WO2011123937A1 - Inhibiteurs de kinases et procédé de traitement du cancer utilisant ceux-ci - Google Patents

Inhibiteurs de kinases et procédé de traitement du cancer utilisant ceux-ci Download PDF

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WO2011123937A1
WO2011123937A1 PCT/CA2011/000366 CA2011000366W WO2011123937A1 WO 2011123937 A1 WO2011123937 A1 WO 2011123937A1 CA 2011000366 W CA2011000366 W CA 2011000366W WO 2011123937 A1 WO2011123937 A1 WO 2011123937A1
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alkyl
alkoxy
heterocycloalkyl
halogen
cancer
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Radoslaw Laufer
Heinz W. Pauls
Miklos Feher
Grace Ng
Yong Liu
Louise G. Edwards
Narendra Kumar B. Patel
Guohua Pan
Tak W. Mak
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University Health Network
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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.
  • TTK protein kinase also known as tyrosine threonine kinase, dual specificity protein kinase TTK, Monopolar Spindle 1 (Mpsl) and Phosphotyrosine-Picked Threonine Kinase (PYT), is a conserved multispecific kinase that is capable of phosphorylating serine, threonine and tyrosine residues when expressed in E. coli (Mills et al., J. Biol. Chem. 22(5): 16000-16006 (1992)). TTK mRNA is not expressed in the majority of physiologically normal tissues in human (Id).
  • TTK mRNA is expressed in some rapidly proliferating tissues, such as testis and thymus, as well as in some tumors (for example, TTK mRNA was not expressed in renal cell carcinoma, was expressed in 50% of breast cancer samples, was expressed in testicular tumors and ovarian cancer samples) (Id). TTK is expressed in some cancer cell lines and tumors relative to normal counterparts (Id.; see also WO 02/068444 Al).
  • 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 TTK inhibitors.
  • TICs tumor-initiating cells
  • cancer stem cells a small subset of cells within the tumor. These cells are termed tumor-initiating cells (TICs) or cancer stem cells. It is thought that the TICs are responsible for drug resistance, cancer relapse and metastasis. Compounds that can inhibit the growth and survival of these tumor-initiating cells can be used to treat cancer, metastasis or prevent recurrence of cancer. Therefore, a need exists for new compounds that can inhibit the growth and survival of tumor- initating cells.
  • indazole compounds are potent kinase inhibitors, such as TTK protein kinase, polo-like kinases 4 (PLK4), Aurora Kinases and CHK kinase (see Example B-F).
  • TTK protein kinase polo-like kinases 4
  • PLK4 polo-like kinases 4
  • CHK kinase CHK kinase
  • these indazole compounds have potent anticancer activity against breast cancer cells, colon cancer cells, lung cancer cells, melanoma cells, prostate cancer cells, ovarian cancer cells, brain cancer cells and pancreatic cancer cells in cell culture study (see Example G).
  • certain indazole TTK inhibitors can inhibit the growth of colon tumor-initiating cells in a cell culture study (see Example H). Based on these discoveries, indazole compounds, pharmaceutical compositions thereof, and methods of treating cancer with the indazole compounds (including reducing the likelihood of recurrence of a
  • the present teachings are directed, at least in part, to an indazole compound represented by the following structural formula:
  • each R 2 is independently selected from: a)-H, -halogen, -CN, -N0 2 , -(CH 2 )o- 2 0R 10 , -(CH 2 )o- 2 NR n R 12 , -(CH 2 )o- 2 S(0)iR 10 , -(CH 2 )o- 2 NR 13 S(0)iR 10 , -(CH 2 )o- 2 NR ,3 S(0)iNR 14 R 15 , -(CH 2 ) 0 .
  • alkyl alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl,
  • heterocycloalkylalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl groups represented by R 2 is optionally substituted with 1 to 5 substituents
  • R 10 is selected from -H, alkyl, cycloalkyl, cycloalkyl(Ci-C 6 )alkyl, heterocycloalkyl, heterocycloalkyl (Ci-C6)alkyl, aryl, aryl(Ci-C6)alkyl, heteroaryl and heteroaryl(Ci-C6)alkyl, wherein each of the alkyl, cycloalkyl, cycloalkyl(Ci-C6)alkyl, heterocycloalkyl,
  • R 13 is -H or an alkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy and (C]-C3)alkoxy;
  • R 14 is -H or an alkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy and (Ci-C 3 )alkoxy;
  • R 15 is selected from -H, alkyl, cycloalkyl, cycloalkyl(d-C 6 )alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C 6 )alkyl, aryl, aryl(d-C6)alkyl, heteroaryl and heteroaryl(Ci-C 6 )alkyl, wherein each of the alkyl, cycloalkyl, cycloalkyl(Ci-C 6 )alkyl, heterocycloalkyl,
  • heterocycloalkyl(Ci-C6)alkyl, aryl, aryl(Ci-C6)alkyl, heteroaryl and heteroaryl(Ci-C 6 )alkyl represented by R 15 is optionally substituted with 1 to 3 substituents independently selected from
  • heterocycloalkyl heterocycloalkyl, heterocycloalkyl(Ci-C3)alkyl, aryl, aryl(Ci-C3)alkyl, heteroaryl and heteroaryl(Ci-C 3 )alkyl, and wherein each of the (Ci-C 6 )alkyl, cycloalkyl, cycloalkyl(Ci-C3)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C3)alkyl, aryl, aryl(C]-C3)alkyl, heteroaryl and heteroaryl(C]-C3)alkyl substituents for the groups represented by R 15 is optionally substituted with halogen, -N0 2 , -CN, (d-C 3 )alkyl, halo(C r C 3 )alkyl, (C,-C 3 )alkoxy(Ci-C 3 )alkyl, (C r C3)alkoxy or hal
  • cycloalkyl, cycloalkyl(Ci-C 3 )alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C 3 )alkyl, aryl, aryl(Ci-C 3 )alkyl, heteroaryl or heteroaryl(Ci-C 3 )alkyl are optionally substituted with 1 to 3 substituents independently selected from -halogen, alkyl, -OR c and -NR a R b ;
  • R a and R b are each independently -H or (C
  • R° is -H, or (Ci-C6)alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -NR g R h , hydroxy and (C]-C 3 )alkoxy;
  • R d is -H or (Ci-C6)alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -NR 8 R h , hydroxy and (Ci-C 3 )alkoxy;
  • R e and R f are each independently -H or (Ci-Ce)alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -NR g R h , hydroxy and (Ci-C 3 )alkoxy;
  • R e and R f together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -NR g R h , -CN, (Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, (d-C 3 )alkoxy, halo(Ci- C 3 )alkoxy, and (Ci-C 3 )alkoxy(Ci-C 6 )alkyl;
  • R g and R h are each independently selected from the group consisting of -H, (Ci-C6)alkyl, halo(Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl;
  • i 0, 1 or 2;
  • n is an integer from 1 to 4.
  • n is an integer from 1 to 4.
  • R 16 is alkyl, R 2 is not -CN.
  • the present teachings include a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I) described above or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present teachings provides a method of treating a subject having cancer comprising administering to the subject an effective amount of a compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present teachings provides a method of inhibiting TTK activity in a subject in need of inhibition of TTK activity, comprising administering to the
  • -7-4820V.1 subject an effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present teachings includes the use of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof in therapy.
  • the therapy is for treating a subject with cancer.
  • the therapy is for inhibiting TTK activity in a subject in need of inhibition of TTK activity.
  • Another embodiment of the present teachings includes the use of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a subject with cancer.
  • Another embodiment of the present teachings includes the use of a compound represented by Structural Formulas (I) or a pharamceutically acceptable salt thereof for the manufacture of a medicament for inhibiting TTK activity in a subject in need of inhibition of TTK activity.
  • the present teachings provide a method of inhibiting the growth of tumor-initiating cells (or cancer stem cells) in a subject who is undergoing an anti-cancer therapy. Such method includes assessing the subject to determine whether the cancer is in remission; and, if the cancer is in remission, then administering to the subject an effective amount of a TTK inhibitor.
  • the present teachings provide a method of reducing the likelihood of recurrence of a cancer in a subject who is undergoing an anti-cancer therapy. Such methods includes assessing the subject to determine whether the cancer is in remission; and, if the cancer is in remission, then administering to the subject an effective amount of a TTK inhibitor.
  • the present teachings are directed to a method of inhibiting the growth of tumor-initiating cells in a subject whose cancer is in remission comprising administering to the subject an effective amount of a TTK inhibitor.
  • the present teachings are directed to a method of reducing the likelihood of recurrence of a cancer in a subject whose cancer is in remission comprising administering to the subject an effective amount of a TTK inhibitor.
  • the present teachings are directed to a method of treating a drug-resistant cancer in a subject comprising administering to the subject an effective amount of a TTK inhibitor. 4820V.1
  • the present teachings are directed to a method of treating a subject with a cancer comprising administering to the subject an effective amount of a compound represented by Structural Formula (I) in combination with an anti-cancer therapy.
  • embodiments of the present teachings include the use of a TTK inhibitor for 5 inhibiting the growth of tumor-iniating cells or reducing the likelihood of recurrence of a cancer in a subject who is undergoing an anti-cancer therapy. Further embodiments of the present teachings includes the use of a TTK inhibitor for inhibiting the growth of tumor-iniating cells or reducing the likelihood of recurrence of a cancer in a subject whose cancer is in remission. Still other embodiments of the present teachings include the use of a TTK inhibitor for treating a o subject with a drug-resistant cancer.
  • the present teachings are directed to a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.
  • Structural Formula (I) or a pharmaceutically acceptable salt thereof.
  • R 2 is -H.
  • R 3 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is optionally substituted with 1 to 3 groups represented by R 6 .
  • R 3 is selected from (C3-C8)cycloalkyl, phenyl, naphthyl,
  • R 3 5 tetrahydropyranyl substituents on the groups represented by R 3 is optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, - ⁇ 3 ⁇ 4, -NR a R b , (Ci-C3)alkyl, halo(Ci- C3)alkyl, (Ci-C 3 )alkoxy and (Ci-C 3 )alkoxy(Ci-C3)alkyl.
  • R 3 is selected from the group consisting of phenyl, thiophenyl, pyridinyl, pyrazolyl, cyclopentyl,
  • R 3 is selected from the group consisting of cyclopentyl, phenyl, thiophenyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, and indolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group of substituents described above.
  • R 3 is selected from5 the group consisting of phenyl, thiophenyl, pyridyl, tetrahydropyranyl and indolyl, each of which is independently selected from the group of substituents described above.
  • R 3 described in the preceding paragraphs is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -OR 0 , (Ci-C3)alkyl, -(Ci-C3)alkylene-NR a R b , phenyl, pyrimidinyl, morpholinyl and benzyl,
  • phenyl, pyrimidinyl, morpholinyl and benzyl substituents are optionally substituted with halogen, (C,-C 3 )alkyl, halo(Ci-C 3 )alkyl, (C r C 3 )alkoxy and (C,-C 3 )alkoxy(C,-C 3 )alkyl;
  • R c is -H, (C]-C 3 )alkyl, pyridinyl or mo ⁇ holinyl; and
  • R a and R b are each independently -H or (Ci- C 3 )alkyl.
  • R 3 described in the preceding paragraphs is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -CI, methyl, -CF 3 , ethyl, 2-propyl, benzyl, phenyl and -CH2NH2.
  • R 4 and R 5 are each independently -H, alkyl, -OR c , -NR a R b , (C C 3 )alkylene-NR a R b , (C r C 3 )alkylene-OR c , cycloalklyl or heterocycloalkyl. In some embodiments, R 4 and R 5 are not both selected from -OR c and -NR a R b .
  • R 3 and R 5 together with the carbon atom to which they are attached form a cycloalkyl or a heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, (Ci-C 3 )alkyl, halo(Ci-C 3 )alkyl, (C]-C 3 )alkoxy, halo(Ci- C 3 )alkoxy, (Ci-C 3 )alkoxy(Ci-C 3 )alkyl.
  • R 4 and R 5 are both -H.
  • R 5 is -H and R 4 is -OH, (Ci-C 3 )alkyl, -(C,-C 2 )alkylene-OH, (C,-C 3 )alkoxy, -NR a R b , -(Ci-C2)alkylene-NR a R b , pyrrolidinyl, piperidinyl, mo ⁇ holinyl or cyclopropyl, wherein R a and R b are each independently -H or (C]-C 3 )alkyl and the pyrrolidinyl, piperidinyl, morpholinyl or cyclopropyl represented by R 4 is optionally substituted with halogen, (Ci-C 3 )alkyl, halo(Ci- C 3 )alkyl, (C,-C 3 )alkoxy and (C,-C 3 )alkoxy(Ci-C 3 )alkyl.
  • each R 6 is independent selected from the group consisting of halogen, -0R C , (C r C 3 )alkyl, -(C r C 3 )alkylene-NR a R b , phenyl,
  • each R 6 is independently selected from the group consisting of halogen, -OR c , (Ci-C3)alkyl, -(Ci- C3)alkylene-NR a R b , phenyl, pyrimidinyl, mo holinyl and benzyl, wherein the phenyl, pyrimidinyl, morpholinyl and benzyl substituents are optionally substituted with halogen, (Ci- C 3 )alkyl, halo(Ci-C 3 )alky., (Ci-C 3 )alkoxy and (C]-C 3 )alkoxy(Ci-C 3 )alkyl; R c is -H,
  • each R 6 is independently selected from the group consisting of -F, -CI, methyl, -CF 3 , ethyl, 2-propyl, benzyl, phenyl and -CH 2 NH 2 .
  • R 8 is -H or (Ci-C 3 )alkyl. Alternatively, R 8 is -H.
  • each R 9 is independently selected from the group consisting of -H, halogen, -CN, -N0 2 , (Cp C 3 )alkyl, halo(Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, (Ci-C 3 )alkoxy(C,-C 3 )alkyl, hydroxy(Ci-C 3 )alkyl or - (Ci-C 3 )alkylene-NR a R b .
  • R is -NH 2 .
  • cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halogen, alkyl, -OR c and -NR a R b .
  • each i is 0, 1 or 2. Alternatively, each i is 2.
  • n is an integer from 1 to 4. Alternatively, n is 1, 2 or 3. In another alternative, n is 1 or 2. In yet another alternatively, n is i .
  • n is an integer from 1 to 4. Alternatively, m is 1 or 2. In yet another alternative, m is 1. p is 0, 1 or 2. Alternatively, p is 0. In another alternative, p is 1.
  • r is an integer from 1 to 4. Alternatively, r is 1 or 2.
  • the present teachings provide an indazole compound represented by the following structural formula:
  • the present teachings provide an indazole compound represented by the following structural formula:
  • R 16 is alkyl, optionally substituted with 1 to 3 substituents independently selected from -halogen, cycloalkyl, cycloalkyl(C]-C3)alkyl, heterocycloalkyl,
  • heterocycloalkyl(Ci-C 3 )alkyl, aryl, aryl(Ci-C 3 )alkyl, heteroaryl, heteroaryl(Ci-C 3 )alkyl, -CN, -N0 2 , -OR c , -NR a R b , -S(0)jR c , -NRdS(0)iRc, -S(0)iNR e R f , C( 0)OR c ,
  • cycloalkyl, cycloalkyl(Ci-C 3 )alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C 3 )alkyl, aryl, aryl(C,-C 3 )alkyl, heteroaryl or heteroaryl(Ci-C 3 )alkyl are optionally substituted with 1 to 3 substituents independently selected from -halogen, alkyl, -OR c and -NR a R b .
  • the present teachings provide a compound represented by a
  • X is a bond or -CR 4 R 5 -, and for structural formula (II), when p is 0, X can additionally be
  • Y is a bond, -NR 14 -, -CR 4 R 5 - or -NR I4 -CR 4 R 5 -;
  • R 3 is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is optionally substituted with 1 to 3 groups represented by R 6 ;
  • R 4 and R 5 are each independently selected from -H, alkyl, -OR c , -NR a R b , (Ci- C 3 )alkylene-NR a R b , -(C,-C 3 )alkylene-OR c , -(C r C 3 )alkylene-OH, cycloalklyl and
  • R 4 and R 5 are not both selected from -OR c and -NR a R b ; or R 3 and R 5 together with the carbon atom to which they are attached form a cycloalkyl or a
  • heterocycloalkyl wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3
  • substituents independently selected from the group consisting of halogen, -CN, (Ci-C3)alkyl, halo(Ci-C 3 )alkyl, (C,-C 3 )alkoxy, halo(Ci-C 3 )alkoxy, (C r C 3 )alkoxy(Ci-C 3 )alkyl;
  • p 0, 1 or 2.
  • the present teachings are directed to a compound represented by a structural formula select
  • compounds represented by structural formula (Ila)-(Va) are represented by a structural formula selected from:
  • Y is a bond or -NR 14 ;
  • R 3 is selected from (C 3 -C 8 )cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, pyridyl, thiophenyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, indolyl, imidazolyl, thiazolyl, benzo[cT
  • the group represented by R 3 is selected from the group consisting of cyclopentyl, phenyl, thiophenyl, pyridyl, piperidinyl, benzo[c][l,2,5]oxadiazolyl, benzo[b]thiophenyl, tetrahydropyranyl, benzo[d]imidazolyl, pyrazoly, isoxazolyl, thiazolyl, quinolinyl,
  • each of the (Cj-C3)alkyl, phenyl, benzyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl substituents on the groups represented by R 3 is optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -N0 2 , -NR a R b , (d-C 3 )alkyl, halo(C r C 3 )alkyl, (C r C 3 )alkoxy and (Ci-C3)alkoxy(Ci-C3)alkyl. Values and alternative values for the remainder of the variables are as described in the first or second embodiment.
  • the group represented by R 3 described in the second, third, fourth or fifth embodiment is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -OR 0 , (d-C 3 )alkyl, -(Ci-C 3 )alkylene-NR a R b , phenyl, pyrimidinyl, morpholinyl and benzyl, wherein the phenyl, pyrimidinyl, morpholinyl and benzyl substituents are optionally substituted with halogen, (d-C 3 )alkyl, halo(Ci-C 3 )alkyl, (d-C 3 )alkoxy and (d- 4820V.1 C 3 )alkoxy(Ci-C 3 )alkyl; R c is -H, (Ci-C 3 )alkyl, pyridinyl or morpholinyl; and R a and R b are each independently -
  • the group represented by R 3 described in the third, fourth or fifth embodiment is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -CI, methyl, ethyl, -CF 3 , 2-propyl, benzyl, phenyl and
  • compounds of the present teachings are represented by a structural formula selected from:
  • W is CH or N when is a double bond, or W is -CHR 7 - or -NR 8 - when is a single bond;
  • R 5 is absent when is a double bond and R 5 is -H or (Ci-C 3 )alkyl when is a single bond;
  • q 1 or 2;
  • R 8 is -H or a (C,-C 3 )alkyl
  • each R 9 is independently selected from -H, -CN, -N0 2 , halogen, -OR c , -NR a R b , -S(0)iR c ,
  • r is an integer from 1 to 4. Values and alternative values for the remainder of the variables are as described for Structural Formula (I) or in the second embodiment.
  • R 7 is -H or (C,-C 6 )alkyl
  • each R 9 is independently selected from the group consisting of -H, halogen, -CN, -N0 2 , (Ci-C 3 )alkyl, halo(C,-C 3 )alkyl, (d-C 3 )alkoxy, (C 1 -C 3 )alkoxy(C,-C 3 )alkyl, hydroxy(C C 3 )alkyl or -(Ci-C 3 )alkylene-NR a R b ; and
  • compounds of the present teachings are represented by a structural formula selected from:
  • the group represented by R 3 is selected from (C 3 -Cs)cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, pyridyl, thiophenyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, indolyl, imidazolyl, thiazolyl, benzo[6?]imidazolyl, benzo[iflthiazolyl, benzo[b]thiophenyl, quinolinyl, tetrahydronaphthalenyl, tetrahydroquinolinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl,
  • the group represented by R 3 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -OR c , (Ci-C 3 )alkyl, - -(Ci-C 3 )alkylene-NR a R b , phenyl, pyrimidinyl, morpholinyl and benzyl, wherein the phenyl, pyrimidinyl, morpholinyl and benzyl substituents are optionally substituted with halogen, (Q- C 3 )alkyl, haloCCrC ⁇ alkyl, (Ci-C 3 )alkoxy and (Ci-C 3 )alkoxy(Ci-C 3 )alkyl; R c is -H,
  • R 3 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -CI, methyl, -CF3, ethyl, 2- propyl, benzyl, phenyl and -CH2NH2.
  • R 4 and R 5 are both -H.
  • R 5 is -H and R 4 is -OH, (Ci-C 3 )alkyl, -(Ci-C 2 )alkylene-OH,(Ci-C 3 )alkoxy, -NR a R b , -(C,-C 2 )alkylene-NR a R b , pyrrolidinyl, piperidinyl, morpholinyl or cyclopropyl, wherein R a and R b are each independently -H or (Ci-C3)alkyl and the pyrrolidinyl, piperidinyl, morpholinyl or cyclopropyl represented by R 4 is optionally substituted with halogen, (Ci-C 3 )alkyl, halo(Ci-C 3 )alkyl, (C
  • R la and R ,b are both -H and values and alternative values for the remainder of the variables are as described in the second, third, fourth, fifth, sixth, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.
  • R la and R lb are both -H; R 2 and R 2b are both -H; and values and alternative values for the remainder of the variables are as described in the second, third, fourth, fifth, sixth, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiment.
  • the present teachings provide a compound represented by a structural formula selected from:
  • R 16 is (Ci- C6)alkyl, optionally substituted with -N(CH 3 ) 2 or 2,6-dimethylmorpholinyl, e.g., in some embodiments, R 16 is selected from methyl, ethyl, (2,6-dimethylmorpholinyl)propyl, and N,N- dimethylaminopropyl. In some embodiments, R 16 is methyl.
  • the present teachings provide a compound represented by a structural formula s
  • the present teachings provide a compound represented by a structural formula selected from:
  • heterocycloalkyl or the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -halogen, -CN, -OR c , -NR a R b , -S(0)iR c , -NR d S(0)iR c ,
  • the present teachings provide a compound represented by a structural formula selected from:
  • R is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is optionally substituted with 1 to 3 groups represented by R 6 ;
  • R 4 and R 5 are each independently selected from -H, alkyl, -OR c , -NR a R b , -(C r
  • R 4 and R 5 are not both selected from -OR c and -NR a R b ; or R 3 and R 5 together with the carbon atom to which they are attached form a cycloalkyl or a heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, -CN, (Ci-C3)alkyl, halo(Ci-C 3 )alkyl, (Cj- C 3 )alkoxy, halo(C,-C 3 )alkoxy, (Ci-C 3 )alkoxy(Ci-C 3 )alkyl;
  • substituents independently selected from the group consisting of halogen, -CN, (Cj- C 6 )alkyl, halo(C,-C 6 )alkyl, (C,-C 3 )alkoxy, halo(Ci-C 3 )alkoxy and (Ci-C 3 )alkoxy(Ci-C 6 )alkyl; and
  • p 0, 1 or 2;
  • the group represented by R 3 is selected from (C 3 -Cs)cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, pyridyl, thienyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrazolyl, oxazolyl, i o isoxazolyl, indolyl, imidazolyl, thiazolyl, benzo[d]imidazolyl, benzo[i ]thiazolyl,
  • 20 tetrahydropyranyl substituents on the groups represented by R 3 is optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, -N0 2 , -NR a R b , (Ci-C )alkyl, halo(Cr C 3 )alkyl, (Ci-C 3 )alkoxy and (Ci-C 3 )alkoxy(Ci-C 3 )alkyl.
  • the group represented by R 3 is selected from phenyl, pyridyl, and thienyl, each of which is optionally substituted with halogen or (C r C 3 )alkyl (e.g., chloro or methyl).
  • R 4 and R 5 are each independently selected from -H, alkyl, -OR c , -NR a R b , cycloalkyl, heterocycloalkyl and -(C]-C 3 )alkylene-heterocycloalkyl, provided that R 4 and R 5 are not both selected from -OR c and -NR a R b .
  • one of R 4 and R 5 is -H and the other is selected from -H, alkyl, -OR c , -NR R b , cycloalklyl, heterocycloalkyl and -(C
  • R 4 and R 5 are -H and the other is selected from -H, (C]-C 3 )alkyl, -OCH 3 , -N(CH 3 ) 2 , (C 3 -C6)cycloalklyl, pyrrolidinyl, piperidinyl, - CH2-morpholinyl and -O-cyclopentyl.
  • R l and R lb are each independently selected from -H and (Ci-C 3 )alkyl substituted with -N(Me)2, and values and alternative values for the remainder of the variables are as described in the sixteenth, seventeenth, eighteenth or nineteenth embodiment.
  • R la and R lb are both -H and values and alternative values for the remainder of the variables are as described in the sixteenth, seventeenth, eighteenth or nineteenth embodiment.
  • R la and R lb are both -H; R 2a and R 2b are both -H; and values and alternative values for the remainder of the variables are as described in the sixteenth, seventeenth, eighteenth or nineteenth embodiment.
  • the present teachings provide the compounds depicted and/or described by name in the Exemplification, as well as neutral forms and pharmaceutically acceptable salts thereof.
  • alkyl used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, “cycloalkylalkyl”, “heterocycloalkylalkyl”, “aralkyl”, “heteroaralkyl” and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e. (Ci-C6)alkyl. As used herein, a "(Ci-C6)alkyl” group is means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.
  • alkylene group is a saturated aliphatic branched or straight-chain divalent hydrocarbon radical. Unless otherwise specified, an alkylene group typically has 1-6 carbon atoms, i.e. (Ci-C6)alkylene.
  • alkenyl means branched or straight-chain monovalent hydrocarbon radical containing at least one double bond. Alkenyl may be mono or polyunsaturated, and may exist in the E or Z onfiguration. Unless otherwise specified, an alkenyl group typically has 2-6 carbon
  • (C2-C 6 )alkenyl means a radical having from 2-6 carbon atoms in a linear or branched arrangement.
  • Alkynyl means branched or straight-chain monovalent hydrocarbon radical containing at least one triple bond. Unless otherwise specified, an alkynyl group typically has 2-6 carbon atoms, i.e. (C 2 -C 6 )alkynyl. For example, “(C 2 -C 6 )alkynyl” means a radical having from 2-6 carbon atoms in a linear or branched arrangement.
  • Alkoxy means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, includes methoxy, ethoxy, propoxy, and butoxy.
  • haloalkyl and “haloalkoxy” means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • halogen means F, CI, Br or I.
  • halogen in a haloalkyl or haloalkoxy is F.
  • aryl group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, means an aromatic hydrocarbon ring system.
  • aryl may be used interchangeably with the terms “aryl ring” “aromatic ring”, “aryl group” and “aromatic group”.
  • An aryl group typically has six to fourteen ring atoms. Examples includes phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like.
  • a "substituted aryl group” is substituted at any one or more substitutable ring atom, which is a ring carbon atom bonded to a hydrogen.
  • Cycloalkyl means a saturated aliphatic cyclic hydrocarbon radical optionally containing one or more double bonds. It can be monocyclic, bicyclic, polycyclic (e.g., tricyclic), fused, bridged, or spiro.
  • monocyclic (C3-C 8 )cycloalkyl means a radical having from 3-8 carbon atoms arranged in a monocyclic ring.
  • a (C3-C8)cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctane.
  • Heterocycloalkyl means a saturated or unsaturated non-aromatic 4-12 membered ring radical optionally containing one or more double bonds. It can be monocyclic, bicyclic, tricyclic, fused, bridged, or spiro.
  • the heterocycloalkyl contains 1 to 4 heteroatoms, which may be the same or different, selected from N, O or S.
  • the heterocycloalkyl ring optionally contains one or more double bonds and/or is optionally fused with one or more aromatic rings (e.g., phenyl ring).
  • the term “heterocycloalkyl” is intended to include all the possible isomeric forms.
  • heterocycloalky examples include, but are not limited to, morpholinyl, thiomorpholinyl, pyiTolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and tetrahydroquinolinyl.
  • heteroaryl "heteroaromatic”, “heteroaryl ring”, “heteroaryl group”,
  • heteroaryomatic ring and “heteroaromatic group”, are used interchangeably herein.
  • Heteroaryl when 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 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur).
  • Heteroaryl includes monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings.
  • heteroaryl includes monocyclic, bicyclic or tricyclic ring systems.
  • Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2- furanyl, 3-furanyl), imidazolyl (e.g., A midazolyl, 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 -pyrrol yl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl,
  • polycyclic aromatic heteroaryl groups examples include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazoiyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.
  • a "substituted heteroaryl group” is substituted at any one or more substitutable ring atom, which is a ring carbon or ring nitrogen atom bonded to a hydrogen.
  • an "arylalkyl” moiety refers to an alkyl group substituted with an aryl group (e.g., phenylmethyl (i.e., benzyl)).
  • a “heteroarylalkyl” moiety refers to an alkyl group substituted with a heteroaryl group.
  • the present teachings also include various isomers and mixtures thereof.
  • “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers).
  • Stereoisomers are compounds which differ only in their spatial arrangement.
  • the present teachings encompass all such forms, including compounds in the form of essentially pure enantiomers, racemic mixtures and tautomers, which includes forms not depicted structurally.
  • a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or structure encompasses all possible stereoisomers, tautomers, geometric isomers or a combination thereof.
  • geometric isomeric purity of the named or depicted geometric isomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight.
  • Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.
  • Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer.
  • the present teachings encompass all enantiomerically-pure, enantiomerically- enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds described herein.
  • 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.
  • a compound When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure").
  • Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • Suitable pharmaceutically acceptable salts of the compounds disclosed herein 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).
  • acidic groups such as carboxylic acids can form pharmaceutically 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.
  • 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.
  • Compounds described herein can inhibit various kinases, including the TT , PLK (such as PLK4), Aurora A, Aurora B and CHK (such as CHK2). Thus, generally, compounds described herein are useful in the treatment of diseases or conditions associated with such kinases.
  • the compounds described herein are TTK, PLK, Aurora A, Aurora B and/or CHK inhibitors, and are useful for treating diseases, such as cancer, associated with such kinase(s).
  • the compounds described herein are TTK inhibitors and are useful for treating diseases associated with TTK, such as cancer.
  • the compounds described herein 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 described herein are PLK inhibitors and are useful in inhibiting PLK activity for the treatment of various conditions such as cancers.
  • the PLK is PLK4, PLK2 and/or PLK1.
  • the PLK is PLK1 and/or PLK4.
  • the PLK is PLK4.
  • the compounds described herein are CHK inhibitors and are useful in inhibiting CHK activity for the treatment of various conditions such as cancers.
  • the compounds described herein inhibit the growth of a tumor.
  • the compounds described herein inhibit the growth of a tumor that overexpresses at least one of TTK, PLK, Aurora A, Aurora B, and CHK.
  • the compounds described herein inhibit the growth of a tumor that overexpresses TTK.
  • Cancers that can be treated (including reduction in the likelihood of recurrence) by the methods of the present teachings 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 selected from leukemia, acute myeloid leukemia, chronic myelogenous leukemia, breast cancer, brain cancer, colon cancer, colorectal cancer, head and neck cancer, hepatocellular carcinoma, lung adenocarcinoma, metastatic melanoma, pancreatic cancer, prostate cancer, ovanrian cancer and renal cancer.
  • 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 breast cancer, colon cancer and lung cancer. In yet another embodiment, the cancer is a breast cancer. In yet another embodiment, the cancer is a basal sub-type breast cancer or a luminal B sub-type breast cancer. In yet another embodiment, the cancer is a basal sub-type breast cancer that overexpresses TTK. In yet another embodiment, the basal sub-type breast cancer is ER
  • the cancer is a soft tissue cancer.
  • 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.
  • 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
  • the soft tissue cancer is a sarcoma selected from the group consisting of a fibrosarcoma, a gastrointestinal sarcoma, a
  • a dedifferentiated liposarcoma a dedifferentiated liposarcoma, a pleomorphic liposarcoma, a malignant fibrous histiocytoma, a round cell sarcoma, and a synovial sarcoma.
  • the present teachings provide methods of inhibiting the growth of tumor-initiating cells or reducing the likelihood of recurrence of a cancer in a subject who is undergoing an anti-cancer therapy.
  • the method comprises the steps of:
  • the method optionally further comprises the step of continuing the anti-cancer therapy until the cancer goes into remission and then the step b) of administering an effective amount of a TTK inhitior (e.g., a compound represented by Structural Formula (I)).
  • a TTK inhibitor e.g., a compound represented by Structural Formula (I)
  • the method optionally further comprises the step of continuing the anti-cancer therapy until the cancer goes into remission and then the step b) of administering an effective amount of a TTK inhitior (e.g., a compound represented by Structural Formula (I)).
  • the present teachings provide methods of inhibiting the growth of tumor-initiating cells or reducing the likelihood of recurrence of a cancer in a subject whose cancer is in remission comprising administering to the subject an effective amount of a TTK inhbitior (e.g, a compound represented by Structural Formula (I)).
  • a TTK inhbitior e.g, a compound represented by Structural Formula (I)
  • the subject has already been treated with an anti-cancer therapy.
  • the subject has already been treated with an anti-cancer therapy and the subject is in remission.
  • the present teachings provide methods of treating a subject with a cancer comprising administering to the subject an effective amount of a compound represented by Structural Formula (I) in combination with an effective anti-cancer therapy.
  • the cancer is a metastatic cancer.
  • a "metastatic cancer” is a cancer that has spread from its primary site to other parts of the body.
  • the present teachings are directed to a method of treating a subject with a drug-resistant cancer.
  • a "drug-resistant cancer” is a cancer that is not responsive to one, two, three, four, five or more drugs that are typically used for the treatment of the cancer.
  • the drug-resistant cancer is mediated by the growth of tumor-initiating cells.
  • tumor-initiating cells refers to preventing or decreasing the rate of the proliferation and/or survival of the tumor-initiating cells.
  • the term "reducing the likelihood of recurrence of a cancer” means partially or totally inhibiting, preventing or delaying the return of a cancer at or near a primary site and/or at a secondary site after a period of remission. It also means that the cancer is less likely to return with treatment described herein than in its absense.
  • the term “remission” refers to a state of cancer, wherein the clinical symptoms or indicators associated with a cancer have disappeared or cannot be detected, typically after the subject has been successfully treated with an anti-cancer therapy.
  • treating a subject with a cancer includes achieving, partially or substantially, one or more of the following: arresting the growth, reducing the extent of the cancer (e.g., reducing size of a tumor), inhibiting the growth rate of the cancer, ameliorating or improving a clinical symptom or indicator associated with the cancer (such as tissue or serum components) or increasing longevity of the subject; and reducing the likelihood of recurrence of the cancer.
  • Suitable methods known in the art can be used for assessing a subject to determine whether the cancer is in remission.
  • the size of the tumor and/or tumor markers can be monitored to determine the state of the cancer.
  • Size of the tumor can be monitored with imaging devices, such as X-ray, MRI, CAT scans, ultrasound, mammography, PET and the like or via biopsy.
  • TTK inhibitors for use in inhibiting the growth of tumor-initiating cells or reducing the likelihood of recurrence of a cancer in a subject can include any of the compounds described herein, including compounds of formulae (I)-(VIII).
  • TTK inhibitors for use in inhibiting the growth of tumor-initiating cells or reducing the likelihood of recurrence of a cancer in a subject does not comprise administering the compound represented by Structural Formula (I) for the treatment of cancer.
  • the TTK inhibitors for use in inhibiting the growth of tumor- initiating cells or reducing the likelihood of recurrence of a cancer in a subject is described in WO2009/024824, the entire teachings of which is incorporated herein by reference.
  • the TTK inhibitor is presented by the followin structural formula:
  • R 1 is selected from Ci ⁇ alkyl, cyclopropyl, cyclopropylmethyl and cyclobutyl; wherein said cyclopropyl may be optionally substituted by methyl; and wherein R 1 may be optionally substituted by one or more R 5 ; m is 0 or 1 ;
  • R 2 is selected from C A aUcyl, C2-6alkenyl, C2-6alknyl, C3. ⁇ 3 ⁇ 4 cycloalkyl, cyclopentenyl, cyclohexenyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl and azepanyl; wherein R 2 may be optionally substituted on carbon by one or more R 6 ; and wherein if R 2 contains a ring -NH- moiety, that nitrogen may be optionally substituted by R 7' ;
  • R 3 is independently selected from fluoro, chloro, bromo, cyano, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, ethenyl, ethynyl, cyclopropyl, methylthio, ethylthio, N-methylamino, NN-dimethylamino, amino and methylsulfonyloxy;
  • n' is an integer selected from 0 to 3; wherein the values of R 3 may be the same or different;
  • R 4 ' is -L-R 8' or R 9' ;
  • L is selected from ethynylene, ethenylene, cyclopropyl and wherein X is a direct bond, -0-, -S-, -NH-, -OS(0) 2 -, -N(CH 3 )- or -N(CH 2 R 10' )-; and wherein L may be optionally substituted on carbon by one or more fluoro; R 5 is cyano or fluoro;
  • R 6 ' is selected from Ci_ 3 alkyl, Ci_ alkoxy, N-( Ci_ 3 alkyl)amino, N,N-( Ci- 3 alkyl) 2 amino, hydroxy, amino, fluoro and cyano;
  • R 7 is selected from Ci. 3 alkyl, cyclopropyl, Cj. 3 alkanoyl and Ci -3 alkylsulfonyl;
  • R 8 and R 10 are each independently selected from chloro, bromo, iodo, cyano, nitro, mercapto, sulfo, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, C 2 -6alkyl, C 2 _6alkenyl, C 2 -6alkynyl, C]. 6 alkoxy, Ci. 6 alkylsulfonyloxy, N-( Ci. 6 alkyl)sulfamoyloxy, N,N- (Ci.
  • R 9 is selected from carboxy, carbamoyl, sulfamoyl, C 3 _6alkyl, C 3 _ 6 alkenyl, C 3 _6alkynyl, C 3 _6alkoxy, C 3 _ 6 alkylsulfinyl, C 3 ⁇ alkylsulfanyl, C 2 - 6 alkylsulfonyloxy , N- (Ci. 6 alkyl)sulfamoyloxy , N,N-(Ci.
  • R 22 and R 35 are independently selected from halo, cyano, nitro, mercapto, sulfo, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, C h alky 1, C2-6alkenyl, C2-6alkynyl, Ci_ 6 alkoxy, N-(C],6alkyl)sulfamoyloxy, N,N-(Ci. 6 alkyl) 2 Sulfamoyloxy, Ci. 6 alkoxycarbonyl, d-ealkanoyl, Ci.
  • R" and R are independently selected from Ci ⁇ alkyl, C2-6alkenyl, C2-6alkynyl,
  • Ci_ 6 alkanoyl carbamoyl, N-(Ci. 6 alkyl)carbamoyl, N,N-(
  • R 20 and R 21 are each independently selected from a direct bond, -0-, -N(R 54 )-, -C(O)-,
  • R 33 and R 34 ' are each independently selected from a direct bond, -0-, -N(R 63 )-, -C(O)-, -N(R 64' )C(0)-, -C(0)N(R 65' )-, -S0 2 N(R 66' )-, -N(R 6T )-C(0)-N(R 68' )-, -OS(0) 2 -, -S(0) 2 0-, -N(R 69' )S(0) 2 N(R 70' )-, -N(R 71' )S0 2 - and -S(0) a - wherein a is 0 to 2;
  • R 46 and R 7 ⁇ are each independently selected from a direct bond, -0-, -N(R 72 )-, -C(O)-, - N(R 73' )C(0)-, -C(0)N(R 74' )-, -S0 2 N(R 75' )-, -N(R 76' )-C(0)-N(R 77' )-, -OS(0) 2 -, -S(0) 2 0-, - N(R 78' )S(0) 2 N(R 79' )-, -N(R 80' )SO 2 - and -S(0) a - wherein a is O to 2;
  • R so and R 51' are each independently selected from a direct bond, -C(O)-, -N(R 8r )C(0)-, -N(R 82' )S0 2 -, -O-C(O)- and -S(0) a - wherein a is 1 or 2;
  • R 48 ' and R 52 are each independently selected from fiuoro, chloro, cyano, nitro, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, sulfo, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, ethenyl, methoxy, ethoxy, formyl, acetyl, acetoxy, N-methylamino, N-ethylamino N,N-dimethylamino, ⁇ , ⁇ -diethylamino, N-ethyl-N-methylamino, N-formylamino, N- acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, ⁇ , ⁇ -dimethylcarbamoyl, N,N- diethylcarbamoyl, N-ethyl-N-methylcarbamoyl,
  • methoxycarbonyl ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N -diethylsulfamoyl and N-ethyl-N-methylsulfamoyl;
  • R 49 ' and R 53 are each independently selected from Ci_6alkyl, C 3 . 6 cycloalkyl,
  • R 70 ,and R 71 are each independently hydrogen or a group selected from and cyclopropyl wherein said group may be optionally substituted on carbon by one or more R 35 ;
  • the TTK inhitor described in WO2009/156315 can be used for inhibiting the growth of tumor-initiating cells or reducing the likelihood of recurrence of a cancer in a subject.
  • the entire teachings of WO2009/156315 is incorporated by reference.
  • the TTK inhibitor of WO2009/156315 is represented by the following structural formula:
  • Rl is an ortho-substituted-aryl group or a heterocyclyl or C3-C7 cycloalkyl group
  • R2 is hydrogen atom or a straight or branched C1-C alkyl, C 2 -Ce alkenyl,
  • R3 is aryl, heterocyclyl or C3-C7 cycloalkyl group
  • R4 is hydrogen atom, hydroxyl or C1 -C6 alkyl group, which group may be optionally cyclized together with one of the atom of the group which R3 may represent so as to form a fused C4-C7 cyclic group;
  • R5 and R6 are each independently hydrogen atom, Ci-Ce alkyl, or are optionally cyclized together with the carbon atom to which they are bonded so as to form a C3-C7
  • cycloalkyl group wherein the groups ortho-substituted-aryl, aryl, heterocyclyl, C3-C7 cycloalkyl, C4-C7 cycloalkyl, Ci-C alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl may be optionally (further) substituted; with the proviso that that the following compounds are excluded:
  • the TTK inhibitor that can be used for inhibiting the growth of tumor-initiating cells or reducing the likelihood of recurrence of a cancer in a subject is a pyridine derivative described WO2010/007756, the entire teaching of which is incorported herein by reference.
  • the anti-cancer therapy is selected from the group consisting of surgery, radiation therapy, immunotherapy, endocrine therapy, gene therapy and administration of an anti-cancer agent.
  • the anti-cancer therapy is radiation therapy.
  • the anti-cancer therapy is immunotherapy.
  • the anti-cancer therapy is administration of an anti-cancer agent.
  • the anti-cancer therapy is surgery.
  • Radiation therapy is the use of radiation to kill, destroy or treat the cancers.
  • Exemplary radiation therapy includes, but is not limited to, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and radioiosotope thereapy (i.e., systemic radioactive isotopes therapy),
  • An endocrine therapy is a treatment that adds, blocks or removes hormones.
  • chemotherapeutic agents that can block the production or activity of estrogen have been used for treating breat cancer.
  • hormonal stimulation of the immune system has been used to treat specific cancers, such as renal cell carcinoma and melanoma.
  • the endocrine therapy comprises administration of natural hormones, synthetic hormones or other synthetic molecules that may block or increase the production of the body's natural hormones.
  • the endocrine therapy includes removal of a gland that makes a certain hormone.
  • a gene therapy is the insertion of genes into a subject's cell and biological tissues to treat diseases, such as cancer.
  • exemplary gene therapy includes, but is not limited to, a germ line gene therapy and a somatic gene therapy.
  • Immunotherapy also called biological response modifier therapy, biologic therapy, biotherapy, immune therapy, or biological therapy
  • Immunotherapy can help the immune system recognize cancer cells, or enhance a response against cancer cells.
  • Immunotherapies include active and passive immunotherapies. Active immunotherapies stimulate the body's own immune system while passive immunotherapies generally use immune system components created outside of the body.
  • active immunotherapies include, but are not limited to vaccines including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, DNA vaccines, viral vaccines, or Tumor-Infiltrating
  • TIL Lymphocyte
  • IL-2 Interleukin-2
  • LAK Lymphokine- Activated Killer
  • Examples of passive immunotherapies include but are not limited to monoclonal antibodies and targeted therapies containing toxins.
  • Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also called tagged, labeled, or loaded antibodies). Naked monoclonal antibodies do not have a drug or radioactive material attached whereas conjugated monoclonal antibodies are joined to, for example, a chemotherapy drug (chemolabeled), a radioactive particle (radiolabeled), or a toxin (immunotoxin).
  • Examples of these naked monoclonal antibody drugs include, but are not limited to Rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B cell non-Hodgkin lymphoma; Trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; Alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B cell chronic lymphocytic leukemia (B-CLL); Cetuximab (Erbitux), an antibody against the EGFR protein used, for example, in combination with irinotecan to treat, for example, advanced colorectal cancer and head and neck cancers; and Bevacizumab (Avastin) which is an antiangiogenesis therapy that works against the VEGF protein and is used, for example, in combination with chemotherapy to treat, for example, metastatic colorectal cancer.
  • Rituximab an antibody against the CD20 antigen used to treat
  • conjugated monoclonal antibodies include, but are not limited to Radiolabeled antibody Ibritumomab tiuxetan (Zevalin) which delivers radioactivity directly to cancerous B lymphocytes and is used to treat, for example, B cell non-Hodgkin lymphoma; radiolabeled antibody Tositumomab (Bexxar) which is used to treat, for example, certain types of non- Hodgkin lymphoma; and immunotoxin Gemtuzumab ozogamicin (Mylotarg) which contains calicheamicin and is used to treat, for example, acute myelogenous leukemia (AML).
  • Zevalin Radiolabeled antibody Ibritumomab tiuxetan
  • Bexxar radiolabeled antibody Tositumomab
  • Mylotarg immunotoxin Gemtuzumab ozogamicin
  • BL22 is a conjugated monoclonal antibody for treating, for example, hairy cell leukemia, immunotoxins for treating, for example, leukemias, lymphomas, and brain tumors, and radiolabeled antibodies such as OncoScint for example, for colorectal and ovarian cancers and ProstaScint for example, for prostate cancers.
  • HERCEPTIN® Trastuzumab
  • Genentech, CA which is a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer
  • REOPRO® abciximab
  • Ceentocor which is an anti-glycoprotein Ilb/IIIa receptor on the platelets for the prevention of clot formation
  • ZENAPAX® (daclizumab) (Roche Pharmaceuticals, Switzerland) which is an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection
  • PANOREXTM which is a murine anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor)
  • BEC2 which is a murine anti-idiotype (GD3 epitope) IgG antibody (ImClone System)
  • IMC-C225 which is a chimeric anti-EGFR IgG antibody
  • -49-4820V.1 is a primatized anti-CD4 antibody (IDEC);
  • IDEC-152 is a primatized anti-CD23 antibody (IDEC/Seikagaku);
  • SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab);
  • 5G1.1 is a humanized anti-complement factor 5 (C5) antibody (Alexion Pharm);
  • D2E7 is a humanized anti-TNF- ⁇ antibody (CAT/BASF);
  • CDP870 is a humanized anti-TNF-a Fab fragment (Celltech);
  • IDEC- 151 is a primatized anti-CD4 IgGl antibody (IDEC)
  • MDX-CD4 is a human anti-CD4 IgG antibody
  • Immunotherapies that can be used in the present teachings include adjuvant
  • cytokines such as granulocyte-macrophage colony- stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-l -alpha, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factors (including TNF-alpha), and interferons (including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide (alum); Bacille Calmette-Guerin (BCG); Keyhole limpet hemocyanin (KLH); Incomplete Freund's adjuvant (IFA); QS-21 ; DETOX; Levamisole; and Dinitrophenyl (DNP), and combinations thereof, such as, for example, combinations of, interleukins, for example, IL-2 with other cytokines, such as
  • the anti-cancer therapy described herein includes administration of an anticancer agent.
  • an “anti-cancer agent” is a compound, which when administered in an effective amount to a subject with cancer, can achieve, partially or substantially, one or more of the following: arresting the growth, reducing the extent of a cancer (e.g., reducing size of a tumor), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator
  • -50-4820V.1 associated with a cancer (such as tissue or serum components) or increasing longevity of the subject.
  • the anti-cancer agent suitable for use in the methods described herein include any anticancer agents that have been approved for the treatment of cancer.
  • the anti- cancer agent includes, but is not limited to, a targeted antibody, an angiogenisis inhibitor, an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a podophyllotoxin, a topoisomerase inhibitor, a hormonal antineoplastic agent and other antineoplastic agents.
  • alkylating agents useful in the methods of the present teachings include but are not limited to, nitrogen mustards (e.g. , mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.).
  • nitrogen mustards e.g. , mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • antimetabolites useful in the methods of the present teachings include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., fluorouracil, floxouridine, Cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin
  • plant alkaloids and terpenoids or derivatives thereof include, but are not limited to, vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine), podophylloto in, and taxanes (e.g., paclitaxel, docetaxel).
  • topoisomerase inhibitor includes, but is not limited to, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate and teniposide.
  • antineoplastic agents include, but are not limited to, actinomycin, anthracyclines (e.g., doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin), bleomycin, plicamycin and mitomycin.
  • the anti-cancer agents that can be used in the present teachings include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin;
  • ametantrone acetate aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium;
  • bropirimine busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin;
  • carmustine carubicin hydrochloride
  • carzelesin cedefingol
  • chlorambucil cirolemycin
  • cladribine crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;
  • estramustine estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; cambine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine
  • hydrochloride hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl ; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
  • lometrexol sodium lomustine; losoxantrone hydrochloride; masoprocol; maytansine;
  • mechlorethamine hydrochloride megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;
  • pegaspargase peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
  • piposulfan piroxantrone hydrochloride
  • plicamycin plicamycin
  • plomestane porfimer sodium
  • porfiromycin prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; pumprazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine;
  • thiotepa tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;
  • vinrosidine sulfate vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.
  • anti-cancer agents/drugs that can be used in the present teachings include, but are not limited to: 20-epi-l,25 dihydroxy vitamin D3; 5-ethynyl uracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine;
  • ambamustine amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide;
  • anastrozole andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1 ; antiandrogen, prostatic carcinoma; antiestrogen;
  • antineoplaston antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;
  • azatyrosine baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A;
  • bizelesin breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;
  • carboxyamidotriazole CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole;
  • collismycin A collismycin B; combretastatin A4; combretastatin analogue; conagenin;
  • crambescidin 816 crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;
  • cyclopentanthraquinones cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
  • cytostatin cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;
  • dexifosfamide dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron;
  • edrecolomab eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane;
  • fadrozole fadrozole; quirabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunomnicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;
  • hypericin ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;
  • imidazoacridones imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
  • kahalalide F lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate;
  • leptolstatin a leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon;
  • leuprolide+estrogen+progesterone leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;
  • meterelin methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
  • monoclonal antibody human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1- based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
  • naloxone+pentazocine napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;
  • parabactin pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate;
  • phosphatase inhibitors picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum- triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone;
  • prostaglandin J2 proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
  • roquinimex rubiginone Bl ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;
  • spongistatin 1 squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide;
  • stromelysin inhibitors sulfinosine
  • superactive vasoactive intestinal peptide antagonist sulfinosine
  • suradista suramin; s ainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
  • thaliblastine thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins
  • the anti-cancer agents that can be used in methods described herein are selected from the group consisting of paclitaxel, docetaxel, 5-fluorouracil , trastuzumab, lapatinib, bevacizumab, letrozole, goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine,
  • capecitabine irinotecan, oxaliplatin, carboplatin, cisplatin, doxorubicin, epirubicin,
  • cyclophosphamide methotrexate, vinblastine, vincristine, melphalan and a combination thereof.
  • the anti-cancer agent and the compound represented by Structural Formula (I) are administered contemporaneously.
  • the anti-cancer agent and the compound can be administered in the same formulation or in different formulations.
  • the compound and the additional anti-cancer agent are administered separately.
  • the subject in the methods described herein has not been previously treated with a TTK inhibitor (e.g., the compound represented by Structural Formula (I)).
  • a TTK inhibitor e.g., the compound represented by Structural Formula (I)
  • an "effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., 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, reducing the extent of a cancer (e.g., reducing size of a tumor), 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) or increasing longevity of the subject.
  • an effective amount of a compound taught herein 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.
  • An effective amount of a compound of the present teachings may be readily determined by one of ordinary skill by routine methods known in the art.
  • an effective amount of a compound taught herein ranges from about 0.1 to about 1000 mg/kg body weight, alternatively about 1 to about 500 mg/kg body weight, and in another alternative, from about 20 to about 300 mg/kg body weight. In another embodiment, an effective amount of a compound taught herein ranges from about 0.5 to about 5000 mg/m 2 , alternatively about from 5 to about 2500 mg/m 2 , and in another alternative from about 50 to about 1000 mg/m 2 . The skilled artisan will appreciate that certain factors may influence the
  • -56-4820V.1 dosage required to effectively treat a subject suffering from cancer or reduce the likelihood of recurrence of a cancer 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" or dosing regime of a subject with an effective amount of the compound of the present teachings may consist of a single administration, or alternatively comprise a series of applications.
  • the compound of the present teachings 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 teachings, or a combination thereof.
  • the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment 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, 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.
  • a "subject” is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, sheep, pigs, horses, and the like
  • laboratory animals e.g., rats, mice, guinea pigs, and the like.
  • the compounds taught herein 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 present teachings 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 taught herein can be suitably formulated into pharmaceutical compositions for administration to a subject.
  • the pharmaceutical compositions of the present teachings 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 present teachings 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 present teachings can generally be prepared in water suitably mixed with a surfactant such as
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary
  • these preparations contain a preservative to prevent the growth of microorganisms.
  • sterile aqueous solutions or dispersion of, and sterile powders of, a compound described herein for the extemporaneous preparation of sterile injectable solutions or dispersions are appropriate.
  • 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, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • the compounds of the present teachings can be formulated with with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine, as tablets, lozenges or pastilles.
  • a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine, as tablets, lozenges or pastilles.
  • the compounds described herein can be formulated in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compounds described herein can be prepared according to the following reaction Scheme 1. Halogenation of an appropriately substituted indazole wherein the indazole is substituted as defined herein provides intermediate 1 that can be reacted with a suitable cross coupling partner, ArMet, in the presence of a metal catalyst (e.g. ArBpin /PdCl 2 (dppf) / Na 2 C0 3 / EtOH / PhMe / mw / 120 °C) .
  • a metal catalyst e.g. ArBpin /PdCl 2 (dppf) / Na 2 C0 3 / EtOH / PhMe / mw / 120 °C
  • haloindazole 2 can be converted into a 3-(trialkylstannyl)-lH-indazole that can be subjected to Stille-type cross-coupling reaction as shown in Scheme 2 (e.g. 1. e&Sn2 / Pd(PPh 3 ) 4 / PhMe 2. Arl /Pd(PPh 3 ) 4 / Cul / THF ref. WO200102369).
  • RG0 2 H / coupling reagent e.g. TBTU, EDCI, DCC
  • compounds described herein, containing trisubstituted indazoles can be 5 prepared as outlined in the following Scheme 4.
  • 5-Nitro-lH-indazole is halogenated with Br2, protected with a suitable indazole protecting group such as tetrahydropyranyl, and subjected to Miyaura-Suzuki cross coupling conditions (e.g. ArBpin /dioxane/H 2 0/ PdChidppf)/ Na 2 C03).
  • Hydrogenation of the intermediate 1 yields lH-indazol-5-amine 2 that can be modified in a reaction with electrophilic reagents (e.g.
  • PrepPak Rxn CX refers to a commercial cation-exchange resin available from Waters.
  • Microwave reactions were performed with a Biotage Initiator microwave reactor.
  • Optical Rotations were measured at the sodium D-line (589.44nM) using an AA-55 Polarimeter from Optical Activity Ltd with a 2.5x100mm unjacketed stainless steel tube at given sample concentrations (c, units of g/lOOmL).
  • dppf 1 , 1 '- B is( dipheny Iphosphino) ferrocene
  • -65-4820V.1 examples a filtration and washing (3 ⁇ 40) of the precipitate provided the desired material with the required purity.
  • Aqueous sodium carbonate (0.55 mL, 2 M) was added to a mixture of 3-iodo-lH- indazole-5-carbaldehyde (153 mg, 0.56 mmol), benzenesulfonamide-3-boronic acid pinacol ester (206 mg, 0.73 mmol) and Pd(PPh 3 ) 4 (39 mg, 0.034 mmol) in toluene (1.5 mL) and ethanol (1.5 mL) under an atmosphere of argon.
  • the vial was sealed and heated in the microwave at 120°C for 3h. Water (25 mL) was added and the product was extracted with ether (200 mL, then 2x75
  • dichloromethane yielded a bright yellow solid (90.7mg).
  • the sample was combined with an earlier batch of impure solid (31 mg, estimated 90% pure) and purified by trituration with dichloromethane (3x2 mL) to give a pale yellow solid (63.9 mg, -30%).
  • Methyl 3-iodo-l H-indazole-5-carboxylate was synthesized according to the method described for N-(3-iodo-lH-indazol-6-yl)-2-(thiophen-2-yl)acetamide utilizing methyl 1H- indazole-5-carboxylate (300 mg, 1.70 mmol), K 2 C0 3 (704 mg, 5.10 mmol), I 2 (864 mg, 3.40 mmol) and DMF (8 mL). Orange solid (415 mg, 81 %).
  • the title compound was synthesized according to the General Method C, utilizing 5- bromo-3-iodo-lH-indazole (150.8 mg, 0.47 mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzenesulfonamide (173.8 mg, 0.61 mmol), PdCl 2 (dppf) DCM (33.8 mg, 0.041 mmol), toluene (5 mL), EtOH (5 mL), and aqueous Na 2 C0 3 (0.93 mL, 2 M, 1.86 mmol). The degassed solution was sealed and heated in a microwave reactor at 120 °C for 2 h.
  • tert-Butyl 2-(2-isopropylphenyl)acetate was synthesized according to the method described for 2- (2,6-diethylphenyl)acetic acid utilizing 2-isopropylphenylboronic acid (200 mg, 1.2 mmol), tert- butyl-bromoacetate ( 150 pL, 1.0 mmol), P(o-tol) 3 (28 mg, 0.091 mmol), Pd 2 (dba) 3 (28 mg, 0.030 mmol), K3PO4 (1.08 g, 5.08 mmol) in THF (5 mL) to give tert-butyl 2-(2- isopropylphenyl)acetate as a yellow solid.
  • reaction mixture was diluted with 20 mL of Et20 and then quenched with saturated aqueous ammonium chloride (20 mL). The reaction mixture was washed with brine, dried with MgS0 4 , and then dried under reduced pressure to give tert-butyl 2-(2,6-diethylphenyl)acetate as
  • tert-Butyl 2-(2-ethyl-6-methylphenyl)acetate was synthesized according to the method described for tert-butyl 2-(2,6-diethylphenyl)acetate utilizing l-ethyl-2-iodo-3-methylbenzene (200 mg, 0.813 mmol), terf-butylacetate ( 121 ⁇ ,, 0.894 mmol), Pd(dba) 2 (23 mg, 0.041 mmol), l ,3-Bis(2,6-diisopropylphenyl)-imidazolium chloride (17 mg, 0.041 mmol), and LiHMDS (1 M in hexanes, 1.87 mL, 1.8 mmol) in toluene (6 mL) to give /erf-butyl 2-(2-ethyl-6- methylphenyl)acetate as a yellow liquid (175 mg, 92%).
  • Ethyl 2-(dimethylamino)-2-(2-ethylphenyl)acetate was synthesized according to the method described for 2-(dimethylamino)-2-phenylacetic acid hydrochloride utilizing l-bromo-2- ethylbenzene (239 mg, 1.9 mmol), NN-dimethylglycine ethyl ester (300 L, 2.1 mmol), Pd[P(t- Bu) 3 ] 2 (49 mg, 0.096 mmol), K3PO4 (937 mg, 4.42 mmol) and toluene (4 mL) to give ethyl 2- (dimethylamino)-2-(2-ethylphenyl)acetate as a yellow oil (306 mg, 68%).
  • the title compound was synthesized according to the method described for 2-(dimethylamino)-2- phenylacetic acid hydrochloride utilizing ethyl 2-(dimethylamino)-2-(2-ethylphenyl)acetate (55 mg, 0.23 mmol). A yellow solid (54 mg, 95%).
  • Ethyl 2-(dimethylamino)-2-o-tolylacetate was synthesized according to the method described for 2-(dimethylamino)-2-phenylacetic acid hydrochloride utilizing l-bromo-2- methylbenzene (300 mg, 1.8 mmol), MN-dimethylglycine ethyl ester (274 pL, 1.9 mmol), Pd[P(t-Bu) 3 ] 2 (45 mg, 0.088 mmol), 3 P0 4 (860 mg, 4.1 mmol), and toluene (4 mL) to give ethyl 2-(dimethylamino)-2-o-tolylacetate as a yellow oil (305 mg, 78%).
  • tert-Butyl 2-phenyl-2-(pyrrolidin-l-yl)acetate was synthesized according to the method described for 2-(dimethylamino)-2-phenylacetic acid hydrochloride utilizing bromobenzene (200 ⁇ -, 1.9 mmol), ieri-butyl 2-(pyrrolidin-l-yl)acetate (390 ⁇ , 2.1 mmol), Pd[P(t-Bu) 3 ] 2 (49 mg, 0.096 mmol), 3 P0 4 (937 mg, 4.42 mmol) and toluene (5 mL) to give ethyl 2-phenyl-2- (pyrrolidin-l-yl)acetate as a brown liquid (480 mg, 96%).
  • Ethyl 2-(dimethylamino)-2-(2-(trifluoromethyl)phenyl)acetate was synthesized according to the method described for 2-(dimethylamino)-2-phenylacetic acid hydrochloride utilizing 1 - bromo-2-(trifluoromethyl)benzene (430 mg, 1.92 mmol), NN-dimethylglycine ethyl ester (300 2.11 mmol), Pd[P(t-Bu) 3 ] 2 (49 mg, 0.096 mmol), K 3 P0 4 (937 mg, 4.42 mmol), and toluene
  • tert-Butyl 2-(2,5-dimethylphenyl)acetate was synthesized according to the method described for tert-butyl 2-(3,5-dimethoxyphenyl)acetate utilizing 2,5-dimethylphenylboronic acid (200 mg, 1.3 mL), 1 ⁇ 2rf-butyl-bromoacetate (164 ⁇ , 1.1 mmol), P(o-tol) 3 (31 mg, 0.10 mmol), Pd 2 (dba) 3 (31 mg, 0.033 mmol), K 3 P0 4 (1.18 g, 5.6 mmol) in THF (6 mL) to give tert-butyl 2-
  • terf-Butyl 2-(2,6-dimethylphenyl)acetate was synthesized according to the method described for /m-butyl 2-(3,5-dimethoxyphenyl)acetate utilizing 2,6-dimethylphenylboronic acid (200 mg, 1.33 mmol), ieri-butyl-bromoacetate (164 pL, 1.1 1 mmol), P(o-tol) 3 (31 mg, 0.100 mmol), Pd 2 (dba) 3 (31 mg, 0.033 mmol), K 3 P0 4 (1.18 g, 5.56 mmol) in THF (6 mL) to give the title compound as ayellow liquid.
  • Ethyl 3-morpholino-2-phenylpropanoate was synthesized according to the method described for ethyl 2-phenyl-3-(pyrrolidin-l-yl)propanoate utilizing ethyl 2-phenylacrylate (220 mg, 1.25 mmol) and morpholine (435 mL, 5 mmol) to give the title compound as a yellow oil (305 mg, 93%).
  • Ethyl 2-phenyl-3-(piperidin- l-yl)propanoate was synthesized according to the method described for ethyl 2-phenyl-3-(pyrrolidin- l-yl)propanoate utilizing ethyl 2-phenylacrylate (250 mg, 1.42mol) and piperidine (0.56 mL, 5.68 mmol) to give the title compoundas a yellow oil (348 mg, 94%).
  • Methyl 2-cyclopentyl-2-(pyrrolidin-l-yl)acetate (0.1 g, 0.5 mmol) was taken into MeOH (10 mL) and stirred with aq NaOH ( 2 M, 7.5 mL, 15 mmol) sealed at 90 °C overnight. Then the reaction was coolded ( 0 °C) and acidified to pH 4-5 with aq HC1 (6 M) and concentrated to dryness.
  • l-Phenylprop-2-yn-l-ol (0.37mL, 3.0 mmol) was added to a suspension of NaH (60% wt, 180 mg, 4.5 mmol) in THF (10 mL) under argon atmosphere at 0°C. After 5 min, Me 2 S0 4 (0.35 mL, 3.7 mmol) was added and stirring was continued for 2.5 h. The reaction was quenched with water (20 mL) and the product was extracted with Et20 (150 mL). The organic layer was washed with brine (20 mL) and dried (Na 2 S0 4 ).
  • methyl-2-(2-bromophenyl)acetate 550 mg, 2.4 mmol
  • 4-pyridine boronic acid 325 mg, 2.64 mmol
  • DME 8 mL
  • Pd(PPh 3 ) 4 140 mg, 0.12 mmol
  • the vial was charged with argon and then placed in the microwave reactor, heating at 120 °C for 20 minutes. Reaction was diluted with 10 mL of EtOAc and then washed with brine. The mixture was dried with MgS0 4 and then by reduced pressure.
  • the title compound was synthesized according to the method described for 2-(pyrrolidin-l-yl)-2- o-tolylacetic acid utilizing glyoxylic acid ⁇ H 2 0 (230 mg, 2.5 mmol), cis-2,6-dimethylmorpholine (288 mg, 2.5 mmol), CH 2 C1 2 (20 mL) and 2-methoxyphenylboronic acid (238 mg, 2.5 mmol) to give the title compound; white solid (380 mg, 58%).
  • the title compound was synthesized according to the method described for 2-(pyrrolidin-l-yi)-2- o-tolylacetic acid utilizing glyoxylic acid ⁇ H 2 0 (460 mg, 5 mmol), 2 M dimethylamine in THF (2.5 mL, 5 mmol), CH2CI2 (25 mL) and 2-methoxyphenylboronic acid (760 mg, 5 mmol) to give the title compound; clear oil (792 mg, 76%).
  • the title compound was synthesized according to the General Method C, utilizing iodo- lH-indazole (Sinova Inc., 30 mg, 0.12 mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzenesulfonamide (42 mg, 0.15 mmol), K 2 C0 3 (34 mg, 0.25 mmol), DME (1 mL), EtOH (1 mL), H 2 0 (0.5 mL) and Pd(PPh 3 ) 4 (14 mg, 0.012 mmol). The degassed solution was sealed and
  • the title compound was synthesized according to the General Method B, utilizing 5- phenyl-1 H-indazole (59 mg, 0.30 mmol ), I 2 (97 mg, 0.38 mmol) and KOH (51 mg, 0.91 mmol) in DMF (2 mL). An off-white solid (81 mg, 83 %).
  • the title compound was synthesized according to the General Method C, utilizing 3-iodo- 5-phenyl- l H-indazole (40 mg, 0.12 mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzenesulfonamide (53 mg, 0.19 mmol), Cs 2 C0 3 (122 mg, 0.37 mmol), DMF (1.6 mL), H 2 0 (0.4 mL) and Pd(PPh 3 ) 4 (7 mg, 0.006 mmol).
  • the degassed solution was sealed and heated in a microwave reactor at 120 °C for 1.5 h.
  • the title compound was synthesized according to the General Method B, utilizing N-(3- iodo-lH-indazol-5-yl)acetamide (62 mg, 0.20 mmol), 3-(4,4,5,5-tetramefhyl-l,3,2-dioxaborolan- 2-yl)benzenesulfonamide (73 mg, 0.26 mmol), KF (23 mg, 0.40 mmol), DMF (1.5mL), H 2 0 (0.37 mL) and Pd(PPh 3 )4 (12 mg, 0.010 mmol).
  • the degassed solution was sealed and heated in a microwave reactor at 120 °C for 2 h.
  • the title compound was synthesized according to the General Method B, utilizing N N- (lH-indazol-5-yl)thiophene-2-carboxamide (0.75 g, 3.1 mmol ), (1.6 g, 6.2 mmol) and K2CO3 (1.3 g, 9.3 mmol) in DMF (11 mL). An off-white solid (0.31 g, 27 %).
  • the title compound was synthesized according to the General Method C, utilizing N-(3- iodo-lH-indazol-5-yl)thiophene-2-carboxamide (63 mg, 0.17 mmol), 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzenesulfonamide (58 mg, 0.20 mmol), CS2CO3 (167 mg, 0.51 mmol), DMF (1.6 mL), H 2 0 (0.4 mL) and Pd(PPh 3 ) 4 (10 mg, 0.008 mmol).
  • the degassed solution was sealed and heated in a microwave reactor at 120 °C for 2 h.
  • the title compound was synthesized according to the General Method C, utilizing N-(3- iodo-lH-indazol-5-yl)thiophene-2-carboxamide (74 mg, 0.20 mmol), 3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (68 mg, 0.24 mmol), Cs2C03 (0.20 g, 0.60 mmol), DMF (1.6 mL), H 2 0 (0.4 mL) and Pd(PPh 3 ) 4 (12 mg, 0.010 mmol).
  • the degassed solution was sealed and heated in a microwave reactor at 120 °C for 1 h.
  • the title compound was synthesized according to the General Method B, utilizing N-(1H- indazol-5-yl)-2-(thiophen-2-yl)acetamide (0.51 g, 2.0 mmol ), (1.0 g, 3.9 mmol) and K2CO3 (0.83 g, 6.0 mmol) in DMF (7 mL). A gray-yellow solid (0.32 g, 42 %).
  • the title compound was synthesized according to the General Method C, utilizing N-(5- iodo-lH-indazol-5-yl)-2-(thiophen-2-yl)acetamide (100 mg, 0.26 mmol), 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzenesulfonamide (96 mg, 0.34 mmol), KF (45 mg, 0.78 mmol), DMF (4 mL), H 2 0 (1 mL) and Pd(PPh 3 ) 4 (15 mg, 0.013 mmol).
  • the degassed solution was sealed and heated in a microwave reactor at 120 °C for 2 h.
  • the title compound was synthesized according to the General Method A utilizing 1H- indazol-5-amine (0.15 g, 1.1 mmol), nicotinic acid (0.14 g, 1.1 mmol), N-ethyl-N- isopropylpropan-2-amine (0.29 mL, 1.7 mmol) and 0-(Benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.38 g, 1.2 mmol) in DMF (4 mL).
  • the title compound was synthesized according to General Method C utilizing N-(3-iodo-lH- indazol-5-yl)nicotinamide (46 mg, 0.13 mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzenesulfonamide (43 mg, 0.15 mmol), KF (15 mg, 0.25 mmol), DMF (1.25 mL), H 2 0 (0.37 mL) and Pd(PPh 3 )4 (7 mg, 0.006 mmol).
  • the degassed solution was sealed and heated in a microwave reactor at 120 °C for 1.5 h.
  • the title compound was synthesized according to the method for 3-(5-(3-phenylureido)- lH-indazol-3-yl)benzenesulfonamide , utilizing a DMF (2 mL) solution of 3-(5-amino-lH- indazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate (100 mg, 0.25 mmol), N-ethyl-N- isopropylpropan-2-amine (0.17 mL, 0.99 mmol) and l ,3-dichloro-2-isocyanatobenzene (49 mg, 0.26 mmol).
  • the title compound was synthesized according to the General Method A utilizing 3-(5-amino- lH-indazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.050 g, 0.12 mmol), rac-2- methoxy-2-phenylacetic acid (0.021 g, 0.12 mmol), N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.6 mmol) and 0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.042 g, 0.13 mmol) in DMF (2 mL).
  • the title compound was synthesized according to the the General Method A utilizing 3-(5- amino-lH-indazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.10 g, 0.26 mmol), (R)-2- methoxy-2-phenylacetic acid (0.044 g, 0.27 mmol), N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.6 mmol) and 0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.086 g, 0.27 mmol) in DMF (2 mL).

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Abstract

La présente invention concerne un composé représenté par la formule structurale (I) : ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également une composition pharmaceutique et son procédé d'utilisation.
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WO2012176856A3 (fr) * 2011-06-24 2013-06-13 Ishihara Sangyo Kaisha, Ltd. Pesticide
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