, 0.058 mmol), the title compound was obtained as an orange solid (8 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, IH), 8.00 (d, J = 8.6 Hz, IH), 7.93 (s, IH), 7.80 (d, J = 8.4 Hz, IH), 7.61 (s, IH), 7.14 (d, J = 8.4 Hz, IH), 6.91 (d, J = 8.3 Hz, IH), 2.86 (s, 3H); MS ESI 356.0 [M + H]+, calcd for [C16Hi3N5O3S + H]+ 356.1.
Example A25. (EVN-G -(( 1 H-indazol-6-yl)methylene V2-oxoindolin-5- vDmethanesulfonamide
Figure imgf000111_0002
According to the method of Example A20, except substituting N-(2- oxoindolin-5-yl)methanesulfonamide (10 mg, 0.044 mmol), the title compound was obtained as an orange solid (2 mg, 13%). 1H NMR (400 MHz, DMSO-(I6) δ 13.29 (s, IH), 10.61 (s, IH), 8.17 (s, IH), 7.86-7.87 (m, 2H), 7.79 (s, IH), 7.61 (s, IH), 7.43 (d, J = 7.8 Hz, IH), 7.11 (d, J = 7.8 Hz, IH), 6.86 (d, J = 8.0 Hz, IH), 2.86 (s, 3H); MS ESI 355.1 [M + H]+, calcd for [C16H13N5O3S + H]+ 355.1.
Example A26. (EVl-G -(H H-indazol-6-vnmethyleneV2-oxoindolin-5-yl)-3- isopropvlurea - I l l -
Figure imgf000112_0001
According to the method of Example A20, except substituting l-isopropyl-3- (2-oxoindolin-5-yl)urea (23 mg, 0.099 mmol), the title compound was obtained as an orange solid (8 mg, 22%). 1H NMR (400 MHz, DMSO-Cl6) δ 13.29 (s, IH), 10.41 (s, IH), 8.16 (s, IH), 8.00 (s IH), 7.87(m, 2H), 7.72 (s, IH), 7.60 (s, IH), 7.45 (d, J = 9.4 Hz, IH), 7.37 (d, J = 7.8 Hz, IH), 6.74 (d, J = 8.1 Hz, IH), 5.76 (d, J = 8.6 Hz, IH), 3.75-3.70 (m, IH), 1.03-1.00 (m, 6H); MS ESI 362.1 [M + H]+, calcd for [C20H19N5O2 + H]+ 362.2.
Example A27. (EV 1 -(3-(T 1 H-benzofdi \ 1.2.31triazol-5-yr)methylene)-2-oxoindolin- 5-yl)-3-isopropylurea
Figure imgf000112_0002
According to the method of Example A20, except substituting l-isopropyl-3- (2-oxoindolin-5-yl)urea (23 mg, 0.099 mmol) and lH-benzo[d][l,2,3]triazole-5- carbaldehyde (15 mg, 0.11 mmol), the title compound was obtained as an orange solid (6 mg, 16%). 1H NMR (400 MHz, DMSO-de) δ 10.44 (s, IH), 8.01 (s IH), 7.75(s, IH), 7.57-7.59 (m, 2H), 7.31 (d, J = 7.6 Hz, IH), 6.74 (d, J = 8.4 Hz, IH), 5.76 (d, J = 7.6 Hz,lH), 3.75-3.70 (m, IH), 1.03-1.00 (d, 6H); MS ESI 363.1 [M + H]+, calcd for [C20H19N5O2 + H]+ 363.2.
Example A28. (E and Z)-3-(3-((lH-indazol-6-yl)methylene)-2-oxoindolin-6- yl)pyridinium 2.2.2-trifluoroacetate
Figure imgf000113_0001
6-(Pyridin-3-yl)indolin-2-one (25 mg, 0.12 mmol) and lH-indazole-6- carbaldehyde (17.4 mg, 0.12 mmol) were heated with stirring in a sealed tube under microwave irradiation at 90 0C for 15 min. The crude mixture was concentrated and purified by prepTLC (SiO2 20 % MeOH/DCM) followed by HPLC. Subsequent recrystalization from MeCN provided the title compound as a dark orange solid (6.2 mg, 12 %) in a (2:1) mixture of E and Z isomers. E-isomer: 1H NMR (400 MHz, CD3OD) 8.97 (br. s., 1 H), 8.67 (br. s., 1 H), 8.45 (d, J=7.83 Hz, 1 H), 8.15 (s, 1 H), 7.76 - 8.01 (m, 5 H), 7.50 (d, J=8.34 Hz, 1 H), 7.22 - 7.29 (m, 2 H); Z-isomer: 1H NMR (400 MHz, CD3OD) δ ppm 9.01 (br. s., 1 H), 8.67 (br. s., 1 H), 8.54 (d, J=7.33 Hz, 1 H), 8.09 (s, 1 H), 7.76 - 8.01 (m, 6 H), 7.43 (d, J=7.58 Hz, 1 H), 7.22 - 7.29 (m, 1 H); MS ESI 339.1 (100) [M + H]+, calcd for [C21H14N4O+ H]+ 339.4.
Example A29. (E)-3-(( 1 H-benzofdl r 1.2.31triazol-5-vnmethyleneV6-(pyridin-3- yl)indolin-2-one
Figure imgf000113_0002
According to the method of Example A 19, utilizing 6-(pyridin-3-yl)indolin-
2-one (37.1 mg, 0.18 mmol) and lH-benzo[d][l,2,3]triazole-5-carbaldehyde (25.8 mg, 0.18 mmol), the title compound was obtained as an orange solid (20 mg, 34 %). 1H NMR (400 MHz, DMSO-d6) δ ppm 15.96 (br.s. lH),10.83 (s, 1 H), 8.86 (br. s., 1 H), 8.57 - 8.61 (m, 1 H), 8.45 (br. s., 0.5 H), 8.18 (br. s., 1 H), 8.05 (d, J=7.83 Hz, 1 H), 7.95 (br. s., 1 H), 7.86 (s, 0.5 H), 7.75 (br. s., 1 H), 7.64 (d, J=7.33 Hz, 1 H), 7.49 (dd, J=7.71, 4.93 Hz, 1 H), 7.22 (d, J=7.58 Hz, 1 H), 7.17 (s, 1 H); 1H NMR (400 MHz, DMF-d7) δ ppm 10.77 (br. s., 1 H), 8.94 (br. s., 1 H), 8.61 - 8.65 (m, 1 H), 8.42 (s, 1 H), 8.13 (t, J=7.96 Hz, 1 H), 7.93 (s, 1 H), 7.90 (d, J=8.84 Hz, 1 H), 7.78 (d, J=7.83 Hz, 1 H), 7.52 (dd, J=7.71, 4.67 Hz, 1 H), 7.33 (s, 1 H), 7.30 (d, J=7.83 Hz, 1 H); MS ESI 340.1 (100) [M + H]+, calcd for [C20H13N5O+ H]+ 340.4.
Example A30. (E)-3-((lH-indazol-5-yl')methyleneV6-(pyridin-3-ylMndolin-2-one
Figure imgf000114_0001
According to the method of Example A 19, utilizing 6-(pyridin-3-yl)indolin- 2-one (25 mg, 0.12 mmol) and lH-indazole-5-carbaldehyde (17.4 mg, 0.12 mmol), the title compound was obtained as an orange solid (7 mg, 17 %). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.32 (br. s., 1 H), 10.81 (s, IH), 9.04 (s, 1 H), 8.89 (d, J=I.26 Hz, 1 H), 8.57 (dd, J=4.55, 1.26 Hz, 1 H), 8.52 (d, J=7.83 Hz, 1 H), 8.25 (s, 1 H), 8.06 - 8.11 (m, 1 H), 8.04 (s, 1 H), 7.87 (d, J=7.83 Hz, 1 H), 7.62 (d, J=8.84 Hz, 1 H), 7.49 (dd, J=7.33, 4.55 Hz, 1 H), 7.38 (dd, J=7.83, 1.26 Hz, 1 H), 7.11 (d, J=LOl Hz, 1 H); MS ESI 339.1 (100) [M + H]+, calcd for [C21Hi4N4O+ H]+ 339.4.
Example A31. (EV3-((lH-indazol-5-yπmethyleneV5-bromoindolin-2-one
Figure imgf000114_0002
The title compound was synthesized according to the method described for Example AI lB except substituting 5-bromooxindole (40 mg, 0.189 mmol) and IH- indazole-5-carbaldehyde (30 mg, 0.208 mmol) to obtain the title compound (6.8 mg, 4.0 %) as a yellow solid. 1E NMR (400 MHz, CD3OD) δ 8.19 (s, IH), 8.17 (s, IH), 7.95 (s, IH), 7.77 (s, IH), 7.76-7.68 (m, 2H), 7.38 (d, J = 8.59 Hz, IH), 6.87 (d, J = 8.59 Hz, IH); MS ESI 340.1 [M + H]+, calcd for [C16H10BrN3O+ H]+ 340.01.
Example A32. (Z)-3-((lH-indazol-6-vOmethylene)-5-fluoroindolin-2-one
Figure imgf000115_0001
The title compound was isolated through resolution of mixed fractions of (E) and (Z) isomers from Example A16 by preparatory-HPLC to obtain 6.1 mg (8.0 %) of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.94 (s, IH), 8.07 (s, IH), 7.94- 7.85 (m, 2H), 7.80 (d, J = 8.59 Hz, IH), 7.49 (d, J = 8.84 Hz, IH), 6.97 (t, J = 9.20 Hz, IH), 6.87-6.81 (m, IH); MS ESI 280.0 [M + H]+, calcd for [C16H10FN3O+ H]+ 280.09.
Example A33. (EV3-(( 1 H-benzoFdl ϊ 1.2.31triazol-5-vnmethyleneV 1 -methylindolin- 2-one
Figure imgf000115_0002
The title compound was synthesized according to the method described for
Example Al IB, except substituting l-methylindolin-2-one (18 mg, 0.124 mmol) and lH-benzo[d][l,2,3]triazole-6-carbaldehyde (20 mg, 0.136 mmol) and then purified by preparatory HPLC to obtain 3.4 mg, 10 % of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.23 (bs, IH), 8.00 (bs, IH), 7.95 (s, IH), 7.84-7.75 (m, IH), 7.59 (d, J = 7.58 Hz, IH), 7.34 (t, J = 8.00 Hz, IH), 7.04 (d, J = 7.83 Hz, IH), 6.92 (d, J = 7.58 Hz, IH), 3.35 (s, 3H); MS ESI 277.0 [M + H]+, calcd for [C16H12N4O + H]+ 277.11.
Example A34. (E)-3-((lH-indazol-6-yl)methylene*)-l-methylindolin-2-one
Figure imgf000116_0001
The desired product was synthesized according to the method described for Example Al IB, except substituting l-methylindolin-2-one (37 mg, 0.249 mmol) and lH-indazole-6-carbaldehyde (40 mg, 0.274 mmol) and then purified by preparatory HPLC to obtain the title compound (12 mg, 17 %) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, IH), 7.96-7.86 (m, 3H), 7.67 (d, J = 7.83 Hz, IH), 7.46 (d, J = 8.08 Hz, IH), 7.33 (t, J = 7.71 Hz, IH), 7.02 (d, J = 7.83 Hz, IH), 6.93 (t, J = 7.71 Hz, IH), 3.31 (s, 3H); MS ESI 276.1 [M + H]+, calcd for [C17H13N3O + H]+ 276.11.
Example A35. (E)-3-((lH-indazol-6-yl)methylene)-5-bromoindolin-2-one
Figure imgf000116_0002
The title compound was synthesized according to the method described for
Example Al IB except substituting 5-bromooxindole (40 mg, 0.189 mmol) and IH- indazole-6-carbaldehyde (30 mg, 0.208 mmol) to obtain 1.0 mg (1.6 %) of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.16 (s, IH), 7.98-7.92 (m, 2H), 7.87 (s, IH), 7.73 (s, IH), 7.44 (d, J = 8.34 Hz, IH), 7.39 (d, J = 8.59 Hz, IH), 6.87 (d, J = 8.34 Hz, IH); MS ESI 340.1 [M + H]+, calcd for [C16Hi0BrN3O+ H]+ 340.01. Example A36. (E)-3-((lH-indazol-6-yπmethylene)-6-chloroindolin-2 -one
Figure imgf000117_0001
The title compound was synthesized according to the method described for Example Al IB except substituting 6-chlorooxindole (30 mg, 0.179 mmol) and IH- indazole-6-carbaldehyde (29 mg, 0.197 mmol) to obtain 22 mg (42 %) of a yellow solid. 1H NMR (400 MHz, de-DMSO) δ 13.30 (s, IH), 10.79 (s, IH), 8.16 (s, IH), 7.90-7.87 (m, 2H), 7.83 (s, IH), 7.56 (d, J = 8.00 Hz, IH), 7.41 (d, J = 8.80 Hz, IH), 6.93-6.88 (m, 2H); MS ESI 296.0 [M + H]+, calcd for [C16Hi0ClN3O + H]+ 296.06.
Example A37. (EVtert-butyl 3-((lH-indazol-6-yDmethylene)-2-oxoindolin-6- ylcarbamate
Figure imgf000117_0002
A. tert-butyl 2-oxoindolin-6-ylcarbamate
A THF (2.5 mL) solution of 6-aminoindolin-2-one (100 mg, 0.675 mmol) and di-t- butyl dicarbonate (155 mg, 0.709 mmol) at rt under N2, was treated with Et3N (0.28 mL, 2.03 mmol). The solvent was removed in vacuo and the residue purified by column chromatography (silica gel, CH2Cl2/Me0H, 98:2 to 95:5) to give 76 mg,
45% of a tan solid. 1U NMR (400 MHz, CDCl3) δ 7.21 (s, IH), 7.10 (d, J = 8.08 Hz,
IH), 6.88 (d, J = 7.58 Hz, IH), 3.45 (s, 2H), 1.51 (s, 9H); MS ESI 249.0 [M + H]+, calcd for [C13Hi6N2O3+ H]+ 249.12.
B. (E)-tert-butyl 3-((lH-indazol-6-yl)methylene)-2-oxoindolin-6-ylcarbamate The synthetic method followed that described in Example AI lB, with a modified purification procedure. The MeOH was removed in vacuo and the residue was treated with 95:5 CH2Cl2MeOH. The resulting precipitate was filtered and washed with 95:5 CH2Cl2/Me0H to obtain the title compound as a yellow-brown solid (40 mg, 35 %). 1H NMR (400 MHz, CD3OD) δ 8.11 (s, IH), 7.89-7.83 (m, 2H), 7.71 (s, IH), 7.52 (d, J = 8.40 Hz, IH), 7.44 (d, J = 9.60 Hz, IH), 7.29 (s, IH), 6.73 (d, J = 8.40 Hz, IH), 1.51 (s, 9H); MS ESI 377.2 [M + H]+, calcd for [C2)H20N4O3 + H]+ 377.16.
Example A38. (E)-3-((lH-indazol-6-yl)methylene)-2-oxoindolin-6-aminium 2.2.2- trifluoroacetate
Figure imgf000118_0001
The title compound was synthesized according to the method described for Example Al 5 except substituting (E)-tert-butyl 3-((lH-indazol-6-yl)methylene)-2- oxoindolin-6-ylcarbamate (31 mg, 0.0823 mmol) to obtain 14 mg (44 %) of a brown solid. 1H NMR (400 MHz, CD3OD) δ 8.09 (s, IH), 7.85 (d, J = 8.59 Hz, IH), 7.82 (s, IH), 7.55 (s, IH), 7.49-7.37 (m, 2H), 6.34 (d, J = 1.77 Hz, IH), 6.23 (dd, J = 8.46, 1.89 Hz, IH); MS ESI 277.0 [M + H]+, calcd for [C16Hi2N4O+ H]+ 277.11.
Example A39. (EV3-((3-iodo-lH-indazol-6-yDmethylene)indolin-2-one
Figure imgf000118_0002
The title compound was synthesized from 3-iodo-lH-indazole-6- carbaldehyde (15 mg, 0.0551 mmol) and oxindole (8 mg, 0.0616 mmol) according to the method described for Example AI lB and purified by column chromatography (silica gel, CH2Cl2/Me0H, 98:2 to 96:4) to obtain 6.9 mg, 33 % of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.89-7.82 (m, 2H), 7.63-7.49 (m, 3H), 7.23 (t, J = 8.21 Hz, IH), 6.91 (d, J = 7.07 Hz, IH), 6.89-6.83 (m, IH); MS ESI 388.0 [M + H]+, calcd for [Ci6H10IN3O + H]+ 387.99.
Example A40: (E & ZV3 -(G -amino- lH-indazol-5-vπmethyleneMndolin-2-one
Figure imgf000119_0001
A. 5-(l,3-dioxolan-2-yl)-2-fluorobenzonitrile
To a solution of 2-fluoro-5-formylbenzonitrile (450 mg, 3 mmol) in toluene (10 mL) was added ethylene glycol (2 mL) and p-toluene sulfonic acid (25 mg). The solution was heated to 70 °C overnight. The solution was cooled to room temperature. Ethyl acetate (100 mL) was added and the solution was washed with sat. sodium bicarbonated (10 mL), water (10 mL) and brine (10 mL), dried over MgSO4 and concentrated to a clear oil (567 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd IH, J = 6.3, 2.3 Hz), 7.74-7.70 (m, IH), 7.27-7.24 (m, IH), 5.80 (s, IH), 4.14-4.08 (m, 4H).
B. 5-(l,3-dioxolan-2-yl)-lH-indazol-3-amine
To a solution of 5-(l,3-dioxolan-2-yl)-2-fluorobenzonitrile (567 mg, 3 mmol) in n- butanol (5 mL) was added hydrazine hydrate (1.47 mL, 30 mmol). The solution was heated to 110 0C for 2 h and cooled to room temperature. The solution was stirred overnight and the resulting precipitate was collected to give the title compound as a white solid (220 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, IH), 7.78 (s, IH), 7.28-7.26 (m, IH), 7.21-7.19 (m, IH), 5.72 (s, IH), 5.37 (bs), 4.08-4.02 (m, 2H), 3.98-3.92 (m, 2H); MS ESI 206.0 [M + H]+, calcd for [C10HnN3O2 + H]+ 206.1. C. i-amino-lH-indazoleS-carbaldehyde
To a solution of 5-(l,3-dioxolan-2-yl)-lH-indazol-3-amine (75 mg, 0.36 mmol) in THF (5 mL) and H2O (0.5 mL) was added p-toluene sulfonic acid (25 mg) and the reaction was stirred overnight at room temperature. Ethyl acetate (75 mL) was added and the solution was washed with sat. sodium bicarbonate (5 mL), brine (2 x 5 mL), dried over MgSO4 and concentrated to give the title compound as an orange solid (52 mg, 89%). 1H NMR (400 MHz, CD3OD) δ 9.68 (s, IH), 8.94 (s, IH), 8.18 (d, IH, J = 7.6 Hz), 7.68 (d, IH, J = 8.4 Hz).
D. tert-butyl 5-formyl-lH-indazol-3-ylcarbamate
To a solution of 3-amino-lH-indazole-S-carbaldehyde (50 mg, 0.31 mmol) in DMF (3 mL) was added di-tert-butyl dicarbonate (135 mg, 0.62 mmol) and triethylamine (0.17 mL, 1.2 mmol). The mixture was stirred overnight and concentrated. The residue was dissolved into ethyl acetate (50 mL), washed with H2O and dried over MgSO4. The title compound was purified by silica gel chromatography (EtOAc/Hex 1:1) as a red solid (25 mg, 30%). 1H NMR (400 MHz, CD3OD) δ 10.07 (s, IH), 8.26-8.02 (m, 3H), 1.73-1.71 (m, 9H).
E. (E) -tert-butyl 5-((2-oxoindolin-3-ylidene)methyl)-lH-indazol-3- ylcarbamate
To a solution of oxindole (13 mg, 0.01 mmol) and tert-butyl 5-formyl-lH- indazol-3 -ylcarbamate (25 mg, 0.01 mmol) in ethanol (1 mL) was added piperidine (1 drop). The mixture was heated to 80 0C for 2 h and cooled to rt. The solution was loaded onto a silica gel column and the title compound was eluted with EtOAc/Hex 4:1 as a red solid (14 mg, 37%). 1H NMR (400 MHz, CD3OD) δ 8.14- 8.02 (m, 2H), 7.90-7.83 (m, 2H), 7.63 (s, IH), 7.24 (bs, IH), 7.00-6.91 (m, 2H), 1.71 (s, 9H).
F. (E andZ)-3-((3-amino-lH-indazol-5-yl)methylene)indolin-2-one
To a solution of (E)-tert-butyl 5-((2-oxoindolin-3-ylidene)methyl)-lH- indazol-3-ylcarbamate (14 mg, 0.04 mmol) in CH2Cl2 (1 mL) was added TFA (0.25 mL) and the reaction was stirred for 3 h. The solution was concentrated to dryness and purified by preparatory HPLC to give the title compound as a 3:2 mixture of E/Z isomers. ESI 277.0 [M + H]+, calcd for [C16H12N4O + H]+ 277.1. E-isomer: Short Retention Time by reverse phase HPLC; 1H NMR (400 MHz, CD3OD) δ 8.93 (s, IH), 8.50 (d, IH, J = 8.6 Hz), 7.82 (s, IH), 7.64 (d, IH, J = 7.7 Hz), 7.41 (d, IH, J = 8.6 Hz), 7.26-7.21 (m IH), 6.94-6.88 (m, 2H). Z-isomer: Long Retention Time by reverse phase HPLC; 1H NMR (400 MHz, CD3OD) δ 8.22 (s, IH), 7.87 (d, IH, J = 8.9 Hz), 7.82 (s, IH), 7.70 (d, IH, J = 7.0 Hz), 7.50 (d, IH, J = 8.8 Hz), 7.26-7.21 (m IH), 7.05 (t, IH, J = 7.6 Hz) 6.94-6.88 (m, IH).
Example A41: (E and Z>3-(G-((E>2-φyridin-2-vnvinylHH-indazol-6- vDmethyleneMndolin-2-one
Figure imgf000121_0001
A. 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-6-carbaldehyde An oven-dried round bottom flask under Ar was charged with 3-iodo-lH- indazole-6-carbaldehyde (50 mg, 0.184 mmol), THF (1.5 mL) and CH2Cl2 (1.0 mL). Methanesulfonic acid (1.4 uL, 0.0221 mmol) was added and the solution cooled with an ice-water bath. A solution of 3,4-dihydro-2H-pyran (41 uL, 0.460 mmol) in CH2Cl2 (0.5 mL) was then added dropwise over 15 minutes and the reaction stirred overnight. The solvents were removed in vacuo and the residue purified by column chromatography (silica gel, 99:1 to 98:2 CH2Cl2/Me0H) to give the title compound as a white powder (16 mg, 25 %). 1H NMR (400 MHz, CDCl3) δ 10.18 (s, IH), 8.13 (s, IH), 7.77 (d, J= 8.4 Hz, IH), 7.62 (d, J = 8.4 Hz, IH), 5.84-5.77 (m, IH), 4.07- 4.02 (m, IH), 3.83-3.75 (m, IH), 2.62-2.51 (m, IH), 2.20-2.10 (m, 2H), 1.86-1.70 (m, 3H); MS ESI 378.9 [M + Na]+, calcd for [C13H13IN2O2 + Na]+ 378.99.
B. Synthesis of (E)-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)- lH-indazole-6-carbaldehyde
In a scintillation vial a solution of 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH- indazole-6-carbaldehyde (24 mg, 0.0673 mmol), 2-vinylpyridine (9.4 uL, 0.0875 mmol), DIPEA (24 uL, 0.135 mmol) and DMF (1.0 mL) was purged with Ar for 20 min. Pd(OAc)2 (1.5 mg, 0.0067 mmol) and P(o-tolyl)3 (6.1 mg, 0.0202 mmol) were then added and the vial was capped and heated to 1000C overnight. The solution was cooled to room temperature and extracted with EtOAc, washing with NH4Cl (sat ), H2O, and brine. The organic layer was dried over MgSO4, the solvent removed in vacuo, and the residue purified by column chromatography (silica gel, 96:4 CH2Cl2/Me0H) to give 17 mg, 77% of a yellow oil which was 70 % pure by NMR. This crude material was used for the subsequent synthetic step. 1H NMR (400 MHz, CD3OD) δ 10.16 (s, IH), 8.59 (s, IH), 8.34 (s, IH), 8.27 (d, J= 8.4 Hz, IH), 7.95- 7.83 (m, 4H), 7.75 (m, IH), 7.68 (d, J = 16.0 Hz, IH), 6.00 (d, J = 9.6 Hz, IH), 4.05-4.01 (m, IH), 3.93-3.86 (m, IH), 2.65-2.56 (m, IH), 2.27-2.10 (m, 2H), 1.92- 1.66 (m, 3H); MS ESI 334.1 [M + H]+, calcd for [C20H)9N3O2 + H]+ 334.16.
C. (E)-3-((3-((E)-2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-6-yl)methylene) indolin-2-one
To a solution of (E)-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)- lH-indazole-6-carbaldehyde (25 mg, 0.0749 mmol), oxindole (10 mg, 0.0749 mmol), and MeOH (1 mL) was added piperidine (1 uL) and the reaction heated to 60 0C for 3 hours. The reaction was cooled to room temperature and the product yellow solid was precipitated with MeOH (1 mL) and then filtered to give l lmg. The filtrate was purified by column chromatography (silica gel, 99:1 to 98:2 CH2Cl2/Me0H) to give an additional 6 mg of product (17 mg total, 50 %). 1H NMR (400 MHz, CDCl3) δ 8.69-8.62 (m, IH), 8.14 (d, J= 8.3 Hz, IH), 8.00-7.91 (m, 3H), 7.77 (d, J= 8.1 Hz, IH), 7.72 (t, J= 8.3 Hz, IH), 7.63 (d, J= 16.9 Hz, IH), 7.53 (m, 2H), 7.44 (b.s., IH), 7.25-7.17 (m, 2H), 6.92-6.86 (m, 2H), 5.77 (d, J = 10.6 Hz, IH), 4.09 (d, J= 9.6 Hz, IH), 3.84-3.74 (m, IH), 2.67-2.53 (m, IH), 2.24-2.13 (m, 2H), 1.85-1.66 (m, 3H); MS ESI 449.2 [M + H]+, calcd for [C28H24N4O2 + H]+ 449.20.
D. (E and Z)-3-((3-((E)-2-(pyridin-2-yl)vinyl)-lH-indazol-6-yl)methylene)- indolin-2-one
To a solution of (E)-3-((3-((E)-2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H- pyran-2-yl)-lH-indazol-6-yl)methylene)indolin-2-one (17 mg, 0.0379 mmol) in MeOH (3 mL) was added /7-TsORH2O (30 mg). The reaction was heated to reflux for 5 hours at which time LC-MS indicated complete consumption of starting material. The MeOH was removed in vacuo and the product extracted into EtOAc washing with NaHCO3 (Sat), H2O, and brine. The organic layer was dried over MgSO4 and the solvent removed to give an orange solid. The solid was titurated 2X with 5:1 hexanes/Et2O while decanting off the solvent to give the orange solid (10 mg, 71 %). The compound was a 3:1 mixture of (E)Z(Z) isomers by analysis of the proton NMR. 1U NMR (400 MHz, d6-DMSO) δ 13.60, 13.50 (s, IH), 10.71, 10.65 (s, IH), 9.01, 7.92 (s, IH), 8.61 (m, IH), 8.33, 8.25 (d, J = 8.5 Hz, IH), 8.08-7.53 (m, 7H), 7.34-7.17 (m, 2H), 6.93-6.82 (m, 2H); MS ESI 365.2 [M + H]+, calcd for [C23H16N4O + H]+ 365.14.
Example A42. (E)-3 -( ( 1 H-indazol-6-v0methylene*)-7-fluoroindolin-2-one
Figure imgf000123_0001
According to the method described in example A6, except substituting 7- fluorooxindole (15 mg , 0.1 mmol) the title compound was prepared as a brown solid (20 mg, 71%). 1H NMR (400 MHz, CD3OD) δ 8.14 (s, IH), 7.69 (s, IH), 7.25 (d, IH, J= 8 Hz), 7.90 (s, IH), 7.48 (dd, 2H, J= 8 Hz, 4 Hz), 7.08 (t, IH, J= 8 Hz), 6.89-6.84 (m, IH); MS ESI [M + H]+, calcd for [C16Hi0FN3O +H]+ 280.09; found m/z 280.1.
Example A43. (E)-3-((lH-indazol-6-vπmethylene)-7-chloroindolin-2 -one
Figure imgf000123_0002
According to the method described in example A6, except substituting 7- chlorooxindole (17 mg , 0.1 mmol), the title compound was prepared as a dark yellow solid (29 mg, 97%). 1H NMR (400 MHz, DMSO) δ 13.33 (s, IH), 11.07 (s, IH), 8.16 (s, IH), 7.90 (m, 3H), 7.55 (d, IH, J= 8 Hz), 7.42 (d, IH, J= 8 Hz), 7.32 (d, IH, J = 8 Hz), 6.88 (t, IH, J = 8Hz); MS ESI [M + H]+, calcd for [C16HioClN30+H]+ 296.06; found m/z 296.1.
Example A44. (E)-3 -(( 1 H-indazol-6-vDmethylene)-7-bromoindolin-2-one
Figure imgf000124_0001
According to the method described in example A6, except substituting 7- bromooxindole (21mg, 0.1 mmol), the title compound was prepared as a yellow solid (6.8 mg, 20%). 1H NMR (400 MHz, CD3OD) δ 8.15 (s, IH), 7.96 (s, IH), 7.93 (d, IH, J = 8Hz), 7.89 (s, IH), 7.62 (d, IH, J= 8 Hz), 7.46 (d, IH, J= 8 Hz), 7.41 (d, IH, J= 8 Hz), 6.81 (t, IH, J= 8 Hz); MS ESI [M + H]+, calcd for [Ci6Hi0BrN3O +H]+ 340.01; found m/z 340.0.
Example A45. (E and ZV3-((lH-indazol-6-vDmethylene)-2-oxoindoline-7- carbonitrile
Figure imgf000124_0002
According to the method described in example A6, except substituting 7- cyanooxindole (32 mg, 0.2 mmol), the title compound was prepared as a mixture of isomers (Z:E = 41:59) and red solid (40 mg, 70%). Z isomer: 1H NMR (400 MHz, DMSO) δ 8.95 (s, IH), 8.17 (m, IH), 8.14 (m, IH), 8.08 (d, IH, J= 7.6 Hz), 7.99 (d, IH, J = 7.6 Hz), 7.85-7.83 (m, IH), 7.62-7.58 (m, IH), 7.16 (t, IH, J = 7.6 Hz). E isomer: 1H NMR (400 MHz, DMSO) δ 8.17 (m, IH), 7.94-7.90 (m, 3H), 7.85-7.83 (m, IH), 7.62-7.58 (m, IH), 7.43 (d, IH, J= 8 Hz), 6.99 (t, IH, J= 8 Hz); MS ESI [M + H]+, calcd for [Ci7Hi0N4O +H]+ 287.09; found m/z 287.1.
Example A46. (E and ZVmethyl 3-((lH-indazol-6-yl)methyleneV2-oxoindoline-7- carboxvlate
Figure imgf000124_0003
According to the method described in example A6, except substituting methyl oxindole-7-carboxylate (23 mg , 0.12 mg), the title compound was prepared as a mixture of isomers (Z:E = 62:38) and yellow solid (36 mg, 91%). Z isomer: 1H NMR (400 MHz, DMSO) δ 13.45 (s, IH), 10.47 (s, IH), 8.95 (s, IH), 8.14 (m, 2H), 8.14 (d, IH, J= 7.6 Hz), 8.06 (d, IH, J= 7.6 Hz), 7.84 (d, IH, J= 8.8 Hz), 7.76 (d, IH, J = 8 Hz), 7.15 (t, IH, J = 8 Hz), 3.89 (s, 3H). E isomer: 1H NMR (400 MHz, CD3OD) δ 8.20 (s, IH), 8.16 (s, IH), 8.00-7.95 (m, 2H), 7.92-7.89 (m, 2H), 7.50 (d, IH, J = 8.8Hz), 7.01 (t, IH, J = 8Hz), 3.99 (s, 3H); MS ESI [M + H]+, calcd for [C18H13N3O3 +H]+ 320.10; found m/z 320.1.
Example A47. (E and Z>3-((lH-indazol-6-vnmethyleneV7- (trifluoromethyl)indolin-2-one
Figure imgf000125_0001
According to the method described in example A6, except substituting 7- (trifluoromethyl)indolin-2-one (40 mg, 0.2 mmol), the title compound was prepared as a mixture of isomers (Z:E = 1:5) and yellow solid (4.6 mg, 7%). Z isomer: 1H NMR (400 MHz, CD3OD) δ 9.00 (s, IH), 8.10 (s, IH), 7.93 (d, IH, J= 8 Hz), 7.89 (s, IH), 7.85 (d, IH, J= 8 Hz), 7.50-7.45 (m, 2H), 7.19 (t, IH, J= 8 Hz). E isomer: 1H NMR (400 MHz, CD3OD) δ 8.15 (s, IH), 8.02 (s, IH), 7.93 (d, IH, J = 8 Hz), 7.89 (s, IH), 7.85 (d, IH, J= 8 Hz), 7.50-7.45 (m, 2H), 7.00 (t, IH, J= 8 Hz); MS ESI [M + H]+, calcd for [Ci7H10F3N3O +H]+ 330.08; found m/z 330.1.
Example A48. (^-l-(3-((lH-indazol-6-vnmethyleneV2-oxoindolin-7-vn-3- isopropyl-urea
Figure imgf000125_0002
A. l-isopropyl-3-(2-oxoindolin- 7-yl)urea To a suspension of 7-aminoindolin-2-one (60 mg, 0.41 mmol) in THF (3 mL) was added DIPEA (0.28 mL, 1.62 mmol), and 2-isocyanatopropane (0.05 mL, 0.49 mmol). The mixture was stirred at rt overnight then filtered. The filter cake was washed with diethyl ether to give the title compound as a pale solid (57.3 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 7.09-7.04 (m, 2H), 6.99-6.95 (m, IH), 3.57 (s, 2H), 2.64 (m, IH), 1.20 (d, 6H, J = 6.4Hz). MS ESI [M + H]+, calcd for [Ci2H15N3O2 +H]+ 234.12; found m/z 234.0.
B. (E)-l-(3-((lH-indazol-6-yl)methylene)-2-oxoindolin-7-yl)-3-isopropyl- urea According to the method described in example A6, except substituting 1- isopropyl-3-(2-oxoindolin-7-yl)urea (57 mg , 0.24 mmol), the title compound was prepared as a yellow solid (61.4 mg, 7O0Zo)1 1H NMR (400 MHz, DMSO) δ 13.29 (s, IH), 10.16 (s, IH), 8.15 (s, IH), 8.00 (s, IH), 7.89 (s, 2H), 7.78 (s, IH), 7.41 (d, IH, J= 8 Hz), 7.35 (d, IH, J= 8 Hz), 7.28 (d, IH, J= 8 Hz), 6.77 (t, IH, J= 8 Hz), 6.09 (d, IH, J = 7.6 Hz), 3.77 (m, IH), 1.12 (s, 3H), 1.10 (s, 3H); MS ESI [M + H]+, calcd for [C20H19N5O2 +H]+ 362.16; found m/z 362.2.
Example A49. (E)-N-(3-((lH-indazol-6-vπmethylene')-2-oxoindolin-7-yl)acetamide
Figure imgf000126_0001
A. N-(2-oxoindolin-7-yl)acetamide
According to the method described in example A48a, 7-aminoindolin-2-one (80 mg , 0.54) was reacted with acetic anhydride (66 mg , 0.65 mmol) to give the title compound as a white solid (82 mg, 80%). 1H NMR (400 MHz, CD3OD) δ 7.13 (d, 2H, J = 8Hz), 6.99 (t, IH, J = 8Hz), 3.57 (s, 2H), 2.16 (s, 3H). MS ESI [M + H]+, calcd for [Ci0H10N2O2 +H]+ 191.08; found m/z 191.0.
B. (E)-N-(3-((lH-indazol-6-yl)methylene)-2-oxoindolin-7-yl)acetamide According to the method described in example A6, except substituting N-(2- oxoindolin-7-yl)acetamide (18 mg , 0.095 mmol), the title compound was prepared as a yellow solid (6.8 mg, 20%). 1H NMR (400 MHz, CD3OD) δ 8.16 (s, IH), 7.94 (m, 3H), 7.54 (d, IH, J= 8Hz), 7.48 (d, IH, J= 8Hz), 7.26 (d, IH, J= 8Hz), 6.89(t, IH, J = 8Hz), 2.19 (s, 3H). MS ESI [M + H]+, calcd for [C18H14N4O2 +H]+ 319.12; found m/z 391.1.
Example A50. (E and ZyN-(3-((lH-indazol-6-vDmethyleneV2-oxoindolin-7- vDformamide
Figure imgf000127_0001
A) N-(2-oxoindolin- 7-yl)formamide
To a suspension of 7-aminooxindole (32 mg, 0.22 mmol) in CH2Cl2 (1 mL) was added EDC (83 mg, 0.43 mmol) and formic acid (12 mg, 0.26 mmol). The reaction mixture was stirred at rt for 2 h and then filtered. The filter cake was washed with diethyl ether to give the title compound as a grey solid (27 mg, 71%). 1H NMR (400
MHz, CD3OD) δ 8.23 (s, IH), 7.20 (d, IH, J= 8 Hz), 7.15 (d, IH, J= 8 Hz), 7.02 (t,
IH, J= 8 Hz), 3.59 (s, 2H); MS ESI [M + H]+, calcd for [C9H8N2O2 +H]+ 177.07; found m/z 177.0.
B. N-(3-((lH-indazol-6-yl)methylene)-2-oxoindolin-7-yl)formamide
According to the method described in example Al, except substituting N-(2- oxoindolin-7-yl)formamide (20 mg, 0.11 mmol), the title compound was prepared as a mixture of isomers (Z:E = 35:65) and dark brown solid (12 mg, 35%). Z isomer: 1H NMR (400 MHz, DMSO) δ 9.88 (s, IH), 8.98 (s, IH), 8..61 (m, IH), 8.12 (s,
IH), 8.02 (s, IH), 7.97 (d, IH, J= 8 Hz), 7.82 (s, IH), 7.61 (d, IH, J= 7.2 Hz), 7.25
(m, IH), 7.01 (t, IH, J = 8 Hz). E isomer: 1H NMR (400 MHz, DMSO) δ 9.88 (s,
IH), 8.26 (s, IH), 8.12 (s, IH), 7.90 (m, 2H), 7.82 (s, IH), 7.53 (m, IH), 7.42 (m,
2H), 6.84 (t, IH, J= 8 Hz); MS ESI [M + H]+, calcd for [C17Hi2N4O2 +H]+ 305.10; found m/z 305.1.
Example A51: fEV3-(l-(lH-indazol-6-vnethylidene)indolin-2-one
Figure imgf000128_0001
A. l-(lH-indazol-6-yl)ethanol
To a solution of lH-indazole-6-carbaldehyde (200 mg, 1.37 mmol) in THF (7 mL) at -780C was added methyl magnesium bromide (1.4 mL, 4.11 mmol) dropwise under argon. The solution was warmed to rt and quenched with saturated ammonium chloride (2 mL). The mixture was extracted into ethyl acetate (3 x 10 mL), dried over MgSO4 and concentrated. The yellow oil was purified by silica gel chromatography (EtO Ac/Hex 4:1) to yield the title compound as a clear oil (135 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, IH), 7.76 (s, IH), 7.50-7.47 (m, 2H), 5.05 (q, 1 H, J = 7.4 Hz), 1.57 (d, 3H, J = 7.2 Hz); MS ESI [M + H]+, calcd for [C9H10N2O +H]+ 163.1; found m/z 163.0.
B. l-(lH-indazol-6-yl)ethanone
To a solution of l-(lH-indazol-6-yl)ethanol (100 mg, 0.6 mmol) in acetone (50 mL) was added PDC (1.11 g, 3 mmol). The mixture was stirred overnight at rt. The mixture was filtered through silica gel and purified by silica gel chromatography (4:1 EtO Ac/Hex) to give the title compound as a brown solid (70 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, IH), 8.23 (s, IH), 8.09-8.08 (m, IH), 7.56-7.54 (m, IH), 2.72 (s, 3H).
C. (E)-3-(l-(lH-indazol-6-yl)ethylidene)indolin-2-one A solution of oxindole (16 mg, 0.12 mmol), pyrrolidine (10 μL, 0.12 mmol) and l-(lH-indazol-6-yl)ethanone (20 mg, 0.12 mmol) in toluene was refluxed in a Dean-Stark trap for 2 h. The solution was then stirred at 50 0C for 72 h. Two equivalents of pyrrolidine were added and the solution was heated to reflux for 48 h. The solution was concentrated and the red residue was purified by preparatory HPLC to give the title compound as an orange solid (5 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, IH), 7.78 (s, IH), 7.70 (d, IH, J = 8.5 Hz), 7.34 (d, IH, J = 8.5 Hz), 7.03 (t, IH, J = 7.6 Hz), 6.81 (d, IH, J = 7.7 Hz), 6.50 (t, IH, J = 7.6 Hz), 6.05 (d, IH, J = 7.7 Hz), 2.82 (s, 3H); MS ESI [M + H]+, calcd for [Ci7Hi3N3O +H]+ 276.1; found m/z 276.0. Example A52 : (E)-3 -((4-chloro- 1 H-indazol-6-yDmethyleneMndolin-2-one
Figure imgf000129_0001
A. (4-chloro- lH-indazol-6-yl)methanol A solution of 4-chloro- lH-indazole-6-carboxylic acid (100 mg, 0.5 mmol) in
THF (1 mL) was cooled to 0°C under argon. Borane (1.4 mL, 1.4 mmol) was added dropwise and the solution was stirred overnight at rt. The reaction was quenched with ice cold sat. sodium bicarbonate, extracted with ethyl acetate (3 x 10 mL), dried over MgSO4 and concentrated to give the title compound as a white solid (60 mg, 66%). MS ESI [M + H]+, calcd for [C8H7ClN2O +H]+ 183.0; found m/z 183.0.
B. 4-chloro- lH-indazole-6-carbaldehyde
To a solution of (4-chloro- lH-indazol-6-yl)methanol (30 mg, 0.18 mmol) in acetone (5 mL) was added PDC (100 mg, 0.27 mmol). The mixture was stirred overnight at rt. The mixture was filtered through celite, the filter cake was washed with ethyl acetate. The solution was washed with water (2 x 10 mL), brine (10 mL), dried over MgSO4 and concentrated to a brown solid (30 mg, 100%). 1H NMR (400 MHz, CD3OD) δ 10.1 (s, IH), 8.21 (s, IH), 8.08 (s, IH), 7.62 (s, IH).
C. (E) -3- ((4-chloro- lH-indazol-6-yl)methylene) indolin-2-one
The compound was synthesized according to the method described for Example Al. Oxindole (8 mg, 0.06 mmol) was reacted with 4-chloro- lH-indazole- 6-carbaldehyde (11 mg, 0.06 mmol) to give the title compound as an orange solid (3 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 8.21 (s, IH), 7.87 (s, IH), 7.82 (s, IH), 7.59 (d, IH, J = 7.8 Hz), 7.48 (s, IH), 7.28 (t, IH, J = 7.9 Hz), 6.95 (d, IH, J = 7.7 Hz), 6.90 (t, IH, J = 8.2 Hz); MS ESI [M + H]+, calcd for [C16HI0CIN3O +H]+ 296.1; found m/z 296.1.
Example A53a: (E)-3-((4-bromo-lH-indazol-6-yl)methyleneMndolin-2-one and A53b: (Z)-3-((4-bromo-lH-indazol-6-yDmethyleneMndolin-2-one
Figure imgf000130_0001
A. (4-bromo-lH-indazol-6-yl)methanol
According to the method of A52A, 4-bromo-lH-indazole-6-carboxylic acid (1 g, 4 mmol) was reacted with borane (6 ml, 6 mmol) to give the title compound as a pale yellow solid (800 mg, 88%). MS ESI [M + H]+, calcd for [C8H7BrN2O +H]+ 227.0, 229.0; found m/z 226.9, 228.9.
B. ^bromo-lH-indazole-ό-carbaldehyde
According to the method of A52B, (4-bromo-lH-indazol-6-yl)methanol was oxidized with PDC to give the title compound as a beige solid (413 mg, 53%). MS ESI [M + H]+, calcd for [C8H5BrN2O +H]+ 225.0, 227.0; found m/z 224.9, 226.9.
C. 3-((4-bromo-lH-indazol-6-yl)methylene)indolin-2-one
According to the method described for Example Al, oxindole (15 mg, 0.11 mmol) was reacted with 4-bromo-lH-indazole-6-carbaldehyde (25 mg, 0.11 mmol) to give the title compound as an orange solid. The E and Z stereoisomers were separated by HPLC.
(E-isomer 7 mg, 19%, HPLC retention time, 11 min). 1H NMR (400 MHz, CD3OD) δ 8.11 (s, IH), 7.87 (s, IH), 7.80 (s, IH), 7.63 (s, IH), 7.56 (d, IH, J = 7.7 Hz), 7.28 (t, IH, J = 7.8 Hz), 6.93 (d, IH, J = 7.7 Hz), 6.89 (t, IH, J = 7.7 Hz); MS ESI [M + H]+, calcd for [Ci6H10BrN3O +H]+ 339.0, 341.0; found m/z 340.0, 342.0. (Z-isomer, 3 mg, 8%, HPLC retention time, 11.8 min) 1H NMR (400 MHz,
DMSO-de) δ 13.75 (s, IH), 10.72 (s, IH), 8.85 (s, IH), 8.41 (s, IH), 8.07 (s, IH), 7.96 (s, IH), 7.73 (d, IH, J = 7.5 Hz), 7.22 (t, IH, J = 7.5 Hz), 7.02 (t, IH, J = 7.4 Hz), 6.85 (d, IH, J = 7.8 Hz); MS ESI [M + H]+, calcd for [C16H10BrN3O +H]+ 339.0, 341.0; found m/z 340.0, 342.0.
Example A54a: (E)-3-((4-(pyridin-4-yl)-lH-indazol-6-vπmethylene)indolin-2-one and A54b: (E)-3-((4-(pyridin-4-yl)-lH-indazol-6-yl)methyleneMndolin-2-one
Figure imgf000131_0001
A. 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde To a solution of 4-bromo-lH-indazole-6-carbaldehyde (225 mg, 1 mmol) in
CH2Cl2 (10 mL) and aqueous KOH (2 mL, 50% wt) at O0C was added TBAB (3 mg, 0.01 mmol) and SEMCl (200 mg, 1.2 mmol). The mixture was stirred at 0°C for 4 h, warmed to rt and extracted with ethyl acetate (100 mL). The organic phase was washed with water (2 x 10 mL) and brine (10 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (1:1 EtOAc/Hex) to give the title compound as a pale yellow solid (280 mg, 82%). 1H NMR (400 MHz, CD3OD) δ 10.02 (s, IH), 8.21-8.19 (m, 2H), 7.80 (s, IH), 5.78 (s, 2H), 3.70-3.65 (m, 2H), 0.95-0.92 (m, 2H), -0.05 (s, 9H).
B. 4- (pyridin-4-yl)-l- ((2- (trimethylsilyl)ethoxy)methyl)- lH-indazole-6- carbaldehyde
To a solution of 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole- 6-carbaldehyde (50 mg, 0.14 mmol) and pyridine boronic acid (20 mg, 0.16 mmol) in 10:1 DMF/water (1 mL) was added K2CO3 (36 mg, 0.26 mmol) and tetrakistriphenylphosphine palladium (7.5 mg, 0.007 mmol). The mixture was heated to 120°C under microwave irradiation for 20 min. Ethyl acetate (20 mL) was added and the solution was washed with water (2 x 5 mL) and brine (5 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (3:1 EtO Ac/Hex) to give the title compound as a pale yellow solid (31 mg, 62%). MS ESI [M + H]+, calcd for [C19H23N3O2Si +H]+ 354.2; found m/z 354.2.
C. 3-((4-(pyridin-4-yl)-lH-indazol-6-yl)methylene)indolin-2-one To a solution of oxindole ( 12 mg, 0.08 mmol) and 4-(pyridin-4-yl)- 1 -((2-
(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (31 mg, 0.087 mmol) in ethanol (2 mL) was added pyrrolidine (20 μL). The mixture was heated to 7O0C for 3 h. The solution was concentrated to dryness and treated with 4M HCl (1 mL) in ethanol (3 mL) at 7O0C for 4 h. The solution was cooled to rt and extracted with ethyl acetate (50 mL), dried over MgSO4 and concentrated to give the title compound as a mixture of E/Z isomers which were separated by preparatory HPLC. (E-isomer 5.4 mg, 18%, HPLC retention time, 6.6 min). ' H NMR (400
MHz, CD3OD) δ 8.94-8.91(m, 2H), 8.44 (s, IH), 8.39 (d, 2H, J = 6.4 Hz), 8.16 (s, IH), 7.93 (s, IH), 7.86 (s, IH), 7.59 (d, IH, J = 7.9 Hz), 7.26 (t, IH, J = 7.8 Hz ), 6.95 (d, IH, 7.7 Hz), 6.86 (t, IH, J = 7.8 Hz); MS ESI [M + H]+, calcd for [C21Hi4N4O +H]+ 339.1; found m/z 339.1. (Z-isomer, 3.3 mg, 12%, HPLC retention time, 7.2 min) 1H NMR (400
MHz, CD3OD) δ 8.92 (d, 2H, J = 5.6 Hz), 8.76 (s, IH), 8.73 (s, IH), 8.48 (d, 2H, J =
6.7 Hz), 8.43 (s, IH), 7.99 (s, IH), 7.71 (d, IH, J = 7.8 Hz), 7.28 (t, IH, J = 7.5 Hz),
7.08 (t, IH, J = 7.9 Hz), 6.90 (d, IH, J = 7.9 Hz); MS ESI [M + H]+, calcd for [C21H14N4O +H]+ 339.1; found m/z 339.1.
Example A55. (E and ZV3-((4-((EV2-(Dyridin-4-vnvinylVlH-indazol-6- vDmethylene)indolin-2-one
Figure imgf000132_0001
A. (E)-4-(2-(pyridin-4-yl)vinyl)-l-((2-(trimethyhilyl)ethoxy)methyl)-lH- indazole-6-carbaldehyde
A solution of 4-(pyridine-4-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- indazole-6-carbaldehyde (50 mg, 0.14 mmol) and 4-pyridylethylene (20 μL, 0.19 mmol) in acetonitrile (1.5 mL) was purged with argon. Palladium acetate (2 mg, 0.007 mmol), tri-o-tolylphosphine (4 mg, 0.014 mmol) and DIPEA (50 μL) was added and the mixture was heated to 7O0C for 16 h. Ethyl acetate (50 mL) was added and the mixture was washed with water (2 x 5 mL), brine (5 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (98:2 EtOAc/MeOH) to give the title compound as a yellow solid (28 mg, 53%). MS ESI [M + H]+, calcd for [C21H25N3O2Si +H]+ 380.2; found m/z 380.2.
B. (E and Z)-3-((4-((E)-2-(pyridin-4-yl)vinyl)-lH-indazol-6-yl)methylene)- indolin-2-one According to the method of A54C, oxindole (10 mg, 0.07 mmol) was reacted with (E)-4-(2-(pyridin-4-yl)vinyl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazole-6- carb-aldehyde (27 mg, 0.06 mmol) and then treated with HCl to give the title compound as a 3:1 mixture of E/Z isomers (4 mg, 28%). MS ESI [M + H]+, calcd for [C23HJ6N4O +H]+ 365.1; found m/z 365.2. E-isomer 1H NMR (400 MHz, DMSO-(I6) δ 8.82-8.79 (m, 2H), 8.20-8.12 (m, 3H), 7.96 (s, IH), 7.81-7.74 (m, 3H), 7.64 (s, IH), 7.52 (d, IH, J = 8.1 Hz), 7.23 (t, IH, J = 7.8 Hz), 6.89 (d, IH, J = 8.0 Hz), 6.88-6.86 (m, IH); Z-isomer 1H NMR (400 MHz, DMSO-(I6) δ 8.97 (s, IH), 8.67 (s, IH), 8.60-8.58 (m, 2H), 8.27 (s, IH), 8.01 (s, IH), 7.91 (d, IH, J = 16.8 Hz), 7.77 (d, IH, J = 7.5 Hz), 7.74 (d, 2H, J = 5.5 Hz), 7.49 (d, IH, J = 16 Hz), 7.23 (t, IH, J = 7.8 Hz), 7.02 (t, IH, J = 7.6 Hz), 6.86 (d, IH, J = 7.6 Hz).
Example A56. (E)-3-((l H-indazol-6-yl)methylene)-7-aminoindolin-2-one
Figure imgf000133_0001
A 13 mg (0.0877 mmol) solution of 7-aminooxindole (T. Nakashima & I. Suzuki, Chem. Pharm. Bull. (1969) 11, 2293) and lH-indazole-6-carbaldehyde (14 mg, 0.0965 mmol) in MeOH (1.0 mL) was treated with piperidine (~1 uL, 0.00877 mmol) and the reaction was heated to 60 0C for 4 hours. The MeOH was then removed in vacuo and the residue treated with 95:5 CH2Cl2/Me0H. The resulting precipitate was filtered and washed with 95:5 CH2Cl2MeOH to obtain the title compound as a orange powder (6.7 mg, 28 %). 1H NMR (400 MHz, CD3OD) δ 8.14 (s, IH), 7.94-7.87 (m, 3H), 7.46 (d, J = 8.19 Hz, IH), 7.31 (d, J = 7.63 Hz, IH), 6.90 (d, J = 7.89 Hz, IH), 6.81 (t, J = 7.79 Hz, IH); MS ESI 277.0 [M + H]+, calcd for [C16H12N4O + H]+ 277.11.
Example A57. (E)-3-f(3-((E)-2-(pyridin-4-yl')vinvn-lH-indazol-6-vnmethyleneV indolin-2-one
Figure imgf000134_0001
A. (E)-3-(2-φyridin-4-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazole-6-carbaldehyde
A solution of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (2.0 g, 4.98 mmol), 4-vinylpyridine (0.69 mL, 6.47 mmol), diisopropylethylamine (1.74 mL, 9.96 mmol) and DMF (50 mL) was purged with Ar gas for 20 min at which time Pd(OAc)2 (112 mg, 0.500 mmol) and P(o-tol)3 (457 mg, 1.50 mmol) were added and the reaction heated to 100 0C for 20 hours. The reaction was cooled to room temperature and partitioned between EtOAc and NH4Cl. The aqueous layer was extracted with EtOAc (3X) and the combined organics washed with water (2X) and brine (2X). The organic layer was dried over
MgSO4 and the EtOAc removed in vacuo. The residue was purified by column chromatography (silica gel, 97:3 CH2Cl2 / MeOH) to give 927 mg, 49 % of the title compound which was used without further purification. MS ESI 380.2 [M + H]+, calcd for [C21H25N3O2Si +H]+ 380.18.
B. (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-l-((2-(trimet}ψlsilyl)ethoxy)methyl^ lH-indazol-6-yl)methylene)indolin-2-one
To a solution of (E)-3-(2-(pyridin-4-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indazole-6-carbaldehyde (927 mg, 2.44 mmol), oxindole (325 mg, 2.44 mmol) and MeOH (20 mL) was added piperidine (24 uL, 0.244 mmol) and the reaction heated to 60 0C for 4 hours. A yellow precipitate crashed out of the reaction medium which was filtered and washed with MeOH to give the title compound (960 mg, 79 %) as a yellow solid. MS ESI 495.3 [M + H]+, calcd for [C29H30N4O2Si +H]+ 495.22.
C. β)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-lH-indazol-6-yl)methylene)-indolin- 2-one
A dry-round bottom was charged with (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-l-((2- (trimethylsilyl)ethoxy)methyl)- 1 H-indazol-6-yl)methylene)indolin-2-one (906 mg, 1.83 mmol), and CH2Cl2 (100 mL) under an atmosphere of N2. Boron trifluoride etherate (2.3 mL, 18.3 mmol) was added dropwise and the reaction was stirred for 4 hours at which time LC-MS indicated complete conversion to the partially de- protected material (E)-3-((l-(hydroxymethyl)-3-((E)-2-(pyridin-4-yl)vinyl)-lH- indazol-6-yl)methylene)-indolin-2-one. The CH2Cl2 was removed in vacuo, and then 150 mL of a 2:1 mixture of EtOH / 2M HCl was added and the reaction heated to 50 0C for 3 hours at which time LC-MS indicated complete conversion to the title compound. The reaction was cooled with an ice-bath and neutralized with NH4OH to pH~8, the EtOH was removed and the suspension filtered washing with water. The dried solid was collected and then titurated and filtered several times with 90:10 CH2Cl2 / MeOH which gave, after drying, the title compound (353 mg, 53 %) as an orange solid. 1H NMR (400 MHz, d6-DMSO) δ 13.57 (s, IH), 10.64 (s, IH), 8.57 (d, J = 5.16 Hz, 2H), 8.38 (d, J = 8.13 Hz, IH), 7.92 (s, IH), 7.87 (d, J = 16.7 Hz, IH), 7.80 (s, IH), 7.71 (d, J = 5.16 Hz, 2H), 7.62-7.53 (m, 3H), 7.23 (t, J = 8.29 Hz, IH), 6.91-6.82 (m, 2H); MS ESI 365.1 [M + H]+, calcd for [C23H16N4O+ H]+ 365.14.
Example A58. (E)-3-((E*)-(3-styryl-lH-indazol-6-vnmethylene)indolin-2-one
Figure imgf000135_0001
A. (E)-3-styryl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde
A solution of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (100 mg, 0.249 mmol), styrene (37 uL, 0.324 mmol), diisopropylethylamine (87 uL, 0.324 mmol) and DMF (2.5 mL) was purged with Ar gas for 20 min at which time Pd(OAc)2 (2.8 mg, 0.0125 mmol) and P(o-tol)3 (11 mg, 0.0374 mmol) were added and the reaction heated to 100 0C for 20 hours. The reaction was cooled to room temperature and partitioned between EtOAc and NH4Cl. The aqueous layer was extracted 3X with EtOAc and the combined organics washed with water (2X) and brine (2X). The organic layer was dried over MgSO4 and the EtOAc removed in vacuo. The residue was purified by column chromatography (silica gel, 5:1 hexanes / EtOAc) to give the title compound (63 mg, 67 %) which was used without further purification. MS ESI 379.2 [M + H]+, calcd for [C22H26N2O2Si +H]+ 379.18.
B. (E)-3-styryl-lH-indazole-6-carbaldehyde
A solution of (E)-3-styryl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (63 mg, 0.166 mmol) in THF (2.0 mL) was treated with TBAF (0.83 mL of a IM solution in THF) and refluxed overnight. The solvent was removed and the residue re-dissolved into EtOAc. The organics were washed with water (2X), brine (2X) and then dried (MgSO4). The solvent was removed and the residue purified by column chromatography (silica gel, 98:2 CH2Cl2ZMeOH) to give the title compound (27 mg, 66 %) which was used without further purification. MS ESI 249.0 [M + H]+, calcd for [Ci6H12N2O +H]+ 249.10. C. (E)-3-((E)-(3-styryl-lH-indazol-6-yl)methylene)indolin-2-one
A solution of (E)-3-styryl-lH-indazole-6-carbaldehyde (27 mg, 0.109 mmol) and oxindole (15 mg, 0.109 mmol) in MeOH (1.0 mL) was treated with piperidine (1 uL. 0.011 mmol) and the reaction stirred at 60 0C for 4 hours. The MeOH was removed and the residue purified by prep-HPLC to give 4.7 mg, 12 % of a yellow powder. 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J = 8.38 Hz, 2H), 7.91-7.86 (m, 2H), 7.71- 7.64 (m, 3H), 7.60-7.49 (m, 2H), 7.42 (t, J = 7.41 Hz, 2H), 7.31 (t, J = 7.49 Hz, IH), 7.26 (t, J = 7.89 Hz, IH), 6.94 (d, J = 7.75 Hz, IH), 6.89 (t, J = 6.86 Hz, IH); MS ESI 364.2 [M + H]+, calcd for [C24HnN3O + H]+ 364.14.
Example A59. (E and Z)-3-((3-((E)-2-methoχystyrylVlH-indazol-6-vnmethyleneV indolin-2-one
Figure imgf000137_0001
The synthetic method followed of that described in Example A58 starting from 2- methoxystyrene (43 uL, 0.324 mmol) and 3-iodo-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (100 mg, 0.249 mmol). Obtained 4.6 mg (4.7 % yield over 3 steps) of a yellow powder after prep-HPLC purification. Was isolated as a 75:25 mixture of (E)I(Z) isomers. 1H NMR (400
MHz, CD3OD) δ 8.91, 7.89 (s, IH), 8.19, 8.09 (d, J = 7.43 Hz, IH), 7.95-7.85 (m,
2H), 7.71-7.67 (m, 2H), 7.58-7.46 (m, 2H), 7.33-7.23 (m, 2H), 7.09-6.98 (m, 2H),
6.96-6.87 (m, 2H), 3.97 (s, 3H); MS ESI 394.2 [M + H]+, calcd for [C25H19N3O2 + H]+ 394.16.
Example A60. fEV3-((3-((EV2-chlorostyryl)-lH-indazol-6-yl)methyleneMndolin-2- one
Figure imgf000137_0002
According to the method described in Example A58 2-chlorostyrene (42 uL, 0.324 mmol) and 3 -iodo- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazole-6-carbaldehyde (100 mg, 0.249 mmol) were reacted to obtain, after prep-HPLC purification, the title compound (2.0 mg, 2.0 %) as a yellow powder. 1H NMR (400 MHz, CD3OD) δ 8.20 (d, J = 8.51, IH), 7.99-7.88 (m, 4H), 7.68 (d, J = 7.32 Hz, IH), 7.60-7.46 (m, 3H), 7.39 (t, J = 7.68 Hz, IH), 7.33-7.23 (m, 2H), 6.94 (d, J = 8.02 Hz, IH), 6.90 (t, J = 7.77 Hz, IH); MS ESI 398.2 [M + H]+, calcd for [C24H16ClN3O + H]+ 398.11. Example A61. (EVmethyl 3-(6-(TE)-(2-oxoindolin-3-ylidene')methvD-lH-indazol-3- vDacrvlate
Figure imgf000138_0001
The synthetic method followed that described in Example A58, starting from methylacrylate (41 uL, 0.457 mmol) and 3-iodo-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (153 mg, 0.381 mmol).
In the final step a yellow solid precipitated from the reaction medium which was filtered and washed with MeOH to give the title compound (3.8 mg, 2.9 %). 1H
NMR (400 MHz, d6-DMSO) δ 13.87 (s, IH), 10.65 (s, IH), 8.25 (d, J = 8.74 Hz, IH), 7.95 (s, IH), 7.93 (d, J = 16.7 Hz, IH), 7.78 (s, IH), 7.57-7.54 (m, 2H), 7.24 (t,
J = 7.28 Hz, IH), 6.90-6.80 (m, 3H), 3.77 (s, 3H); MS ESI 346.2 [M + H]+, calcd for
[C20Hi5N3O3 + H]+ 346.12.
Example A62 (Ey5-bromo-3-(G-((E)-2-(pyridin-4-ylWinylVlH-indazol-6-vn- methylene)indolin-2-one
Figure imgf000138_0002
A. (E)-5-bromo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-l-((2-
(trimethylsilyl)ethoxy)-methyl)-lH4ndazol-6-yl)methylerιe)indolin-2-one The title compound was prepared from 5-bromooxindole (36 mg, 0.171 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (65 mg, 0.171 mmol) as described in Example A57 part B to give, after silica gel column chromatography (Eluent: 98:2 CH2Cl2ZMeOH) the title compound as a yellow oil (75 mg, 77 %). MS ESI 573.4 [M + H]+, calcd for [C29H29BrN4O2Si + H]+ 573.13.
B. (E)-5-bromo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-lH-indazol-6- yl)methylene)-indolin-2-one A solution of (E)-5-bromo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-l-((2-(trimethylsilyl)- ethoxy)methyl)-lH-indazol-6-yl)methylene)indolin-2-one (75 mg, 0.131 mmol) in 12 mL of a 2:1:1 mixture of MeOH / EtOH / 4M HCl was heated to 80 0C for 24 hours. LC-MS indicated a mixture of the title compound plus a partially deprotected methoxymethyl indazole compound (see Example A63). The solvents were removed and the mixture was purified by prep-HPLC to give 7.3 mg (13 %) of the title compound as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.87 (s, IH), 10.82 (s, IH), 8.76 (d, J = 5.78 Hz, 2H), 8.45 (d, J = 8.00 Hz, IH), 8.23-8.13 (m, 3H), 8.04 (s, IH), 7.96 (s, IH), 7.73 (d, J = 16.6 Hz, IH), 7.64 (s, IH), 7.60 (d, J = 7.81 Hz, IH), 7.43 (d, J = 7.31 Hz, IH), 6.87 (d, J = 8.11 Hz, IH); MS ESI 443.3 [M + H]+, calcd for [C23H15BrN4O+ H]+ 443.05.
Example A63. (E^-S-bromo^-fd-fmethoxymethylVS-^EVΣ-φyridin^-vπvinvπ- lH-indazol-6-yl)methylene)indolin-2-one
Figure imgf000139_0001
The title compound (4.0 mg, 7.0 % of a yellow powder) was isolated by prep-HPLC as a bi-product from the final deprotection step in Example A62. 1H NMR (400 MHz, d6-DMSO) δ 10.84 (s, IH), 8.75 (d, J = 4.81 Hz, 2H), 8.48 (d, J = 8.54 Hz, IH), 8.24 (s, IH), 8.18-8.10 (m, 3H), 7.88 (s, IH), 7.75 (d, J = 16.8 Hz, IH), 7.67- 7.61 (m, 2H), 7.43 (d, J = 7.53 Hz, IH), 6.87 (d, J = 8.28 Hz, IH), 5.83 (s, 2H), 3.33 (s, 3H); MS ESI 487.3 [M + H]+, calcd for [C25Hi9BrN4O2 + H]+ 487.08.
Example A64. (E and Zy3-((3-(2-(pyridin-4-v0ethylHH-mdazol-6-vπmethylene')- indolin-2-one
Figure imgf000140_0001
A. 4-(2-(pyridin-4-yl)ethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole- 6-carbaldehyde
A solution of (E)-3 -(2-(pyridin-4-yl)viny I)-I -((2-(trimethylsilyl)ethoxy)methyl)- IH- indazole-6-carbaldehyde (see Example A2 for preparation) (58 mg, 0.153 mmol) in
EtOAc (5.0 mL) was purged with Ar gas for 10 min at which time 6 mg of 10 %
Pd/C (Degussa type) was added. The reaction was then purged briefly with H2 <g) and then stirred under an atmosphere of H2 (g) for 5 hours. The reaction was then filtered through a pad of celite, washed with EtOAc, and the solvent removed to give the title compound (54 mg, 93 %) as a yellow oil. MS ESI 382.2 [M + H]+, calcd for
[C21H27N3O2Si + H]+ 382.20.
B. 3-((3-(2-φyridin-4-yl)ethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazol-6-yl)-methylene)indolin-2-one
A solution of 3-(2-(pyridin-4-yl)ethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazole-6-carbaldehyde (54 mg, 0.142 mmol), oxindole (19 mg, 0.142 mmol) in
MeOH (2.0 mL) was treated with piperidine (1.5 uL, 0.0142 mmol) and the reaction heated to 60 0C and stirred for 4 hours at which time the solvent was removed and the residue purified by column chromatography (silica gel, 96:4 CH2Cl2ZMeOH) to give the title compound (57 mg, 80 %) as a yellow film. MS ESI 497.2 [M + H]+, calcd for [C29H32N4O2Si + H]+ 497.24.
C. (E and Z)-3-((3-(2-(pyridin-4-yl)ethyl)-lH-indazol-6- yl)methylene)indolin-2-one
A solution of 3-((3-(2-(pyridin-4-yl)ethyl)-l-((2-(trimethylsilyl)ethoxy)-methyl)-lH- indazol-6-yl)methylene)indolin-2-one (57 mg, 0.115 mmol) in THF (3 mL) was treated with TBAF (0.58 mL of a 1.0 M solution in THF) and the reaction heated at reflux for 20 hours. The solvent was removed and the residue re-dissolved into EtOAc. The organics were washed with water (2X), brine (2X) and then dried (MgSO4). The solvent was removed and the residue purified by column chromatography (silica gel, 93:7 CH2Cl2/Me0H) to give a yellow solid which was impure by LC-MS. The mixture was further purified by prep-HPLC to give 11.3 mg, 27 % of the title compound as a 76:24 mixture of (E)Z(Z) geometric isomers. 1H NMR (400 MHz, CD3OD) δ 8.79, 7.87 (s, IH), 8.69, 8.66 (d, J = 6.52 Hz, 2H), 7.98- 7.73 (m, 4H), 7.74, 7.62 (d, J = 8.36 Hz, IH), 7.66, 7.44 (d, J = 8.44 Hz, IH), 7.25, 7.05 (t, J = 7.79 Hz, IH), 6.95-6.84 (m, 2H), 3.53, 3.51 (s, 4H); MS ESI 367.2 [M + H]+, calcd for [C23H18N4O+ H]+ 367.16.
Example A65. (E & ZV3-((3-((EV4-(trifluoromethvnstyrvn-lH-indazol-6-vn- methyleneVindolin-2-one
A. fi)-3-((3-(4-(trifluoromethyl)styryl)-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indazol-6-yl)methylene)indolin-2-one
The synthetic method followed that described in Example A57, parts A and B starting from 4-trifluoromethylstyrene (48 uL, 0.324 mmol) and 3-iodo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (100 mg, 0.249 mmol) to obtain the title compound (49 mg, 35 %). MS ESI 562.2 [M + H]+, calcd for [C3IH30F3N3O2Si + H]+ 562.21.
B. (E and Z)-3-((3-((E)-4-(trifluoromethyl)styryl)-lH-indazol-6-yl)- methylene)-indolin-2-one
The synthetic method followed that described in Example A64, part C starting from (E)-3 -((3-(4-(trifluoromethyl)styryl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- indazol-6-yl)methylene)indolin-2-one (49 mg, 0.087 mmol). Following prep-HPLC purification, the title compound was obtained of a yellow powder (4.5 mg, 12 %) which consisted of a 72:28 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) δ 8.92, 7.89 (two s, IH), 8.27, 8.16 (two d, J = 8.45 Hz, IH), 7.98-7.83 (m, 3H), 7.70-7.56 (m, 5H), 7.26, 7.06 (two t, J = 8.24 Hz, IH), 7.64 (s, IH), 6.95-6.86 (m, 2H); MS ESI 432.2 [M + H]+, calcd for [C25H16F3N3O + H]+ 432.13. Example A66. (E and Z)-3-((3-((E)-3-(4-methylpiperazin-l-vD-3-oxoprop-l-enyl)- lH-indazol-6-yr)methylene)indolin-2-one
Figure imgf000142_0001
A. l-(4-methylpiperazin-l-yl)prop-2-en-l-one
A dry round-bottom flask was charged with 1-methylpiperazine (0.15 mL, 1.36 mmol), diisopropylethylamine (0.65 mL, 3.72 mmol) and CH2Cl2 (6 mL) and then the solution was cooled with an ice-water bath. Acryloyl chloride (0.10 mL, 1.24 mmol) was then added dropwise and the reaction was allowed to warm to room temperature. After 3 hours TLC indicated reaction completion. The CH2Cl2 was removed and the residue taken up in EtOAc, washed with NaHCO3 (sat ) (IX), brine (2X) and then dried over MgSO4. The EtOAc was removed in vacuo which yielded after drying, the title compound as an orange-brown oil. (400 MHz, CDCl3) 6.57 (dd, J1 = 16.8 Hz, J2 = 10.5 Hz, IH), 6.29 (d, J = 16.8 Hz, IH), 5.70 (d, J = 10.5 Hz, IH), 3.73 (bs, 2H), 3.60 (bs, 2H), 2.46-2.41 (m, 4H), 2.34 (s, 3H); MS ESI 155.0 [M + H]+, calcd for [C8H14N2O+ H]+
B. (E and Z)-3-((3-((E)-3-(4-methylpiperazin-l-yl)-3-oxoprop-l-enyl)-lH- indazol-6-yl)methylene)indolin-2-one The synthetic method followed of that described in Example A2 with a modified purification. A yellow oil was obtained which was titurated and sonicated with 1 :5 Et2O/hexanes which after decanting off the solvent gave 4.7 mg (8.5 % yield over 3 steps) of an orange-yellow powder as a 73:27 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) δ 8.93, 7.97 (s, IH), 8.17, 8.06 (d, J = 8.33 Hz, IH), 7.98-7.87 (m, 2H), 7.69-7.58 (m, 2H), 7.46, 7.42 (d, J = 15.5 Hz, IH), 7.25 (t, J = 7.77 Hz, IH), 7.07-6.85 (m, 2H), 3.95-3.78 (m, 4H), 2.68-2.55 (bs, 4H), 2.41 (s, 3H); MS ESI 414.2 [M + H]+, calcd for [C24H23N5O2 + H]+ 414.19. Example A67: fEV3-((lH-indazol-6-vnmethyleneVlH-Dyrrolor23-b1pyridin-2(3H)- one
Figure imgf000143_0001
To a mixture of lH-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and lH-indazole-6-carbaldehyde (29.2 mg, 0.2 mmol) in MeOH (2 mL) was added 1 drop of piperidine via syringe needle. The resulting mixture was refluxed for 2 h (oil temp. 70 0C) and then cooled to rt. The resulting precipitate was collected by suction filtration to give the title compound as a yellow solid (37 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, IH, NH), 11.25 (s, IH, NH), 8.16 (s, IH), 8.10 (d, J = 5.2 Hz, IH), 7.93-7.87 (m, 4H), 7.44 (d, J = 8.8 Hz, IH), 6.90 (dd, J = 7.6 Hz, 5.6 Hz, IH); MS ESI 263.0 [M + H]+, calcd for [C15H10N4O + H]+ 263.1.
Example A68: (EV3-((lH-indazol-5-vnmethyleneVlH-pyrrolor2.3-blρyridin-2f3HV one
Figure imgf000143_0002
The title compound (50mg, 95 %) was synthesized as an orange solid according to the method described for Example A67 using lH-pyrrolo[2,3- b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and lH-indazole-5-carbaldehyde (29.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, IH, NH), 11.20 (s, IH, NH), 8.21 (s, 2H), 8.09 (d, J = 5.2 Hz, IH), 7.94 (d, J = 8.0 Hz, IH), 7.89 (s, IH), 7.72 (d, J = 8.8 Hz, IH), 7.68 (d, J = 8.4 Hz, IH), 6.91 (dd, J = 8.0 Hz, 5.6 Hz, IH); MS ESI 263.0 [M + H]+, calcd for [C15Hi0N4O + H]+ 263.1.
Example A69: (E and ZV3-((lH-indazol-6-vπmethyleneV5-bromo-lH-pyrrolor2.3- blpyridin-2(3HVone
Figure imgf000144_0001
The title compound (50mg, 95 %) was synthesized as a green solid according to the method described for Example A67 using 5-bromo-lH-pyrrolo[2,3-b]pyridin-
2(3H)-one (21.3 mg, 0.1 mmol) and lH-indazole-6-carbaldehyde (14.6 mg, 0.1 mmol). 1H NMR indicated 56:44 mixture of E/Z isomers. E isomer: 1H NMR (400
MHz, DMSO-d6) δ 13.38 (s, IH, NH), 11.45 (s, IH, NH), 8.38 (d, J = 2.0 Hz, IH),
8.25 (d, J = 2.0 Hz, IH), 8.19 (s, IH), 8.01 (s, IH), 7.93 (s, IH), 7.90 (d, J = 2.0 Hz,
IH), 7.45 (dd, J = 8.4 Hz, 2.0 Hz, IH); Z isomer: δ 13.46 (s, IH, NH), 11.45 (s, IH,
NH), 8.94 (s, IH), 8.21 (d, J = 2.0 Hz, IH), 8.19 (s, IH), 8.15 (s, IH), 7.99 (dd, J = 8.8 Hz, 1.6 Hz, IH), 7.94 (d, J = 8.4 Hz, IH), 7.85 (d, J = 8.0 Hz, IH); MS ESI
341.0 [M + H]+, calcd for [C15H9BrN4O + H]+ 341.1.
Example A70: fEV3-(6-((EV(2-oxoindolin-3-ylidene)methylVlH-indazol-3- vDacrylic acid
Figure imgf000144_0002
a) (E)-3-(6-cyano-lH-indazol-3-yl)acrylic acid
To a mixture of S-formyl-lH-indazole-ό-carbonitrile (34 mg, 0.2 mmol) and malic acid (104 mg, 1 mmol) in pyridine (3 mL) was added 2 drops of piperidine. The resulting mixture was refluxed for 1 h (oil temp. 130 0C) before cooling to 0 0C. the reaction was quenched with ice, followed by 2M HCl (30 mL). The resulting mixture was extracted with EtOAc (30 mL + 15 mL). The combined extracts were washed with 2 M HCl and dried (Na2SO4). Evaporation of the solvents gave the title compound (29 mg, 68%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 14.13 (s, IH, NH), 12.55 (brs, IH, CO2H), 8.31 (d, J = 8.0 Hz, IH), 8.24 (s, IH), 7.86 (d, J = 16.4 Hz, IH), 7.56 (d, J = 8.0 Hz, IH), 6.75 (d, J = 16.4 Hz, IH); MS ESI 214.0 [M + H]+, calcd for [C11H8N2O3 + H]+ 214.1. b) (E)-3-(6-formyl-lH-indazol-3-yl)acrylic acid
To a solution of (E)-3-(6-cyano-lH-indazol-3-yl)acrylic acid (25 mg, 0.12 mmol) in acetic acid/pyridine (2 mL/4 mL) was added a solution of sodium hypophophite (42 mg, 0.48 mmol) in H2O (2 mL), followed by Raney-Nickel 2400 (slurry in H2O, 0.1 mL). The resulting mixture was heated at 55 0C (oil temp.) for 1 h before cooling to rt. H2O (20 mL) was added and the mixture was extracted with EtOAc (30 mL x 2). The combined extracts were washed with 2M HCl (10 mL x 2), H2O (10 mL x 2), brine (10 mL) and dried (Na2SO4). Removal of the solvent gave the title compound (18 mg, 72%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 14.12 (s, IH, NH), 12.24 (brs, IH, CO2H), 10.01 (s, IH, CHO), 8.26 (d, J = 8.8 Hz, IH), 8.22 (s, IH), 7.87 (d, J = 16.0 Hz, IH), 7.71 (d, J = 8.8 Hz, IH), 6.76 (d, J = 16.4 Hz, IH); MS ESI 217.0 [M + H]+, calcd for [CnH8N2O3 + H]+ 217.1. c) (E)-3-(6-((E)-(2-oxoindolin-3-ylidene)methyl)-lH-indazol-3-yl)acrylic acid
The title compound (7 mg, 21 %) was synthesized as an orange solid according to the method described for Example A67 using oxindole (13.3 mg, 0.1 mmol) and (E)-3-(6-formyl-lH-indazol-3-yl)acrylic acid (21.6 mg, 0.1 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (br. s, IH, NH), 10.64 (s, IH, CO2H), 8.20 (d, J = 8.4 Hz, IH), 7.94 (s, IH), 7.85 (d, J = 16.4 Hz, IH), 7.78 (s, IH), 7.58-7.53 (m, 2H), 7.24 (t, J = 7.6 Hz, IH), 6.88 (d, J = 8.0 Hz, IH), 6.84 (t, J = 7.8 Hz, IH), 6.75 (d, J = 16.0 Hz, IH); MS ESI 332.1 [M + H]+, calcd for [Ci9H13N3O3 + H]+ 332.1.
Example A71: (E)-3-(6-(fE & ZVf2-oxo-lH-pyrrolor2.3-blpyridin-3(2H)-ylidene)- methyl)- 1 H-indazol-3 -vDacrylic acid
Figure imgf000145_0001
The title compound (13 mg, 39 %) was synthesized as an orange solid according to the method described for Example A67 using lH-pyrrolo[2,3- b]pyridin-2(3H)-one (13.4 mg, 0.1 mmol) and (E)-3-(6-formyl-lH-indazol-3- yl)acrylic acid (21.6 mg, OΛ mmol). The 1H NMR indicated a 5:2 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 11.25 (br. s, IH), 8.21 (d, J = 8.4 Hz, IH), 8.12-8.07 (m, 2H), 7.6 (s, IH), 7.93 (s, IH), 7.82 (d, J = 16.0 Hz, IH), 7.55 (d, J = 8.4 Hz, IH), 6.90 (dd, J = 8.4 Hz, 3.2 Hz, IH), 6.75 (d, J = 16.0 Hz, IH); MS ESI 332.1 [M + H]+, calcd for [Ci8Hi2N4O3 + H]+ 332.1.
Example A72: fEV3-f(3-((EV2-fpyridin-2-yl)vinvn-lH-indazol-6-vnmethylene)- lH-Dyrrolo[23-blpyridin-2(3H)-one
Figure imgf000146_0001
The title compound (7 mg, 21 %) was synthesized as yellow solid according to the method described for Example A67 using lH-pyrrolo[2,3-b]pyridin-2(3H)- one (9.3 mg, 0.07 mmol) and (E)-3-(2-(pyridin-2-yl)vinyl)-lH-indazole-6- carbaldehyde (17 mg, 0.068 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.53 (s, IH,
NH), 11.27 (s, IH, NH), 8.62 (d, J = 4.0 Hz, IH), 8.35 (d, J = 8.4 Hz, IH), 8.12 (d, J
= 5.2 Hz, IH), 8.02-7.89 (m, 4H), 7.82 (t, J = 8.0 Hz, IH), 7.69 (d, J = 7.6 Hz, IH),
7.63 (d, J = 16.8 Hz, IH), 7.56 (d, J = 8.4 Hz, IH), 7.28 (t, J = 6.0 Hz, IH), 6.91 (dd, J = 7.6 Hz, 5.6 Hz, IH); MS ESI 366.1 [M + H]+, calcd for [C22Hi5N5O + H]+ 366.1.
Example A73: (E and Z)-3-(lH-indazol-6-yliminon'ndolin-2-one
Figure imgf000146_0002
To a mixture of isatin (147 mg, 1 mmol) and 6-aminoindazole (133 mg, 1 mmol) in EtOH (5 mL) was added 2 drops of acetic acid. The resulting mixture was capped and microwaved 60 min at 120 0C. After cooling to it, the precipitate was collected by suction filtration to give 135 mg (48%) of title compound as yellow solid. 1H NMR indicated a 85:15 mixture of E/Z isomers. 1H NMR (400 MHz,
DMSO-d6) δ 13.04 (s, IH, NH), 11.00 (s, IH, NH), 8.09 (s, IH), 8.36 (d, J = 8.4 Hz,
IH), 7.32 (t, J = 8.0 Hz, IH), 7.07 (s, IH), 6.89 (t, J = 8.0 Hz, IH), 7.77 (d, J = 8.4
Hz, IH), 6.66 (t, J = 7.6 Hz, IH), 6.32 (d, J = 7.6 Hz, IH); MS ESI 263.0 [M + H]+, calcd for [C15H10N4O + H]+ 263.1.
Example A74: (E and ZV3-(lH-indazol-6-ylimino)-5-methylindolin-2-one
Figure imgf000147_0001
To a mixture of 5-methylisatin (80.5 mg, 0.5 mmol) and 6-aminoindazole (66.5 mg, 0.5 mmol) in EtOH (2 mL) was added 1 drops of acetic acid. The resulting mixture was capped and microwaved 30 min at 120 0C. After cooling to rt, it was stirred for 5 min at rt and the resulting precipitate was collected by suction filtration to give the title compound (35 mg, 28 %) as an orange red solid. 1H NMR indicated a 80:20 mixture of E/Z isomers. 1U NMR (400 MHz, DMSO-d6) δ 13.03 (s, IH, NH), 10.89 (s, IH, NH), 8.10 (s, IH), 7.84 (d, J = 8.8 Hz, IH), 7.15 (d, J = 7.2 Hz, IH), 7.07 (s, IH), 6.81-6.74 (m, 2H), 6.17 (s, IH), 2.49 (s, 3H, CH3); MS ESI 277.0 [M + H]+, calcd for [C16Hi2N4O + H]+ 277.1.
Example A75: (E and Z)-3-(lH-indazol-6-yliminoV5-fluoroindolin-2-one
Figure imgf000147_0002
The title compound (76mg, 54 %) was synthesized as a dark red solid according to the method described for Example A74 using 5-fluoroisatin (82.5 mg, 0.5 mmol) and 6-aminoindazole (66.5 mg, 0.5 mmol). 1H NMR analysis indicated a 79:21 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, IH, NH), 11.03 (s, IH, NH), 8.11 (s, IH), 7.87 (d, J = 8.4 Hz, IH), 7.22 (dt, J = 9.2 Hz, 2.8 Hz, IH), 6.90 (dd, J = 8.4 Hz, 4.4 Hz, IH), 6.82-6.77 (m, IH), 5.98 (dd, J = 8.0 Hz, 2.0 Hz, IH); MS ESI 281.0 [M + H]+, calcd for [C15H9FN4O + H]+ 281.1.
Example A76: (E and Z)-3-(lH-indazol-6-yliminoV6-bromoindolin-2-one
Figure imgf000148_0001
The title compound (82 mg, 48 %) was synthesized as a orange red solid according to the method described for Example A74 using 6-bromoisatin (113 mg, 0.5 mmol), 6-aminoindazole (73 mg, 0.55 mmol). 1H NMR indicated a 83:17 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, IH, NH), 10.93 (brs, IH, NH), 8.09 (s, IH), 7.84 (d, J = 8.4 Hz, IH), 7.08 (s, IH), 7.05 (d, J = 1.6 Hz, IH), 6.92 (dd, J = 8.0 Hz, 1.6 Hz, IH), 6.77 (dd, J = 8.4 Hz, 1.2 Hz, IH), 6.27 (d, J = 8.0 Hz, IH); MS ESI 341.1 [M + H]+, calcd for [C15H9BrN4O + H]+ 341.1.
Example A77: (E and Z)-3-(lH-indazol-5-yliminoMndolin-2-one
Figure imgf000148_0002
The title compound (165 mg, 63 %) was synthesized as a yellow solid according to the method described for Example A74 using isatin (147 mg, 1 mmol), 5-aminoindazole (133 mg, 1 mmol) and 2 drops of HOAc. 1H NMR indicated a 5:1 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, IH, NH), 11.00 (s, IH, NH), 8.07 (s, IH), 7.64 (d, J = 8.8 Hz, IH), 7.35 (s, IH), 7.31 (t, J = 7.6 Hz, IH), 7.07 (dd, J = 9.2 Hz, 1.6 Hz, IH), 6.88 (d, J = 8.0 Hz, IH), 6.67 (t, J = 8.0 Hz, IH), 6.45 (d, J = 7.6 Hz, IH); MS ESI 263.0 [M + H]+, calcd for [C15H10N4O + H]+ 263.1.
Example A78: (E and ZV3-(lH-indazol-5-ylimino)-5-methylindolin-2-one
Figure imgf000149_0001
The title compound (83 mg, 60 %) was synthesized as a brown solid according to the method described for Example A74 using 5-methylisatin (80.5 mg,
0.5 mmol), 5-aminoindazole (66.5 mg, 0.5 mmol). 1H NMR indicated a 78:22 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, IH, NH),
10.86 (s, IH, NH), 8.08 (s, IH), 7.64 (d, J = 8.4 Hz, IH), 7.36 (s, IH), 7.14 (d, J =
8.4 Hz, IH), 7.07 (dd, J = 8.8 Hz, IH), 6.79 (d, J = 8.0 Hz, IH) 6.33 (s, IH), 1.89 (s, 3H); MS ESI 277.0 [M + H]+, calcd for [Cj6H12N4O + H]+ 277.1.
Example A79: (E and Z)-3-(lH-indazol-5-ylimino)-5-fluoroindolin-2-one
Figure imgf000149_0002
The title compound (62 mg, 43 %) was synthesized as a brick red solid (instead of stirring at rt, 1 mL OfH2O was added to crash out the product) according to the method described for Example A74 using 5-fluoroisatin (82.5 mg, 0.5 mmol), 5-aminoindazole (66.5 mg, 0.5 mmol). IH NMR indicated a 3:1 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, IH), 11.00 (s, IH), 8.10 (s, IH), 6.67 (d, J = 8.8 Hz, IH), 7.39 (s, IH), 7.22 (dt, J = 9.2 Hz, 2.4 Hz, IH), 7.10 (dd, J = 8.8 Hz, 1.6 Hz, IH), 6.90 (dd, J = 8.8 Hz, 4.4 Hz, IH), 6.14 (dd, J = 8.8 Hz, 2.8 Hz, IH); MS ESI 281.0 [M + H]+, calcd for [C15H9FN4O + H]+ 281.1.
Example A80 (EV3-(nH-indazol-6-yl)methyleney5-chloroindolin-2-one
Figure imgf000150_0001
The title compound was prepared according to the procedure described in Example Al, except substituting 5-chlorooxindole (21 mg, 0.13 mmol) to give 6.3 mg of a yellow solid (29 %). 1H NMR (400 MHz, CD3OD) δ 8.17 (s, IH), 7.96 (s, IH), 7.94 (d, J = 8.0 Hz, IH), 7.88 (s, IH), 7.59 (d, J = 4.0 Hz, IH), 7.45 (d, J = 8.0 Hz, IH), 7.25 (dd, J = 8.0, 4.0 Hz, IH), 6.92 (d, J = 4.0 Hz, IH); MS ESI 296.0 [M + H]+, calcd for [C16HI0CIN3O + H]+ 296.06.
Example A81. (E and Z)-3-((lH-indazol-6-yOmethyleneV5-methylindolin-2-one
Figure imgf000150_0002
The title compound was prepared according to the procedure described in Example Al, except substituting 5-methyloxindole (18 mg, 0.12 mmol) to give 15 mg of a yellow solid (43 %). A mixture of (E)- and (Z)- isomers (89:11 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.14 (s, IH), 7.91 (d, J = 8.0 Hz, IH), 7.89 (s, IH), 7.84 (s, IH), 7.48 (s, IH), 7.45 (d, J = 8.0 Hz, IH), 7.07 (d, J = 8.0 Hz, IH), 6.82 (d, J = 8.0 Hz, IH), 2.18 (s, 3H); MS ESI 276.1 [M + H]+, calcd for [C17Hj3N3O + H]+ 276.11. Example A82. (E and ZV3-((lH-indazol-6-vπmethyleneV5-(trifluoromethyr)- indolin-2-one
Figure imgf000151_0001
The title compound was prepared according to the procedure described in Example Al, except substituting 5-trifluoromethyl-oxindole (28 mg, 0.14 mmol) to give 2.2 mg of a yellow solid (7 %). A mixture of (E and Z)- isomers (40:60 by NMR) was obtained. 1H NMR (400 MHz, de-DMSO) δ 13.43 (br s, IH), 11.07 (br s, IH), 8.98
(s, IH), 8.21 (s, IH), 8.14(s, IH), 8.05 (d, J = 8.5 Hz, IH), 7.93 (d, J = 12.4 Hz, IH),
7.84 (d, J = 8.4 Hz, IH), 7.57 (d, J = 8.0 Hz, IH), 7.00 (d, J = 8.0 Hz, IH); MS ESI 330.1 [M + H]+, calcd for [C17H10F3N3O + H]+ 330.08.
Example A83. (E and ZV3-((lH-indazol-6-yl)methylene)-5-methoxyindolin-2-one
Figure imgf000151_0002
The title compound was prepared according to the procedure described in Example Al, except substituting 5-methoxyoxindole (22 mg, 0.14 mmol) to give 12.3 mg as a yellow solid (31 %). A mixture of (E)- and (Z)- isomers (84:16 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.14 (s, IH), 7.95-7.87 (m, 3H), 7.46 (d, J
= 8.8 Hz, IH), 7.23 (s, IH), 6.84 (s, 2H), 3.62 (s, 3H); MS ESI 292.1 [M + H]+, calcd for [C17H13N3O2 + H]+ 292.10.
Example A84. (EV5-chloro-3-((3-((EV2-(pyridin-4-vnvinvn-lH-indazol-6- yl)methylene)indolin-2-one
Figure imgf000152_0001
According to the procedure for the synthesis of (E)-3-((3-((E)-2-(pyridin-4- yl)vinyl)-lH-indazol-6-yl)methylene)indolin-2-one (Example A57), except substituting 5-chlorooxindole (14 mg, 0.08 mmol), the title compound was prepared as an orange solid (13.5 mg, 42 %). 1H NMR (400 MHz, (I6-DMSO) δ 13.63 (br s, IH), 10.78 (br. s, IH), 8.56 (d, J = 4.0 Hz, 2H), 8.40 ( d, J = 10.0 Hz, IH), 7.91 (s, IH), 7.89 (d, J = 13.2 Hz, 2 H), 7.72 (d, J = 3.5 Hz, 2H), 7.57 (d, J = 12.0 Hz, IH), 7.52 (d, J = 12.0 Hz, 2H), 7.30 (d, J = 10.0 Hz, IH), 6.90 (d, J = 11.5 Hz, IH); MS ESI 399.2 [M + H]+, calcd for [C23H15ClN4O + H]+ 399.09.
Example A85. (EV5-methyl-3-((3-((EV2-(pyridin-4-vnvinvn-lH-indazol-6- yl)methyleneMndolin-2-one
Figure imgf000152_0002
According to procedure for the synthesis of (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)- lH-indazol-6-yl)methylene)indolin-2-one, except substituting 5-methyloxindole (9 mg, 0.06 mmol) to give the title compound as an orange solid (5.9 mg, 26 %). 1H
NMR (400 MHz, (I6-DMSO) δ 13.58 (br s, IH), 10.53 (br s, IH), 8.57 (br s, 2H),
8.36 ( d, J = 8.0 Hz, IH), 7.93-7.46 (m, 8H), 7.06 (d, J = 8.0 Hz, IH), 6.79 (d, J =
5.8 Hz, IH), 2.16 (s, 3H); MS ESI 379.2 [M + H]+, calcd for [C24H18N4O + H]+ 379.15. Example A86. (EV5-methoxy-3-((3-((EV2-(pyridin-4-vnvinvn-lH-indazol-6- yl)methylene)indolin-2-one
Figure imgf000153_0001
According to procedure for the systhesis of (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-lH- indazol-6-yl)methylene)indolin-2-one, except substituting 5-methoxyoxindole (11 mg, 0.068 mmol) to give the title compound as an orange solid (13.6 mg, 51 %). 1H
NMR (400 MHz, (I6-DMSO) δ 13.58 (br s, IH), 10.45 (br s, IH), 8.57 (d, J = 6.0 Hz,
2H), 8.37 ( d, J = 8.5 Hz, IH), 7.93 (s, IH), 7.87 (d, J = 16.6 Hz, 1 H), 7.79 (s, IH),
7.71 (d, J = 6.0 Hz, 2H), 7.57 (d, J = 2.3 Hz, IH), 7.54 (d, J = 6.3 Hz, IH), 7.18 (d, J = 10.0 Hz, IH), 6.86 (dd, J = 8.8, 2.5 Hz, IH) 6.80 (d, J = 8.3 Hz, IH), 3.6 (s, 3H);
MS ESI 395.2 [M + H]+, calcd for [C24H18N4O2 + H]+ 395.14.
Example A87. (E and Z)-5-methoxy-3-(G-((EV2-(pyridm-2-yr)vinylVlH-indazol-6- yl)methylene)indolin-2-one
Figure imgf000153_0002
According to procedure for the synthesis of (E)-3-((3-((E)-2-(pyridin-2-yl)vinyl)- lH-indazol-6-yl)methylene)indolin-2-one (Example A41), except substituting 5- methoxyoxindole (14 mg, 0.086 mmol), the title compound was prepared as an orange solid (8.8 mg, 26 %). A mixture of (E)- and (Z)- isomers (80:20 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.59-57 (m, IH), 8.28 (d, J = 8.5 Hz, IH), 7.95 (d, J = 16.6 Hz, IH), 7.92-7.89 (m, 2H), 7.86 (dd, J = 7.5, 1.8 Hz, IH), 7.75 (d, J = 8.0 Hz, IH), 7.65 (d, J = 16.6 Hz, IH), 7.59 (dd, J = 8.8, 1.3 Hz, IH), 7.33 (ddd, J - 7.5, 5.0, 1.3 Hz, IH), 7.27 (t, J = 1.3 Hz, IH), 6.86-6.85 (m, 2H), 3.85 (s, 3H); MS ESI 395.2 [M + H]+, calcd for [C24H18N4O2 + H]+ 395.14.
Example A88. 2-((EV2-(6-(fE)-(5-methoxy-2-oxoindolin-3-ylidene)methylVlH- indazol-3-yl)vinyl)pyridine 1 -oxide
Figure imgf000154_0001
A round bottom flask was charged with (E)-5-methoxy-3-((3-((E)-2-(pyridin- 2-yl)vinyl)-lH-indazol-6-yl)methylene)indolin-2-one (25 mg, 0.063 mmol), wCPBA (13 mg, 0.076 mmol), and dichloromethane (4 mL). The reaction was stirred at rt for 24 hrs. Solvent was removed in vacuo and the residue was loaded onto a silica gel column. Elution with 90:10 CH2Cl2ZMeOH gave 9 mg (35 %) of the title compound as an orange solid. 1H NMR (400 MHz, CD3OD) δ 8.41 (d, J = 6.0 Hz, IH), 8.31 (d, J = 8.5 Hz, IH), 8.19 (d, J = 16.3 Hz, IH), 8.14 (d, J = 8.0 Hz, IH), 8.04 (d, J = 17.1 Hz, IH), 7.91 (d, J = 16.1 Hz, 2H), 7.67-7.60 (m, 2H), 7.47-7.43 (m, IH), 7.25 (s, IH), 6.85 (s, 2H), 3.64 (s, 3H); MS ESI 411.2 [M + H]+, calcd for [C24Hi8N4O3 + H]+ 411.14.
Example A89. (E and ZV3-(G-αH-pwol-2Λ4πH-indazol-6-vnmethyleneMndolin- 2-one
Figure imgf000154_0002
A. 3-(lH-pyrrol-2-yl)-lH-indazole-6-carbaldehyde A mixture of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (50 mg, 0.12 mmol), l-Oert-butoxycarbonyO-lH-pyrrol^-ylboronic acid (40 mg, 0.19 mmol), Pd(PPh3)4 (15 mg, 0.012 mmol) and 2M Na2CO3 (0.19 mL, 0.37 mmol) in DME/H2O (2 mL/1 mL) was degassed by evacuation and blanketed with Ar. The reaction mixture was sealed and heated with stirring under microwave irradiation at 125 0C for 60 min. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using EtOAc (2 %) in DCM as the eluent to provide a pale yellow solid (39 mg, 71 %). The solid was dissolved in THF (8 mL) and treated with IM TBAF (0.44 mL, 0.44 mmol); the resulting reaction mixture was heated under reflux for 16 h. The crude reaction mixture was concentrated under reduced pressure. Ethyl acetate (5 mL) was added and the solution was washed with brine (2 x 10 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using EtOAc (20 %) in DCM as the eluent to provide the title compound a pale yellow solid (4.3 mg, 24%). 1H NMR (400 MHz, CDCl3) δ ppm 10.11 (s, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.09 (s, IH), 7.72 (d, J = 8.0 Hz, 1 H), 6.92 (s, 1 H), 6.79 (d, J= 2.2 Hz, 1 H), 6.28 (s, IH); MS ESI 212.0 (100) [M + H]+, calcd for [C12H9N3O + H]+ 212.07.
B. (E and Z)-3-((3-(lH-pyrrol-2-yl)-lH-indazol-6-yl)methylene)indolin-2- one
According to the procedure described in Al, except substituting 3-(lH-pyrrol-2-yl)- lH-indazole-6-carbaldehyde (6.9 mg, 0.033 mmol), the title compound was prepared as a yellow solid (6.8 mg, 64 %). A mixture of (E)- and (Z)- isomers (83:17 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J = 8.5 Hz, IH), 7.96 (d, J = 19.1 Hz, 2H), 7.69 (d, J = 7.8 Hz, IH), 7.49 (d, J = 8.3 Hz, IH), 7.24 (t, J = 7.5, 1.0 Hz, IH), 6.94-6.91 (m, 2H), 6.88 (t, J = 7.8 Hz, IH), 6.80 (d, J = 2.5 Hz, IH), 6.29 (t, J = 3.5 Hz, IH); MS ESI 327.1 [M + H]+, calcd for [C20H14N4O + H]+ 327.12.
Example A90. (E and Z)-3-((3-αH-indol-2-viπH-indazol-6-vnmethylene)indolin- 2-one
Figure imgf000156_0001
A. 3-(lH-indol-2-yl)-lH-indazole-6-carbaldehyde
According to the procedure for the synthesis of 3-(lH-pyrrol-2-yl)-lH-indazole-6- carbaldehyde, except substituting l-(tert-butoxycarbonyl)-lH-indol-2-ylboronic acid (39 mg, 0.15 mmol), the title compound was prepared as a beige solid (4.4 mg, 14%). 1H NMR (400 MHz, CDCl3) δ ppm 10.18 (s, 1 H), 9.09 (s, IH), 8.29 (d, J = 8.8 Hz, 1 H), 8.06 (s, IH), 7.85 (d, J = 8.0 Hz, IH), 7.73 (d, J = 7.8 Hz, IH), 7.47 (d, J =8.0 Hz, IH), 7.0520-7.15 (m, 2H); MS ESI 262.1 (100) [M + H]+, calcd for [C16H11N3O + H]+ 262.09. B. (E and Z)-3-((3-(lH-indol-2-yl)-lH-indazol-6-yl)methylene)mdolin-2-one
According to the procedure for the synthesis of (E)-3-((lH-indazol-6- yl)methylene)indolin-2-one, except substituting 3-((3-(lH-indol-2-yl)-lH-indazol-6- yl)methylene)indolin-2-one (4.6 mg, 0.018 mmol), the title compound was prepared as a yellow solid (2.2 mg, 33 %). A mixture of (E)- and (Z)- isomers (66:34 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.30 (d, J = 8.5 Hz, IH), 7.93 (d, J = 4.3 Hz, IH), 7.92 (s, IH), 7.71 (d, J = 8.0 Hz, IH), 7.65 (d, J = 7.8 Hz, IH), 7.59 (dd, J = 7.5, 1.0 Hz, IH), 7.48 (dd, J = 8.0, 0.8 Hz, IH), 7.26 (t, J = 7.3 Hz, IH), 7.19-7.14 (m, 2H), 7.09-7.03 (m, IH), 6.95 (d, J = 7.5 Hz, IH), 6.90 (td, J = 7.5, 1.0 Hz, IH); MS ESI 377.2 [M + H]+, calcd for [C24H16N4O + H]+ 377.13.
Example A91. (E)-3-((3-(thiophen-2-yl)-lH-indazol-6-yl)methylene)indolin-2-one
Figure imgf000157_0001
A. 3-(thiophen-2-yl)-lH-indazole-6-carbaldehyde
A mixture of lH-indazole-6-carbaldehyde (50 mg, 0.18 mmol), thiophen-2- ylboronic acid (47 mg, 0.37 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and 2M Na2CO3 (0.28 mL, 0.55 mmol) in DME/H2O (2 mL/1 mL) was heated under reflux for 16 hours. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc (10 to 20 %) in DCM as the eluent to provide the title compound as a pale yellow solid (29 mg, 70 %). 1U NMR (400 MHz, CD3OD) δ ppm 10.09 (s, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 8.09 (s, 1 H), 7.72 (d, J= 8.5 Hz, 1 H), 7.69 (d, J= 3.8 Hz, 1 H), 7.48 (d, J= 5.0 Hz, 1 H), 7.19 (dd, J = 4.8, 3.8 Hz, 1 H); MS ESI 229.0 (100) [M + H]+, calcd for [Ci2H8N2OS + H]+ 229.04.
B. (E)-3-((3-(thiophen-2-yl)-lH-indazol-6-yl)methylene)indolin-2-one According to the procedure for the synthesis of (E)-3-((lH-indazol-6- yl)methylene)indolin-2-one, except substituting 3-(thiophen-2-yl)-lH-indazole-6- carbaldehyde (29 m 0.13 mmol), the title compound was prepared as a yellow solid (19.7 mg, 45 %). 1H NMR (400 MHz, (I6-DMSO) δ 10.64 (br s, IH), 8.22 (d, J = 8.5 Hz, IH), 7.92 (s, IH), 7.79 (s, 2H), 7.61 (d, J = 7.5 Hz, 1 H), 7.59 (d, J = 5.0 Hz, 1 H), 7.53 (d, J = 8.0 Hz, IH), 7.26-7.20 (m, 2H), 6.89 (d, J = 7.5 Hz, IH), 6.85 (t, J = 7.5 Hz, IH); MS ESI 344.1 [M + H]+, calcd for [C20Hi3N3OS + H]+ 344.08.
Example A92. fEV3-((3-(thiazol-2-ylVlH-indazol-6-vnmethyleneMndolin-2-one
Figure imgf000158_0001
A. 3-(thiazol-2-yl)-lH-indazole-6-carbaldehyde
A mixture of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (100 mg, 0.25 mmol), 2-(tributylstannyl)thiazole (85 mg, 0.23 mmol), Pd2(dba)3 (23 mg, 0.025 mmol), P(O-ToI)3 (15 mg, 0.05 mmol), and Et3N (0.05 mL, 0.30 mmol) in DMF (2 mL) was degassed by evacuation and refilling with Ar. The reaction mixture was sealed and heated with stirring under microwave irradiation at 125 0C for 2 h. Ethyl acetate (5 mL) was added and the solution was washed with brine (2 x 20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using EtOAc (10 %) in hexanes as the eluent to provide a pale yellow solid (33 mg, 37 %). The solid was dissolved in THF (10 mL) and IM TBAF (0.47 mL, 0.47 mmol) was added. The resulting reaction mixture was heated under reflux for 16 h. The crude reaction mixture was concentrated under reduced pressure. Ethyl acetate (5 mL) was added and the solution was washed with brine (2 x 10 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using EtOAc (40 %) in hexanes as the eluent to provide the title compound a pale yellow solid (4.6 mg, 8%). 1H NMR (400 MHz, CDCl3) δ ppm 10.18 (s, 1 H), 8.70 (d, J= 8.5 Hz, 1 H), 8.08 (s, IH), 8.01 (d, J = 3.0 Hz, 1 H), 8.86 (d, J = 8.5 Hz, IH), 7.43 (d, J = 3.3 Hz, 1 H); MS ESI 230.0 (100) [M + H]+, calcd for [CnH7N3OS + H]+ 230.03.
B. (E)-3-((3-(thiazol-2-yl)-lH-indazol-6-yl)methylene)indolin-2-one According to the procedure for the synthesis of (E)-3-((lH-indazol-6- yl)methylene)indolin-2-one, except substituting 3-(thiazol-2-yl)-lH-indazole-6- carbaldehyde (4.6 mg, 0.02 mmol), the title compound was prepared as a yellow solid (2.3 mg, 36%). 1H NMR (400 MHz, (I6-DMSO) δ 13.75 (br. s, IH), 10.64 (br. s, IH), 8.44 (d, J = 8.5 Hz, IH), 8.03 (d, J =3.3 Hz, IH), 7.96 (s, IH), 7.80-7.78 (m , 2H), 7.60 (d, 7.3 Hz, IH), 7.58 (d, J = 7.5 Hz, 1 H), 7.25 (td, J = 7.5, 1.0 Hz, 1 H), 6.88 (d, J = 7.8 Hz, IH), 6.85 (td, J = 7.5, 1.0 Hz, IH); MS ESI 345.1 [M + H]+, calcd for [Ci9Hi2N4OS + H]+ 345.07.
Example A93. (E and ZV3-((3-(pyridin-3-yl)-lH-indazol-6-yl)methyleneMndolin-2- one
Figure imgf000159_0001
A. 3-(pyridin-3-yl)-lH-indazole-6-carbaldehyde
A mixture of S-iodo-lH-indazole-ό-carbaldehyde (50 mg, 0.18 mmol), pyridin-3- ylboronic acid (27 mg, 0.22 mmol), PdCl2(PPh3)2 (13 mg, 0.018 mmol) and 2M
Na2CO3 (0.10 mL, 0.18 mmol) in DME/H2O/EtOH (1.4 mL/0.4 mL/0.2 mL) was degassed by evacuation and refilling with Ar. The reaction mixture was sealed and heated with stirring under microwave irradiation at 125 0C for 60 min. The crude reaction mixture was concentrated under reduced pressure. Ethyl acetate (5 mL) was added and the solution was washed with brine (2 x 20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using MeOH (5 %) in DCM as the eluent to provide the title compound a pale yellow solid (24 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1
H), 8.88 (d, J= 2.3 Hz, 1 H), 8.69 (d, J = 4.8 Hz, IH), 8.16 (d, J = 8.5 Hz, 1 H), 8.10 (s, 1 H), 7.92 (d, J= 8.0 Hz, 1 H), 7.82 (d, J= 8.5 Hz, 1 H), 7.45 (dd, J = 8.0, 5.0 Hz,
1 H); MS ESI 224.0 (100) [M + H]+, calcd for [Ci3H9N3O + H]+ 224.07.
B. (E and Z)-3-((3-(pyridin-3-yl)-lH-indazol-6-yl)methylene)indolin-2-one According to the procedure for the synthesis of (E)-3-((lH-indazol-6- yl)methylene)indolin-2-one, except substituting 3-(pyridin-3-yl)-lH-indazole-6- carbaldehyde (24 mg, 0.11 mol), the title compound was prepared as a yellow solid (9.2 mg, 25 %). A mixture of (E)- and (Z)- isomers (83:17 by NMR) was obtained. 1H NMR (400 MHz, d6-DMSO) δ 10.65 (br s, IH), 9.23 (s, IH), 8.62 (d, J = 5.0 Hz, IH), 8.41 (d, J = 7.5 Hz, IH), 8.21 (d, J = 8.5 Hz, IH), 7.97 (s, IH), 7.80 (s, IH), 7.62 (d, J = 7.5, IH), 7.58-7.53 (m, 2H), 7.24 (t, J = 7.8 Hz, IH), 6.89 (d, J = 7.8 Hz, IH), 6.85 (t, J = 7.3 Hz, IH); MS ESI 339.1 [M + H]+, calcd for [C21Hi4N4O + H]+ 339.12.
Example A94. (E and ZV5-chloro-3-((3-(pyridin-3-yl)-lH-indazol-6-vnmethyleneV indolin-2-one
Figure imgf000160_0001
According to the procedure for the synthesis of 3-((3-(pyridin-3-yl)-lH-indazol-6- yl)methylene)indolin-2-one, except substituting 5-chlorooxindole (5.3 mg, 0.031 mmol) the title compound was prepared as a yellow solid (6.5 mg, 54 %). A mixture of (E)- and (Z)- isomers (68:32 by NMR) was obtained. 1H NMR (400 MHz, (I6-
DMSO) δ 13.77 (br s, IH), 10.80 (br s, IH), 9.24 (d, J = 1.5 Hz, IH), 8.63 (dd, J =
4.8, 1.8 Hz, IH), 8.41 (dt, J = 7.8, 1.8 Hz, IH), 8.28 (d, J = 8.5 Hz, IH), 8.21-8.16 (m, IH), 7.98 (s, IH), 7.89 (s, IH), 7.57 (t, J = 4.5, IH), 7.55-7.52 (m, IH), 7.31 (dd,
J = 8.3, 2.3 Hz, IH), 6.91 (d, J = 8.3 Hz, IH); MS ESI 373.1 [M + H]+, calcd for
[C2]H13ClN4O + H]+ 373.08.
Example A95. (E and ZV3-((3-(αuinoHn-3-ylVlH-indazol-6-vnmethylene')indolin- 2-one
Figure imgf000160_0002
A. 3-(quinolin-3-yl)-lH-indazole-6-carbaldehyde
According to the procedure for the synthesis of 3-(pyridin-3-yl)-lH-indazole-6- carbaldehyde, except substituting quinolin-3-ylboronic acid (38 mg, 0.22 mmol), the title compound was obtained as a beige solid (15 mg, 30%). 1H NMR (400 MHz, CDCl3) δ ppm 10.19 (s, 1 H), 9.61 (d, J = 2.0 Hz, 1 H), 8.73 (d, J = 2.0 Hz, IH), 8.27 (d, J = 8.3 Hz, IH), 8.21 (d, J = 8.3 Hz, IH), 8.13 (s, IH), 7.98 (d, J =8.3 Hz, IH), 7.87 (dd, J= 8.5, 1.3 Hz, 1 H), 7.80 (ddd, J = 8.3, 7.0, 1.5 Hz, IH), 7.66 (ddd, J = 8.3, 7.0, 1.3 Hz, IH); MS ESI 274.0 (100) [M + H]+, calcd for [Ci7HnN3O + H]+ 274.09. B. (E and Z)-3-((3-(quinolin-3-yl)-lH-indazol-6-yl)methylene)indolin-2-one
According to the procedure for the systhesis of (E)-3-((lH-indazol-6-yl)methylene)- indolin-2-one, except substituting 3-(quinolin-3-yl)-lH-indazole-6-carbaldehyde (8 mg, 0.03 mol), the title compound was obtained as a yellow solid (4.3 mg, 38 %). A mixture of (E)- and (Z)- isomers (94:6 by NMR) was obtained. 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br s, IH), 10.66 (br. s, IH), 9.61 (d, J = 2.0 Hz, IH), 9.04 (d, J = 2.3 Hz, IH), 8.47 (d, J = 8.8Hz, IH), 8.22 (d, J = 7.8 Hz, IH), 8.08 (d, J = 8.0 Hz, IH), 8.01 (s, IH), 7.83 (s, IH), 7.80 (td, J = 6.8, 1.3 Hz, IH), 7.68 (t, J = 7.8, IH), 7.64 (d, J = 7.8 Hz, IH), 7.61 (d, J = 7.8 Hz, IH), 7.25 (t, J = 7.8 Hz, IH), 6.90 (d, J = 8.3 Hz, IH), 6.86 (t, J = 7.8 Hz, IH); MS ESI 389.1 [M + H]+, calcd for [C25H16N4O + H]+ 389.13.
Example A96. (E and ZV3-((3-(6-(4-methylpiperazin-l-yl)pyridin-3-yD-lH-indazol- 6-yl)methylene)indolin-2-one
Figure imgf000161_0001
A. 3-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indazole-6-carbaldehyde According to the procedure for the synthesis of 3-(pyridin-3-yl)-lH-indazole-6- carbaldehyde, except substituting l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxa- borolan-2-yl)pyridin-2-yl)piperazine (67 mg, 0.22 mmol), the title compound was obtained as a beige solid (57 mg, 99%). 1H NMR (400 MHz, CD3OD) δ ppm 10.11 (s, 1 H), 8.73 (d, J = 2.3 Hz, 1 H), 8.16 (dd, J = 8.8, 2.3 Hz, IH), 8.14 (s, IH), 8.09 (d, J = 8.3 Hz, IH), 7.72 (d, J =8.5 Hz, IH), 7.05 (d, J= 8.8 Hz, 1 H), 3.83-3.78 (m, 4H), 3.01 (t, J = 5.0 Hz, 4H), 2.67 (s, 3H); MS ESI 322.1 (100) [M + H]+, calcd for [C18H19N5O + H]+ 322.16.
B. (E and Z)-3-((3-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indazol-6- yl)methylene)-indolin-2-one
According to the procedure for the synthesis of (E)-3-((lH-indazol-6- yl)methylene)indolin-2-one, except substituting 3-(6-(4-methylpiperazin-l- yl)pyridin-3-yl)-lH-indazole-6-carbaldehyde (40 mg, 0.12 mol), the title compound was prepared as a yellow solid (4.9 mg, 9 %). A mixture of (E)- and (Z)- isomers (79:21 by NMR) was obtained. 1H NMR (400 MHz, (I6-DMSO) δ 13.34 (br. s, IH), 10.64 (br. s, IH), 8.76 (d, J = 2.3 Hz, IH), 8.14 (dd, J = 8.8, 2.5 Hz, 2H), 7.91 (s, IH), 7.79 (s, IH), 7.62 (d, J = 7.8, IH), 7.48 (d, J = 8.0 Hz, IH), 7.24 (t, J = 7.5 Hz, IH), 6.99 (d, J = 9.0 Hz, IH), 6.89 (d, J =7.8 Hz, IH), 6.85 (t, J = 7.3 Hz, IH), 3.57 (t, J = 4.5 Hz, 4H), 2.42 (t, J = 5.0 Hz, 4H), 2.23 (s, 3H); MS ESI 437.2 [M + H]+, calcd for [C26H24N6O + H]+ 437.20.
Example A97. (E and Z)-5-methoxy-3-((3-(6-(4-methylpiperazin-l-yl)pyridin-3-ylV lH-indazol-6-yl)methylene)indolin-2-one
Figure imgf000162_0001
According to the procedure for the synthesis of 3-((3-(6-(4-methylpiperazin-l- yl)pyridin-3-yl)-lH-indazol-6-yl)methylene)indolin-2-one (Example A97), except substituting 5-methoxyoxindole (28 mg, 0.087 mol), the title compound was prepared as a yellow solid (14.4 mg, 35 %). A mixture of (E)- and (Z)- isomers (83:17 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) 8.74 (d, J = 2.3 Hz, IH), 8.14 (dd, J = 8.8, 2.3 Hz, IH), 8.07 (d, J = 8.5 Hz, IH), 7.87 (d, J = 10.0 Hz, 2H), 7.49 (d, J = 8.3 Hz, IH), 7.26 (s, IH), 7.01 (d, J = 8.8, IH), 6.83 (s, 2H), 3.75- 3.69 (br. m, 4H), 3.62 (s, 3H), 2.82-2.76 (br. m, 4H), 2.51 (s, 3H); MS ESI 467.2 [M + H]+, calcd for [C27H26N6O2 + H]+ 467.21.
Example A98. (E and Z)-3-(f3-flH-pyrazol-5-vn-lH-indazol-6-vnmethylene)- indolin-2-one
Figure imgf000163_0001
A. 3-(lH-pyrazol-5-yl)-lH-indazole-6-carbaldehyde
According to the procedure for the synthesis of 3-(pyridin-3-yl)-lH-indazole-6- carbaldehyde, except substituting lH-pyrazole-5-boronic acid (25 mg, 0.22 mmol), the title compound was prepared as a beige solid (5.3 mg, 13%). 1H NMR (400 MHz, CD3OD) δ ppm 10.13 (s, 1 H), 8.44-8.32 (br. m, 1 H), 8.14 (s, IH), 7.78 (d, J = 1.8 Hz, 1 H), 7.75 (d, J = 8.3 Hz, 1 H), 6.90 (d, J= 2.0 Hz, 1 H); MS ESI 213.0 (100) [M + H]+, calcd for [C11H8N4O + H]+ 213.07.
B. (E and Z)-3-((3-(lH-pyrazol-5-yl)-lH-indazol-6-yl)methylene)indolin-2- one
According to the procedure for the synthesis of (E)-3-((lH-indazol-6- yl)methylene)indolin-2-one, except substituting 3-(lH-pyrazol-5-yl)-lH-indazole-6- carbaldehyde (5.3 mg, 0.025 mmol), the title compound was prepared as a yellow solid (4.4 mg, 54 %). A mixture of (E)- and (Z)- isomers (78:22 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.35 (br. s, IH), 7.92-7.89 (m, 2H), 7.79- 7.77 (m, IH), 7.68 (d, J = 7.8 Hz, IH), 7.53 (d, J = 8.5 Hz, IH), 7.25 (t, J = 7.5 Hz, IH), 6.94-6.86 (m, 3H); MS ESI 328.1 [M + H]+, calcd for [C19H13N5O + H]+ 328.11.
Example A99. (E and ZV3-((4-(pyridin-3-ylVlH-indazol-6-vDmethyleneMndolin-2- one
Figure imgf000164_0001
A. 3-(pyridin-4-yl)-lH-indazole-6-carbaldehyde
According to the procedure for the synthesis of 3-(pyridin-3-yl)-lH-indazole-6- carbaldehyde, except substituting pyridin-4-ylboronic acid (27 mg, 0.22 mmol), the title compound was obtained as a beige solid (3.7 mg, 9%). 1H NMR (400 MHz, CD3OD) δ ppm 10.15 (s, 1 H), 8.69 (d, J = 6.3 Hz, 2 H), 8.32 (d, J = 8.8 Hz, 1 H), 8.22 (s, IH), 8.10 (d, J = 6.3 Hz, 2 H), 7.84 (d, J= 6.3 Hz, 1 H); MS ESI 224.0 (100) [M + H]+, calcd for [C13H9N3O + H]+ 224.07.
B. (E and Z)-3-((4-(pyridin-3-yl)-lH-indazol-6-yl)methylene)indolin-2-one According to the procedure for the systhesis of (E)-3-((lH-indazol-6-yl)methylene)- indolin-2-one, except substituting 3-(pyridin-4-yl)-lH-indazole-6-carbaldehyde (3.9 mg, 0.017 mol), the title compound was prepared as a yellow solid (4.8 mg, 81 %). A mixture of (E)- and (Z)- isomers (64:36 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.69 (d, J = 6.0 Hz, 2H), 8.30 (d, J = 8.5 Hz, IH), 8.13 (d, J = 6.0 Hz, 2H), 7.97 (s, IH), 7.90 (s, IH), 7.67 (d, J = 8.0 Hz, IH), 7.63 (d, J = 8.9 Hz, IH), 7.26 (t, J = 8.0 Hz, IH), 6.94 (d, J = 8.0 Hz, IH), 6.89 (t, J = 7.8 Hz, IH); MS ESI 339.1 [M + H]+, calcd for [C21Hi4N4O + H]+ 339.12.
Example AlOO. (E and Z)-3-((3-(pyrimidin-5-ylVlH-indazol-6-yl)methylene)- indolin-2-one
Figure imgf000165_0001
A. 3-(pyrimidin-5-yl)-lH-indazole-6-carbaldehyde
According to the procedure for the synthesis of 3-(lH-pyrrol-2yl)-lH-indazole-6- carbaldehyde, except substituting pyrimidin-5-ylboronic acid (34 mg, 0.15 mmol), the title compound was obtained as a beige solid (8.1 mg, 30%). 1H NMR (400 MHz, CD3OD) δ ppm 10.15 (s, 1 H), 9.44 (s, 2H), 9.21 (s, IH), 8.26 (d, J = 8.5 Hz, 1 H), 8.23 (t, J = 1.3 Hz, IH), 7.84 (dd, J = 8.5, 1.3 Hz, IH); MS ESI 225.0 (100) [M + H]+, calcd for [C12H8N4O + H]+ 225.07.
B. (E and Z)-3-((3-(pyrimidin-5-yl)-lH-indazol-6-yl)methylene)indolin-2-one According to the procedure for the synthesis of (E)-3-((lH-indazol-6- yl)methylene)indolin-2-one, except substituting 3-(pyrimidin-5-yl)-lH-indazole-6- carbaldehyde (8.5 mg, 0.038 mol), the title compound was prepared as a yellow solid (1.2 mg, 9 %). A mixture of (E)- and (Z)- isomers (63:37 by NMR) was obtained. 1H NMR (400 MHz, CD3OD) δ 9.47 (s, 2H), 9.22 (s, IH), 8.24 (d, J = 8.5 Hz, IH), 7.97 (s, IH), 7.90 (s, IH), 7.66 (d, J = 7.8 Hz, IH), 7.63 (d, J =8.5 Hz, IH), 7.26 (t, J = 8.0 Hz, IH), 6. 49 (d, J = 8.0 Hz, IH), 6.88 (t, J = 7.8 Hz, IH); MS ESI 340.1 [M + H]+, calcd for [C20Hi3N5O + H]+ 340.11.
Example AlOl : fEy3-fG-ffEV2-φyridin-4-ylWinylVlH-indazol-6-vnmethyleneV lH-pyrrolor2.3-blpyridin-2(3HVone
Figure imgf000165_0002
The title compound (64 mg, 64 %) was synthesized as orange red solid according to the method described for Example AIlB from lH-pyrrolo[2,3- b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and E)-3-(2-(ρyridin-4-yl)vinyl)-lH- indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, IH, NH), 11.28 (s, IH, NH), 8.57 (d, J = 5.6 Hz, 2H), 8.39 (d, J = 8.4 Hz, IH), 8.12 (d, J = 4.8 Hz, IH), 7.95 (s, 2H), 7.90 (d, J = 6.4 Hz, IH, partially overlapping with the peak at 7.87 ppm), 7.87 (d, J = 16.4 Hz, IH, partially overlapping with the peak at 7.90 ppm), 7.71 (d, J = 5.6 Hz, 2H), 7.57 (d, J = 8.0 Hz, IH, partially overlapping with the peak at 7.56 ppm), 7.56 (d, J = 16.4 Hz, IH, partially overlapping with the peak at 7.57 ppm), 6.91 (dd, J = 7.6 Hz, 5.2 Hz, IH); MS ESI 366.1 [M + H]+, calcd for [C22Hi5N5O + H]+ 366.1.
Example A 102 (EV3 -((3 -cvclopropyl- 1 H-indazol-6-yr)methylene*)indolin-2-one
Figure imgf000166_0001
A. 3-<yclopropyl-l-((2-(trimethylsilyI)ethoxy)methyl)-lH-iridazole-6- carbaldehyde
A degassed mixture of 3-iodo-l-((2-(trimethylsilyI)ethoxy)methyl)-lH-indazole-6- carbaldehyde (51 mg, 0.12 mmol), cyclopropylboronic acid (21 mg, 0.24 mmol), powdered K3PO4 (103 mg, 0.48 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) in PhMe (2 mL) and H2O (0.1 mL) was heated with stirring in a sealed tube under Ar at 95 -100 0C for 1 d. The crude mixture was concentrated and purified by prepTLC (SiO2 5:1 hexanes/EtOAc) to provide the title compound as a clear oil (40 mg, quant): 1H NMR (400 MHz, CDCl3) δ ppm 10.13 (s, 1 H), 8.02 (s, 1 H), 7.87 (d, J=8.28 Hz, 1 H), 7.70 (d, J=8.28 Hz, 1 H), 5.71 (s, 2 H), 3.54 (d, J=8.53 Hz, 2 H), 2.19 - 2.28 (m, 1 H), 1.06 - 1.12 (m, 4 H), 0.89 (d, J=8.28 Hz, 2 H), -0.07 (s, 9 H); MS ESI 317.1 [M + H]+, calcd for [C17H24N2O2Si + H]+ 317.5. B. fiJ-S-fβ-cyclopropyl-l-fβ-ftrimethylsilyljethoxyjmethylj-lH-indazol-ό- yl)methyl-ene) indolin-2-one
According to the method of Example A19, indolin-2-one (17 mg, 0.13 mmol) and 3- cyclopropyl-l-^-OrimethylsilyOethoxy^ethyO-lH-indazole-ό-carbaldehyde (40 mg, 0.13 mmol) were reacted to obtain crude product. The crude mixture was purified by prepTLC (SiO2 2 % MeOH in DCM) to provide the title compound as a yellow solid (48 mg, 88 %). MS ESI 432.2 [M + H]+, calcd for [C25H29N3O2Si+ H]+ 432.6.
C. (E)-3-((3-cyclopropyl-lH-indazol-6-yl)methylene)indolin-2-one A mixture of (E)-3-((3-cyclopropyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazol-6-yl)methylene)indolin-2-one (47 mg, 0.11 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 10 mL, 10 mmol) in anh. THF (30 mL) was refluxed under Ar for 18 h. The reaction mixture was then concentrated to a brown oil, which was diluted with H2O, extracted (2 % MeOH in DCM), washed (H2O (2x), brine), dried (Na2SO4, and MgSO4) and concentrated under reduced pressure. The material was suspended in DCM, collected by filtration and washed with xs. DCM to afford the title compound as a yellow solid (7.0 mg, 21 %). 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (d, J=8.53 Hz, 1 H), 7.86 (s, 1 H), 7.78 (s., 1 H), 7.65 (d, J=8.03 Hz, 1 H), 7.42 (d, J=8.78 Hz, 1 H), 7.23 (t, J=8.03 Hz, 1 H), 6.92 (d, J=7.78 Hz, 1 H), 6.87 (t, J=7.65 Hz, 1 H), 2.26 - 2.36 (m, 1 H), 1.04 - 1.11 (m, 4 H); MS ESI 302.1 [M + H]+, calcd for [C19H15N3O + H]+ 302.3.
Example A103 (EV3-(f3-r(EV2-(4-methylthiazol-5-vnvinylVlH-indazol-6- yl)methyl-ene)indolin-2-one
Figure imgf000167_0001
A, (E)-3-(2-(4-methylthiazol-5-yl)vinyl)-l-((2-(Mmet^lsilyl)ethojιy)methyl)- lH-indazole-6-carhaldehyde A degassed mixture of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (70 mg, 0.17 mmol), 4-methyl-5-vinylthiazole (44 mg, 0.35 mmol), N- ethyl-N-isopropylpropan-2-amine (DIPEA, 45 mg, 0.35 mmol), Pd(OAc)2 (3.9 mg, 0.017 mmol) and P(O-MeC6H4)S (16 mg, 0.052 mmol) in anhydrous MeCN (2 mL) were heated with stirring in a sealed tube under Ar at 90 0C for 1 d. The crude mixture was later concentrated under reduced pressure and purified by prepTLC (SiO2 5:1 hexanes/EtOAc) to provide the title compound (30 mg, 43 %): 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1 H), 8.64 (s, 1 H), 8.12 (s, 1 H), 8.06 (d, J=8.28 Hz, 1 H), 7.83 (d, 1 H), 7.64 (d, J=16.06 Hz, 1 H), 7.12 (d, J=16.31 Hz, 1 H), 5.82 (s, 2 H), 3.62 (t, J=8.28 Hz, 2 H), 2.62 (s, 3 H), 0.92 (t, J=8.28 Hz, 2 H), -0.05 (s, 9 H); MS ESI 400.2 [M + H]+, calcd for [C20H25N3O2SSi + H]+ 400.6.
B. (E)-3-(2-(4-methylthiazol-5-yl)vinyl)-lH-indazole-6-carbaldehyde A mixture of (E)-3-(2-(4-methylthiazol-5-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)- methyl)-lH-indazole-6-carbaldehyde (30 mg, 0.075 mmol) and tetrabutyl- ammonium fluoride (1.0 M in THF, 0.37 mL, 0.37 mmol) in anh. THF (10 mL) was refluxed under Ar for 1 d. The reaction mixture was then concentrated under reduced pressure and purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound (15 mg, 74 %) as a tan solid (7.0 mg, 21 %). MS ESI 270.0 [M + H]+, calcd for [Ci4H11N3OS + H]+ 270.3. C. (E)-3-((3-((E)-2-(4-methylthiazol-5-yl)viψl)-lH-indazol-6-yl)methylene)- indolin-2-one
According to the method of Example A 19, indolin-2-one (7.5 mg, 0.056 mmol) and 3(E)-3-(2-(4-methylthiazol-5-yl)vinyl)-lH-indazole-6-carbaldehyde (15 mg, 0.059 mmol) were reacted to obtain crude product. The crude mixture was concentrated under reduced pressure and triturated with DCM, followed by MeCN to provide the title compound as a yellow solid (3.0 mg, 13 %). IH NMR (400 MHz, DMF-^7) δ ppm 13.67 (br. s., 1 H), 10.66 (br. s., 1 H), 9.01 (s, 1 H), 8.41 (d, J=8.03 Hz, 1 H), 7.86 (s, 1 H), 7.78 (d, J = 16.1 Hz, 1 H), 7.73 (d, J=8.03 Hz, 1 H), 7.61 (d, J=8.28 Hz, 1 H), 7.26 - 7.35 (m, 2 H), 7.02 (d, J=7.78 Hz, 1 H), 6.90 (t, J=7.28 Hz, 1 H), 2.62 (s, 3 H); MS ESI 385.1 [M + H]+, calcd for [C22H16N4OS + H]+ 385.4. Example A104 (E and ZV3-f(3-((EV2-(pyrazin-2-vnvinylVlH-indazol-6- yl)methylene)-indolin-2-one
Figure imgf000169_0001
A. fi)-3-(2-(pyrazin-2-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazole-6-carbaldehyde
A degassed mixture of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (70 mg, 0.17 mmol), 2-vinylpyrazine (27 mg, 0.25 mmol), N-ethyl-N- isopropylpropan-2-amine (DIPEA, 45 mg, 0.35 mmol), Pd(OAc)2 (3.9 mg, 0.017 mmol) and P(O-MeC6HLO3 (16 mg, 0.052 mmol) in anh MeCN (2.5 mL) was heated with stirring in a sealed tube under microwave irradiation at 120 0C for 40 min. The crude mixture was later concentrated under reduced pressure and purified by prepTLC (SiO2 2:1 hexanes/EtOAc) to provide the title compound as a colorless solid (28 mg, 43 %): 1H NMR (400 MHz, CDCl3) δ ppm 10.18 (s, 1 H), 8.73 (s, 1 H), 8.60 (br. s., 1 H), 8.47 (d, J=2.26 Hz, 1 H), 8.14 - 8.18 (m, 2 H), 8.07 (d, J=16.06 Hz, 1 H), 7.84 (d, J=8.53 Hz, 1 H), 7.61 (d, J=16.31 Hz, 1 H), 5.85 (s, 2 H), 3.61 (t, J=8.28 Hz, 2 H), 0.94 (t, J=8.53 Hz, 2 H), -0.05 (s, 9 H); MS ESI 381.2 [M + H]+, calcd for [C20H24N4O2Si + H]+ 381.5.
B. (E)-3-((3-((E)-2-(pyrazin-2-yl)vinyl)-l-((2-(Mmethylsilyl)etto^ indazol-6-yl)methylene)indolin-2-one The title compound was synthesized according to the method of Example A 19, utilizing indolin-2-one (10.0 mg, 0.075 mmol) and (E)-3-(2-(pyrazin-2-yl)vinyl)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (28 mg, 0.074 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 2 % MeOH/DCM) to provide the title compound to as a yellow material (20 mg, 55 %); MS ESI 496.3 [M + H]+, calcd for [C28H29N5O2Si + H]+ 496.6.
C. (E & Z)-3-((3-((E)-2-φyrazin-2-yl)vinyl)-lH-indazol-6-yl)methylene)indolin- 2-one A degassed mixture of (E)-3-((3-((E)-2-(pyrazin-2-yl)vinyl)-l-((2-(trimethylsilyl)- ethoxy)methyl)-lH-indazol-6-yl)methylene)indolin-2-one (20 mg, 0.040 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 0.6 mL, 0.6 mmol) in anh. THF (10 mL) was refluxed under Ar for 1 d. The reaction mixture was then concentrated under reduced pressure and purified by prepTLC (SiO2 12 % MeOH/DCM) and trituration with DCM to provide the title compound as a 1.5:1.0 (E:Z) mixture of isomers: a yellow solid (1.7 mg, 12 %). IH NMR (400 MHz, DMF-^7) δ ppm 9.33 (s, 0.35 H), 9.16 (d, J=1.51 Hz, 1.0 H), 8.84 - 8.87 (m, 1.1 H), 8.70 (t, J=2.26 Hz,
1.0 H), 8.60 (d, J=8.78 Hz, 0.6 H), 8.51 (d, J=8.28 Hz, 0.45 H), 8.37 - 8.46 (m, 1.6 H), 8.26 (d, J=5.52 Hz, 1.0 H), 8.04 (s, 0.6 H), 8.02 (d, J=7.53 Hz, 0.39 H), 7.92 -
7.98 (m, 1.7 H), 7.79 (d, J=8.03 Hz, 0.60 H), 7.41 - 7.49 (m, 1.1 H), 7.05 - 7.25 (m,
2.1 H); MS ESI 366.2 [M + H]+, calcd for [C22H15N5O+ H]+ 366.4.
Example A105 (E and ZV3-((3-(fEV2-α-memyl-lH-imidazol-2-yr)vinvn-lH- indazol-6-yl)methylene)indolin-2-one
Figure imgf000170_0001
A. (E)-3-(2-(l-methyl-lH-imidazol-2-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)- methyl)-lH-indazole-6-carbaldehyde
The title compound was synthesized according to the method of Example A 103, utilizing l-methyl-2-vinyl-lH-imidazole (35 mg, 0.32 mmol) and 3-iodo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (100 mg, 0.23 mmol). Purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound (15 mg, 74 %) as a tan oil (41.6 mg, 47 %). 1H NMR (400 MHz, CD3OD) δ ppm 10.09 (s, 1 H), 8.22 (t, J=LOO Hz, 1 H), 8.13 (d, J= 8.53 Hz,l H), 7.78 (dd, J=8.53, 1.25 Hz, 1 H), 7.68 (d, J=16.06 Hz,l H), 7.43 (d, J=16.06 Hz, 1 H), 7.13 (d, J=1.25 Hz, 1 H), 7.05 (d, J=LOO Hz, 1 H), 5.84 (s, 2 H), 4.89 9s, 3H), 3.63 (t, J=8.03 Hz, 1 H), 0.87 (t, J=8.03 Hz, 2 H), -0.10 (s, 9 H); MS ESI 383.2 [M + H]+, calcd for [C20H26N4O2Si+ H]+ 383.5. B. (E)-3-((3-((E)-2-(l-methyl-lH-imidazol-2-yl)virψl)-l-((2-(trimethylsilyl)- ethoxy)methyl)-lH-indazol-6-yl)methylene)indolin-2-one
Synthesized according to the method of Example A19, utilizing indolin-2-one (14.5 mg, 0.11 mmol) and (£)-3-(2-(l -methyl- lH-imidazol-2-yl) vinyl)- 1 -((2- (trimethylsilyl)-ethoxy)methyl)-lH-indazole-6-carbaldehyde (41.6 mg, 0.11 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound to as a yellow material (35.4 mg, 65%); MS ESI 498.4 [M + H]+, calcd for [C28H3iN5O2Si + H]+ 498.7. C. (E and Z)-3-((3-((E)-2-(l-methyl-lH-imidazol-2-yl)vinyl)-lH-indazol-6- yl)methylene)-indolin-2-one hydrochloride
A sealed, degassed mixture of (£)-3 -((3 -((2s)-2-(l -methyl- lH-imidazol-2-yl)vinyl) 1 -((2-(trimethylsilyl)ethoxy)methy I)- 1 H-indazol-6-yl)methylene)indolin-2-one (35.4 mg, 0.071 mmol) in EtOH (4 mL) and aq HCl (4 M, 1 mL) was heated at 75-80 0C under Ar for 1 d. The reaction mixture was cooled to rt, diluted with MeCN (10 mL) and Et20 (5 mL) and stored at -20 0C overnight. The precipitate was collected by filtration, washed with MeCN to provide the titile compound as a 1.5:1.0 (E:Z) mixture of isomers: a yellow solid (14.5 mg, 51 %). 1H NMR (400 MHz, CD3OD) δ ppm 8.93 (s, 0.44 H), 8.25 (d, J=8.28 Hz, 1.00 H), 8.13 (d, J=8.53 Hz, 0.65 H), 8.02 - 8.06 (m, 0.45 H), 8.02 (s, 1.78 H), 7.92 - 8.00 (m, 1.78 H), 7.86 - 7.91 (m, 1.47 H), 7.58 - 7.71 (m, 5.0 H), 7.53 (d, J=16.81 Hz, 1.29 H), 7.25 (t, J=7.65 Hz, 1.52 H), 7.05 (t, J=7.78 Hz, 0.66 H), 6.94 (d, J=7.78 Hz, 1.01 H), 6.83 - 6.91 (m, 1.73 H), 4.04 (s, 2.46 H), 4.03 (s, 1.41 H); MS ESI 368.1 [M + H]+, calcd for [C22H17N5O+ H]+ 368.4.
Example A106 (E and ZV3-[f3-(rEV2-f4-f(dimethylamino)methylVphenyll- ethenyl}-lH-indazol-6-yl)methylidene]-1.3-dihvdro-2H-indol-2-one 2.2.2- trifluoroacetate
Figure imgf000172_0001
A. (E)-3-(4-((dimethylamino)methyl)styryl)-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indazole-6-carbaldehyde
The title compound was synthesized according to the method of Example A 103, utilizing N,N-dimethyl-l-(4-vinylphenyl)methanamine (42 mg, 0.26 mmol) and 3- iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (70 mg, 0.17 mmol). Purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound to as a pale orange gum (33.4 mg, 44 %). 1H ΝMR (400 MHz, CD3OD) δ ppm 10.13 (s, 1 H), 8.27 (m, 2 H), 7.81 (d, J=9.29 Hz, 1 H), 7.69 (d, J=8.28 Hz, 2 H), 7.61 (d, J=16.6 Hz, 1 H), 7.50 (d, J=16.6 Hz, 1 H), 7.43 (d, J=8.28 Hz, 2 H), 5.86 (s, 2 H), 3.82 (s, 2 H), 3.62 (t, J=8.03 Hz, 1 H), 2.50 (s, 6 H), 0.87 (t, J=8.03 Hz, 2 H), -0.09 (s, 9 H); MS ESI 436.3 [M + H]+, calcd for [C25H33N3O2Si+ H]+ 436.6.
B. (E)-3-((3-(4-((dimethylamim)methyl)styryl)-l-((2-(trimethylsilyl)ethoxy)- methyl)-lH-indazol-6-yl)methylene)indolin-2-one
Synthesized according to the method of Example A 19, utilizing indolin-2-one (10.4 mg, 0.0.78 mmol) and (£>3-(4-((dimethylamino)methyl)styryl)-l-((2- (trimethylsilyl)-ethoxy)methyl)-lH-indazole-6-carbaldehyde (33.4 mg, 0.077 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound to as as a 1.5-2.0: 1.0 (E:Z) mixture of isomers: a yellow solid (29.1 mg, 67 %): 1H NMR (400 MHz, CD3OD) δ ppm 9.09 - 9.14 (s, 0.31 H), 8.22 (d, J=8.28 Hz, 0.84 H), 8.09 (d, J=8.53 Hz, 0.34 H), 7.83 - 7.87 (m, 1.25 H), 7.61 - 7.69 (m, 4.02 H), 7.56 - 7.60 (m, 1.69 H), 7.50 (s, 0.61 H), 7.36 - 7.48 (m, 3.85 H), 7.24 (t, J=7.78 Hz, 1.48 H), 7.03 (t, J=7.28 Hz, 0.48 H), 6.92 (d, J=7.53 Hz, 1.01 H), 6.81 - 6.89 (m, 1.49 H), 5.80 (s, 0.60 H), 5.78 (s, 1.52 H), 3.59 - 3.65 (m, 2.20 H), 2.37 - 2.42 (m, 7.40 H), 0.89 (t, J=8.28 Hz, 3.05 H), -0.09 (s, 9 H); MS ESI 551.4 [M + H]+, calcd for [C33H38N4O2Si + H]+ 551.8.
C. (E and Z)-3-[(3-{(E)-2-[4-((dimethylamino)methyl)phenyl]-ethenyl}-lH- indazol-6-yl)methylidene]-l,3-dihydro-2H-indol-2-one 2,2,2-trifluoroacetate The title compound was synthesized according to the method of Example A105-C utilizing (£>3-((3-(4-((dimethylamino)methyl)styryl)- 1 -((2-(trimethylsilyl)ethoxy)- methyl)-lH-indazol-6-yl)methylene)indolin-2-one (29.1 mg, 0.052 mmol). The crude reaction mixture was concentrated under reduced pressure to dryness, triturated with Et2O and DCM. Later the material was purified by prepTLC (SiO2 30 % MeOH/DCM) followed by prep HPLC to provide the title compound as a 1.7:
1.0 (E:Z) mixture of isomers: a yellow solid (1.8 mg, 6 %); 1H NMR (400 MHz,
D2O) δ ppm 7.93 - 8.36 and 5.96 - 7.33 (m, 13 H), 3.82 (br. s., 2 H), 2.62 (br. s., 6
H); MS ESI 421.2 [M + H]+, calcd for [C27H24N4O + H]+ 421.5.
Example A107 (E and Z)-3-(f3-((EV3-(4-methylpiDerazine-l-carbonvnstyryl)-lH- indazol-6-yl)methylene)indolin-2-one 2,2.2-trifluoroacetate
Figure imgf000173_0001
A. (E)-3-(3-(4-methylpiperazine-l-carbonyl)styryl)-l-((2-
(trimethylsilyl)ethoxy)-methyl)-lH-indazole-6-carbaldehyde The title compound was synthesized according to the method of Example A 103, utilizing l-[(3-ethenylphenyl)carbonyl]-4-methylpiperazine (76 mg, 0.33 mmol) and 3 -iodo- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazole-6-carbaldehyde (100 mg, 0.25 mmol). Purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound to as a colorless material (30.1 mg, 24 %). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1 H), 8.27 (s, 1 H), 7.80 (m, 1 H), 7.71 (s, 1 H), 7.65 (d, J=16.6 Hz, 1 H), 7.56 - 7.60 (m, 1 H), 7.57 (s, 1 H), 7.48 - 7.55 (m, 2 H), 7.35 (d, J=7.28 Hz, 1 H), 5.86 (s, 2 H), 3.69 - 3.90 (m, 2 H), 3.63 (t, J=7.91 Hz, 2 H), 3.43 - 3.56 (m, 2 H), 2.40 - 2.64 (m, 4 H), 2.35 (s, 3 H), 0.88 (t, J=7.91 Hz, 2 H), -0.09 (m, 9 H); MS ESI 505.4 [M + H]+, calcd for [C28H36N4O3Si+ H]+ 505.7.
B. (3E & 3Z)-3-((3-((E)-3-(4-methylpiperazine-l-carbonyl)styryl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH4ndcuol-5-yl)methylene)indolin-2-one The title compound was synthesized according to the method of Example A 19, utilizing indolin-2-one (7.9 mg, 0.059 mmol) and f£>3-(3-(4-methylpiperazine-l- carbonyl)-styryl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazole-6-carbaldehyde (30.1 mg, 0.060 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound as a -2.5:1 (E:Z) mixture of isomers: a yellow solid (21.6 mg, 59 %): 1H NMR (400 MHz, CD3OD) δ ppm 9.06 (s, 0.22 H), 8.20 (d, J=8.28 Hz, 0.72 H), 8.07 (d, J=8.53 Hz, 0.27 H), 7.94 - 7.96 (m, 0.98 H), 7.92 (d, J= 9.0 Hz, 0.82 H), 7.84 (s, 0.82 H), 7.72 - 7.79 (m, 2.53 H), 7.45-7.66 H), 7.31 - 7.36 (m, 1.29 H), 7.18 - 7.25 (m, 1.30 H), 7.01 (t, J=7.40 Hz, 0.42 H), 6.90 (d, J= 7.78 Hz, 0.83 H), 5.78 (s., 0.57 H), 5.77 (s, 1.24 H), 3.75-3.90 (m, 2.28 H), 3.58-3.68 (m, 2.63 H), 3.45-3.57 (m, 2.43 H), 2.39 - 2.62 (m, 4.67 H), 2.36 (s, 3.53 H), 0.84-0.93 (t, J=7.91 Hz, 2.63 H), -0.09 (s, 9.81 H); MS ESI 505.4 [M - CH2CH2SiMe3 - Me + H]+, calcd for [C30H26N5O3*+ H]+ 505.6.
C. (E and Z)-3-((3-((E)-3-(4-methylpiperazine-l-carbonyl)styryl)-lH-indazol- 6-yl)methylene)indolin-2-one 2,2,2-trifluoroacetate
A degassed mixture of (3E)-3-((3-((E)-3-(4-methylpiperazine-l-carbonyl)styryl)-l- ((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazol-5-yl)methylene)indolin-2-one (21.6 mg, 0.035 mmol), tetrabutylammonium fluoride (1.0 M in THF, 0.05 mL, 0.05 mmol) and activated molecular sieves (4 A) in anh. THF (5 mL) was refluxed under Ar for 1 d. The reaction mixture diluted with MeOH, filtered, concentrated under reduced pressure and purified by prepHPLC to provide the title compound as a -4:1 (E:Z) mixture of isomers: a yellow solid (2.8 mg, 14 %). 1H NMR (400 MHz, CD3OD) δ ppm 8.88 (s, 0.28 H), 8.26 (d, J=8.28 Hz, 1.00 H), 8.15 (d, J=8.28 Hz, 0.29 H), 7.98 (d, J=8.28 Hz, 0.37 H), 7.88 - 7.91 (m, 1.65 H), 7.82 - 7.87 (m, 1.51 H), 7.79 (s, 1.14 H), 7.52 - 7.71 (m, 5.35 H), 7.42 (d, J=7.53 Hz, 1.13 H), 7.25 (t, J=7.78 Hz, 1.19 H), 7.05 (d, J=7.53 Hz, 0.28 H), 6.94 (d, J=8.03 Hz, 1.01 H), 6.84 - 6.91 (m, 1.15 H), 3.36 - 3.81 (m, 4.22 H), 3.06 - 3.28 (m, ~4 H), 2.98 (s, 3.42 H); MS ESI 490.3 [M + H]+, calcd for [C30H27N5O2 + H]+ 490.6.
A108 (E and ZV3-(T3-((EV2-(6-(4-methylDiDerazin-l-vnpyridin-3-ylWinylVlH- indazol-6-vDmethyleneMndolin-2-one
Figure imgf000175_0001
A. l-Methyl-4-(5-vinylpyridin-2-yl)piperazine
A sealed, degassed mixture of powdered KOH (123 mg, 2.2 mmol) and 1,2- dibromoethane (0.05 mL, 0.6 mmol) in anh THF (2 mL) under Ar was heated under microwave irradiation at 95 0C for 70 min. The reaction mixture was then cooled to rt and treated with Pd(OAc)2 (5.0 mg, 0.022 mmol), PPh3 (11.5 mg, 0.044 mmol), 1 -methyl-4-(5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (120 mg, 0.39 mmol) and degassed MeOH (2 mL). The sealed reaction mixture was heated again under microwave irradiation at 95 0C for 60 min. The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound a colorless gum (0.18 g, quant): 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J=2.26 Hz, 1 H), 7.73 (dd, J=8.91, 2.38 Hz, 1 H), 6.82 (d, J=9.03 Hz, 1 H), 6.62 (dd, J=I 7.82, 11.04 Hz, 1 H), 5.63 (d, 1 H), 5.12 (d, J=10.79 Hz, 4 H), 3.52 - 3.66 (m, 4 H), 2.50 - 2.61 (m, 4 H), 2.35 (s, 3 H); MS ESI 204.0 [M + H]+, calcd for [Ci2H17N3+ H]+ 204.3.
B. (E)-3-(2-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)vinyl)-l-((2-(trimethylsilyl)- ethoxy)methyl)-lH-indazole-6-carbaldehyde
The title compound was synthesized according to the method of Example A 103, utilizing l-methyl-4-(5-vinylpyridin-2-yl)piperazine (65 mg, 0.32 mmol) and 3- iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (100 mg, 0.25 mmol). Purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound to as a pale orange material (46 mg, 39 %). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1 H), 8.34 (d, J=2.26 Hz, 1.0 H), 8.24 - 8.28 (m, 2 H), 8.00 (dd, J=8.91, 2.38 Hz, 1 H), 7.80 (d, J=8.78 Hz, 1 H), 7.51 (d, J=16.56 Hz, 1 H), 7.36 (d, J=16.56 Hz, 1 H), 6.97 (d, J=9.29 Hz, 1 H), 5.85 (s, 2 H), 3.77 - 3.87 (m, 4 H), 3.63 (t, J=7.91 Hz, 2 H), 3.06 - 3.15 (m, 4 H), 2.75 (s, 3 H), 0.88 (t, J=8.03 Hz, 2 H), -0.09 (s, 9 H); MS ESI 478.3 [M + H]+, calcd for [C26H35N5O2Si + H]+ 478.7.
C. (E & Z)-3-((3-((E)-2-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)vinyl)-lH- indazol-6-yl)methylene)-l-((2-(trimetnylsilyl)ethoxy)methyl)indolin-2-one The title compound was synthesized according to the method of Example A 19, utilizing indolin-2-one (8.3 mg, 0.062 mmol) and (E)-3-(2-(6-(4-methylpiperazin-l- yl)pyridin-3 -yl)vinyl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazole-6- carbaldehyde (46 mg, 0.096 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound as a (E :Z) mixture of isomers: a yellow solid (22.5 mg, 40 %); MS ESI 593.4 [M+ H]+, calcd for [C34H40N6O2Si + H]+ 593.8.
D. (E & Z)-3-((3-(β)-2-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)vinyl)-lH- indazol-6-yl)methylene) indolin-2-one dihydrochloride
The title compound was prepared according to the method of Example A105-C utilizing (E & ZJ-3-((3-((E)-2-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)vinyl)-lH- indazol-6-yl)-methylene)-l-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one (22.5 mg, 0.038 mmol). The crude reaction mixture was stored at -20 0C overnight. The precipitate was collected by filtration, washed with MeCN to provide the titile compound as a -4:1 (E:Z) mixture of isomers: a yellow solid (6.9 mg, 34 %). 1H NMR (400 MHz, CD3OD) δ ppm 8.87 (s, 0.16 H), 8.56 (d, J=9.54 Hz,1.0 H), 8.33
(s, 0.95 H), 8.26 (d, J=8.28 Hz, 0.72 H), 8.14 (d, J=9.54 Hz, 0.23 H), 7.98 (d, J=8.53
Hz, 0.20 H), 7.85 - 7.91 (m, 1.56 H), 7.68 (d, J=7.03 Hz, 0.25 H), 7.65 (d, J=7.78
Hz, 0.86 H), 7.50 - 7.61 (m, 3.31 H), 7.25 (t, J=7.53 Hz, 1.03 H), 7.05 (t, J=8.03 Hz,
0.24 H), 6.94 (d, J=7.53 Hz, 0.73 H), 6.84 - 6.91 (m, 0.93 H), 4.49 (br. s., 1.66 H), 3.73 (br. s., 3.84 H), 3.34 - 3.52 (m, 1.47 H), 3.03 (s, 2.78 H); MS ESI 463.2 [M +
H]+, calcd for [C28H26N6O + H]+ 462.5. Example A109: (E and ZV5-bromo-3-((3-((EV2-(pyridin-4-vnvinvn-lH-indazol-6- vDmethyl-ene)- 1 H-pyrrolor2.3-blpyridin-2(3HVone
Figure imgf000177_0001
The title compound (64 mg, 64 %) was synthesized as a greenish yellow solid according to the method described for Example A67 (oil temp 75 0C, reflux 2 h) using 5-bromo-lH-pyrrolo[2,3-b]pyridin-2(3H)-one (42.6 mg, 0.2 mmol) and (E)- 3-(2-(pyridin-4-yl)vinyl)-lH-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR indicated 7:6 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 5.2 Hz, 2H), 8.34 (d, J = 8.4 Hz, IH), 8.26 (d, IH), 8.22 (s, IH), 8.12 (d, J = 8.8 Hz, IH), 8.03 (s, IH), 7.93 (d, IH), 7.89 (d, J = 16.8 Hz, IH), 7.72 (t, J = 4.8 Hz, 2H), 7.55 (d, J = 16.0 Hz, IH); MS ESI 444.3 [M + H]+, calcd for [C22H14BrN5O + H]+ 444.0.
Example Al 10: (E and ZVethyl 3-(6-((EV(2-oxo-lH-pyrrolor2.3-blpyridin-3(2HV ylidene)methvD- 1 H-indazol-3-vOacrylate
Figure imgf000177_0002
The title compound (46 mg, 64 %) was synthesized as a brown solid according to the method described for Example A67 (oil temp 75 0C, reflux 2 h) using lH-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and (E)-ethyl 3-(6- formyl-lH-indazol-3-yl)acrylate (48.8 mg, 0.2 mmol). 1H NMR indicated 7:3 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.30 (br. s, IH, NH), 11.20 (br. s, IH, NH), 8.26 (d, J = 8.8 Hz, IH), 8.11 (d, J = 5.5 Hz, IH, partially overlapping with the peak at 8.09 ppm), 8.09 (d, J = 6.4 Hz, IH, partially overlapping with the peak at 8.11 ppm), 7.95 (d, J = 17.2 Hz, IH, partially overlapping with the peak at 7.93 ppm), 7.93 (s, IH, partially overlapping with the peak at 7.95 ppm), 7.87 (d, J = 7.6 Hz, IH), 7.56 (d, J = 8.0 Hz, IH), 6.90 (dd, J = 7.6 Hz, 4.8 Hz, IH), 6.81 (d, J = 16.4 Hz, IH), 4.23 (q, J = 6.8 Hz, 2H), 1.29 (t, J = 6.8 Hz, 3H); MS ESI 361.1 [M + H]+, calcd for [C20H16N4O3 + H]+ 361.1.
Example Al 11: fEVethyl 3-(6-((EV(5-methoxy-2-oxoindolin-3-ylidene>)methvn-lH- indazol-3 -vDacrylate
Figure imgf000178_0001
The title compound (60 mg, 77 %) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75 0C, reflux 2 h) using 5-methoxyoxindole (26.8 mg, 0.2 mmol) and (E)-ethyl 3-(6-formyl-lH- indazol-3-yl)acrylate (48.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (brs, IH, NH), 10.44 (s, IH, NH), 8.26 (d, J = 8.4 Hz, IH), 7.96 (s, IH), 7.92 (d, J = 16.4 Hz, IH), 7.77 (s, IH), 7.56 (d, J = 8.4 Hz, IH), 7.14 (d, IH), 6.90-6.80 (m, 3H), 4.23 (q, J = 7.2 Hz, 2H), 3.58 (s, 3H), 2.29 (t, J = 7.2 Hz, 3H); MS ESI 390.3 [M + H]+, calcd for [C22Hi9N3O4 + H]+ 390.1.
Example Al 12. ffiV5-methoxy-3-((3-(6-moφholinopyridin-3-yD-lH-indazol-6-yl)- methylene)indolin-2-one
Figure imgf000178_0002
A. 3-(6-morpholinopyridin-3-yl)-lH-indazole-6-carbaldehyde According to procedure for the synthesis of 3-(pyridin-3-yl)-lH-indazole-6- carbaldehyde, except substituting 2-(4-morpholino)pyridine-5-boronic acid pinacol ester (64 mg, 0.22 mmol), the title compound was prepared as a yellow powder (35 mg, 62%). 1H NMR (400 MHz, de-DMSO) δ ppm 13.71 (br s, IH), 10.14 (s, 1 H), 8.77 (d, J = 1.9 Hz, 1 H), 8.02-8.18 (m, 2H), 8.15 (dd, J = 8.9 Hz, 2.5, IH), 7.64 (d, J = 8.6 Hz, IH), 7.00 (d, J = 8.8 Hz, IH), 3.73 (t, J = 4.5 Hz, 4H), 3.53 (t, J = 5.1 Hz, 4H); MS ESI 309.1 (100) [M + H]+, calcd for [C17H16N4O2 + H]+ 309.13.
B. (E)-5-methoxy-3-((3-(6-morpholinopyridin-3-yl)-lH-indazol-6 yl)methylene)-indolin-2-one According to procedure for the synthesis of (E)-3-((lH-indazol-6- yl)methylene)indolin-2-one, except substituting 3-(6-morpholinopyridin-3-yl)-lH- indazole-6-carbaldehyde (35 mg, 0.11 mmol), the title compound was preapred as an orange powder (22 mg, 42 %). 1H NMR (400 MHz, de-DMSO) δ 13.37 (br s, IH), 10.43 (br s, IH), 8.79 (d, J = 2.2 Hz, IH), 8.17 (d, J = 8.6 Hz, 2H), 7.93 (s, IH), 7.79 (s, IH), 7.49 (d, J = 8.0 Hz, IH), 7.21 (d, J = 1.8 Hz, IH), 7.00 (d, J = 9.0 Hz, IH), 6.85 (dd, J = 8.5, 2.0 Hz, IH), 6.80 (d, J =8.6 Hz, IH), 3.73 (t, J = 4.6 Hz, 4H), 5.59 (s, 3H), 3.53 (t, J = 4.8 Hz, 4H); MS ESI 454.3 [M + H]+, calcd for [C26H23N5O2 + H]+ 454.18.
Example Al 13: (E)-3-((3-((EV2-fpyridin-3-yl)vinvn-lH-indazol-6-vnmethylene)- indolin-2-one
Figure imgf000179_0001
The title compound (61 mg, 84 %) was synthesized as a yellow solid according to the method described for Example A67 (oil temp 75 0C, reflux 90 min) using oxindole (26.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-lH-indazole- 6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, IH, NH), 10.64 (s, IH, NH), 8.91 (s, IH), 8.48 (d, J = 4.4 Hz, IH), 8.36 (d, J = 8.4 Hz, IH), 8.20 (d, J = 8.4 Hz, IH), 7.90 (s, IH), 7.80 (s, IH), 7.73 (d, J = 16.8 Hz, IH), 7.61 (d, J = 7.2 Hz, IH, partially overlapping with the peak at 7.60 ppm), 7.60 (d, J = 17.2 Hz, IH, partially overlapping with the peak at 7.61 ppm), 7.54 (d, J = 8.4 Hz, IH), 7.43 (dd, J = 7.8 Hz, 4.8 Hz, IH), 7.24 (t, J = 7.8 Hz, IH), 6.89 (d, J = 7.6 Hz, IH), 6.85 (t, J = 7.8 Hz, IH); MS ESI 365.1 [M + H]+, calcd for [C23H16N4O + H]+ 365.1.
Example Al 14: (E and ZV3-((3-((E>2-(pyridin-3-vnvinvn-lH-indazol-6- vDmethyleneV 1 H-pyrrolo[2.3-b1pyridin-2(3H')-one
Figure imgf000180_0001
The title compound (59 mg, 81 %) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75 0C, reflux 90 min) using lH-pyrrolo[2,3-b]ρyridin-2(3H)-one (26.8 mg, 0.2 mmol) and (E)-3-(2- (pyridin-3-yl)vinyl)-lH-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR indicated 5:2 mixture of Z/E isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, IH, NH), 11.30 (s, IH, NH), 8.95 (s, IH), 8.91 (d, IH), 8.47 (d, J = 4.4 Hz, IH), 8.31 (d, J = 8.4 Hz, IH), 8.19 (d, J = 7.2 Hz, IH), 8.13-8.07 (m, 4H), 7.72 (d, J = 16.8 Hz, IH), 7.59 (d, J = 17.2 Hz, IH), 7.42 (dd, J = 8.0 Hz, 4.4 Hz, IH), 7.50 (dd, J = 7.2 Hz, 5.6 Hz, IH); MS ESI 444.3 [M + H]+, calcd for [C22H15N5O + H]+ 366.1.
Example Al 15: (E and ZV5-methoxy-3-((3-((EV2-(pyridin-3-yl)vinyl)-lH-indazol- 6-vDmethylene)indolin-2-one
Figure imgf000180_0002
The title compound (53 mg, 67 %) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75 0C, reflux 90 min) using 5-methyoxyoxindole (32.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)- lH-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR indicated 4:1 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.50 (br. s, IH, NH), 10.44 (s, IH, NH), 8.91 (d, IH), 8.48 (d, J = 4.8 Hz, IH), 8.36 (d, J = 8.4 Hz, IH), 8.20 (d, J = 7.6 Hz, IH), 7.92 (s, IH), 7.79 (s, IH), 7.73 (d, J = 16.8 Hz, IH), 7.59 (d, J = 16.4 Hz, IH), 7.54 (d, J = 8.8 Hz, IH), 7.43 (dd, J = 8.0 Hz, 5.2 Hz, IH), 7.19 (d, IH), 6.86 (dd, J = 8.4 Hz, 2.0 Hz, IH), 6.81 (d, J = 8.4 Hz, IH), 3.78 (s, 3H); MS ESI 395.2 [M + H]+, calcd for [C24H18N4O2 + H]+ 395.1.
Example Al 16. (E)-3-((3-(6-(dimethylamino)pyridin-3-yl)-lH-indazol-6-yl)methyl- ene)-5 -methoxyindolin-2-one
Figure imgf000181_0001
A.
According to the procedure for the synthesis of 3-(pyridin-3-yl)-lH-indazole-6- carbaldehyde, except substituting 2-(dimethylamino)pyridine-5-boronic acid hydrate (41 mg, 0.22 mmol), the title compound was prepared as a yellow powder (14 mg, 29%). 1H NMR (400 MHz, d6-DMSO) δ ppm 10.13 (s, 1 H), 8.72 (d, J = 2.4 Hz, 1 H), 8.17-8.16 (m, 2H), 8.09 (dd, J = 8.4, 2.1 Hz, IH), 7.62 (d, J = 8.9 Hz, IH), 6.79 (d, J = 8.8 Hz, IH), 3.09 (s, 6H); MS ESI 267.0 (100) [M + H]+, calcd for [C15H14N4O + H]+ 267.12.
B. (E)-3-((3-(6-(dimethylamino)pyridin-3-yl)-lH4ndazol-6-yl)rnethylene)-5- methoxyindolin-2-one According to the procedure for the synthesis of (E)-3-(( 1 H-indazol-6-yl)- methylene)-indolin-2-one, except substituting 3-(6-(dimethylamino)pyridin-3-yl)- lH-indazole-6-carbaldehyde (14 mg, 0.053 mol), the title compound was prepared as a red solid (2.9 mg, 13 %). 1H NMR (400 MHz, de-DMSO) δ 13.30 (br. s, IH), 10.43 (br s, IH), 8.75 (s, IH), 8.15 (d, J = 8.7 Hz, IH), 8.11 (d, J = 8.4 Hz, IH), 7.92 (s, IH), 7.78 (s, IH), 7.47 (d, J = 7.7 Hz, IH), 7.22 (s, IH), 6.86-6.79 (m, 3H), 3.60 (s, 3H), 3.10 (s, 6H); MS ESI 412.2 [M + H]+, calcd for [C24H2iN5O2 + H]+
Example Al 17. 4-(TEV2-(6-((EV(5-methoxy-2-oxoindolin-3-ylidene)methylHH- indazol-3-v0vinyDpyridine 1 -oxide
Figure imgf000182_0001
According to the procedure for the synthesis of 2-((E)-2-(6-((E)-(5-methoxy-
2-oxoindolin-3-ylidene)methyl)-lH-indazol-3-yl)vinyl)pyridine 1-oxide (Example A88), except substituting (E)-5-methoxy-3-((3-((E)-2-(pyridin-4-yl)vinyl)-lH- indazol-6-yl)methyl-ene)indolin-2-one (8.1 mg, 0.021 mmol), the title compound was prepared as an orange solid (1.3 mg, 15 %.). 1H NMR (400 MHz, DMSO-d6) δ 13.55 (br. s, IH), 10.45 (s, IH), 8.35 (d, J = 8.6 Hz, IH), 8.20 (d, J = 6.8 Hz, 2H), 7.93 (s, IH), 7.79-7.72 (m, 4H), 7.55 (d, J = 14.3 Hz, IH), 7.54 (d, J = 8.9 Hz, IH), 7.17 (d, J = 2.7 Hz, IH), 6.86 (dd, J = 8.5, 2.7 Hz, IH), 6.80 (d, J = 8.5 Hz, IH), 3.60 (s, 3H); MS ESI 411.2 [M + H]+, calcd for [C24H18N4O3 + H]+ 411.14.
Example Al 18. (E and ZV5-methoxy-3-((3-((E>3-f4-methvIρiperazin-l-ylV3- oxoprop- 1 -enylV 1 H-indazol-6-v0methyleneMndolin-2-one
Figure imgf000182_0002
The synthetic method followed that described in Example A66 starting from 5- methoxyoxindole (10 mg, 0.0583 mmol) and (E)-3-(3-(4-methylpiperazin-l-yl)-3- oxoprop- 1 -enyl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazole-6-carbaldehyde (25 mg, 0.0.0583 mmol) to give 2.5 mg of the title compound as an 85:15 mixture of (E)I(Z) isomers. 1H NMR (400 MHz, CD3OD) 8.95, 7.80 (s, IH), 8.21-8.16 (m, IH), 7.97-7.87 (m, 2H), 7.59 (d, J = 7.52 Hz, IH), 7.45 (d, J = 15.7 Hz, IH), 7.32, 7.22 (s, IH), 6.85 (s, 2H), 3.84, 3.63 (s, 3H), 3.90-3.75 (m, 4H), 2.62-2.48 (br. s, 4H), 2.34 (s, 3H); MS ESI 444.2 [M + H]+, calcd for [C25H25N5O3 + H]+ 444.20.
Example Al 19. (EV3-(f3-(rEV2-f3-chloroρyridin-4-vnvinvn-lH-indazol-6- v0methyl-ene)-5-methoxyindolin-2-one
Figure imgf000183_0001
A. 3-chloro-4-vinylpyridine
A dry round-bottom flask containing with methyltriphenylphosphonium iodide (632 mg, 1.77 mmol) and THF (25 mL) was cooled with an ice-water bath and the suspension treated with w-BuLi (1.0 mL of a 1.6M solution in hexanes) and the reaction stirred for 0.5 hours. The solution was cooled to -78 0C and 3- chloroisonicotinaldehyde (250 mg, 1.77 mmol) was added portion-wise and then the reaction was allowed to warm to room temperature over 4 hours. The reaction was quenched with AcOH (0.10 mL) and the THF removed in vacuo. The residue was dissolved in EtOAc and then washed with water (2X), and brine (2X), the organic layer dried (MgSO4) and the EtOAc was removed. The residue was purified by column chromatography, silica gel (99:1 to 98:2 CH2Cl2 / MeOH) to give the title compound (135 mg, 55 %) as a yellow oil. MS ESI 140.0 [M + H]+, calcd for [C7H6ClN+ H]+ 140.03.
B. β)-3-((3-((E)-2-(3-chloropyridin-4-yl)vinyl)-lH-indazol-6-yl)methylene)- 5-methoxyindolin-2-one The synthetic method followed that described in Example A57 starting from 3- chloro-4-vinylpyridine (42 mg, 0.299 mmol) and 3-iodo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (100 mg, 0.249 mmol) with a modified purification procedure. The title compound was purified by prep- HPLC to give 4.0 mg of an orange-red powder. 1H NMR (400 MHz, CD3OD) δ 8.97 (s, IH), 8.67 (s, IH), 8.50 (d, J = 5.20 Hz, IH), 8.11-7.84 (m, 6H), 7.33 (s, IH), 6.86-6.78 (m, 2H), 3.85 (s, 3H); MS ESI 429.2 [M + H]+, calcd for [C24H17ClN4O2 + H]+ 429.11.
Example A120: N-f (EV2-oxo-3-((3-((EV2-(pyridin-4-vnvinvn-lH-indazol-6-vn- methyleneMndolin-7-y0acetamide
Figure imgf000184_0001
A. N-((E)-2-oxo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-l-((2-
(trimethylsilyl)ethoxy)-methyl)-lH-indazol-6-yl)methylene)indolin-7-yl)acetamide According to the method of A57B, N-(2-oxoindolin-7-yl)acetamide (30 mg, 0.16 mmol) was reacted with (E)-3-(2-(pyridin-4-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy) methyl)- lH-indazole-6-carbaldehyde (60 mg, 0.16 mmol) to give the title compound as an orange solid (64 mg, 72%). MS ESI 552.3 [M + H]+, calcd for [C31H33N5O3Si +H]+ 552.2. B. N-((E)-2-oxo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-lH-indazol-6- yl)methylene)-indolin-7-yl)acetamide
According to the method of A57C, N-((E)-2-oxo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-6-yl)methylene)indolin-7- yl)acetamide (64 mg, 0.11 mmol) was treated with boron trifluoride etherate, followed by 2 N HCl to give the title compound as an orange solid (33 mg, 71%). 1H NMR (400 MHz, d6-DMSO) δ 10.33 (s, IH), 9.42 (s, IH), 8.85 (d, J = 6.2 Hz, 2H), 8.46-8.30 (m, 4H), 7.98(s, IH), 7.87-7.78 (m, 2H), 7.80 (s, IH), 7.63 (d, J = 8.2 Hz, IH), 7.42-7.35 (m, 2H), 6.81 (t, J = 8.1 Hz, IH), 2.05 (s, 3H); MS ESI 422.1 [M + H]+, calcd for [C25H19N5O2+ H]+ 422.2. Example A121: tert-butyl (EV2-oxo-3-((3-((EV2-(Dyridin-4-vnvinylVlH-indazol-6- yOmethyleneMndolin-5-ylcarbamate
Figure imgf000185_0001
The title compound (102 mg, 76 %) was synthesized as orange-yellow solid according to the method described for Example Al IB from tert-butyl 2-oxoindolin- 5-ylcarbamate (70 mg, 0.282 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-lH-indazole- 6-carbaldehyde (70 mg, 0.282 mmol). 1H NMR (400 MHz, d6-DMSO) δ 13.53 (s, IH), 10.47 (s, IH), 9.14 (s, IH), 8.55 (d, J = 6.5 Hz, 2H), 8.33 (d, J = 8.8 Hz, IH), 7.88-7.83 (m, 3H), 7.74 (s, 2H), 7.69 (d, J = 6.5 Hz, 2H), 7.56-7.50 (m, 2H), 6.75 (d, J = 8.2 Hz, IH), 1.34 (s, 9H); MS ESI 480.3 [M + H]+, calcd for [C28H25N5O3 + H]+ 480.20.
Example A122: (EV5-amino-3-((3-((EV2-(pyridin-4-vnvinylVlH-indazol-6-vn- methylene)indolin-2-one bis('2.2.2-trifluoroacetate)
Figure imgf000185_0002
/erf-Butyl (E)-2-oxo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-lH-indazol-6-yl)- methyl-ene)indolin-5-ylcarbamate (13 mg, 0.027 mmol) was dissolved into CH2Cl2 (1.0 mL) and then trifluoroacetic acid (0.1 mL) was added and the reaction stirred for 1 hour. The solvent was removed and the residue titurated with ether/EtOAc to give after drying 4.6 mg, 29 % of the title compound as an orange powder. 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J = 5.8 Hz, 2H), 8.31 (d, J = 8.7 Hz, IH), 8.21-8.12 (m, 3H), 7.97 (s, IH), 7.88 (s, IH), 7.70 (d, J = 16.8 Hz, IH), 7.62-7.57 (m, 2H), 7.18 (d, J = 8.8 Hz, IH), 6.99 (d, J = 8.6 Hz, IH); MS ESI 380.1 [M + H]+, calcd for [C23Hi7N5O + H]+ 380.15.
Example Al 23 : (E)-3-(( 1 H-indazol-6-v0methyleneV5-hvdroxyindolin-2-one
Figure imgf000186_0001
A. 5-Hydroxyindolin-2-one
An oven-dried flask was charged with BBr3.SMe2 (2.80 g, 9.20 mmol) and 1,2-dichloroethane (15 mL). 5-Methoxyindolin-2-one (0.3Og, 1.84 mmol) was then added and the mixture was heated to reflux for 18 hours. The reaction was then cooled to room temperature and quenched with MeOH (1.0 mL). The mixture was then extracted into EtOAc washing with brine (3X). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo; the resulting residue was then purified by column chromatography (silica gel, 94:6 to 92:8, CH2Cl2/Me0H) to give 144 mg, 53 % of a beige powder. MS ESI 149.9 [M + H]+, calcd for [C8H7NO2+ H]+ 150.06
B. (E)-3-((lH-indazol-6-yl)methylene)-5-hydroxyindolin-2-one
The title compound was synthesized according to the method described for Example AIlB from 5-Hydroxyindolin-2-one (16 mg, 0.107 mmol) and precipitation with 98:2 CH2Cl2MeOH to obtain the title compound (18 mg, 60 %). 1H NMR (400 MHz, CD3OD) δ 8.14 (s, IH), 7.92 (d, J = 8.0 Hz, IH), 7.87 (s, IH), 7.85 (s, IH), 7.44 (d, J = 8.0 Hz, IH), 7.15 (s, IH), 6.75 (d, J = 8.2 Hz, IH), 6.69 (d, J = 8.2 Hz, IH); MS ESI 278.0 [M + H]+, calcd for [Ci6H11N3O2 + H]+ 278.09.
Example A124: (EV5-hvdroxy-3-((3-((E)-2-fpyridin-4-vnvinylVlH-indazol-6- yl)methylene)indolin-2-one 2.2.2-trifluoroacetate
Figure imgf000187_0001
The title compound was synthesized according to the method described in Example A57 from 5-Hydroxyindolin-2-one (10 mg, 0.107 mmol) with a modified purification procedure. The title compound was purified by preparatory HPLC to give 10 mg, 30 % of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J = 6.5 Hz, 2H), 8.35 (d, J = 8.8 Hz, IH), 8.27 (d, J = 6.5 Hz, 2H), 8.24 (d, J = 16.4 Hz, IH), 7.94 (s, IH), 7.88 (s, IH), 7.83 (d, J = 16.4 Hz, IH), 7.61 (d, J = 8.1 Hz, IH), 7.13 (s, IH), 6.77 (d, J = 8.2 Hz, IH), 6.71 (d, J = 8.2 Hz, IH); MS ESI 381.1 [M + H]+, calcd for [C23H16N4O2 + H]+ 381.13.
Example A125: (E and ZVN-(2-(dimethylamino)ethyl)-N-methyl-3-(6-((E)-(5- methyl-2-oxoindolin-3-ylidene)methyl)- 1 H-indazol-3-yl)acrylamide
Figure imgf000187_0002
A. (E)-N-(2-(dimethylamino)ethyl)-3-(6-formyl-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indazol-3-yl)-N-methylacrylamide
A dry round-bottom flask was charged with Nl,Nl,N2-trimethylethane-l,2- diamine (0.32 mL, 2.50 mmol), diisopropylethylamine (0.87 mL, 5.00 mmol) and CH2Cl2 (12 mL) and the solution cooled with an ice-water bath. Acryloyl chloride (0.20 mL, 2.50 mmol) was added dropwise and the reaction allowed to warm to room temperature. After 3 hours the solvent was removed and the residue purified by column chromatography (silica gel, 88:10:2, CH2Cl2/Me0H/7M NH3 in MeOH) to give 50 mg of a crude oil to which was added 3-iodo-l-((2- (tτimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (105 mg, 0.262 mmol), DMF (5 mL) and diisopropylethylamine (0.091 mL, 0.524 mmol). The mixture was degassed by bubbling Argon through the solution for 15 min. Pd(OAc)2 (3.0 mg, 0.013 mmol) and P(o-tolyl)3 (12 mg, 0.039 mmol) were then added and the reaction heated to 110 0C for 18 hours. The mixture was cooled to room temperature, NaHCθ3(Sat.) (5 mL) was added, and the product extracted (3X) with EtOAc. The organic layer was washed with water (2X) and brine (2X), and then dried over MgSO4. After removal of solvent the residue was purified by column chromatography (silica gel, 93:6:1, CH2Cl2/Me0H/7M NH3 in MeOH) to give 41 mg, 41 % of a red-orange oil. MS ESI 431.2 [M + H]+, calcd for [C22H34N4O3Si + H]+ 431.25.
B. (E and Z)-N-(2-(dimethylamino)ethyl)-N-methyl-3-(6-((E)-(5-methyl-2- oxoindolin-3-ylidene)methyl)-lH-indazol-3-yl)acrylamide The title compound was synthesized according to the method described in
Example A57 from 5-methylindolin-2-one (8.0 mg, 0.0535 mmol) and (E)-N-(2- (dimethylamino)ethyl)-3-(6-formyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- indazol-3-yl)-N-methylacrylamide (23 mg, 0.0535 mmol) with a modified purification procedure. The product was extracted into EtOAc after the final deprotection step and washed with NaHCO3(SaO (2X)» brine (2X) and the organic layer dried over MgSO4. After removal of solvent the resulting film was titurated with Et2O/hexanes to give after drying 9.4 mg, 41% yield of a yellow solid which was a 77:23 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) δ 8.94, 7.91 (s, IH), 8.20, 8.16 (d, J = 8.7 Hz, IH), 7.98-7.93 (m, IH), 7.84 (s, IH), 7.59, 7.43 (d, J = 8.2 Hz, IH), 7.52-7.42 (m, 2H), 7.08 (d, J = 7.2 Hz, IH), 6.82, 6.78 (d, J = 7.6 Hz, IH), 3.77-3.68 (m, 2H), 3.60, 3.13 (s, 3H), 2.68-2.61 (m, 2H), 2.37 (s, 6H), 2.19 (s, 3H); MS ESI 430.3 [M + H]+, calcd for [C25H27N5O2 + H]+ 430.22.
Example A126: (E)-N-(2-(dimethylamino)ethvn-3-r6-((EV(5-methoxy-2- oxoindolin-3 -ylidene)methvD- 1 H-indazol-3 -y D-N-methylacrylamide 2,2,2- trifluoroacetate
Figure imgf000189_0001
The title compound was synthesized according to the method described in Example A57 from 5-methoxyindolin-2-one (8.0 mg, 0.0535 mmol) and (E)-N-(2- (dimethylamino)ethyl)-3-(6-formyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- indazol-3-yl)-N-methylacrylamide (23 mg, 0.0535 mmol) with a modified purification procedure. The final compound was purified by preparatory-HPLC to give 4.0 mg, 17% of a yellow powder. 1H NMR (400 MHz, CD3OD) δ 8.17 (d, J = 8.6 Hz, IH), 8.02 (d, J = 15.7 Hz, IH), 7.94 (s, IH), 7.88 (s, IH), 7.59 (d, J = 8.1 Hz, IH), 7.44 (d, J = 15.5 Hz, IH), 7.21 (s, IH), 6.86 (s, 2H), 3.95-3.90 (m, 2H), 3.63 (s, 3H), 3.46-3.42 (m, 2H), 3.36 (s, 3H), 3.03 (s, 6H); MS ESI 446.3 [M + H]+, calcd for [C25H27N5O3 + H]+ 446.22.
Example A127: (EV5-isoDropyl-3-fG-f(EV2-(pyridin-4-yl)vinyl)-lH-indazol-6- yl)methylene)indolin-2-one 2.2.2-trifluoroacetate
Figure imgf000189_0002
A. 5-isopropylindolin-2-one
A mixture of 5-bromoindolin-2-one (106 mg, 0.500 mmol), isopropenylboronic acid pinacol ester (0.14 mL, 0.750 mmol), K3PO4 (212mg, 1.00 mmol), water (ImL) and H-BuOH (4mL) was briefly sonicated in a microwave vial and then purged with argon for 15 min. Tris(dibenzyldeneacetone)dipalladium (9.2 mg, 0.010 mmol) and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (19 mg, 0.040 mmol) were added, the vial sealed and heated in microwave reactor at 110 0C for 1 hour. The solvent was removed and the residue purified by column chromatography (silica gel, 2:1, hexanes/EtOAc) to give 40 mg, 46% of 5- isopropenylindolin-2-one as a beige solid; 5-isopropenylindolin-2-one (15 mg, 0.0866 mmol) was then dissolved into MeOH and the solution purged with N2 (g). 2 mg of 10 % Pd/C (Degussa type) was then added and the mixture purged briefly with H2 (g). The mixture was stirred under 1 atm of H2 (g>for 3 hours and then filtered through a pad of celite. The solvent was removed to give 15 mg, 99 % of the product as an off-white solid. MS ESI 176.0 [M + H]+, calcd for [C11H13NO + H]+ 176.11. B. β)-5-isopropyl-3-((3-(β)-2-(pyridin-4-yl)vinyl)-lH-indazol-6- yl)methylene)indolin-2-one 2,2,2-trifluoroacetate
The title compound was synthesized according to the method described in Example A57 from 5-isopropylindolin-2-one (7.0 mg, 0.040 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (15 mg, 0.040 mmol) with a modified purification procedure. The final compound was purified by preparatory-HPLC to give 3.1 mg, 19 % yield of a yellow powder. 1H NMR (400 MHz, CD3OD) δ 8.72 (d, J = 6.7 Hz, 2H), 8.36 (d, J = 8.1 Hz, IH), 8.26 (d, J = 6.7 Hz, 2H), 8.24 (d, J = 16.3 Hz, IH), 7.96 (s, IH), 7.87 (s, IH), 7.78 (d, J = 16.3 Hz, IH), 7.64 (d, J = 6.7 Hz, IH), 7.53 (s, IH), 7.15 (d, J = 6.5 Hz, IH), 6.86 (d, J = 7.9 Hz, IH), 2.77-2.72 (m, IH), 1.12 (d, J = 6.9 Hz, 6H); MS ESI 407.2 [M + H]+, calcd for [C26H22N4O + H]+ 407.19.
Example A128: (E and ZV2-oxo-3-((3-(fEV2-(pyridin-4-vnvinylVlH-indazol-6- yDmethylene)indoline-5-carbonitrile
Figure imgf000190_0001
The title compound was synthesized according to the method described in
Example A57 from 2-oxoindoline-5-carbonitrile (10 mg, 0.063 mmol) and (E)-3-(2- (pyridin-4-yl)vinyl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazole-6- carbaldehyde (25 mg, 0.063 mmol) with a modified purification procedure. The product was precipitated with EtOAc and filtered washing with EtOAc to give 4.5 mg, 30% of a yellow powder which was a 65:35 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, d6-DMSO) δ 14.04, 13.94 (s, IH), 11.24, 11.22 (s, IH), 9.01, 8.42 (s, IH), 8.83 (d, J = 5.5 Hz, 2H), 8.50-8.17 (m, 3H), 8.03 (s, IH), 7.99 (s, IH), 7.86 (s, IH), 7.81-7.65 (m, 3H), 7.07, 7.01 (d, J = 8.4 Hz, IH); MS ESI 390.1 [M + H]+, calcd for [C24H15N5O + H]+ 390.14.
Example A129: (E and ZVN-(2-(dimethylaminotethyl>N-methyl-2-oxo-3-(T3-((E)- 2-(pyridin-4-vDvinylHH-indazol-6-yl)methyleneMndoline-5-sulfonamide
Figure imgf000191_0001
A. N-(2-(dimethylamino)ethyl)-N-methyl-2-oxoindoline-5-sulfonamide
To a solution of Nl5Nl, N2-trimethylethane-l,2-diamine (26 uL, 0.20 mmol) in THF (2 mL) was added 2-oxoindoline-5-sulfonyl chloride (30 mg, 0.130 mmol) and the reaction stirred for 3 hours. The solvent was removed and the crude material used for the next step. MS ESI 298.0 [M + H]+, calcd for [Ci3H19N3O3S + H]+
298.12.
B. (E and Z)-N-(2-(diimthylamino)ethyl)-N-methyl-2-oxo-3-((3-((E)-2-(pyridin-4- yl)vinyl)-lH-ina\aol-6-yl)methylene)indoline-5-sulfonamide
The title compound was synthesized according to the method described in Example A57 from N-(2-(dimethylamino)ethyl)-N-methyl-2-oxoindoline-5- sulfonamide and (E)-3-(2-(pyridin-4-yl)vinyl)-l -((2-(trimethylsilyl)ethoxy)methyl)- lH-indazole-6-carbaldehyde (25 mg, 0.065 mmol) with a modified purification procedure. The product was extracted into EtOAc, and washed with NaHCO3(Sat) (2X), brine (2X) and the organic layer dried over MgSO4. After removal of solvent the resulting yellow solid was titurated with Et2O/hexanes to give after drying 1.5 mg, 4.1 % yield of a yellow solid which was a 77:23 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) δ 9.01, 8.03 (s, IH), 8.55-8.45 (m, 2H), 8.30-8.05 (m, 3H), 7.96-7.76 (m, 2H), 7.75-7.65 (m, 3H), 7.58-7.51 (m, IH), 7.10, 7.07 (d, J = 8.6 Hz, IH), 3.05-2.99 (m, 2H), 2.90, 2.72 (m, 2H), 2.80, 2.63 (s, 3H), 2.57, 2.34 (s, 6H); MS ESI 529.2 [M + H]+, calcd for [C28H28N6O3S + H]+ 529.20.
Example A130: (E and ZV5-G-(dimethylamino)propylaminoV3-((3-((E>2-(pyridin- 4-vD-vinyl)- 1 H-indazol-6-yl')methylene)indolin-2-one
Figure imgf000192_0001
A mixture of mono(4-((E)-2-(6-((E)-(5-ammonio-2-oxoindolin-3-ylidene)methyl)- lH-indazol-3-yl)vinyl)pyridinium) di(2,2,2-trifluoroacetate) (10 mg, 0.016 mmol), K2CO3 (11 mg, 0.082 mmol) and DMF (1.0 mL) was cooled to 0 0C and then 3- bromo-N,N-dimethylpropan-l -amine hydrobromide (4.0 mg, 0.0164 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 18 hours. EtOAc (1OmL) was added and the mixture washed with brine (3X). The organic layer was dried over MgSO4 and the solvent removed to give a red gum which was titurated with ether/EtOAc (~10:l) three times while decanting the mother liquor to give after drying 2.4 mg, 32 % of a red powder which was a 85:15 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) δ 9.03, 7.93 (s, IH), 8.55-
8.49 (m, 2H), 8.23 (d, J = 8.3 Hz, IH), 7.82-7.73 (m, 2H), 7.68-7.64 (m, 2H), 7.59-
7.50 (m, 2H), 7.11, 7.10 (s, IH), 6.71-6.64 (m, 2H), 4.54-4.50 (m, 2H), 2.40-2.34 (m, 2H), 2.25, 2.22 (s, 6H), 2.18-2.10 (m, 2H); MS ESI 465.2 [M + H]+, calcd for [C28H28N6O + H]+ 465.24.
Example A131: (E and ZV3-((3-((EV2-(pyridin-4-vnvinvn-lH-indazol-5-vn- methylene)indolin-2-one hydrochloride
Figure imgf000193_0001
A. 3-iodo-l H-indazole-5-carbaldehyde
To a solution of 1 H-indazole-5-carbaldehyde (315.2 mg, 2.16 mmol), K2CO3 (598.8 mg, 4.33 mmol) in DMF (2.5 mL) was added dropwise a solution of I2 (938 mg, 3.7 mmol) in DMF (2.5 mL) and the reaction allowed to stir for three hours. An aqueous solution consisting OfNa2S2O4 (511 mg) / K2CO3 (35 mg) / H2O (3.5 mL) was then added and the solution stirred for two hours. Water (3OmL) and aqueous sodium hydrogen sulfate (IM, 1OmL) was added and the product was extracted with ethyl acetate (350 mL); this organic layer was washed with brine (3x25mL). The aqueous layer was then extracted with dichloromethane (3x75mL), this second organic layer was also washed with brine (25mL). TLC indicated product present in both, so the residues were combined and purified by chromatography (1Og silica SPE tube, Silicycle, 5% ethyl acetate in dichloromethane) to yield a beige solid (203mg, 35%). A precipitate that formed in the original aqueous layer was collected by vacuum filtration to give after drying a beige solid (first crop 135.6 mg, 23 %; second crop 147 mg, 25%). 1H NMR (400 MHz, CDCl3 plus a drop of CD3OD) δ 10.03 (s, IH), 8.00 (s, IH), 7.95 (d, J= 8.8 Hz, IH), 7.54 (d, J= 8.8 Hz, IH).
B. 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-5-carbaldehyde To a suspension of S-iodo-lH-indazole-ό-carbaldehyde (126.6 mg, 0.46 mmol) in CH2Cl2 (5 mL) and 50 % aq. KOH (1.0 mL) was added tetrabutylammonium bromide (3.4 mg, 0.01 mmol) and the solution cooled to 0 0C. (2-(Chloromethoxy)ethyl)trimethylsilane (0.10 mL, 0.56 mmol) was then added dropwise and the reaction stirred at 0 0C for 1.5 hours. The solution was then transferred to a sep. funnel containing ethyl acetate (200 mL) and the organic layer was washed with water (2 x 20 mL) and brine (20 mL), dried (Na2SO4) and the solvent removed in vacuo. The resulting residue was adsorbed onto silica using dichloromethane - methanol to dissolve, and evaporated to dryness. Chromatography (1Og silica SPE tube, Silicycle, 50-100 % dichloromethane in hexane, 10% ethyl acetate in dichloromethane) to give 88 mg, 47 %. 1H NMR: (400 MHz, CDCl3) δ 10.12 (s, IH), 8.05 (m, 2H), 7.67 (d, J = 9.2 Hz, IH), 5.77 (s, 2H), 3.60 (m, 2H), 0.90 (m, 2H), -0.048 (s, 9H).
C. fi)-3-(2-φyridin-4-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazole-5-carbaldehyde
To a suspension of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole- 5-carbaldehyde (87mg, 0.22 mmol), NaOAc (36 mg, 0.44mmol), "Bu4NCl (61 mg, 0.44 mmol), and Pd(OAc)2 (8.0 mg, 0.036 mmol) in DMF (2 mL) under argon was added 4-vinylpyridine (0.05 mL, 0.46 mmol). The resulting mixture was heated in a sealed vial at 1000C for 14 hours. Ethyl acetate (200 mL) was added and the solution was washed with water (20 mL) and brine (3 x 20 mL), dried over Na2SO4 and concentrated. The residue was chromatographed (5g silica SPE tube, Silicycle, 1-2% MeOH in CH2Cl2, repeated for mixed fractions) gave the title compound as a yellow solid (43 mg, 52%). 1H NMR (400 MHz, CDCl3 plus a drop of CD3OD) δ 10.07 (s, IH), 8.52 (m, 3H), 7.97 (d, J= 8.4 Hz, IH), 7.67 (d, J= 8.8 Hz, IH); 7.60 (d, J= 16.4 Hz, IH); 7.48 (m, 3H); 5.73 (s, 2H), 3.56 (m, 2H), 0.86 (m, 2H), -0.12 (s, 9H).
D. β and Z)-3-((3-(β)-2-φyridin-4-yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)- methyl)-lH-indazol-5-yl)metnylene)indolin-2-one A solution of piperidine (0.2M in EtOH, 0.10 mL, 0.02 mmol) was added to a suspension of oxindole (16.5 mg, 0.12 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-5-carbaldehyde (42.5 mg, 0.11 mmol) in EtOH (4 mL). The reaction was then heated to 750C for 15 hrs. The solvent was evaporated in vacuo. MeOH was added and the resulting suspension was sonicated, but the solution was still cloudy even after EtOAc was added. The solid was removed by filtration and the solvent evaporated in vacuo. Chromatography (5g silica SPE tube, Silicycle, 2% MeOH in CH2Cl2) gave a yellow solid (35 mg, 64%, 55:45 mixture of E/Z isomers). 1H NMR (400 MHz, CDCl3 plus a drop of CD3OD) δ 9.77 (s, 0.45H), 8.63 (m, 1.9H), 8.42 (s, 0.55H), 8.18 (s, 0.45H), 8.14 (dd, J= 8.8, 1.2 Hz, 0.45H), 8.00 (s, IH), 7.83-7.42 (m, 7H), 7.26 (t, J = 7.6 Hz, IH), 7.09 (t, J= 7.6 Hz, 0.45H), 6.94-6.88 (m, 1.6H), 5.80 (s, 0.55H), 5.77 (s, 0.45H), 3.64 (m, 2H), 0.95 (m, 2H), -0.02 (s, 5H), -0.03 (s, 4H). E. (E and Z)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-lH-indazol-5-yl)methylene)- indolin-2-one hydrochloride
According to the method of A57C and D, 3-((3-((E)-2-(pyridin-4-yl)vinyl)-l- ((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazol-5 -yl)methylene)indolin-2-one (13.1 mg, 0.026 mmol) was treated with boron trifluoride etherate, followed by 2 N HCl (water / EtOH) treatment. Suction filtration gave a solid which was rinsed with 1 : 1 EtOH : water (2 x 1 mL). Pumping under high vacuum gave an orange solid (7.3 mg, 69%, 55:45 mixture of E/Z isomers, HCl salt). 1H NMR (400 MHz, CD3OD) δ 9.83 (s, 0.4H), 8.73 (m, 2H), 8.59 (s, 0.6H), 8.33-8.20 (m, 3.5H), 7.95 (m, IH), 7.91-7.87 (m, IH), 7.80-7.63 (m, 3H), 7.25 (t, J= 8.4 Hz, IH), 7.07 (t, J= 7.6 Hz, 0.4H), 6.96-6.87 (m, 1.6H); MS ESI 365.2 [M + H]+, calcd for [C23H16N4O + H]+ 365.14.
Example A132: (E and ZV5-methoxy-3-((3-((EV2-(6-(4-methylpiperazin-l- yl)pyridin-3-vπvinvπ-lH-indazol-6-vπmethylene)indolin-2-one dihydrochloride
Figure imgf000195_0001
A. 5-methoxy-3-(E & Z)-((3-((E)-2-(6-(4-methylpiperazin-l-yl)-pyridin-3- yl)vinyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-6-yI)methylene)indolin- 2-one The title compound was synthesized according to the method of Example A 19, utilizing 5-methoxyindolin-2-one (14.7 mg, 0.090 mmol) and (E)-3-(2-(6-(4- methylpiperazin- 1 -yl)pyridine-3-yl)vinyl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- indazole-6-carbaldehyde (Example A108-B: 41 mg, 0.086 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 5 % MeOH/DCM) to provide the title compound as a (E :Z) mixture of isomers: a yellow solid (11.5 mg, 21 %); 1H NMR (400 MHz, CD3OD) δ ppm 8.29 (d, J=2.26 Hz, 1 H), 8.22 (d, J=8.03 Hz, 1 H), 7.92 - 7.97 (m, 2 H), 7.86 (s, 1 H), 7.57 (d, J=8.53 Hz, 1 H), 7.50 (d., J= 16.6 Hz, 1 H), 7.30 (d., J= 16.6 Hz, 1 H), 7.20 (br. s, 1 H), 6.89 (d, J=9.03 Hz, 1 H), 6.84 (s, 2 H), 5.77 (s, 2 H), 3.58 - 3.67 (m, 9 H), 2.55 - 2.62 (m, 4 H), 2.37 (s, 3 H), 0.88 (t, J=8.16 Hz, 2 H), -0.09 (s, 9 H) ;MS ESI [M+ 2H-CH2CH2SiMe3J+ 523.4, calcd for [C35H42N6O3Si+ H]+ 623.8.
B. (E and Z)-5-methoxy-3-((3-((E)-2-(6-(4-metnylpiperazin-l-yl)pyridin-3- yl)vinyl)-lH-indazol-6-yl)methylene)indolin-2-one dihydrochloride To a DCM (50 niL) solution of 5-methoxy-3-(E & Z)- ((3-((E)-2-(6-(4- methylpiperazin- 1 -yl)-pyridin-3-yl)vinyl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- indazol-6-yl)methyl-ene)indolin-2-one (0.85 g, 1.36 mmol) was added BF3 OEt2 (1.7 mL, 13.6 mmol) at 0° C. The cooling bath was removed and the reaction mixture was stirred for 4 h. After removal of the solvent under reduced pressure, the residue was heated in EtOH (40 mL) and 2 M aq HCl (20 mL) at 60 0C overnight. The reaction was then stored at 5 0C overnight. A red precipitate was collected and washed separately with EtOAc, MeCN and Et2O to provide the title compound as as a 3.3:1 (E:Z) mixture of isomers: an orange-red powder (0.32 g, 42 %). 1H NMR (400 MHz, CD3OD) δ ppm 8.87 (s, 0.3 H), 8.53 - 8.61 (m, 1.0 H), 8.28 - 8.32 (m, IH), 8.26 (d, J= 8.53 Hz, 0.7 H), 8.13 (d, J= 8.28 Hz, 0.3 H), 8.00 (t, J= 7.99 Hz, 0.3 H), 7.95 - 8.02 (m, 1.5 H), 7.83 - 7.90 (m, 3.3 H), 7.30 (d, J= 2.3 Hz, 0.3 H), 7.24 (s, 0.7 H), 6.84 (s, 1.4 H), 6.76 - 6.84 (m, 0.4 H), 4.39 - 4.59 (br.s, 2 H), 3.64 - 3.85 (br.s., 4 H), 3.63 (s, 3 H), 3.32 - 3.60 (br.s., 2 H), 3.03 (s, 3 H); MS ESI [M+ H]+ 493.3, calcd for [C29H28N6O2+ H]+ 493.6.
Example A 133 : (Z)-3 -(( 1 H-indazol-6-yl)methylene)-4-bromoindolin-2-one
Figure imgf000196_0001
The title compound was synthesized according to the method of Example A19, utilizing 4-bromoindolin-2-one (50 mg, 0.23 mmol) and lH-indazole-6- carbaldehyde (34.5 mg, 0.23 mmol). On completion the reaction mixture was stored at rt overnight. Filtration and rinsing with xs EtOH provided the title compound as an orange solid (30 mg, 38 %). 1H NMR (400 MHz, DMSO-^6) δ ppm 13.36 (br. s., 1 H), 10.91 (br. s., 1 H), 8.78 (s, 1 H), 8.73 (s, 1 H), 8.13 (s, 1 H), 7.80 (d, J=SJS Hz, 1 H), 7.65 (d, J=8.28 Hz, 1 H), 7.22 (d, J=8.28 Hz, 1 H), 7.16 (t, J=US Hz, 1 H), 6.88 (d, J=7.78 Hz, 1 H) ;MS ESI [M+ H]+ 340.1/341.9, calcd for [Ci6H10BrN3O+ H]+ 340.0/342.0.
Example A134: (EV3-((lH-indazol-6-vπmethyleneV5-chloro-lH-pyrrolo[3.2- blpyridin-2GHVone
Figure imgf000197_0001
The title compound (40 mg, 67 %) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75 0C, reflux 30 min) using 5-chloro-lH-pyrrolo[3,2-b]pyridin-2(3H)-one (33.7 mg, 0.2 mmol) and IH- indazole-6-carbaldehyde (29.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, IH), 10.90 (s, IH), 8.93 (s, IH), 8.37 (d, J = 8.4 Hz, IH), 8.17 (s, IH), 7.93 (s, IH), 7.89 (d, J = 8.4 Hz, IH), 7.39 (d, J = 8.4 Hz, IH), 7.35 (d, J = 8.0 Hz, IH); MS ESI 297.0 [M + H]+, calcd for [Ci5H9ClN4O + H]+ 297.1.
Example A 135 : (E)-3-(( 1 H-indazol-6-yQmethylene>5 ,6-dimethoxyindolin-2-one
Figure imgf000197_0002
The title compound (43 mg, 67 %) was synthesized as an orange yellow solid according to the method described for Example A67 (oil temp 75 0C, reflux 90 min) using 5,6-dimethoxyindolin-2-one (38.6 mg, 0.2 mmol) and lH-indazole-6- carbaldehyde (29.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMS0-d6) δ 13.26 (s, IH), 10.36 (s, IH), 8.14 (s, IH), 7.95-7.85 (m, 2H), 7.57 (s, IH), 7.46-7.37 (m, IH), 7.24 (s, IH), 6.52 (s, IH), 3.78 (s, 3H), 3.53 (s, 3H); MS ESI 322.1 [M + H]+, calcd for [C18H15N3O3 + H]+ 322.1.
Examples A 136(a): (Ey3-(G-f4-(tøimemylamino)methvnst\τvn-lH-indazol-6- vD-methylene>5-methoxyindolin-2-one 2.2.2-trifluoroacetate and A136(b): (Z)-3- ((3-(4-((dimethylamino')methyl)styrylVlH-indazol-6-yl)-methylene)-5- methoxyindolin-2-one 2.2.2-trifluoroacetate
Figure imgf000198_0001
Piperidine (0.01 mL, 0.1 mmol) was added to a solution of 5- methoxyoxindole (52 mg, 0.32 mmol) and (E)-3-(4-((dimethylamino)methyl)styryl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazole-6-carbaldehyde (contaminated with TBAF from previous deprotection attempt, 95.5 mg, 0.22 mmol) in EtOH (5 mL). The reaction was then heated to 750C for 25 hrs. The solvent was evaporated in vacuo. Chromatography (5g silica SPE tube, Silicycle, 5-10% MeOH in CH2Cl2) gave a brown oil (105 mg, contained product and TBAF by NMR). The residue was dissolved in EtOAc (100 mL) and washed with brine (3 x 15 mL), dried over Na2SO4 and the solvent was evaporated in vacuo to give 3-((3-(4- ((dimethylamino)methyl)styryl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazol-6- yl)methylene)-5-methoxyindolin-2-one as a brown oil (1 lOmg, used without further purification).
According to the method of A57C, 3-((3-(4-((dimethylamino)methyl)styryl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazol-6-yl)methylene)-5-methoxyindolin- 2-one (19 mg, 0.033 mmol) was treated with boron trifluoride etherate, followed by 2 N HCl (water / EtOH) treatment. The solvents were removed in vacuo using additional EtOH to azeotropically remove water. The residue was dissolved in MeOH / EtOAc and filtered to remove solid, then the solvent was evaporated in vacuo. Purification by prep-HPLC gave the title compound (E isomer, first eluting fraction, 94% by HPLC) as an orange solid (11 mg, 60% yeild,). 1H NMR (400 MHz, CD3OD) δ ppm 8.26 (d, J=8.5 Hz, 1 H), 7.88 (d, J=9.3 Hz, 2 H), 7.80 (d, J=8.3 Hz, 2 H), 7.61 (s, 2 H), 7.51 - 7.58 (m, 3 H), 7.26 (s, 1 H), 6.84 (s, 2 H), 4.34 (s, 2 H), 3.63 (s, 3 H), 2.89 (s, 6 H); MS ESI 451.2 [M + H]+, calcd for [C28H26N4O2+ H]+ 451.22. The second eluting fraction was the Z-isomer (5 mg, 30%). 1H NMR (400 MHz, CD3OD) δ ppm 8.89 (s, 1 H), 8.15 (d, J=9.0 Hz, 1 H), 7.99 (dd, J=9.0, 1.3 Hz, 1 H), 7.90 (s, 1 H), 7.81 (d, J=8.3 Hz, 2 H), 7.57 - 7.61 (m, 2 H), 7.53 (d, J=8.3 Hz, 2 H), 7.33 (d, J=2.0 Hz, 1 H), 6.85 (dd, J=8.4, 2.4 Hz, 1 H), 6.80 (d, J=8.4 Hz, 1 H), 4.34 (s, 2 H), 3.84 (s, 3 H), 2.89 (s, 6 H); MS ESI 451.2 [M + H]+, calcd for [C28H26N4O2+ H]+ 451.22.
Figure imgf000199_0001
The title compound (E/Z=3:l, 63 mg, 84 %) was synthesized as an orange solid according to the method described for Example A67 (oil temp 70 0C, reflux 60 min) using 5-chloro-lH-pyrrolo[3,2-b]pyridin-2(3H)-one (33.7 mg, 0.2 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-lH-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) E isomer: δ 13.83 (s, IH), 10.92 (s, IH), 8.91 (s, IH), 8.57 (d, J = 6.0 Hz, 3H), 8.37 (d, J = 8.8 Hz, IH), 7.95 (s, IH), 7.90 (d, J = 16.4 Hz, IH), 7.75-7.70 (m, 2H), 7.57 (d, J = 16.8 Hz, IH), 7.41 (d, J = 8.0 Hz, IH), 7.36 (d, J = 8.4 Hz, IH); Z isomer: δ 13.80 (s, IH), 11.03 (s, IH), 9.15 (s, IH), 8.57 (d, J = 6.0 Hz, 2H, buried under the doublet at 8.57), 8.34 (d, J = 8.4 Hz, IH, partially overlapping with the doublet at 8.37), 8.25 (d, J = 9.2 Hz, IH), 8.20 (s, IH), 7.86 (d, J = 14.4 Hz, IH, partially overlapping with the doublet at 7.90), 7.75-7.70 (m, buried under the multiplet 7.75-7.70), 7.56 (d, J = 16.8 Hz, IH), 7.32 (d, J = 8.0 Hz, IH), 7.28 (d, J = 8.0 Hz, IH); MS ESI 400.0 [M + H]+, calcd for [C22Hi4ClN5O + H]+ 400.1.
Example A138: (EV5.6-dimethoxy-3-((3-((E)-2-(pyridin-4-vnvinylVlH-indazol-6- yl)methylene)indolin-2-one
Figure imgf000200_0001
The title compound (36 mg, 42 %) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75 0C, reflux 90 min) using 5,6-dimethoxyindolin-2-one (38.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-4- yl)vinyl)-lH-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz,
DMSO-d6) δ 13.54 (s, IH), 10.39 (s, IH), 8.60-8.53 (m, 2H), 8.35 (d, J = 7.2 Hz,
IH), 7.94 (s, IH), 7.87 (d, J = 16.4 Hz, IH), 7.75-7.67 (m, 2H), 7.63-7.50 (m, 3H),
7.25 (s, IH), 6.53 (s, IH), 3.80 (s, 3H), 3.55 (s, 3H); MS ESI 425.2 [M + H]+, calcd for [C25H20N4O3 + H]+ 425.1.
Example A139: (E and ZV5-bromo-3-fG-((EV2-(pyridin-3-vnvinvn-lH-indazol-6- yl)methyleneMndolin-2-one
Figure imgf000200_0002
The title compound (E:Z=1:4, 73 mg, 83 %) was synthesized as a dark yellow solid according to the method described for Example A67 (oil temp 75 0C, reflux 2 h) using 5-bromoindolin-2-one (44.5 mg, 0.21 mmol) and (E)-3-(2-(pyridin- 3-yl)vinyl)-lH-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, IH), 10.84 (s, IH), 8.99 (s, IH), 8.91 (s, IH), 8.48 (d, J = 4.4 Hz, IH), 8.30 (d, J = 8.4 Hz, IH), 8.19 (d, J = 8.0 Hz, IH), 8.16-8.10 (m, 3H), 8.04 (s, IH), 7.71 (d, J = 16.8 Hz, IH), 7.59 (d, J = 17.2 Hz, IH), 7.43 (dd, J = 7.6 Hz, J = 4.8 Hz, IH), 7.39 (dd, J = 8.0 Hz, J = 1.2 Hz, IH); MS ESI 443.3 [M + H]+, calcd for [C23H15BrN4O + H]+ 443.1.
Figure imgf000201_0001
The title compound (E/Z=5:4, 75 mg, 84 %) was synthesized as a yellow solid according to the method described for Example A67 (oil temp 75 0C, reflux 2 h) using 5-bromo-lH-pyrrolo[2,3-b]pyridin-2(3H)-one (44.5 mg, 0.21 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-lH-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 0.45 H), 13.56 (s, 0.48 H), 11.50 (s, 0.91 H), 8.94 (s, 0.43H), 8.91 (s, 0.97H), 8.48 (d, J = 3.6 Hz, 0.99H), 8.43-8.37 (m, 0.98 H), 8.33 (d, J = 8.0 Hz, 0.52 H), 8.28-8.17 (m, 2.36H), 8.11 (d, J = 8.8 Hz, 0.50H), 8.03 (s, 0.56H), 7.94 (s, 1.02H), 7.77-7.69 (2 doublets partially overlapping, J = 17.2 Hz, 1.07H, vinylic proton), 7.64-7.54 (m, 1.54H), 7.45-7.41 (2 doublets overlapping, J = 8.8 Hz, 1.00H); MS ESI 444.3 [M + H]+, calcd for [C22H14BrN5O + H]+ 444.1.
Example A141: methyl 4-((EV2-(6-((ZV(2-oxoindolin-3-ylidene)methvn-lH- indazol-3 -vDvinvDbenzoate
Figure imgf000201_0002
The title compound (40 mg, 83 %) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75 0C, reflux 150 min) using indolin-2-one (26.6 mg, 0.2 mmol) and (E)-methyl 4-(2-(6-formyl-lH- indazol-3-yl)vinyl)benzoate (61.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ
13.60 (s, IH), 10.70 (s, IH), 9.00 (s, IH), 8.29 (d, J = 8.0 Hz, IH), 8.08 (d, J = 8.4 Hz, IH), 8.00 (s, IH), 7.98 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.4 Hz, IH, partially overlapping with the doublet at 7.74), 7.74 (d, J = 17.2 Hz, IH, partially overlapping with the doublet at 7.77), 7.63 (d, J = 17.2 Hz, IH), 7.23 (t, J = 7.6 Hz, IH), 7.01 (t, J = 7.6 Hz, IH), 6.84 (d, J = 7.6 Hz, IH), 3.86 (s, 3H); MS ESI 422.3 [M + H]+, calcd for [C26H19N3O3 + H]+ 422.1.
Figure imgf000202_0001
The title compound (E/Z = 2:1, 60 mg, 67 %) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75 0C, reflux 150 min) using 5-methoxyindolin-2-one (32.6 mg, 0.2 mmol) and (E)-methyl 4-(2- (6-formyl-lH-indazol-3-yl)vinyl)benzoate (61.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) E isomer: δ 13.25 (s, br, IH), 10.45 (s, IH), 8.37 (d, J = 8.0 Hz, IH), 7.98 (d, J = 8.4 Hz, 2H), 7.93 (s, IH), 7.89 (d, J = 8.0 Hz, 2H), 7.79 (s, IH), 7.76 (d, J = 16.8 Hz, IH), 7.64 (d, J = 16.8 Hz, IH), 7.54 (d, J = 8.4 Hz, IH), 7.19 (d, J = 2.0 Hz, IH), 6.86 (dd, J = 8.4 Hz, 2.0 Hz, IH), 6.80 (d, J = 8.0 Hz, IH), 3.86 (s, 3H), 3.6 (s, 3H); Z isomer: δ 13.25 (s, br, IH), 10.50 (s, IH), 9.02 (s, IH), 8.29 (d, J = 8.4 Hz, IH), 8.09 (d, J = 8.4 Hz, IH), 7.99 (s, IH), 7.98 (d, J = 8.4 Hz, 2H, buried by doublet at 7.98), 7.89 (d, J = 8.0 Hz, 2H, buried by doublet at 7.89), 7.74 (d, J = 16.8 Hz, IH), 7.63 (d, J = 16.4 Hz, IH), 7.47 (d, J = 2.0 Hz, IH), 6.80 (d, IH, buried by doublet at 6.80), 6.74 (d, 8J = 8.4 Hz, IH), 3.86 (s, 3H), 3.78 (s, 3H); MS ESI 452.3 [M + H]+, calcd for [C27H21N3O4 + H]+ 452.2.
Example A143: methyl 4-((EV2-(6-((E and Z)-(2-oxo-lH-pyrrolof2.3-b1pyridin- 3(2HVylidene)methylHH-indazol-3-yl)vinyDbenzoate
Figure imgf000203_0001
The title compound (E/Z = 9:1, 62 mg, 73 %) was synthesized as a yellow solid according to the method described for Example A67 (oil temp 75 0C, reflux 120 min) using lH-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and (E)- methyl 4-(2-(6-formyl-lH-indazol-3-yl)vinyl)benzoate (61.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 15.53 (s, IH), 11.27 (s, IH), 8.38 (d, J = 8.0 Hz, IH), 8.11 (d, J = 4.4 Hz, IH), 7.98 (d, J = 8.4 Hz, 2H), 7.95-7.87 (m, 5H), 7.76 (d, J = 16.8 Hz, IH), 7.64 (d, J = 17.2 Hz, IH), 7.55 (d, J = 8.4 Hz, IH), 6.91 (dd, J = 7.2 Hz, J = 5.6 Hz, IH), 3.86 (s, 3H); MS ESI 423.2 [M + H]+, calcd for [C25H18N4O3 + H]+ 423.1.
Example A144: 4-((E)-2-r6-((EV(2-oxoindolin-3-ylidene)methyl)-lH-indazol-3- yDvinvDbenzoic acid
Figure imgf000203_0002
The title compound (17 mg, 21 %) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75 0C, reflux 90 min) using indolin-2-one (26.6 mg, 0.2 mmol) and (E)-4-(2-(6-formyl-lH-indazol-3- yl)vinyl)benzoic acid (58.4 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.49 (s, IH), 12.90 (s, br, IH), 10.64 (s, IH), 8.37 (d, J = 8.4 Hz, IH), 7.97 (d, J = 8.4 Hz, 2H), 7.91 (s, IH), 7.86 (d, J = 8.0 Hz, 2H), 7.80 (s, IH), 7.74 (d, J = 16.8 Hz, IH), 7.63 (d, J = 15.6 Hz, IH partially overlapping with the singlet at 7.62), 7.62 (s, IH partially overlapping with the doublet at 7.63), 7.24 (t, J = 7.4 Hz, IH), 6.91-6.82 (m, 2H); MS ESI 408.2 [M + H]+, calcd for [C25HnN3O3 + H]+ 408.1.
Example A 145 : 4-((E)-2-(6-((E)-(5 -methoxy-2-oxoindolin-3-ylidene)methylV 1 H- indazol-3-vDvinvObenzoic acid
Figure imgf000204_0001
The title compound (20 mg, 23 %) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75 0C, reflux 90 min) using 5-methoxylindolin-2-one (32.6 mg, 0.2 mmol) and (E)-4-(2-(6-formyl-lH- indazol-3-yl)vinyl)benzoic acid (58.4 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO- d6) δ 13.50 (s, IH), 12.90 (s, br, IH), 10.45 (s, IH), 8.37 (d, J = 8.4 Hz, IH), 7.96 (d, J = 8.0 Hz, 2H), 7.92 (s, IH), 7.86 (d, J = 8.0 Hz, 2H), 7.79 (s, IH), 7.74 (d, J = 16.8 Hz, IH), 7.63 (d, J = 16.4 Hz, IH), 7.54 (d, J = 8.4 Hz, IH), 7.19 (s, IH), 6.86 (dd, J = 8.8 Hz, J = 2.4 Hz, IH), 6.80 (d, J = 8.4 Hz, IH), 3.60 (s, 3H); MS ESI 438.2 [M + H]+, calcd for [C26H]9N3O4 + H]+ 438.1.
Figure imgf000204_0002
The title compound (E/Z = 10:3, 54 mg, 66 %) was synthesized as a yellow solid according to the method described for Example A67 (oil temp 75 0C, reflux 450 min) using lH-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and (E)-4- (2-(6-formyl-lH-indazol-3-yl)vinyl)benzoic acid (58.4 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.52 (s, IH), 11.27(s, IH), 8.32 (d, J = 8.8 Hz, IH), 8.11 (t, J = 5.2 Hz, 2H), 7.97-7.89 (m, 4H), 7.84 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 16.8 Hz, IH), 7.63 (d, J = 16.4 Hz, IH), 7.53 (d, J = 8.4 Hz, IH), 6.91 (dd, J = 7.2 Hz, J = 5.2 Hz, IH); MS ESI 409.2 [M + H]+, calcd for [C24Hi6N4O3 + H]+ 409.1.
Example A147: (E)-3-((3-(pyridin-3-ylethvnyl)-lH-indazol-6-yl)methylene)indolin- 2-one
Figure imgf000205_0001
The title compound (30 mg, 83 %) was synthesized as a yellow solid according to the method described for Example A67 (oil temp 75 0C, reflux 2 h) using indolin-2-one (13.3 mg, 0.1 mmol) and 3-(pyridin-3-ylethynyl)-lH-indazole-
6-carbaldehyde (24.7 mg, 0.1 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s,
IH), 10.64 (s, IH), 8.90 (s, IH), 9.64 (d, J = 4.4 Hz, IH), 8.12 (d, J = 8.0 Hz, IH),
8.03 (d, J = 8.0 Hz, IH), 7.96 (s, IH), 7.80 (s, IH), 7.60-7.50 (m, 3H), 7.24 (t, J =
7.8 Hz, IH), 6.89 (d, J = 7.6 Hz, IH) 6.84 (t, J = 7.8 Hz, IH); MS ESI 363.1 [M + H]+, calcd for [C23H14N4O + H]+ 363.1.
Example A 148 : (E)S -methoxy-3 -((3-(pyridin-3-ylethvnyl)- 1 H-indazol-6- yl)methylene)indolin-2-one
Figure imgf000205_0002
The title compound (34 mg, 53 %) was synthesized as a orange red solid according to the method described for Example A67 (oil temp 75 0C, reflux 2 h) using 5-methoxylindolin-2-one (29 mg, 0.18 mmol) and 3-(pyridin-3-ylethynyl)-lH- indazole-6-carbaldehyde (40 mg, 0.163 mmol), followed by additional 90 min with additional 5-methoxylindolin-2-one (5.8 mg, 0.036 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, br, IH, NH), 10.46 (s, IH, NH), 8.90 (s, IH), 8.63 (d, J = 4.4 Hz, IH), 8.12 (dt, J = 8.0 Hz, IH), 8.04 (d, J = 8.4 Hz, IH), 7.98 (s, IH), 7.79 (s, IH), 7.58 (d, J = 8.4 Hz, IH), 7.52 (dd, J = 8.0 Hz, J = 4.8 Hz, IH), 7.13 (d, J = 1.6 Hz, IH), 6.86 (dd, J = 8.0 Hz, J = 2.4 Hz, IH), 6.80 (d, J = 8.4 Hz, IH), 3.59 (s, 3H); MS ESI 393.2 [M + H]+, calcd for [C24H16N4O2 + H]+ 393.1.
Example A149: (E and Z)-3-((3-(T4-(dimethylamino)Dhenyl)ethvnvn-lH-indazol-6- yl)methylene)indolin-2-one
Figure imgf000206_0001
To a solution of S-iodo-lH-indazole-ό-carbaldehyde (136 mg, 0.5 mmol),
Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol) in DMF (3 mL) was added Et3N (5 mL), followed by 4-ethynyl-N,N-dimethylaniline (109 mg, 0.75 mmol). The resulting mixture was heated at 100 0C (oil temp.) for 45 min. After removal of Et3N, the residue was loaded directly onto a silical gel column. Flash chromatography (eluent: hex to hex/ethyl acetate = 5:1 to 1:1, to ethyl acetate) gave the crude 3-((4-(dimethylamino)phenyl)ethynyl)-lH-indole-6-carbaldehyde as greenish brown solid, which was redissolved in MeOH (20 mL). 2-Oxindole (53.2 mg, 0.4 mmol) and piperidine (10 drops) were added and the resulting mixture was refluxed (oil temp 75 0C ) for 2 h. Additional 2-oxindole (13.3 mg) was added and the mixture was refluxed for another hour. After cooling to rt, the reaction mixtrue was suction filtered and the filter cake was rinsed with MeOH (10 mL). The filtrate was concentrated to about 0.5 mL and diluted with EtOAc (8 mL). Hexane (15 mL) was added and the resulting precipitate was collected by suction filtration to give the title compound (63mg, 31 % over 2 steps) as a golden solid (E:Z = 9:1). 1H NMR (400 MHz, DMSO-d6) δ 13.40 (s, br, IH), 10.64 (s, IH), 7.93 (d, J = 8.4 Hz, IH), 7.91 (s, IH), 7.79 (s, IH), 7.57 (d, J - 7.2 Hz, IH), 7.53 (d, J = 8.8 Hz, IH), 7.47 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 7.6 Hz, IH), 6.89 (d, J = 7.6 Hz, IH), 6.84 (t, J = 7.4 Hz, IH), 6.75 (d, J = 8.8 Hz, 2H), 2.97 (s, 6H); MS ESI 405.2 [M + H]+, calcd for [C26H20N4O + H]+ 405.2.
Figure imgf000207_0001
The title compound (E/Z=3:4, 65 mg, 88 %) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75 0C, reflux 3 h) using 5-bromoindolin-2-one (32 mg, 0.15 mmol) and 3-(6-(4-methylpiperazin-l- yl)ρyridin-3-yl)-lH-indazole-6-carbaldehyde (46 mg, 0.143 mmol). 1H NMR (400 MHz, DMSO-d6) E isomer: δ 13.41 (s, IH), 10.80 (s, IH), 8.76 (s, IH), 8.20-8.03 (m, 2H), 7.91 (s, IH), 7.87 (s, IH), 7.67 (d, IH), 7.48-7.40 (m, 2H), 7.99 (d, J = 8.8 Hz, IH), 6.86 (d, J = 8.0 Hz, IH), 3.57 (t, 4H), 2.41 (t, 4H), 2.23 (s, 3H); Z isomer: δ 13.48 (s, IH), 10.84 (s, IH), 9.02 (s, IH), 8.76 (s, IH), 8.20-8.03 (m, 5H), 7.38 (d, J = 8.0 Hz, IH), 6.98 (d, J = 9.6 Hz, IH), 6.80 (d, J = 8.0 Hz, IH), 3.57 (t, 4H), 2.41 (t, 4H), 2.23 (s, 3H); MS ESI 515.4 [M + H]+, calcd for [C26H23BrN6O + H]+ 515.1.
Example A151. (E)-5-methoxy-3-((3-(2-(4-methylpiperazin-l-yl)pyrimidin-5-yl)- lH-indazol-6-yl)methyleneMndolin-2-one
Figure imgf000207_0002
A. 3-(2-(4-methylpiperazin-l-yl)pyrimidin-5-yl)-lH-indazole-6-carbaldehyde A mixture of lH-indazole-6-carbaldehyde (50 mg, 0.18 mmol), 2-(4- Methylpiperazin-l-yl)pyrimidine-5-boronic acid pinacol ester (70 mg, 0.22 mmol), Pd(PPh3)4 (13 mg, 0.018 mmol) and 2M Na2CO3 (0.10 mL, 0.22 mmol) in DME/H2O/EtOH (1.4 mL/0.4 mL/0.2 mL) was sealed and heated with stirring under microwave irradiation at 125 0C for 120 min. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using MeOH (5% to 10 %) in DCM as the eluent to provide the title compound as a pale yellow solid (47 mg, 80 %). 1H NMR (400 MHz, CD3OD) δ ppm 10.12 (s, 1 H), 8.91 (s, 2 H), 8.14 (s, 1 H), 8.09 (d, J= 8.6 Hz, 1 H), 7.74 (d, J= 8.4 Hz, 1 H), 3.94 (t, J= 4.5 Hz, 4 H), 2.56 (t, J= 4.9 Hz, 4 H), 2.37 (s, 3 H); MS ESI 323.1 (100) [M + H]+, calcd for [Ci7H18N6O + H]+ 323.2.
B. (E)-5-methoxy-3-(β-(2-(4-methylpiperazin-l-yl)pyrimidin-5-yl)-lH- indazol-6-yl)methylene)indolin-2-one A round bottom flask was charged with 3-(2-(4-methylpiperazin-l-yl)pyrimidin-5- yl)-lH-indazole-6-carbaldehyde (26 mg, 0.80 mmol), 5-methoxyoxindole (13 mg, 0.80 mmol), piperidine (0.8 uL, 0.008 mmol) and MeOH (2 mL). The reaction was then heated to 6O0C for 4 hrs. An orange precipitate formed which was further precipitated by cooling to room temperature. The orange solid was then filtered and washed with MeOH (5 mL) giving 9.8 mg, 26 % of the title compound. 1H NMR (400 MHz, de-DMSO) δ 13.46 (s, IH), 10.44 (s, IH), 8.97 (s, 2H), 8.18 (d, J = 8.5 Hz, IH), 7.94 (s, IH), 7.78 (s, IH), 7.48 (d, J = 8.8 Hz, IH), 7.20 (s, IH), 6.85 (d, J = 10.6 Hz, IH), 6.80 (d, J = 9.0 Hz, IH), 3.82 (br t, 4H), 3.59 (s, 3H), 2.39 (br t, 4H), 2.23 (s, 3H); MS ESI 468.3 [M + H]+, calcd for [C26H25N7O2 + H]+ 468.2.
Example A152. (E & ZV3-((3-(2-(4-memylpiperazin-l-ylkrvτimidin-5-ylVlH- indazol-6-yl)methylene)-5-(trifluoromethoxy)indolin-2-one
Figure imgf000209_0001
According to the procedure for the synthesis of (E)-5-methoxy-3-((3-(2-(4- methylpiperazin- 1 -yl)pyrimidin-5-yl)- 1 H-indazol-6-yl)methylene)indolin-2-one, except substituting 5-trifluoromethoxyoxindole (14 mg, 0.065 mmol), the title compound was prepared as a yellow solid (17.6 mg, 52 %). A mixture of (E)- and (Z)- isomers (83:17 by NMR) was obtained. 1H NMR (400 MHz, (I6-DMSO) 13.51 (s, IH), 10.85 (s, IH), 8.97 (s, 2H), 8.18 (d, J = 8.2 Hz, IH), 7.92 (s, IH), 7.94 (s, IH), 7.48-7.46 (m, 2H), 7.27 (d, J = 9.2 Hz, IH), 6.96 (d, J = 8.4 Hz, IH), 3.82 (br t, 4H), 2.39 (br t, 4H), 2.23 (s, 3H); MS ESI 522.3 [M + H]+, calcd for [C26H22F3N7O2 + H]+ 522.2.
Example Al 53. (E and Z>3-(f3-(3-flH-tetrazol-5-vnphenvn-lH-indazol-6- yl)methylene)-5-methoxyindolin-2-one
Figure imgf000209_0002
A. 3-(3-(lH-tetrazol-5-yl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazole-6-carbaldehyde
A mixture of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6- carbaldehyde (100 mg, 0.25 mmol), 3-(tetrazol-5-yl)phenylboronic acid (57 mg, 0.30 mmol), Pd(PPh3)4 (18 mg, 0.025 mmol) and 2M Na2CO3 (0.13 mL, 0.25 mmol) in DMEZH2OZEtOH (2.8 mLZ0.8 mLZ0.4 mL) was degassed by evacuation and blanketed with Ar. The reaction mixture was sealed and heated with stirring under microwave irradiation at 125 0C for 4 hours. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using MeOH (5% to 10 %) in DCM as the eluent to provide a white solid (40 mg, 38 %). 1H NMR (400 MHz, CD3OD) δ ppm 10.10 (s, 1 H), 8.59 (s, 1 H), 8.25 (s, 1 H), 8.21 (d, J= 8.5 Hz, 1 H), 8.11 (d, J= 7.9 Hz, 1 H), 8.04 (d, J= 8.3 Hz, 1 H), 7.77 (d, J= 8.4 Hz, 1 H), 7.67 (t, J= 7.8 Hz, 1 H), 5.88 (s, 2 H), 3.66 (t, J = 8.1 Hz, 2 H), 0.89 (t, J = 8.0 Hz, 2 H), -0.10 (s, 9 H); MS ESI 421.1 (100) [M + H]+, calcd for [C21H24N6O2Si + H]+ 421.2.
B. (E and Z)-3-((3-(3-(lH-tetrazol-5-yl)phenyl)-l-((2-(trimethylsilyl)ethoxy)- methyl)- 1 H-indazol-6-yl)methylene)-5-methoxyindolin-2-one
According to the procedure for the synthesis of (E)-5-methoxy-3-((3-(2-(4- methylpiperazin-l-yl)pyrimidin-5-yl)-lH-indazol-6-yl)methylene)indolin-2-one, except substituting 3-(4-( 1 H-tetrazol-5-yl)phenyl)- 1 -((2-(trimethylsilyl)ethoxy)- methyl)-lH-indazole-6-carbaldehyde (40 mg, 0.094 mmol), the title compound was prepared as an orange solid (39 mg, 73 %). A mixture of (E)- and (Z)- isomers (77:23 by NMR) was obtained. 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, IH), 8.69 (s, IH), 8.36 (d, J = 8.7 Hz, IH), 8.25 (d, J = 7.8 Hz, IH), 8.21 (s, IH), 8.13 (d, J = 8.2 Hz, IH), 7.81-7.77 (m, 2H), 7.66 (d, J = 8.6 Hz, IH), 7.13 (d, J = 2.5 Hz, IH), 6.88-6.80 (m, 2H), 5.90 (s, 2H), 3.66 (t, J = 8.3 Hz, 2H), 3.58 (s, 3H), 0.84 (t, J = 8.1 Hz, 2H), -0.11 (s, 9H); MS ESI 566.3 [M + H]+, calcd for [C30H31N7O3Si + H]+ 566.2.
C. (E and Z)-3-((3-(3-(lH-tetrazol-5-yl)phenyl)-lH-indazol-6-yl)methylene)- 5-methoxyindolin-2-one
A round bottom flask was charged with (E and Z)-3-((3-(4-(lH-tetrazol-5- yl)phenyl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazol-6-yl)methylene)-5- methoxyindolin-2-one (35 mg, 0.062 mmol), concentrated HCl (1 mL), and EtOH (2 mL). The reaction was then heated to 72 0C for 4 hrs. A red precipitate formed which was further precipitated by cooling to room temperature. The red solid was then filtered and washed with MeOH (2 mL) giving 15 mg, 56 % of the title compound. A mixture of (E)- and (Z)- isomers (78:22 by NMR) was obtained. 1H NMR (400 MHz, (I6-DMSO) 13.71 (br. s, IH), 10.47 (s, IH), 8.70 (s, IH), 8.34 (d, J = 8.5 Hz, IH), 8.27 (d, J = 7.8 Hz, IH), 8.11 (d, J = 7.0 Hz, IH), 8.01 (s, IH), 7.81- 7.76 (m, 2H), 7.59 (d, J = 8.6 Hz, IH), 7.21 (d, J = 2.2 Hz, IH), 6.87 (dd, J= 8.5, 2.4 Hz, IH), 6.81 (d, J = 8.4 Hz, IH), 3.60 (s, 3H); MS ESI 436.3 [M + H]+, calcd for [C24HnN7O2 + H]+ 436.1.
Example A154. (E and Z)-3-((3-(4-(morDholinomethyl')styryl)-lH-indazol-6-yl)- methylene)indolin-2-one
Figure imgf000211_0001
A. (E)-3-(4-(morpholinomethyl)styryl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazole-6-carbaldehyde According to the method of example A57A, 3-iodo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde (402 mg, 1 mmol) was reacted with 4-(4-vinylbenzyl)morpholine (304 mg, 1.5 mmol) to give the title compound upon silica gel purification (1:1 hexane/ethyl acetate) as a yellow solid (120 mg, 25 %). MS ESI 478.3 [M + H]+, calcd for [C27H35N3O3Si + H]+ 478.2. B. (E)-3-((3-(4-(morpMinomethyl)styryl)-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-indazol-6-yl)methylene)indolin-2-one
According to the method of A57B, oxindole (39 mg, 0.29 mmol) was reacted (E)-3- (4-(morpholinomethyl)styryl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-indazole-6- carbaldehyde (116 mg, 0.25 mmol) to give the title compound as a yellow solid upon silica gel purification (95:5 CH2Cl2/Me0H) (95 mg, 64%). MS ESI 593.5 [M + H]+, calcd for [C35H40N4O3Si + H]+ 593.3
C. (E)-3-((3-(4-(morpholirwmethyl)styryl)-lH-ind(πol-6-yl)methylene)indolin-
2-one
According to the method of A57C, (E)-3-((3-(4-(moφholinomethyl)styryl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazol-6-yl)methylene)indolin-2-one (95 mg,
0.16 mmol) was treated with boron trifluoride etherate, followed by 2 N HCl to give the title compound as an orange solid (33 mg, 42%). 1H NMR (400 MHz, CD3OD) δ 8.21 (d, J = 8.4 Hz, IH), 7.85 (d, J = 6.0 Hz), 7.78(d, J = 8.2 Hz, 2H), 7.66 (d, J = 7.6 Hz, IH), 7.53-7.58 (m, 5H), 7.24 (t, J = 7.7 Hz, IH), 6.93 (d, J = 7.6 Hz, IH), 6.87 (td, J = 6.7 Hz, 0.9 Hz, IH), 4.39 (s, 2H), 4.05-4.09 (m, 2H), 3.72-3.78 (m, 2H), 3.40-3.43 (m, 2H), 3.21-3.26 (m, 2H); MS ESI 463.3 [M + H]+, calcd for [C29H26N4O2+ H]+ 463.2.
Example A155. (E and Z)-3-((3-(6-(4-methylpiperazin-l-vnDyridin-3-yl)-lH- indazol-5-yl)methylene)indolin-2-one
Figure imgf000212_0001
A. (E)-3-((3-iodo-lH-indazol-5-yl)methylene)indolin-2-one
Piperidine (0.01 mL, 0.1 mmol) was added to a suspension of oxindole (72 mg, 0.54 mmol) and S-iodo-lH-indazole-S-carbaldehyde (146 mg, 0.54 mmol) in EtOH (10 mL). On heating to 750C, the suspended solid dissolved, and a new precipitate formed. Heating was continued at 750C for 14 hrs. After the mixture was cooled to room temperature, suction filtration and rinsing with EtOH (4x2mL) gave 3-((3- iodo-lH-indazol-5-yl)methylene)indolin-2-one (yellow solid, 131.9mg, 63%). 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br. s, IH), 10.61 (br. s, IH), 7.84 (s, IH), 7.77 (m, 2H), 7.69 (d, J = 8.8 Hz, IH), 7.60 (d, J = 8.0 Hz, IH), 7.23 (m, IH), 6.88 (d, J = 8.0 Hz, IH), 6.84 (m, IH); MS ESI 388.0 [M + H]+, calcd for [Ci6HiOlN3O+ H]+ 388.0.
B. (E and Z)-3-((3-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-lH-indazol-5- yl)methylene)-indolin-2-one
The reaction was carried out according to the method of example A93-A, except substituting 3-((3-iodo-lH-indazol-5-yl)methylene)indolin-2-one (29.9 mg, 0.077 mmol) and l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxa-borolan-2-yl)pyridin-2- yl)piperazine (26.9 mg, 0.089 mmol). Purification using chromatography (1Og silica SPE tube, Silicycle, 5-15% MeOH in dichloromethane) yielded a dark yellow product (14.7 mg) contaminated with a compound identified as 3-(6-(4- methylpiperazin- 1 -yl)pyridin-3-yl)- 1 H-indazole-5 -carbaldehyde by LC-MS . Piperidine (0.2M in EtOH, 0.02 mL, 4 umol) was added to a solution of this crude material (10 mg) and oxindole (2.5 mg, 19 umol) in EtOH (1 mL) and the resulting mixture was heated at 8O0C for 14h. After the solvent was evaporated, chromatography (5g silica SPE tube, Silicycle, 5-15% MeOH in dichloromethane) yielded the title compound as a yellow solid (60:40mixture of E:Z isomers, 3.6 mg, 15%,). 1H NMR (400 MHz, CD3OD) δ ppm 9.47 (s, 0.4 H), 8.87 (m, 0.4 H), 8.75 (s, 0.6 H), 8.38 (s, 0.6 H), 8.29 (m, 0.8 H), 8.17 (m, 0.6 H), 7.92 (m, 1 H), 7.80 (m, 0.6 H), 7.76-7.67 (m, 2 H), 7.59 (m, 0.4 H), 7.23 (m, 1.2 H), 7.09-7.01 (m, 1.6 H), 6.96-6.87 (m, 1.8 H), 3.80-3.72 (br m, 4 H), 2.90-2.82 (br m, 4 H), 2.58 (s, 1.2 H), 2.55 (s, 1.8 H); MS ESI 437.2 [M + H]+, calcd for [C26H24N6O + H]+ 437.2.
Example B: PLK4 Inhibition Assay
Active PLK4 was purified from an E. coli expression system as an amino terminal GST fusion of residues 1-391 of human PLK4. The protein was purified from clarified cell extracts after induction at 150C overnight using glutathione sepharose, gel permeation chromatography, and ion exchange (Resource Q). The resulting protein was dephosphorylated with lambda phosphatase (NEB cat# P0753), and resolved from the phosphatase using gluthione sepharose. The dephosphorylated GST-PLK4 was stored in aliquots at -8O0C until use.
PLK4 activity was measured using an indirect ELISA detection system. Dephosphorylated GST-PLK4 (4 nM) was incubated in the presence of 15 μM ATP (Sigma cat# A7699), 50 mM HEPES-Na2+ pH 7.4, 10 mM MgCl2, 0.01% Brij 35 (Sigma cat# 03-3170), in a 96 well microtitre plate pre-coated with MBP (Millipore cat# 30-011). The reaction was allowed to proceed for 30 minutes, followed by 5 washes of the plate with Wash Buffer (50 mM TRIS-Cl pH 7.4 and 0.2% Tween 20), and incubation for 30 minutes with a 1:3000 dilution of primary antibody (Cell Signaling cat# 9381). The plate was washed 5 times with Wash Buffer, incubated for 30 minutes in the presence of secondary antibody coupled to horse radish peroxidase (BioRad cat# 1721019, 1:3000 concentration), washed an additional 5 times with Wash Buffer, and incubated in the presence of TMB substrate (Sigma cat# T0440). The colourimetric reaction was allowed to continue for 5 minutes, followed by addition of stop solution (0.5 N sulphuric acid), and quantified by detection at 450 nm with either a monochromatic or filter based plate reader (Molecular Devices M5 or Beckman DTX880, respectively).
Compound inhibition was determined at either a fixed concentration (10 μM) or at a variable inhibitor concentration (typically 50 μM to 0.1 μM in a 10 point dose response titration). Compounds were pre-incubated in the presence of enzyme for 15 minutes prior to addition of ATP and the activity remaining quantified using the above described activity assay. The % Inhibition of a compound was determined using the following formula; % Inhibition = 100 x (1 - (experimental value - background value)/(high activity control - background value)). The IC50 value was determined using a non-linear 4 point logistic curve fit (XLfit4, IDBS) with the formula; (A+(B/(l+((x/C)ΛD)))), where A = background value, B = range, C = inflection point, D = curve fit parameter.
Example C: PLKl Inhibition Assay
PLKl inhibition was determined using the Z-Lyte assay kit from Invitrogen (cat# PV3802). The assay was performed using the recommended manufacturer's instructions with 25 μM ATP and 8 nM PLKl (Invitrogen cat # PV3501). The % inhibition values were determined according to the manufacturer's directions and IC50 values were obtained using a non-linear 4 point logistic curve fit (XLfit4, IDBS)
Example D: PLK2 Inhibition Assay
PLK2 inhibition was determined using the Z-Lyte assay kit from Invitrogen (cat# PV3802). The assay was performed using the recommended manufacturer's instructions with 60 μM ATP and 133 nM PLK2 (Invitrogen cat # PV4204). The % inhibition values were determined according to the manufacturer's directions and IC50 values were obtained using a non-linear 4 point logistic curve fit (XLfit4, IDBS) Example E: Aurora A Inhibition Assay
Aurora A inhibition was determined using the Z-Lyte assay kit from Invitrogen. The assay was performed using the recommended manufacturer's instructions with 20 μM ATP and 12 nM Aurora A (Invitrogen cat # PV3612). The % inhibition values were determined according to the manufacturer's directions and IC50 values were obtained using a non-linear 4 point logistic curve fit (XLfit4, IDBS)
Example F: Aurora B Inhibition Assay Aurora B inhibition was determined using the Z-Lyte assay kit from
Invitrogen. The assay was performed using the recommended manufacturer's instructions with 128 μM ATP and 28 nM Aurora B (Invitrogen cat # PV3970). The % inhibition values were determined according to the manufacturer's directions and IC50 values were obtained using a non-linear 4 point logistic curve fit (XLfit4, IDBS)
In Tables 1 to 5 below, IC50 values for PLK4, PLKl, PLK2, Aurora A and Aurora B Kinases are indicated as "A," "B," and "C," for those less than or equal to 5 μM; those greater than 5 μM and less than or equal to 50 μM; and those greater than 50 μM, respectively. The relative inhibition percentages at a dose of 10 μM are indicated as "X" and "Y" for those equal to or greater than 50% inhibition and those less than 50% inhibition, respectively. The relative inhibition percentages at a dose of 1 μM are indicated as "W" and "Z" for those equal to or greater than 50% inhibition and those less than 50% inhibition, respectively. As shown in Tables 1 and 2, numerous compounds of the invention are effective PLK inhibitors, in particular PLK4 inhibitors. In addition, a numer of compounds of the invention, as shown in Tables 1-5, inhibit Aurora kinases, in particular Aurora B kinase, in addition to PLK4.
Table 1: Inhibition Data of PLK4, PLKl, PLK2, Aurora A and Aurora B Kinases
Compound # IC50 Ranges
PLK4 PLKl PLK2 Aurora A Aurora B
Example Al A B B Y A
Example A33 B C — __ .. Example A4 B B — ~ —
Example A2 A B Y A A Example A3 A B X Y B Example A7 A B
Example A23 A B — ~ —
Example A27 B B — —
Example A21 A B — — —
Example A24 A B — —
Example A14 A C — — —
Example A17 B B — —
Example A29 A C — — — OQ CQQ OQ 03 P
Example A39 A — — —
Example A19 B B —
Example A28 B — — — —
Example A40 B — — — —
Example A5 A B A A Example A34 B
Example A9 A A __ __
Table 2: Inhibition Data of PLK4, PLKl, PLK2, Aurora A and Aurora B Kinases
Compound # PLK4 PLKl PLK2 Aurora A Aurora B
Example All A C Y X X
Example A8 B B .. ..
Example AlO A A —
Example A15 A B — —
Example A38 A B Y B A
Example A25 A A ~ —
Example A20 A A ~ ~ —
Example A26 A B Y A Y Example A12 A B
Example A37 B C C Y A
Example A22 A X X B Example A13 A Y X Y Example A16 A A A A
Example A32 A B Y X A
Example A35 A C Y Y A Example A36 A B Y C A
Example A6 A B A A A
Example A31 A C B Y X
Example A18 A B -- — —
Example A30 B C — — —
Example A41 A C C A A
Table 3: Inhibition Data of PLK4, PLKl, PLK2, Aurora A and Aurora B Kinases
Compound # PLK4 PLKl PLK2 Aurora A Aurora B Example A42 A C X A A
Example A43 A C X B A Example A44 A
Example A45 B — — ~ ~
Example A46 A — — ~ —
Example A47 C C C C B
Example A48 A — " — —
Example A49 A C X — — Example A50 A
Example A51 A — ~ B
Example A52 A — — ~ —
Example A53a A Y X A Example A53b A __
Example A54a A C X X A Example A54b A
Example A55 A — — ~ A
Example A56 A C A A A
Example A57 A Y X A A
Example A58 A Y Y A A
Example A59 A Y Y A A
Example A60 A Y Y A A
Example A61 A Y Y A A
Example A62 A Y Y A A
Example A63 A Y Y — . Example A64 A X
Example A65 A
Example A66 A
Example A67 A X X X X
Example A68 A
Example A69 A X X X X
Table 3: Inhibition Data of PLK4, PLKl, PLK2, Aurora A and Aurora B Kinases
Compound # PLK4 PLKl PLK2 Aurora A Aurora B
Example A70 A
Example A71 A X A
Example A72 A X A
Example A73 A
Example A74 A
Example A75 B
Example A76 B
Example A77 B
Example A78 A
Example A79 B
Example A80 A Y Y A A
Example A81 A Y Y A A
Example A82 A
Example A83 A X X X A
Example A84 A Y Y A A
Example A85 A Y Y A A
Example A86 A Y Y X A
Example A87 A Y Y X A
Example A88 A A
Example A89 A A
Example A90 A
Example A91 A B
Example A92 A Example A93 A Y Y A A
Example A94 A Y Y C A
Example A95 A
Example A96 A X A
Example A97 A A
Example A98 A
Example A99 A
Table 4: Inhibition Data of PLK4, PLKl, PLK2, Aurora A and Aurora B Kinases
Compound # IC50 Ranges
PLK4 PLKl PLK2 Aurora A Aurora B Example AlOO A Y Y X A
Example AlOl A Y Y X A
Example A102 A — — — —
Example A103 A Y Y X A
Example A104 A Y Y A A
Example A105 A ~ ~ — ~
Example A106 A Y — X A
Example Al 07 A X Y A A
Example A108 A Y Y A A
Example A109 A Y Y A A
Example AIlO A Y Y A A
Example AlIl A Y Y A —
Example Al 12 A Y Y A A
Example Al 13 A Y Y A A
Example Al 14 A Y Y A A
Example Al 15 A Y Y A A
Example Al 16 A Y Y A A
Example Al 17 A Y Y A A
Example Al 18 A Y Y A A
Example Al 19 A Y Y A A
Example A120 A Y Y A A
Example A121 A — __ A Example A122 A A
Example A123 A A A
Example A124 A A A
Example A125 A X A
Example A126 A X A
Example A127 A A A
Example A128 A A A
Example A129 A A
Figure imgf000220_0001
Figure imgf000221_0001
Example G: Kinase Selectivity Assays
The inhibitory activity of selected compounds of the invention was evaluated against a panel of 45 different kinase enzymes by CEREP, France. The assays were performed using standard HTRF assay methods as documented by CEREP against the human orthologues of AbI kinase, Aktl/PKBa, AMPKa, BMX kinase (Etk), Brk, CaMK2a, CaMK4, CDC2/CDK1 (cycB), CDK2 (cycE), CHKl, CHK2, c-Met kinase, CSK, EphB4 kinase, ERKl, ERK2 (P42mapk), FGFR2 kinase, FGFR4 kinase, FLT-I kinase (VEGFRl), FLT-3 kinase, Fyn kinase, IGFlR kinase, IRK (InsR), JNK 2, KDR kinase (VEGFR2), Lck kinase, Lyn kinase, MAPKAPK2, MEK1/MAP2K1, p38a kinase, p38d kinase, p38g kinase, PDGFRb kinase, PDKl, PKA, PKCa, PKCbI, PKCb2, PKCg, Ret kinase, ROCK2, RSK2, Src kinase, Syk, and TRKA. The % Inhibition was determined by the formula; % Inhibition = 100 x ( 1 - (experimental value - background value)/(high activity control - background value)), and tabulated below.
Table 6: Percent Inhibition Values For Examples Al, A5, A41, A60, A97 and A132 at 10 μM Concentration
Figure imgf000221_0002
Figure imgf000222_0001
Table 6 shows the percent inhibition values obtained for Examples Al, A5, A41, A60, A97 and A 132 at 10 μM concentration. From this inhibition data it is apparent that certain kinases, e.g. AbI, FGFR2, FLT-I, FLT-3, KDR, Lyn, PDGFRbeta Ret and TRKA kinases are stongly inhibited (i.e. >95%) by compounds of the invention at 10 μM. For a number of compounds, IC50 values were estimated against kinases of interest based on Millipore protocols. Kinase assays at Millipore were performed using a radiolabeled phosphopeptide filter binding detection system, in duplicate, at each compound concentration. The ATP substrate concentration in the reactions was at the Km for each enzyme.
To allow for a more direct comparison of compound inhibition, an IC50 value was estimated from the inhibition determined at three compound concentrations. Several assumptions were made to allow this calculation using a 4 parameter non linear curve fit model, including full inhibition set at 100%, no inhibition set to 0%, and a curve fit parameter set at 1. The inflection point was reported as the estimated IC50.
In Table 7, IC50 value estimates against the Receptor Tyrosine Kinase family (e.g. AbI, FGFR2, FLT-I, KDR, Lyn, and PDGFRβ) are indicated as "A," "B," and "C," for those less than or equal to 5 μM; those greater than 5 μM and less than or equal to 50 μM; and those greater than 50 μM, respectively. These activities may impart additional therapeutic benefit to these compounds.
Table 7. IC50 value estimates against AbI, FGFR2, FLT-I, KDR, Lyn, and PDGFRβ
Figure imgf000223_0001
Example H: PLK3 Inhibition Assay
PLK3 inhibition was determined using the Z-Lyte assay kit from Invitrogen (cat# PV3802). The assay was performed using the recommended manufacturer's instructions with 100 μM ATP and 21 nM PLK3 (Invitrogen cat # PV3812). The % inhibition values were determined according to the manufacturer's directions and IC50 values were obtained using a non-linear 4 point logistic curve fit (XLfit4, IDBS). The majority of the compounds of the invention tested in this assay inhibited PLK3 with IC50 values of less than or equal to 0.5 μM; certain compound examples including A2, A6, A26, A45, A49, A125, A127, A148, A149, A152 and A153 exhibited PLK3 IC50 values of greater than 0.5 μM. Example I: Cancer Cell Line Data of Compounds of the Invention
Breast cancer cells (MCF-7, MDA-MB-468, HCC 1954), colon cancer cells (SW620) and lung cancer cells (A549), together with human mammary epithelial primary cells (HMEC), were seeded (1000 to 4000 per 80μl per well depending on the cell growth rate) into 96 well plates, 24 hours before compound overlay.
Compounds were prepared as 1OmM stock solutions in 100% DMSO which were diluted with DMEM (Dulbecco's Modified Eagle's Medium) cell growth Medium (Invitrogen, Burlington, ON, Canada) containing 10% FBS (Fetal Bovine Serum) to concentrations ranging from 5OnM to 250μM. Aliquots (20μl) from each concentration were overlaid to 80μl of the pre-seeded cells in the 96 well plates to make final concentrations of 1OnM to 50μM. The cells were cultured for 5 days before the Sulforhodamine B assay (SRB) was performed to determine the compound's cell growth inhibition activity.
Sulforhodamine B (purchased from Sigma, Oakville, ON, Canada) is a water-soluble dye that binds to the basic amino acids of the cellular proteins. Thus, colorimetric measurement of the bound dye provides an estimate of the total protein mass that is related to the cell number, the cells are fixed in situ by gently aspirating off the culture media and adding 50μl ice cold 10% Tri-chloroacetic Acid (TCA) per well and incubate at 40C for 30-60 min, The plates are washed with water five times and allowed to air dry for 5min. Addition of 50μl 0.4%(w/v) SRB solution in 1% (v/v) acetic acid to each well and incubatation for 30min at RT completes the staining reaction. Following staining, plates are washed four times with 1% acetic acid to remove unbound dye and then allowed to air dry for 5min. The stain is solubilized with lOOμl of 1OmM Tris pH10.5 per well. Absorbance is read at 570nm. The percentage (%) of relative growth inhibition was calculated by comparing to DMSO treated only cells (100%). GIso's were determined for compounds with cytotoxic activity. The GI50 was calculated using GraphPad PRISM software (GraphPad Software, Inc., San Diego, CA, USA). GI50 (growth inhibition) is the compound concentration that causes 50% inhibition of cell growth. In Table 8 below, GI50 value ranges for several compound examples against a luminal breast cancer cell line (MCF-7), two basal breast cancer cell line (MDA- MB-468, HCC 1954), a lung cancer cell line (A549), a colon cancer cell line (SW- 620) and primary breast cells (HMEC) are given. The example compounds demonstrated varying growth inhibition/cell killing activity against cancer cells of luminal breast cancer and basal breast cancer cell, lung cancer and colon cancer. In general, these compounds showed less activity against normal cells as exemplified by HMEC. The GI50 ranges are indicated as "A," "B," "C," and "D," for values less than or equal to 5 μM; those greater than 5 uM and less than or equal to 20 μM; those greater than 20 μM and less than or equal to 50 μM; and those greater than 50 μM, respectively.
Table 8: Cell Growth Inhibition Data
Example Cell Line GI50 Range
#
M MCCFI -7 MDA-MB-468 HCC-1954 SW-620 A-549 HMEC
A2 D B —
A4 B B —
A6 B B —
AlO C C —
A19 B A —
A32 B B —
A31 A A —
A41 A A C B B D
A59 A A B A B ~
A84 A A B A D D
A91 A A A A — B
A96 A A A A A —
A97 A A A A A C
A103 A A B A B D
A106 A A A A A B
A108 A A A A A A
A109 A A D A A D
A127 A A A A B —
A147 C B D C D —
A150 A A A A A
In addition to the cell lines tested as described above, selected compounds have been assayed against an extended panel. These include: breast cancer cell lines (T47 D, MDA-MB-231, HS578T, BT474, SKBR3, HCC 1954), a lung cancer cell line (H358), brain cancer cell lines (A172, Hs683, SK-N-SH), Colon cancer cell lines (Colo 205, CT-15, HCTl 16+/-, HCTl 16+/+), ovarian cancer cell lines (OVCAR-3, SK-OV-3, SW 626), a melanoma cell line (518A2), a prostate cancer cell line (PC-3) and an immortalized breast cell line (184A1). The sulforhodamine B assay (SRB) described above was use to assay test compounds against the extended panel (Table 9). The GI50 ranges are indicated as "A," "B," "C," and "D," for values less than or equal to 5 μM; those greater than 5 μM and less than or equal to 20 μM; those greater than 20 μM and less than or equal to 50 μM; and those greater than 50 μM, respectively.
Table 9: Cell Growth Inhibition Data
Figure imgf000226_0001
Some compounds of the invention, although inhibiting the isolated PLK-4 enzyme activity, generally failed to inhibit the growth of Breast Cancer cell lines, i.e.,. Compound examples A7, A9, A70 and Al 11 had GI50 values > 50 μM on the MCF- 7, MDA-MB-468 and T47D Breast cancer cell lines.
Example J: In vitro Angiogenesis Assay.
Compounds of the invention had micromolar and submicromolar activity against Receptor Tyrosine Kinases (RTKs) such as FGFR2, VEGFRl, VEGFR2 and PDGFRbeta. Activity against these RTKs can result in antiangiogenic activity which is associated with slowed tumor growth and/or tumor regression. To measure the effects of these compounds they were tested in an angiogenisis assay as described below. Note that compound Example A57 showed anti-agiogenic effects at micromolar concentrations (Figure 1).
HUV-EC-C cells were obtained from the American Type Culture Collection
(ATCC, CRL- 1730), and were used at early passage for the assay. The in vitro Angiogenesis Assay Kit (Chemicon) was used according to the manufacturer's recommendation. An ice-cold mixture of ECMatrix was transferred into a precooled
96-well plate. After the matrix solution had solidified (>1 hr incubation at 37 °C),
8,000 cells were mixed with the appropriate inhibitor concentration (in 100 microlitres EGM-2) and plated into each well. After incubation at 37 °C for 4 hr, tube formation was inspected. Two methods, pattern recognition and branch point counting, were used to quantify the progression of angiogenesis and expressed as a percentage of the control tube count (Figure 1).
While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

What is claimed is:
1. A compound represented by the following structural formula:
Figure imgf000228_0001
or a pharmaceutically acceptable salt thereof, wherein: ring A is an optionally substituted 5- or 6-membered aromatic ring; ring B is an optionally substituted phenyl ring; and ring C is a 5-membered heteroaromatic ring wherein one of X1-X3 is N, one of X1-X3 is NR5, and one of X1-X3 is N or CR6;
Z is =N- or =CR3-, provided that when Z is =N-,
Figure imgf000228_0002
C6 alkyl, then ring A is not phenyl or phenyl substituted with halogen or trifluoromethyl;
R3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, provided when
Figure imgf000228_0003
each of R4 and R5 independently is -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O)2(Cl-Co alkyl) or -S(O)2(phenyl), wherein each said alkyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and C1-C6 haloalkoxy, and wherein each said phenyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C 1 -C6 alkyl, C 1 -C6 haloalkyl, C 1 -C6 alkoxy and C 1 -C6 haloalkoxy;
R6 is hydrogen, halogen, nitro, cyano, R', -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)OR, -SOR, -SO2R, -SO3R1, -SO2N(R)2, -NRS(O)R1, -NRSO2R1, -NRC(O)N(R)2, -NRC(O)ON(R)2, or -NRSO2N(R)2; and each R independently is hydrogen, Ci-10 aliphatic, phenyl or 5-6 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C 1 -C6 haloalkoxy, and wherein each of the phenyl and heteroaryl groups represented by R, and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, or
N(R)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of =O, =S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, Ci-6 haloalkyl, C1-6 hydroxyalkyl, amino, Cj-6 alkylamino, C1-6 dialkylamino, Q-6 aminoalkyl, (Ci-6 alkylamino)Ci-6 alkyl, (C1-6 dialkylamino)Ci-6 alkyl, (pheny^C^ alkyl, (5-6 membered heteroary I)C1-6 alkyl, Ci-6 alkoxy, C1-6 haloalkoxy, Ci-6 alkylcarbonyloxy, C1-6alkoxycarbonyl, Ci-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl; and each R' independently is Ci-I0 aliphatic, phenyl or 5-14 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, Ci-δ alkylamino, Ci-όdialkylamino, -C(O)(C1-C6 alkyl), -C(O)(C 1-C6 haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(C 1-C6 alkyl), -C(O)O(C 1-C6 haloalkyl),-C(O)O(phenyl), -OC(O)(C 1 -C6 alkyl), -OC(O)(C 1 -C6 haloalkyl), -OC(O)(phenyl),
-S(O)2(C1-C6 alkyl), -S(O)2(Cl-Co haloalkyl) and -S(O)2(phenyl), and wherein each of the phenyl and heteroaryl groups represented by R', and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R' independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, non-aromatic heterocyclic group, Ci-s alkylamino, Q-6 dialkylamino, -C(O)(C 1-C6 alkyl), -C(O)(C 1-C6 haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(C 1-C6 alkyl), -C(O)O(Cl- C6 haloalkyl),-C(O)O(phenyl), -OC(O)(C1-C6 alkyl), -OC(O)(C1-C6 haloalkyl), -OC(O)(phenyl), -S(O)2(Cl-CO alkyl), -S(O)2(C1-C6 haloalkyl), and -S(O)2(phenyl).
2. The compound of Claim 1, wherein the compound is represented by the following structural formula:
Figure imgf000231_0001
or a pharmaceutically acceptable salt thereof, wherein: each OfY1, Y2, Y3 and Y4 independently is -N or -CH; and ring A and ring B are optionally substituted.
3. The compound of Claim 2, wherein the compound is represented by a structural formula selected from:
Figure imgf000231_0002
Figure imgf000232_0001
Figure imgf000233_0001
or a pharmaceutically acceptable salt thereof, wherein ring A and ring B are optionally substituted.
4. The compound of Claim 3, wherein the compound is represented by a structural formula selected from:
Figure imgf000233_0002
Figure imgf000234_0001
Figure imgf000234_0002
Figure imgf000234_0003
Figure imgf000234_0004
or a pharmaceutically acceptable salt thereof, wherein ring A and ring B are optionally substituted.
5. The compound of Claim 4, wherein the compound is represented by the following structural formula:
Figure imgf000235_0001
or a pharmaceutically acceptable salt thereof, wherein ring A and ring B are optionally substituted.
The compound of Claim 5, wherein:
R3 is -H, C1-C6 alkyl or C1-C6 haloalkyl; each R' independently is C1-10 aliphatic, phenyl or 5-6 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and wherein each of the phenyl and heteroaryl groups represented by R', and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R' independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, C1-C6 haloalkoxy.
The compound of Claim 6, wherein: phenyl ring A is optionally substituted with one or more substituents Qa, and phenyl ring B is optionally substituted with one or more substituents Qb, each of Qa and Qb independently is selected from the group consisting of halogen, -X-R1, -NO2, -CN, -NCS, Ak1, Ar1, (CM0 alkyleneJ-Ar1, (C2-I0 alkenylene)-Ar\ -O-[CH2]P-O-, -S-[CH2]P-S- and -[CH2]q-, wherein X is -C(O)O-, -C(O)-, -C(S)-, -OC(O)-, -C(O)N(R2)-, -C(S)N(R2)-, -OC(O)N(R2)-, -S(O)-, -S(O)2-, -SO3-, -SO2NR2-, -0-, -S-, -NR2-, -NR2C(O)-, -NR2S(O)-, -NR2C(O)O-, -NR2C(O)ONR2-, -N(R2)C(O)NR2-, -NR2SO2NR2- or -NR2SO2-; each R1 independently is: i) hydrogen; ii) a C6-I4 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, -NO2, -CN, -NCS, Ak10, (C1-10 alkylene)-Ar10, (C2-10 alkenylene)-Ar10, -C(O)OR10, -C(O)R10, -C(S)R10, -OC(O)R10, -C(O)N(R11J2, -C(S)N(R1 \ -OC(O)N(R1 ')2, -S(O)R12, -S(O)2R12, -SO3R12, -SO2N(R1 ^2, -OR10, -SR10, -N(R11J2, -NR11C(O)R10, -NR11S(O)R12, -NR11C(O)OR12, -N(R1 ^C(O)N(R1 \ -NR1 ' SO2N(R1 x)2 and -NR1 ! SO2R12; or iii) a Ci-I0 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, -NO2, -CN, -NCS, Ar10, -C(O)OR10, -C(O)R10, -C(S)R10, -OC(O)R10, -C(O)N(R1 \ -C(S)N(R1 *)2, -OC(O)N(R11^, -S(O)R12, -S(O)2R12, -SO3R12, -SO2N(R11J2, -OR10, -SR10,
-N(R11)2, -NR11C(O)R10, -NR11S(O)R12, -NR11C(O)OR12, -N(R1 ^C(O)N(R1 ')2, -NRnSO2N(Rn)2 and -NR11SO2R12, provided that R1 is other than hydrogen when X is -S(O)-, -S(O)2-, -SO3-, -NR2S(O)- or -NR2SO2-; and each R2 independently is R1, -CO2R1, -SO2R1 or -C(O)R1, or, taken together with NR1, forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of =0, =S, halogen, nitro, cyano, hydroxy, Q-6 alkyl, C1-6haloalkyl, Cj-6 hydroxyalkyl, amino, C1-6alkylamino, Cw dialkylamino, C1-6aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl,
(5-6 membered heteroarytyCj-s alkyl, C1-6 alkoxy, Cj-6 haloalkoxy, C1-6 alkylcarbonyloxy, C 1-5 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl; each R10 independently is: i) hydrogen; ii) a C6-I4 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Cj-10 alkyl, C1-I0 haloalkyl, (C1-10 haloalkoxy)Ci-10 alkyl, (Ci-10 alkoxy)Ci-10alkyl, C1-10 hydroxyalkyl, Ci-1O aminoalkyl, (Ci-I0 alkylamino)Ci-10 alkyl,
(Ci-IO dialkylamino)C MO alky 1, (phenyl)Ci-io alkyl, (5-6 membered heteroaryOCi.io alkyl, amino, CMO alkylamino, C1-1O dialkylamino, Ci-10 alkoxy, CMO haloalkoxy, C1-I0 alkylcarbonyloxy, C1-1O alkoxycarbonyl and Ci-I0 alkylcarbonyl; or iii) a CMO alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, CMO haloalkyl, C1-I0 alkoxy, Ci-I0 haloalkoxy, amino, CMO alkylamino, CMO dialkylamino, Ci-I0 alkylcarbonyloxy, C1-I0 alkoxycarbonyl, CM0 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; each R1 ' independently is R10, -CO2R10, -SO2R10 or -C(O)R10, or
-N(R1 % taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of =0, =S, halogen, nitro, cyano, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, amino, Ci-6 alkylamino, Ci-6 dialkylamino, Ci-6 aminoalkyl, (Ci-6 alkylamino)Ci-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, C1-6 alkoxy, Ci-6 haloalkoxy, C1-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl; and each R12 is independently is: i) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 alkyl, C1-10 haloalkyl, (C i .i o haloalkoxy)C1-10 alkyl, (Ci-10 alkoxy)Ci-io alkyl, C1-I0 hydroxyalkyl, Ci-I0 aminoalkyl, (CMO alkylamino)Ci-i0 alkyl, (Ci-IO dialkylamino)Ci-io alkyl, amino, Cj-10 alkylamino, C1-I0 dialkylamino, Ci-I0 alkoxy, CMO haloalkoxy, Ci-I0 alkylcarbonyloxy, Ci-I0 alkoxycarbonyl and CMO alkylcarbonyl; or ii) a Ci-I0 alkyl group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, CMO haloalkyl, Ci-I0 alkoxy, CM0 haloalkoxy, amino, CMO alkylamino, CMO dialkylamino, Ci-I0 alkylcarbonyloxy, Ci-I0 alkoxycarbonyl, CMO alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C 1 -C3 alkoxy and C 1 -C3 haloalkoxy; each Ak1 independently is a Ci-I0 aliphatic group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, -N(R21)2, -C(O)N(R21)2, -C(O)N(R21)2, -NR21C(O)R21, -SO2R22, -SO2N(R21);,, -NR21SO2R22, -NR21C(O)OR21, -OC(O)N(R21)2, -NR21C(O)N(R21)2, -NRC(O)ON(R)2, -NR21SO2N(R21)2, -OR21, -SR21, CMO haloalkoxy, -C(O)R21, -C(O)OR21 and -OC(O)R21; each Ak10 independently is a Ci-I0 alkyl group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(Cj-6 alkyl), Ci -6 haloalkoxy, amino, Ci-6 alkylamino, Q-6 dialkylamino, Ci^ alkylcarbonyloxy, Ci^ alkoxycarbonyl and Ci.6 alkylcarbonyl; each Ar1 independently is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ci-10 alkyl, C1-10 haloalkyl, (Ci-I0 haloalkoxy)C1-10alkyl, (Ci-I0 alkoxy)Ci.io alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-I0 alkylamino)Ci. io alkyl, (Ci.iodialkylamino)Ci.io alkyl, -N(R21)2, -C(O)N(R21)2, -C(O)N(R21)2, -NR21C(O)R21, -SO2R22, -SO2N(R2 %, -NR21SO2R22, -NR21C(O)N(R21)2, -NRC(O)ON(R)2, -NR21SO2N(R21)2, -OR21, -SR21, Ci-I0 haloalkoxy, -C(O)R21, -C(O)OR21, -OC(O)R21, phenyl and 5-6 membered heteroaryl, wherein said phenyl and said 5-6 membered heteroaryl 5 are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; each Ar10 independently is a C6-I4 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-I0 alkyl), -S(Ci0 alkyl), C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)Ci-i0 alkyl, (Ci-10 alkoxy)Ci-io alkyl, Ci-I0 hydroxyalkyl, (Ci-IO aminoalkyl, (Cj.io alkylamino)Ci.io alkyl, (Ci-I0 dialkylamino)Ci-10 alkyl, (phenyl)Ci.io alkyl, (5-6 membered heteroaryl)Ci.i0 alkyl, amino, Ci-I0 alkylamino, Ci-I0 dialkylamino, Ci-I0 haloalkoxy, Ci.ioalkylcarbonyloxy, Cj- loalkoxycarbonyl and Ci-I0 alkylcarbonyl; and each R21 independently is hydrogen, Ci-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and Cl- C3 haloalkoxy, and whrein the alkyl group represented by R21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, Cl-
C3 alkoxy and C1-C3 haloalkoxy; or N(R21)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, =0, C1-C3 alky, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and amino; each R22 independently C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy, and whrein the alkyl group represented by R22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and Cl- C3 haloalkoxy; each p is 1, 2 or 3; and each q is 2, 3, 4 or 5.
8. The compound of Claim 7, wherein each R2 is -H or C1-C6 alkyl.
9. The compound of Claim 8, wherein the compound is represented by the following structural formula:
Figure imgf000240_0001
or a pharmaceutically acceptable salt thereof, wherein each of n and m independently is 0, 1 or 2; each of R4 and R5 independently is -H, C1-C6 alkyl, phenyl, -C(O)(Cl-CO alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O)2(Cl-Co alkyl) or -S(O)2(phenyl), wherein each said phenyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, and wherein each said alkyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy and phenyl;
R7 is -H, F, Cl or methyl; the optionally substituted 5-6 membered heteroaryl group represented by each of R and R' independently is an optionally substituted furanyl group, an optionally substituted imidazolyl group, an optionally substituted isoxazolyl group, an optionally substituted oxadiazolyl group, an optionally substituted oxazolyl, an optionally substituted pyrazolyl group, an optionally substituted pyrrolyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyridazinyl group, an optionally substituted thiazolyl group, an optionally substituted triazolyl group, an optionally substituted tetrazolyl group or an optionally substituted thienyl group; and the 5-6 membered heteroaryl group in the substituents for the groups represented by each of R and R' independently is a furanyl group, an imidazolyl group, an isoxazolyl group, an oxadiazolyl group, an oxazolyl, a pyrazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thiazolyl group, a triazolyl group, a tetrazolyl group or a thienyl group.
10. The compound of Claim 9, wherein the compound is represented by a structural formula selected from:
Figure imgf000242_0001
Figure imgf000242_0002
or a pharmaceutically acceptable salt thereof, wherein: one of Qa and Qb is halogen, -NO2, -CN, Ak1 , Ar1 , (C i -10 alkylene)-Ar', (C1-I0 alkenylene)-Ar1 or -X-R1; and the other of Qa and Qb is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
11. The compound of Claim 10, wherein each of R4 and R5 independently is -H, C1-C6 alkyl, phenyl, -C(O)(Cl-CO alkyl), -C(O)(phenyl), -C(O)O(Cl-CO alkyl), -C(O)O(phenyl), -S(O)2(Cl-CO alkyl) or -S(O)2(phenyl).
12. The compound of Claim 11 , wherein both of Qa and Qb are independently halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
13. The compound of Claim 10, wherein the compound is represented by a structural formula selected from:
Figure imgf000243_0001
Figure imgf000243_0002
or a pharmaceutically acceptable salt thereof.
14. The compound of Claim 13, wherein the compound is represented by a structural formula selected from:
Figure imgf000243_0003
(X) and
Figure imgf000244_0001
or a pharmaceutically acceptable salt thereof.
15. The compound of Claim 14, wherein the compound is represented by the following structural formula:
Figure imgf000244_0002
or a pharmaceutically acceptable salt thereof.
16. The compound of Claim 13, wherein the compound is represented by a structural formula selected from:
Figure imgf000245_0001
Figure imgf000245_0002
or a pharmaceutically acceptable salt thereof.
17. The compound of any one of Claims 7-11 and 13-16, wherein:
X is -C(O)-, -C(S)-, -C(O)N(R2)-, -OC(O)N(R2)-, -SO2NR2-, -0-, -S-, -NR2-, -NR2C(O)-, -NR2C(O)O-, -NR2C(O)ONR2-, -N(R2)C(O)NR2-, -NR2SO2NR2- or -NR2SO2-; each R1 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted CM0 alkyl group; and each Ak1 independently is an optionally substituted C1-10 alkyl group; and each Ar1 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6haloalkyl, (C1-6 haloalkoxy)C I-6 alky 1, (C1-6 alkoxy)C1-6 alkyl, C1-6hydroxyalkyl, (C1-6 aminoalkyl, (d-ealkylamino)^ alkyl, (C1-6 dialkylamino)C1-6 alkyl, -NR21 2, -C(O)NR21 2, -C(O)NR21 2, -NR21C(O)R21, -S(O)2R22, -SO2NR21 2, -NR21SO2R22, -NR21C(O)NR22 2,
-NR21SO2NR21 2, -OR21, -SR21, C1-6 haloalkoxy, -C(O)R21, -C(O)OR21, - OC(O)R21, phenyl, benzyl and 5-6 membered heteroaryl.
18. The compound of Claim 17, wherein: each Ak10 independently is an optionally substituted C1-6 alkyl group; each Ar10 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6haloalkyl, (C1-6 haloalkoxy)C1-6 alkyl, (C1-6 alkoxy)C i ^ alkyl, C i ^ hydroxyalkyl, C i -6 aminoalkyl, (C i -β alkylamino)C i .6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, benzyl, phenyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, Ci^alkylamino, C1-6 dialkylamino, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alky lcarbonyl; each R10 independently is: i) hydrogen; ii) a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci-6 alkyl, Ci^ haloalkyl, (Ci-6 haloalkoxy)^ alkyl, (Ci-6 alkoxy)Ci^ alkyl, Ci-6 hydroxyalkyl, (Ci-6 aminoalkyl, (Ci-6 alky lamino)C I-6 alkyl, (C1-6 dialkylamino)C I-6 alkyl, amino, Ci-όalkylamino, Ci-6 dialkylamino, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl; or iii) a C1-]O alkyl group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, Ci-6 haloalkyl, Ci-6alkoxy, Ci-6 haloalkoxy, amino, C1-6 alkylamino, Ci-6 dialkylamino, C1-6 alkylcarbonyloxy, Ci-6alkoxycarbonyl, Ci-6 alkylcarbonyl and phenyl; and each R1 ' independently is R10, -CO2R10, -SO2R10 or -C(O)R10, or
-N(R1 !)2 taken together is a 5-6 membered non-aromatic heterocyclic group optionally substituted with halogen, hydroxy, nitro, cyano, =0, C1-C3 alky, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and amino; each R12 independently is: i) a phenyl group or a 5-6 membered heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Q-6 aliphatic, C I-6 haloalkyl, (C1-6 haloalkoxy)Ci-6alkyl, (C1-6 alkoxy)C1-6 alkyl, Q-6 hydroxyalkyl, (C1-6 aminoalkyl, (C1-6 alkylamino)d^ alkyl,
(Ci-6 dialkylamino)C I-6 alkyl, amino, C1-6 alkylamino, Ci-6 dialkylamino, C1^ alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, Ci^alkoxycarbonyl and Cj-6 alkylcarbonyl; or ii) a C1-1O alkyl group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, Cj-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, amino, Ci-6 alkylamino, C^ dialkylamino, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl, C I-6 alkylcarbonyl and phenyl; and each R21 independently is hydrogen, Ci-6 alkyl or optionally substituted phenyl; and each R22 independently is Ci-6 alkyl or optionally substituted phenyl.
19. The compoud of Claim 18, wherein each R1 independently is i) hydrogen; ii) a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Aklo, (Ci-iOalkylene)-Ar10, (C2-I0 alkenylene)- Ar10, -OR10, -SR10, -OC(O)N(R11J2, -N(R1 \ -C(O)NR1 *,
-NR11C(O)R10, -N(R11XXO)N(R1 \ -NR11SO2N(R11^, -NR11SO2R12, -SO2N(Rπ)2, -OC(O)R10 -C(O)OR10 and -C(O)R10; or iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ar10, -OR10, -SR10, -N(R1 ')2, -OC(O)R10, -C(O)OR10 and -C(O)R10; and each Ak1 independently is a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C1-6 alkyl), -S(C1-6 alkyl), C1-6 haloalkoxy, amino,
C1-6 alkylamino, Ci-6 dialkylamino,
Figure imgf000248_0001
Ci-6 alkoxycarbonyl and C1-6 alkylcarbonyl; and each Ar1 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(C1-6 alkyl), C1-6 alkyl, C1-6haloalkyl, (C1- 6 haloalkoxy)C1-6 alkyl, (C1-6 alkoxy)C I-6 alkyl, C1-6 hydroxyalkyl, (Ci-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (Ci-6 dialkylamino)Ci-6 alkyl, (phenyl)C i^ alkyl, (5-6 membered heteroaryl)Ci-6 alkyl, amino, Ci-6 alkylamino, Ci-6 dialkylamino, Ci-6 haloalkoxy, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl.
20. The compound of Claim 19, wherein each R10 independently is i) hydrogen, ii) a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, Cl- C3 alkoxy and C1-C3 haloalkoxy, or iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloalkoxy and phenyl; each R12 independently i) a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy, or ii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloalkoxy and phenyl; and each Ar10 independently is a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
21. The compound of Claim 20, wherein: the optionally substituted 5-6 membered heteroaryl group represented by each of R1, R10, R12, R21, R22, Ar1 and Ar10 independently is an optionally substituted furanyl group, an optionally substituted imidazolyl group, an optionally substituted isoxazolyl group, an optionally substituted oxadiazolyl group, an optionally substituted oxazolyl, an optionally substituted pyrazolyl group, an optionally substituted pyrrolyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyridazinyl group, an optionally substituted thiazolyl group, an optionally substituted triazolyl group, an optionally substituted tetrazolyl group or an optionally substituted thienyl group; and the 5-6 membered heteroaryl group in the substituents for the groups represented by Ar1 independently is a furanyl group, an imidazolyl group, an isoxazolyl group, an oxadiazolyl group, an oxazolyl, a pyrazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thiazolyl group, a triazolyl group, a tetrazolyl group or a thienyl group.
22. The compound of any one of Claims 9-16, wherein: one of Qa and Qb of each of Structural Formulas (II), (III) and (IV) independently is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(Cl-Co alkyl), -C(O)NH2, -C(O)NH(Cl-Co alkyl), -C(O)N(Cl-Co alkyl)2, -SO2NH2, -SO2NH(Cl-CO alkyl), -SO2N(C 1-C6 alkyl)2, -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -SH, -S(Cl-Co alkyl), -S(C1-C6 haloalkyl), -NH2, -NH(Cl-CO alkyl), -N(Cl-CO alkyl)2, , -NHC(O)(C 1 -C6 alkyl), -NHC(O)O(C 1 -C6 alkyl), -NHC(O)NH2,
-NHC(O)NH(Cl-CO alkyl), -NHC(O)N(Cl-CO alkyl)2, -NHC(O)ONH2, -NHC(O)ONH(Cl-Co alkyl), -NHC(O)ON(C 1-C6 alkyl)2, -NHSO2NH2, -NHSO2NH(Cl-Co alkyl), -NHSO2N(Cl-Co alkyl)2 or -NHSO2(Cl-Co alkyl), and the other Qa and Qb of each of Structural Formulas (II), (III) and (IV) independently is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy; or each Qa in Structural Formulas (VIII), (X), (XII) and (XIII), and each Qb in Structural Formulas (IX), (XI) and (XIV) are each independently halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(Cl-Co alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(Cl-Co alkyl)2, -SO2NH2,
-SO2NH(Cl-Co alkyl), -SO2N(Cl-Co alkyl)2, -OH, -O(C1-C6 alkyl), -0(Cl- C6 haloalkyl), -SH, -S(Cl-CO alkyl), -S(Cl-CO haloalkyl), -NH2, -NH(Cl- C6 alkyl), -N(Cl-Co alkyl)2, , -NHC(O)(Cl-Co alkyl), -NHC(O)O(Cl-Co alkyl), -NHC(O)NH2, -NHC(O)NH(Cl-CO alkyl), -NHC(O)N(Cl-CO alkyl)2, -NHC(O)ONH2, -NHC(O)ONH(C 1 -C6 alkyl), -NHC(O)ON(C 1 -C6 alkyl)2, -NHSO2NH2, -NHSO2NH(Cl-Co alkyl), -NHSO2N(Cl-Co alkyl)2 or -NHSO2(Cl-Co alkyl).
23. The compound of any one of Claims 9- 16, wherein: one of Qa and Qb of each of Structural Formulas (II), (III) and (IV) independently is halogen, hydroxy, cyano, nitro, Ph, -CH2Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(C1-C6 alkyl)(Ph), -SO2NH(Ph), -SO2N(Cl-Co alkylXPh), -O(Ph), -S(Ph), -NH(Ph), -N(Cl-CO alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(C 1-C6 alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(Cl-CO alkyl)(Ph), -NHSO2NH(Ph), -NHSO2N(C 1-C6 alkyl)(Ph) or -NHSO2(Ph), wherein each Ph independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, Cl- C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy, and the other Qa and Qb of each of (II), (III) and (IV) independently is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy; or each Qa in Structural Formulas (VIII), (X), (XII) and (XIII), and each
Qb in Structural Formulas (IX), (XI) and (XIV) are independently halogen, hydroxy, cyano, nitro, Ph, -CH2Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(Cl-CO alkyl)(Ph), -SO2NH(Ph), -SO2N(Cl-Co alkyl)(Ph), -O(Ph), -S(Ph), -NH(Ph), -N(Cl-Co alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(Cl-Co alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(Cl-Co alkylXPh), -NHSO2NH(Ph), -NHSO2N(Cl-Co alkyl)(Ph) or -NHSO2(Ph), wherein each Ph is a phenyl group independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C 1 -C3 haloalkoxy.
24. The compound of Claim 9, wherein the compound is represented by a structural formula selected from:
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000252_0002
or a pharmaceutically acceptable salt thereof, wherein: one of Qa and Qb is halogen, -NO2, -CN, Ak1, Ar1, (C1-10 alkylene)-Ar\ (C1-10 alkenylene)-Ar1 or -X-R1; and the other of Qa and Qb is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
25. The compound of Claim 24, wherein: each R6 independently is hydrogen, halogen, nitro, cyano, R', -OR, -SR or -N(R)2; and each R independently is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6alkenyl, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl; or
N(R)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, =0, C1-C3 alky, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and amino; and each R' independently is optionally substituted Ci-6alkyl, optionally substituted C2-6alkenyl, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl.
26. The compound of Claim 25, wherein R' is -CH2-(optionally-substituted phenyl), -CtbCoptionally-substituted 5-6 membered heteroaryl), -CH2-CH2-(optionally-substituted phenyl), -CH2-CH2-(optionally-substituted 5-6 membered heteroaryl), CH=CH-(optionally-substituted phenyl) or -CH=CH2-(optionally-substituted 5-6 membered heteroaryl).
27. The compound of Claim 26, wherein R' is -CH2-(optionally-substituted phenyl), -CH2-(optionally-substituted pyridyl), -CH2-CH2-(optionally- substituted phenyl), -CH2-CH2-(optionally-substituted pyridyl), CH=CH-(optionally-substituted phenyl) or -CH=CH2-(optionally-substituted pyridyl).
28. The compound of Claim 27, wherein each of R4 and R5 is -H, C1-C6 alkyl, phenyl, -C(O)(C1-C6 alkyl), -C(O)(phenyl), -C(O)O(C1-C6 alkyl), -C(O)O(phenyl), -S(O)2(C 1 -C6 alkyl) or -S(O)2(phenyl).
29. The compound of Claim 28, wherein R6 is hydrogen, halogen, nitro, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S(C1-C6 alkyl), -S(C1-C6 haloalkyl), amino, C1-C6 alkylamino, C1-C6 dialkylamino, phenoxy or phenyl, wherein each of the alkyl and alkoxy groups represented by R6 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, C1-C3 alkoxy and C1-C3 haloalkoxy, and wherein each of the phenyl and phenoxy groups represented by R6 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino,
C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
30. The compound of Claim 29, wherein both of Qa and Qb are independently halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy.
31. The compound of Claim 25, wherein R6 is an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl.
32. The compound of Claim 31, wherein the phenyl and 5-6 membered heteroaryl represented by R6 are independently and optionally substituted with one or more substitutents selected from the group consisting of: halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy.
33. The compound of Claim 32, wherein R6 is an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrrolyl group, an optionally substituted pyrazolyl, an optionally substituted thiazolyl, an optionally substituted pyrimidinyl, or an optionally substituted thienyl.
34. The compound of Claim 29, wherein the compound is represented by a structural formula selected from:
Figure imgf000254_0001
(XV),
Figure imgf000255_0001
Figure imgf000255_0002
Figure imgf000255_0003
(XVIII),
Figure imgf000256_0001
Figure imgf000256_0002
or a pharmaceutically acceptable salt thereof.
35. The compound of Claim 34, wherein the compound is represented by a structural formula selected from:
Figure imgf000256_0003
Figure imgf000257_0001
Figure imgf000257_0002
Figure imgf000258_0001
or a pharmaceutically acceptable salt thereof.
36. The compound of Claim 35, wherein the compound is represented by a structural formula selected from:
Figure imgf000258_0002
(XXVII),
Figure imgf000259_0001
(XXVIII) and
Figure imgf000259_0002
or a pharmaceutically acceptable salt thereof.
37. The compound of Claim 36, wherein the compound is represented by a structural formula selected from:
Figure imgf000259_0003
(XXX),
Figure imgf000260_0001
Figure imgf000260_0002
(XXXIII),
Figure imgf000261_0001
(XXXIV) and
Figure imgf000261_0002
or a pharmaceutically acceptable salt thereof.
38. The compound of any one of Claims 24-29 and 31-37, wherein:
X is -C(O)-, -C(S)-, -C(O)N(R2)-, -OC(O)N(R2)-, -SO2NR2-, -O-, -S-, -NR2-, -NR2C(O)-, -NR2C(O)O-, -NR2C(O)ONR2-, -N(R2)C(O)NR2-,
-NR2SO2NR2- or -NR2SO2-; each R1 independently is i) hydrogen; ii) an optionally substituted phenyl group or an optionally substituted 5-6 membered heteroaryl group; or iii) an optionally substituted Ci-10 alkyl group; and each Ak1 independently is an optionally substituted C1-10 alkyl group; and each Ar1 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-6 alkyl, C^haloalkyl, (C1-6 haloalkoxy)C1-6 alkyl, (C1-6
Figure imgf000262_0001
C1-6 hydroxyalkyl, (Ci-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, -NR21 2, -C(O)NR21 2, -C(O)NR21 2, -NR21C(O)R21, -S(O)2R22, -SO2NR21 2, -NR21SO2R22, -NR21C(O)NR22 2, -NR21SO2NR21 2, -OR21, -SR21, Cw haloalkoxy, -C(O)R21, -C(O)OR21, - OC(O)R21, phenyl, benzyl and 5-6 membered heteroaryl.
39. The compound of Claim 38, wherein: each Ak10 independently is an optionally substituted C1-6 alkyl group; each Ar10 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Ci-6 alkyl, C1-6 haloalkyl, (C1-6 haloalkoxy)^^ alkyl, (Ci-6 alkoxy)Ci-6 alkyl, Ci-6 hydroxyalkyl, (Ci-6 aminoalkyl, (Ci-6 alky lamino)C I-6 alkyl, (Ci-6 dialkylamino)C I-6 alkyl, benzyl, phenyl, Ci-ealkoxy, Ci-6 haloalkoxy, amino, Ci-6 alkylamino, Ci-6dialkylamino, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl; each R10 independently is: i) hydrogen; ii) a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, Q-6 alkyl, Ci-δhaloalkyl, (Ci-6 haloalkoxy)C I-6 alkyl, (Ci-6 alkoxy)C I-6 alkyl, Ci-6 hydroxyalkyl, (Ci-6 aminoalkyl, (Ci-6 alky lamino)C I-6 alkyl, (Ci-6 dialkylamimOCi-ό alkyl, amino, Ci^alkylamino, Q-6 dialkylamino, Ci-6 alkoxy, Ci-6 haloalkoxy, Cj-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl; or iii) a C1-Io alkyl group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, C1-6haloalkyl, Ci-6 alkoxy, Q-6 haloalkoxy, amino, d-δalkylamino, Cj-6 dialkylamino, C1-6 alkylcarbonyloxy, C i ^ alkoxycarbonyl, C i .6 alkylcarbonyl and phenyl; and each R11 independently is R10, -CO2R10, -SO2R10 or -C(O)R10, or -N(R1 % taken together is a 5-6 membered non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, =0, C 1 -C3 alky, C 1 -C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and amino; each R12 independently is: i) a phenyl group or a 5-6 membered heteroaryl group, each of which independently is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-6 aliphatic, Ci-6 haloalkyl, (Ci-6
Figure imgf000263_0001
alkyl, (Ci-6 alkoxy)C I-6 alkyl, Ci-6 hydroxyalkyl, (Ci-6aminoalkyl, (Ci-6 alkylamino)Ci-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, amino, Ci-όalkylamino, C1-6 dialkylamino, C1-6 alkoxy, C]-6 haloalkoxy, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl; or ii) a Ci-io alkyl group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, hydroxy, Ci-6 haloalkyl, Cj-6 alkoxy, Cj-6 haloalkoxy, amino,
Figure imgf000263_0002
Ci-6 dialkylamino, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonyl and phenyl; and each R21 independently is hydrogen, Ci-6 alkyl or optionally substituted phenyl; and each R22 independently is Ci-6 alkyl or optionally substituted phenyl.
40. The compoud of Claim 39, wherein each R1 independently is i) hydrogen; ii) a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ak10, (C1-10 alkylene)-Ar10, (C2-10 alkenylene)- Ar10, -OR10, -SR10, -OC(O)N(R1 \ -N(Rn)2, -C(O)NR11, -NR11C(O)R10, -N(R11XXO)N(R11^, -NR11SO2N(R1 ^2, -NR11SO2R12, -SO2N(Rn)2, -OC(O)R10 -C(O)OR10 and
-C(O)R10; or iii) a Ci-io alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, Ar10, -OR10, -SR10, -N(R11^, -OC(O)R10, -C(O)OR10 and -C(O)R10; and each Ak1 independently is a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C1-O aIlCyI), -S(Ci-6 alkyl), Ci-β haloalkoxy, amino, C1-6alkylamino, d-όdialkylamino, Ci-6 alky lcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl; and each Ar1 independently is a phenyl group or a 5-6 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(C1-6 alkyl), C1-6 alkyl, C1-6haloalkyl, (Ci- 6 haloalkoxy)Ci-6 alkyl, (Ci-6 alkoxy)Ci-6 alkyl, Ci-6 hydroxyalkyl, (Ci-6 aminoalkyl, (Ci-6 alkylamino)C I-6 alkyl, (Ci-6 dialkylamino)C I-6 alkyl, (phenyl)C I-6 alkyl, (5-6 membered heteroary I)Ci-6 alkyl, amino, Ci-6 alkylamino, Ci-όdialkylamino, Ci-6 haloalkoxy, Ci-6 alky lcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl.
41. The compound of Claim 40, wherein each R10 independently is i) hydrogen, ii) a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, Cl- C3 alkoxy and C1-C3 haloalkoxy, or iii) a Ci-I0 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloalkoxy and phenyl; each R12 independently i) a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy, or ii) a Ci-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkoxy, C1-C3 haloalkoxy and phenyl; and each Ar10 independently is a phenyl group or a 5-6 membered heteroaryl group, each of which is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
42. The compound of Claim 41 , wherein: the optionally substituted 5-6 membered heteroaryl group represented by each of R1, R10, R12, R21, R22, Ar1 and Ar10 independently is an optionally substituted furanyl group, an optionally substituted imidazolyl group, an optionally substituted isoxazolyl group, an optionally substituted oxadiazolyl group, an optionally substituted oxazolyl, an optionally substituted pyrazolyl group, an optionally substituted pyrrolyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyridazinyl group, an optionally substituted thiazolyl group, an optionally substituted triazolyl group, an optionally substituted tetrazolyl group or an optionally substituted thienyl group; and the 5-6 membered heteroaryl group in the substituents for the groups represented by Ar1 independently is a furanyl group, an imidazolyl group, an isoxazolyl group, an oxadiazolyl group, an oxazolyl, a pyrazolyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thiazolyl group, a triazolyl group, a tetrazolyl group or a thienyl group.
43. The compound of Claim 42, wherein: one of Qa and Qb of each of Structural Formulas (V) - (VII) independently is halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)(C 1-C6 alkyl), -C(O)NH2, -C(O)NH(C 1-C6 alkyl), -C(O)N(C 1-C6 alkyl)2, -SO2NH2, -SO2NH(C 1-C6 alkyl), -SO2N(Cl-Co alkyl)2, -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -SH, -S(C1-C6 alkyl), -S(C1-C6 haloalkyl), -NH2, -NH(C 1-C6 alkyl), -N(C1-C6 alkyl)2, , -NHC(O)(C 1 -C6 alkyl), -NHC(O)O(C 1 -C6 alkyl), -NHC(O)NH2,
-NHC(O)NH(C1-C6 alkyl), -NHC(O)N(C 1-C6 alkyl)2, -NHC(O)ONH2, -NHC(O)ONH(Cl -C6 alkyl), -NHC(O)ON(C 1-C6 alkyl)2, -NHSO2NH2, -NHSO2NH(C 1-C6 alkyl), -NHSO2N(Cl-Co alkyl)2 or -NHSO2(Cl-Co alkyl), and the other Qa and Qb of each of Structural Formulas (V) - (VII) independently is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy; or each Qa in Structural Formulas (XV) - (XV), (XXI) - (XXIII) and (XXVII) - (XXXII), and each Qb in Structural Formulas (XVIII) - (XX), (XXIV) - (XXVI) and (XXXIII) - (XXXV) are each independently halogen, hydroxy, cyano, nitro, C 1 -C6 alkyl, C 1 -C6 haloalkyl, -C(O)(C 1 -C6 alkyl),
-C(O)NH2, -C(O)NH(C 1-C6 alkyl), -C(O)N(C 1-C6 alkyl)2, -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2N(Cl-Co alkyl)2, -OH, -O(C1-C6 alkyl), -0(Cl- C6 haloalkyl), -SH, -S(C1-C6 alkyl), -S(Cl-Co haloalkyl), -NH2, -NH(Cl- C6 alkyl), -N(C1-C6 alkyl)2, , -NHC(O)(C 1-C6 alkyl), -NHC(O)O(C 1-C6 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1-C6 alkyl), -NHC(O)N(C 1-C6 alkyl)2, -NHC(O)ONH2, -NHC(O)ONH(C 1-C6 alkyl), -NHC(O)ON(C 1-C6 alkyl)2, -NHSO2NH2, -NHSO2NH(Cl-CO alkyl), -NHSO2N(Cl-CO alkyl)2 or -NHSO2(C 1-C6 alkyl).
44. The compound of Claim 42, wherein: one of Qa and Qb of each of Structural Formulas (V) - (VII) independently is halogen, hydroxy, cyano, nitro, Ph, -CH2Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(C 1-C6 alkyl)(Ph), -SO2NH(Ph), -SO2N(C 1-C6 alkyl)(Ph), -O(Ph), -S(Ph), -NH(Ph), -N(Cl-Co alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(C 1-C6 alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(C 1 -C6 alkyl)(Ph), -NHSO2NH(Ph),
-NHSO2N(C 1-C6 alkyl)(Ph) or -NHSO2(Ph), wherein each Ph is a phenyl group independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy, and the other Qa and Qb of each of Structural Formulas (V) - (VII) independently is halogen, hydroxy, nitro, cyano, amino, methyl, methoxy, halomethyl or halomethoxy; or each Qa in Structural Formulas (XV) - (XV), (XXI) - (XXIII) and (XXVII) - (XXXII), and each Qb in Structural Formulas (XVIII) - (XX), (XXIV) - (XXVI) and (XXXIII) - (XXXV) are independently halogen, hydroxy, cyano, nitro, Ph, -CH2Ph, -C(O)Ph, -C(O)NH(Ph), -C(O)N(C 1-C6 alkylXPh), -SO2NH(Ph), -SO2N(Cl-Co alkyl)(Ph), -0(Ph), -S(Ph), -NH(Ph), -N(C1-C6 alkyl)(Ph), -NHC(O)(Ph), -NHC(O)O(Ph), -NHC(O)NH(Ph), -NHC(O)N(C 1-C6 alkyl)(Ph), -NHC(O)ONH(Ph), -NHC(O)ON(C 1-C6 alkylXPh), -NHSO2NH(Ph), -NHSO2N(C 1 -C6 alkyl)(Ph) or -NHSO2(Ph), wherein each Ph is a phenyl group independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
45. The compound of any one of Claims 1-7, wherein the compound is represented by a structural formula selected from:
Figure imgf000268_0001
or a pharmaceutically acceptable salt thereof, wherein:
R6 is optionally substituted phenyl, optionally substituted 5-12 membered heteroaryl, -CH2-(optionally substituted phenyl), -CH2-(optionally substituted 5-12 membered heteroaryl), -CH2-CH2-(optionally substituted phenyl), -CH2-CH2-(optionally substituted 5-12 membered heteroaryl), -CH=CH-(optionally substituted phenyl), -CH=CH-(optionally substituted 5- 12 membered heteroaryl), -CH=CH-C(O)O(optionally substitutued C1-6 alkyl), or -CH=CH-OC(O)(optionally substituted C1-6 alkyl).
46. The compound of Claim 45, wherein the compound is represented by a structural formula selected from:
Figure imgf000269_0001
or a pharmaceutically acceptable salt thereof.
47. The compound of Claim 46, wherein the compound is represented by a structural formula selected from:
Figure imgf000269_0002
; and
Figure imgf000270_0001
or a pharmaceutically acceptable salt thereof.
48. The compound of Claim 47, wherein the compound is represented by a structural formula selected from:
Figure imgf000270_0002
or a pharmaceutically acceptable salt thereof, wherein R7 is -H, -F, -Cl or methyl.
49. The compound of Claim 48, wherein the compound is represented by a structural formula selected from:
Figure imgf000271_0001
or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
50. The compound of Claim 49, wherein the compound is represented by a structural formula selected from:
Figure imgf000271_0002
and
Figure imgf000272_0001
or a pharmaceutically acceptable salt thereof.
51. The compound of any one of Claims 45-47, wherein R4 and R5 are each independently -H, C1-C6 alkyl, phenyl, -C(O)(Cl-Co alkyl), -C(O)(phenyl), -C(O)O(Cl-CO alkyl), -C(O)O(phenyl), -S(O)2(Cl-Co alkyl) or -S(O)2(phenyl), wherein each phenyl in the group represented by R4 and R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, -0(Ci-6 alkyl), Ci-6 haloalkyl, C1-6 haloalkoxy, cyano and nitro.
52. The compound of any one of Claims 45-51 , wherein the 5- 12 membered heteroaryl in the group represented by R6 is selected from the group consisting of pyridyl, thiazolyl, pyrazinyl, thiophenyl, indolyl, quinolinyl, pyrrolyl, pyrazolyl, and pyrimidinyl, each of which is optionally substituted.
53. The compound of Claim 52, wherein:
Qa and Qb are each independently halogen, cyano, -NR1R2, -NR2C(O)R1, -C(O)OR1, -OC(O)R1, -C(O)NR1R2, -NR2C(O)OR1, -N(R^C(O)NR1R2, -OR1, -SO2NR1R2, -NR2SO2R1, Ci-6 alkyl, phenyl or 5-
12 membered heteroaryl, wherein the C]-6 alkyl represented by Q3 and Qb is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(Ci-6 alkyl), Ci-6 haloalkoxy, amino, Ci-όalkylamino,
Figure imgf000272_0002
Q-6 alkylcarbonyloxy, Q-6 alkoxycarbonyl and Ci-6 alkylcarbonyl; and the phenyl or the 5-12 membered heteroaryl represented by Qa and Qb is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6alkyl), -S(C1^6 alkyl), C1-6 alkyl, C1-6 haloalkyl, (Ci-6 haloalkoxy)C I-6 alkyl, (Ci-6 alkoxy)Ci-6 alkyl, C1-6 hydroxyalkyl, (C1-6 aminoalkyl), (Ci-6 alky lamino)C I-6 alkyl, (Ci-6 dialkylamino)Ci-6 alkyl, (phenyl)Ci-6 alkyl, (5-6 membered heteroaryl)C]^ alkyl, amino, C1-6 alky lamino, Ci-6dialkylamino, C1-6 haloalkoxy, Ci-6 alkylcarbonyloxy, C1^ alkoxycarbonyl and C1-6 alkylcarbonyl;
R1 and R2 are each independently -H- or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SH, -0(Ci-3 alkyl),
-S(Ci-3 alkyl) and Ci-6 haloalkoxy; the phenyl or the 5-12 membered heteroaryl in the group represented by R6 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(Ci-6 alkyl), Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 haloalkoxy)C1-6 alkyl, (Ci-6 alkoxy)C i-6 alkyl, Ci-6 hydroxyalkyl, (Ci-6 aminoalkyl), (Ci-6 alkylamino)C I-6 alkyl, (Ci-6 dialkylamino)Ci-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, amino, C1-6alkylamino, C1-6dialkylamino, Ci-6 haloalkoxy, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonyl, -(CH2)o-3-N-piperidinyl, -(CH2)0-3-N-morpholinyl, -(CH2)0-3-7V-pyrrolidinyl and -(CH2)o-3-N~(CH2)o-3-piperazinyl, wherein the N-piperazinyl is optionally N '-substituted with Ci-6 alkyl or Ci-6 acyl; and the Ci-6 alkyl in the group represented by R6 is optionally substituted one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(Ci-6 alkyl), Ci-6 haloalkoxy, amino, Ci-6 alkylamino, Ci-6 dialky lamino, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl.
54. The compound of Claim 53 wherein the phenyl or the 5-12 membered heteroaryl in the group represented by R6 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(Ci-6 alkyl), Ci-6 alkyl, Ci-6 haloalkyl, (Ci- 6 haloalkoxy)C1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl,
Figure imgf000274_0001
(C1-6 aminoalkyl, (Ci-6 alkylamino)C I-6 alkyl, (C1-6 dialkylamino)Ci ^ alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroary I)C1-6 alkyl, amino, Ci-6 alkylamino, Ci-όdialkylamino, Ci-6 haloalkoxy, C1-6 alky lcarbonyloxy, C1-6 alkoxycarbonyl and C1-6 alkylcarbonyl.
55. The compound of Claim 53 or 54, wherein:
Qa is halogen, cyano, -NR1R2, -NR2C(O)R1, -C(O)OR1, -OC(O)R1, -N(R^C(O)NR1R2, -OR1, C1-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -SH, -0(Ci-6 alkyl), -S(C1-6 alkyl) and C]-6 haloalkoxy;
Qb is halogen, Ci-3 alkyl, Ci-3 haloalkyl, Cj_3 alkoxy, or Ci-3 haloalkoxy; and the phenyl, the 5-12 membered heteroaryl and the C1-6 alkyl in the group represented by R6 is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -0(Ci-6 alkyl), Ci-6 alkyl, Ci-6 haloalkyl and Ci-6 haloalkoxy.
56. The compound of Claim 55, wherein: Qa is -OH, Ci-6 alkoxy or Ci-6 haloalkoxy; and the phenyl, the 5-12 membered heteroaryl and the Ci-6 alkyl in the group represented by R6 are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, methyl, methoxy and trifluoromethyl.
57. The compound of Claim 1 wherein the compound is represented by a structural formula selected from
Figure imgf000275_0001
or a pharmaceutically acceptable salt thereof, wherein:
Qa is -H, halogen, -NH2, (d-oalky^amine or Ci-6 alkoxy; R6 is phenyl, 5-6 membered heteroaryl, -CH=CH-( phenyl), -CH=CH-(5-6 membered heteroaryl), -C≡C-(phenyl), -C≡C-(5-6 membered heteroaryl) wherein each phenyl and heteroaryl in the group represented by R6 is optionally substituted with halogen, C1-6 alkyl, Ci-6 haloalkyl, (Ci-βaminoalkyl), (Ci-6 alkylamino)C I-6 alkyl, (Ci-6 dialkylamino)C I-6 alkyl, (phenyl)C I-6 alkyl, amino, Ci-6 alkylamino, Ci-6 dialkylamino, -(CH2)0.3-N-piperidinyl, -(CH2)0-3-N- morpholinyl, -(CH2)0-3-N-pyrrolidinyl and -(CH2)o-3-N-piperazinyl, wherein the N-piperazinyl is optionally N'-substituted with Ci-6 alkyl or Ci-βacyl.
58. The compound of Claim 57 wherein each heteroaryl in the group represented by R6 is pyridinyl, pyrimidinyl or pyrazinyl and each is optionally substituted halogen, Ci-6 alkyl, C]-6 haloalkyl,
Figure imgf000275_0002
alkyl, (Ci-6 dialkylamino)C]-6 alkyl, (phenyl)C I-6 alkyl, amino, Ci-6 alkylamino, C1-6dialkylamino, N-piperidinyl, N-morpholinyl, N-pyrrolidinyl and N-piperazinyl, wherein the N-piperazinyl is optionally N '-substituted with C1-6 alkyl or C1^aCyI.
59. The compound of Claim 1, wherein the compound is represented by the following structural formula:
Figure imgf000276_0001
60. The compound of Claim 59, wherein the compound is represented by a structural formula selected from the group consisting of:
Figure imgf000276_0002
or a pharmaceutically acceptable salt thereof, wherein: each R6 is independently hydrogen, halogen, nitro, cyano, R', -OR, -SR or -N(R)2; each R is independently hydrogen, optionally substituted C 1-6 alky 1, optionally substituted C2-6alkenyl, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl; or
N(R)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, =0, C1-C3 alky, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and amino; and each R' independently is optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted phenyl or optionally substituted 5-14 membered heteroaryl.
61. The compound of Claim 60, wherein R4 and R5 are each independently -H, C1-C6 alkyl, phenyl, -C(O)(C1-C6 alkyl), -C(O)(phenyl), -C(O)O(Cl-Co alkyl), -C(O)O(phenyl), -S(O)2(Cl-CO alkyl) or -S(O)2(phenyl).
62. The compound of Claim 61, wherein Qa and Qb are each independently selected from the group consisting of halogen, -NO2, -CN, Ak1, Ar1, (Ci-10 alkylene)-Ar', (Ci-1O alkenylene^Ar1 and -X-R1, wherein: each Ak1 independently is a C1-Io aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -N(R21)2, -C(O)N(R21)2, -C(O)N(R21)2, -NR21C(O)R21, -SO2R22, -SO2N(R21)2, -NR21SO2R22, -NR21C(O)OR21, -OC(O)N(R21)2, -NR21C(O)N(R21)2, -NRC(O)ON(R)2, -NR21SO2N(R21)2,
-OR21, -SR21, Ci-I0 haloalkoxy, -C(O)R21, -C(O)OR21 and -OC(O)R21 each Ar1 independently is a phenyl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(C-6 alkyl), Ci-6 alkyl, Q-6 haloalkyl, (Ci- 6 haloalkoxy)Ci-6 alkyl, (Ci-6 alkoxy)C I-6 alkyl, Ci^hydroxyalkyl, (Ci-6 aminoalkyl, (Ci-6 alkylamino)Ci-6 alkyl, (Ci-6 dialkylamino)C I-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)Ci-6alkyl, amino, Ci-6 alkylamino, Ci-6 dialkylamino, Ci-6 haloalkoxy, Cj-6 alky lcarbonyloxy, Q-6 alkoxycarbonyl and Ci-6 alkylcarbonyl; and
X is -C(O)-, -C(S)-, -C(O)N(R2)-, -OC(O)N(R2)-, -SO2NR2-, -0-, -S-, -NR2-, -NR2C(O)-, -NR2C(O)O-, -NR2C(O)ONR2-, -N(R2)C(O)NR2-,
-NR2SO2NR2- or -NR2SO2-.
63. The compound of Claim 62, wherein R6 is hydrogen, halogen, -N(R)2, optionally substituted phenyl, optionally substituted 5-14 membered heteroaryl, -CH2-(optionally substituted phenyl), -CH2-(optionally substituted 5-12 membered heteroaryl), -CH2-CH2-(optionally substituted phenyl), -CH2-CH2-(optionally substituted 5-12 membered heteroaryl), -CH=CH-(optionally substituted phenyl), -CH=CH-(optionally substituted 5- 12 membered heteroaryl), -CH=CH-C(O)O(C 1-C6 alkyl), -CH=CH- OC(O)(C1-C6 alkyl)-
64. The compound of Claim 63, wherein R4 and R5 are each independently -H or C1-C3 alkyl.
65. The compound of Claim 64, wherein Qa and Qb are each independently halogen, cyano, -NR1R2, -NR2C(O)R1, -C(O)OR1, -OC(O)R1, -N(R^C(O)NR1R2, -OR1, C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(Ci-6 alkyl), Ci-6 haloalkoxy, amino, Ci-6 alkylamino, Ci-6 dialkylamino, Ci-6 alkylcarbonyloxy, Ci-6 alkoxycarbonyl and Ci-6 alkylcarbonyl; phenyl or 5-12 membered heteroaryl, wherein the phenyl or the 5-12 membered heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci-6 alkyl), -S(Ci-6 alkyl), Ci-6 alkyl, d-ehaloalkyl, (Ci- 6 haloalkoxy)C]-6 alkyl, (C1-6 alkoxy)^ alkyl, C1-6 hydroxyalkyl, (Ci-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroary I)Ci-6 alkyl, amino, Ci-6 alkylamino, C1-6dialkylamino, Ci-6 haloalkoxy, Ci-6 alky lcarbonyloxy, C]-6 alkoxycarbonyl and C1-6 alkylcarbonyl; R1 and R2 are each independently -H- or Cl-Cό alkyl.
66. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a compound of any one of Claims 1-65 or a pharmaceutically acceptable salt thereof.
67. A method of treating a subject having cancer, comprising administering a therapeutically effective amount of a compound represented by the following structural formula:
Figure imgf000279_0001
or a pharmaceutically acceptable salt thereof, wherein: ring A is an optionally substituted 5- or 6-membered aromatic ring; ring B is an optionally substituted phenyl ring; and ring C is a 5-membered heteroaromatic ring wherein one of X1-X3 is N, one of X1-X3 is NR5, and one of X1-X3 is N or CR6; Z is =N- or =CR3-;
R3 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; each of R4 and R5 independently is -H, C 1 -C6 alkyl, phenyl,
-C(O)(C1-C6 alkyl), -C(O)(phenyl), -C(O)O(C1-C6 alkyl), -C(O)O(phenyl), -S(O)2(C1-C6 alkyl) or -S(O)2(phenyl), wherein each said alkyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy and
C1-C6 haloalkoxy, and wherein each said phenyl in the groups represented by R4 and R5 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;
R6 is hydrogen, halogen, nitro, cyano, R', -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)OR,
-SOR1, -SO2R', -SO3R', -SO2N(R)2, -NRS(O)R1, -NRSO2R1, -NRC(O)N(R)2, -NRC(O)ON(R)2, or -NRSO2N(R)2; and each R independently is hydrogen, C1-10 aliphatic, phenyl or 5-6 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, and wherein each of the phenyl and heteroaryl groups represented by R, and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or
N(R)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of =0, =S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6alkylamino, C1-6dialkylamino, Cj-6 aminoalkyl, (C1-6 alkylamino)C i-6 alkyl, (Ci-6 dialkylamino)C I-6 alkyl, (pheny I)C1-6 alkyl, (5-6 membered heteroaryl)C 1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, Ci-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl; and each R' independently is C1-I0 aliphatic, phenyl or 5-14 membered heteroaryl, wherein said aliphatic is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, Ci-6 alkylamino, Cj-6 dialkylamino, -C(O)(C1-C6 alkyl),
-C(O)(C 1-C6 haloalkyl), -C(O)(phenyl), -C(O)O(C 1-C6 alkyl), -C(O)O(Cl- C6 haloalkyl),-C(O)O(phenyl), -OC(O)(C 1-C6 alkyl), -OC(O)(Cl-Co haloalkyl), -OC(O)(phenyl), -S(O)2(Cl-CO alkyl), -S(O)2(Cl-CO haloalkyl) and -S(O)2(phenyl), and wherein each of the phenyl and heteroaryl groups represented by R', and the phenyl and heteroaryl groups in the substituents for the aliphatic group represented by R' independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, C1-C6 haloalkoxy, non-aromatic heterocyclic group, C1-6 alkylamino, C1-6dialkylamino, -C(O)(Cl-Co alkyl), -C(O)(Cl-Co haloalkyl), -C(O)(phenyl), -C(O)(non-aromatic heterocyclic group), -C(O)O(Cl-Co alkyl), -C(O)O(C 1 -C6 haloalkyl),-C(O)O(phenyl), -OC(O)(C 1 -C6 alkyl),
-OC(O)(C1-C6 haloalkyl), -OC(O)(phenyl), -S(O)2(Cl-Co alkyl), -S(O)2(Cl-Co haloalkyl), and -S(O)2(phenyl).
68. A method of treating a subject with cancer comprising adminstering to the subject an effect amount of the compound of any one of Claims 1-66 or a pharmaceutically acceptable salt thereof.
69. The method of Claim 67 or 68, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform, ovarian cancer, lymphoma, leukemia, melanoma, sarcoma, paraneoplasia, osteosarcoma, germinoma, glioma and mesothelioma.
70. The method of Claim 69, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma mutiform and ovarian cancer.
71. The method of Claim 70, wherein the cancer is breast cancer.
72. The method of Claim 71, wherein the cancer is a basal sub-type breast cancer or a luminal B sub-type breast cancer.
73. The method of Claim 67 or 68, wherein the cancer is a soft tissue cancer.
74. The method of Claim 73, wherein the soft tissue cancer is a sarcoma selected from the group consisting of a fibrosarcoma, a gastrointestinal sarcoma, a leiomyosarcoma, a dedifferentiated liposarcoma, a pleomorphic liposarcoma, a malignant fibrous histiocytoma, a round cell sarcoma, and a synovial sarcoma.
75. The method of any one of Claims 67-74, further comprising co-administering an additional therapeutic agent.
76. The method of Claim 75, wherein the additional therapeutic agent is an anticancer drug.
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