WO2012048411A1 - Inhibiteurs de plk4 et méthode de traitement du cancer à l'aide de ceux-ci - Google Patents

Inhibiteurs de plk4 et méthode de traitement du cancer à l'aide de ceux-ci Download PDF

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WO2012048411A1
WO2012048411A1 PCT/CA2011/001144 CA2011001144W WO2012048411A1 WO 2012048411 A1 WO2012048411 A1 WO 2012048411A1 CA 2011001144 W CA2011001144 W CA 2011001144W WO 2012048411 A1 WO2012048411 A1 WO 2012048411A1
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alkyl
independently
compound
phenyl
group
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Heinz W. Pauls
Sze-Wan Li
Peter Brent Sampson
Bryan T. Forrest
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University Health Network
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • Protein kinases have been the subject of extensive study in the search for new therapeutic agents in various diseases, for example, cancer. Protein kinases are known to mediate intracellular signal transduction by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell.
  • the polo-like kinase (PLK) family of serine/threonine kinases comprises at least four known members: PLK1, PLK2 (also known as Snk), PLK3 (also known as Fnk or Prk) and PLK4 (also known as Sak).
  • PLK4 is the least understood and most divergent member of the PLK family.
  • the N-terminal catalytic domain of PLK4 has a different substrate specificity from that of PLK1 -3.
  • PLK4 also has a divergent C-terminus comprising only a single polo-box sequence, not the tandem PB sequences in PLK1-3, that appears to act as a homodimerization domain rather than a localization domain (Lowery et al., (2005) Oncogene 24: 248-259).
  • PLK4 is known to be involved in the control of mitotic entry and exit, and a regulator of centrosome duplication (Habedanck et al. Nature Cell Biology 7: 1140-1 146, 2005).
  • PLK4 transcripts increase from S through M phase, and the protein is ubiquitylated and destroyed by the anaphase promoting complex (APC) (Hudson et al. Curr. Biol. 11 : 441- 446, 2001 ; Fode et al. Mol. Cell. Biol. 16: 4665 ⁇ 1672, 1996).
  • APC anaphase promoting complex
  • PLK4 is required for late mitotic progression (Fode et al. PNAS. 91 : 6388-6392, 1994; Hudson et al. Curr. Biol.
  • PLK4 knockout mice are embryonic lethal (E7.5), with a marked increase in mitotic and apoptotic cells (Hudson et al. Curr. Biol. 11 : 441 ⁇ 446, 2001). PLK4 is
  • HDAC histone deacetylase
  • PLK4 has been reported to be over expressed in colorectal tumors with expression reported as low in adjacent normal intestinal mucosa (Macmillian et al. Ann. Surg. Oncol. 8: 729-740, 2001).
  • PLK4 mRNA has been reported to be over expressed in some tumor cell lines (Hitoshi, et al, U.S. Patent Application No. US 2003/0027756).
  • HPV-associated anogenital and oropharyngeal cancers The E7 oncoprotein triggers centrosome overduplication through a pathway that involves the concurrent formation of multiple daughters at single maternal centrioles.
  • the HPV- 16 E7 oncoprotein has been used as a tool to dissect abnormal centriole biogenesis and several lines of evidence identify PLK4 as a crucial player in this process (Duensing et al Environ. Mol. Mutagen. 50: 741-747, 2009).
  • an increased level of PL 4 transcription is found in keratinocytes stably expressing HPV-16 E7.
  • HPV-16 E7 to upregulate PL 4 mRNA was found to depend on its ability to degrade the retinoblastoma (pRb) protein, suggesting a role of E2F-mediated gene transcription in deregulation of PLK4 (Korzeniewski et al, AACR Meeting, Washington, 2010, Abstr. 5354). These results identify PLK4 as a target for small molecule inhibition to prevent centriole abnormalities, mitotic infidelity and malignant progression in HPV-associated cancers.
  • 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 PL 4 inhibitors.
  • spiro cyclopropyl indolinone compounds are potent kinase inhibitors, such as polo-like kinases 4 (PLK4) and Aurora Kinases. Based on these discoveries, spiro cyclopropyl indolinone compounds, pharmaceutical compositions thereof, and methods of treating cancer with the spiro cyclopropyl indolinone compounds are disclosed herein. [0008] Dislcosed herein are PLK-4 inhibitors and pharmaceutically acceptable salts thereof.
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a PLK-4 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • Another embodiment of the invention is a method of treating a subject having cancer comprising administering to the subject an effective amount of a PLK-4 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the invention is a method of inhibiting Aurora B and/or
  • PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4 comprising administering to the subject an effective amount of a a PLK-4 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the invention is the use of a PLK-4 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof in therapy.
  • the therapy is for treating a subject with cancer.
  • the therapy is for inhibiting Aurora B and/or PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4.
  • Another embodiment of the invention is the use of a PLK-4 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a subject with cancer.
  • Another embodiment of the invention is the use of a PLK-4 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting Aurora B and/or PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4.
  • Another embodiment of the invention is a PLK-4 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof for use in treating a subject with cancer.
  • Another embodiment of the invention is a PLK-4 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof for use in inhibiting Aurora B and/or PLK-4 in a subject in need of inhibition of Aurora B and/or PLK-4.
  • the disclosed PLK-4 inhibitor is a compound represented by
  • Structural Formula (I) Exemplary stereoisomers of Structural Formula (I) are represented by Structural Formulas (II and (HI):
  • each R a is independently Ci -6 alkoxy.
  • R a is methoxy
  • each R b is independently halogen, -OH, -SH, nitro, cyano, amino, C i -6 alkyl, C i -6 haloalkyl, or C i -6 alkoxy
  • R 4 is -H or C] -6 alkyl
  • R' independently is selected from -(C0-3 alkyl)-N-azetidinyl, wherein the N- azetidinyl is optionally substituted with Ci -6 alkyl, Ci -6 alkoxy or (Ci ⁇ dialkylamine), -(C0.3 alkyl)-7V-piperazinonyl, wherein the N-piperazinonyl is optionally N' -substituted with Ci -6 alkyl, N-piperazinyl, wherein the N-piperazinyl is optionally substituted with Ci -6 alkyl and optionally N' -substituted with methyl; and
  • each n independently is 0, 1 , 2 or 3;
  • the compound is not 5'-methoxy-2-(3-(4-(4-methylpiperazin-l - yl)phenyl)-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indolin]-2'-one, 5'-methoxy-2-(3-(4- (piperazin-l-yl)phenyl)-lH-indazol-6-yl)spiro[cyclopropane-l ,3'-indolin]-2'-one, l '-methyl-2-(3- (4-(piperazin- 1 -yl)phenyl)- 1 H-indazol-6-yl)spiro[cyclopropane-l ,3'-indolin]-2'-one, 5'-methoxy- 1 '-methyl-2-(3-(4-(4-methylpiperazin- 1 -yl)phenyl)- 1 H-indazol-6-
  • R B is methyl or methoxy; and the remainder of the variables in Structural Formulas (I)-(III) are as defined above.
  • R B is methyl or methoxy
  • R 4 is -H or methyl
  • the remainder of the variables in Structural Formulas (I)-(III) are as defined above.
  • each of R A and R B is independently halogen, cyano, -NR' R 2 , -NR 2 C(0)R' , -N(R 2 )C(0)NR'R 2 , -OR 1 or Ci -6 alkyl, wherein the Ci -6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -0(C] -6 alkyl), and Ci-6 haloalkoxy;
  • each R 1 is independently -H or Ci -6 alkyl, wherein the C
  • each R 2 is independently -H or Ci_6 alkyl
  • R 4 is -H or C,. 6 alkyl; R independently is an optionally substituted monocyclic heterocyclyloxy group.
  • the heterocyclyl in the heterocyclyloxy group represented by R' is selected from azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydrothienyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl, oxathiolanyl, dioxolanyl and dioxanyl; which is optionally
  • R' is selected from a group consisting of piperidinyloxy, pyrrolidinyloxy, azetidinyloxy, piperazinyloxy, morpholinyloxy and thiomorpholinyloxy; optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -SH, nitro, cyano, amino, C
  • R' is piperidinyloxy group, wherein the piperidinyloxy group is optionally N' -substituted with C 2-6 alkyl; and
  • each n independently is 0, 1 , 2 or 3;
  • the compound is not 5'-methoxy-2-(3-(4-(l-methylpiperidin-4-yloxy)phenyl)-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indolin]-2'- one.
  • R a is methyl or methoxy; and the remainder of the variables in Structural Formulas (I)-(III) are as defined above.
  • R a is methyl or methoxy
  • R b is methyl or methoxy
  • R 4 is -H or methyl
  • the remainder of the variables in Structural Formulas (I)-(III) are as defined above.
  • the disclosed PLK-4 inhibitor is a compound represented by Structural Formula (IV):
  • Structural Formula (IV) Exemplary stereoisomers of Structural Formula (IV) are represented by Structural Formulas V) and (VI):
  • each R a is independently, Ci -6 alkyl, or Ci -6 alkoxy;
  • each R b is independently, -OH, -SH, nitro, cyano, amino, Ci -6 alkyl, C
  • R 4 is -H or Ci -6 alkyl
  • R' independently is selected from -(Ci-3 alkyl)-N-piperazinyl, wherein the N- piperazinyl is optionally substituted with Ci_6 alkyl and optionally ' -substituted with Ci -6 alkyl, and -(Co-2 alkyl)-N-morpholinyl, wherein the N-morpholinyl is optionally substituted with Ci -6 alkyl; and
  • each n independently is 0, 1 , 2 or 3;
  • the compound is not 5'-methoxy-2-(3-(4- (mo holinomethyl)styryl)- 1 H-indazol-6-yl)spiro [cyclopropane- 1 ,3 '-indolin] -2'-one, 5 '-methoxy - 2-(3-(4-(2-morpholinoethyl)styryl)-l H-indazol-6-yl)spiro[cyclopropane-l ,3'-indolin]-2'-one, 2- (3-(4-(morpholinomethyl)styryl)- l H-indazol-6-yl)spiro [cyclopropane-l ,3'-indolin]-2'-one, ⁇ - methyl-2-(3-(4-(mo ⁇ holinomethyl)styryl)-l H-indazol-6-yl)spiro[cyclopropane-l ,3'-me
  • R a is methyl or methoxy; and the remainder of the variables in Structural Formulas (IV)-(VI) are as defined above.
  • R a is methyl or methoxy
  • R b is methyl or methoxy
  • the remainder of the variables in Structural Formulas (IV)-(VI) are as defined above.
  • R a is methyl or methoxy
  • R b is methyl or methoxy
  • R 4 is -H or methyl
  • each of R a and R b is independently halogen, cyano, -NR'R 2 , -NR 2 C(0)R' , -N(R 2 )C(0)NR' R 2 , -OR 1 or Ci -6 alkyl, wherein the Ci -6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -0(Ci_6 alkyl), and C ) - haloalkoxy;
  • each R 1 is independently -H or Ci -6 alkyl, wherein the C
  • each R is independently -H or C
  • R 4 is -H or C 1 -6 alkyl
  • R independently is an optionally substituted monocyclic heterocyclyloxy group
  • the heterocyclyl in the heterocyclyloxy group represented by R' is selected from azetidinyl, morpholinyl, thiomorpholinyl, pyrrol idinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydrothienyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl, oxathiolanyl, dioxolanyl and dioxanyl; which is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -SH, nitro,
  • R' is a piperidinyloxy group, wherein the piperidinyloxy group is optionally N' -substituted with C 2-6 alkyl;
  • each n independently is 0, 1 , 2 or 3;
  • the compound is not 2-(3-(4-(l-methylpiperidin-4-yloxy)styryl)-lH- indazol-6-yl)spiro[cyclopropane-l ,3'-indolin]-2'-one or 5'-methoxy-2-(3-(4-(l -methylpiperidin- 4-yloxy)styryl)-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indolin]-2'-one.
  • R a is methyl or methoxy; and the remainder of the variables in Structural Formulas (IV)-(VI) are as defined above.
  • R a is methyl or methoxy
  • R b is methyl or methoxy
  • the remainder of the variables in Structural Formulas (IV)-(VI) are as defined above.
  • R A is methyl or methoxy
  • R B is methyl or methoxy
  • R 4 is -H or methyl
  • each of R A and R B independently is halogen, cyano, -NR'R 2 , -NR 2 C(0)R',
  • Ci -6 alkyl represented by R A and R B is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(Ci -6 alkyl), -S(Ci- 6 alkyl), Ci -6 haloalkoxy, amino, Ci. 6 alkylamino, Ci -6 dialkylamino, Ci -6 alkylcarbonyloxy, Ci -6
  • each R 1 is independently -H or Ci- 6 alkyl, wherein the Ci -6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SH, -0(C, -3 alkyl), -S(C,. 3 alkyl) and Ci -6 haloalkoxy;
  • each R 2 is independently -H or Ci- 6 alkyl
  • R 4 independently is -H, C, -6 alkyl, phenyl, -C(0)(Ci -6 alkyl), -C(0)(phenyl), -C(0)0(C, -6 alkyl), -C(0)0(phenyl), -S(0) 2 (C,.
  • each alkyl in the groups represented by R 4 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, -C(0)NH 2 , phenyl, 5-6 membered heteroaryl, Ci -6 alkoxy, C 1-6 alkylamino, Ci -6 dialkylamino and Ci-6 haloalkoxy, and wherein each phenyl in the groups represented by R 4 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, Ci -6 alkyl, C
  • the bicyclic heterocycle in the bridged (bicyclic heterocyclyl)Co-6 alkyl group is selected from the group consisting of 2-oxa-5- aza-bicyclo[2.2. l]hept-5-yl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-thia-3-azabicyclo[3.2.1 ]octanyl,
  • R' is (8-oxa-3-azabicyclo[3.2.1]octanyl)- methyl;
  • each n independently is 0, 1, 2 or 3.
  • R a is methyl or methoxy; and the remainder of the variables in Structural Formulas (IV)-(VI) are as defined above.
  • R a is methyl or methoxy
  • R b is methyl or methoxy
  • the remainder of the variables in Structural Formulas (IV)-(VI) are as defined above.
  • R a is methyl or methoxy
  • R b is methyl or methoxy
  • R 4 is -H or methyl
  • each of R a and R b independently is halogen, cyano, -NR'R 2 , -NR 2 C(0)R' ,
  • R a and R b are optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, -OH, -SH, -0(C, -6 alkyl), -S(C
  • each R 1 is independently -H or Ci -6 alkyl, wherein the Ci -6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -SH, -0(Ci -3 alkyl), -S(C ]-3 alkyl) and Ci -6 haloalkoxy;
  • each R 2 is independently -H or Ci -6 alkyl
  • R 4 independently is -H, C, -6 alkyl, phenyl, -C(0)(C, -6 alkyl), -C(0)(phenyl), -C(0)0(C, -6 alkyl), -C(0)0(phenyl), -S(0) 2 (C,.
  • each alkyl in the groups represented by R 4 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, -C(0)NH 2 , phenyl, 5-6 membered heteroaryl, Ci- 6 alkoxy, Ci -6 alkylamino, Ci -6 dialkylamino and Ci -6 haloalkoxy, and wherein each phenyl in the groups represented by R 4 independently is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, Ci -6 alkyl, Ci -6 haloalkyl, Ci- alkoxy and C
  • R' independently is (NR c R d )Co -6 alkyl.
  • R' is selected from a group consisting of (Ci -6 alkyl)(C i -6 lkoxyalkyl)amino-Ci -6 alkyl or di-(Ci -6 alkoxyalkyl)amino-Ci. 6 alkyl.
  • R' is (ethyl)(2-methoxyethyl)aminomethyl.
  • R' is bis- (2-methoxyethyl)aminomethyl;
  • R c is Ci- 6 alkyl, or Ci -6 alkoxyalkyl
  • R d is Ci- 6 alkoxyalkyl
  • each n independently is 0, 1, 2 or 3.
  • R a is methyl or methoxy; and the remainder of the variables in Structural Formulas (IV)-(VI) are as defined above.
  • R a is methyl or methoxy
  • R b is methyl or methoxy
  • the remainder of the variables in Structural Formulas (IV)-(VI) are as defined above.
  • R a is methyl or methoxy
  • R b is methyl or methoxy
  • R 4 is -H or methyl
  • the remainder of the variables in Structural Formulas (IV)-(VI) are as defined above.
  • Specific examples of compounds of the invention include those exemplified in the examples below, stereoisomers thereof, and pharmaceutically acceptable salts thereof, as well as neutral forms thereof.
  • Tautomeric forms exist when a compound is a mixture of two or more structurally distinct compounds that are in rapid equilibrium. Certain compounds of the invention exist as tautomeric forms. For example, the structures below encompass the compounds of Structural
  • the compounds of the invention contain at least two chiral centers and a cyclopropane and, therefore, exist as stereoisomers, such as isomers about the cyclopropane (i.e., cis/trans isomers), enantiomers, and/or diastereomers.
  • stereoisomers such as isomers about the cyclopropane (i.e., cis/trans isomers), enantiomers, and/or diastereomers.
  • Ring A and Ring B are cis and
  • Ring A and Ring B are trans.
  • Ring A and Ring B are cis means Ring A and Ring B are both on the same side of the cyclopropane whereas the language “Ring A and Ring B are trans” means Ring A and Ring B are on different sides of the cyclopropane.
  • Stereoisomers of the cis/trans variety are also referred to as geometric isomers.
  • the compounds of the invention depicted by Structural Formula (I) and (IV) include the pure cis isomer, the pure trans isomer, and mixtures thereof, including cis/trans mixtures enriched in the cis geometric isomer and cis/trans mixtures enriched in the trans geometric isomer.
  • Structural Formulas (II), (III), (V) and (VI) depict a cis relationship between Ring A and B. It is to be understood that both cis and trans forms of Structural Formulas (I) and (II) with respect to Rings A and B are encompassed within the invention.
  • 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 both geomeric isomers in the mixture.
  • Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer.
  • the invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds of the invention.
  • 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 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%o, 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.
  • compositions disclosed herein include pharmaceutically acceptable salts of the compounds disclosed herein.
  • the disclosed compounds have basic amine groups and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable
  • pharmaceutically acceptable acid addition salts of the compounds of the invention include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p- toluenesulfonic, and tartaric acids).
  • Compounds of the invention with acidic groups such as carboxylic acids can form 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.
  • 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.
  • halo as used herein means halogen and includes chloro, fluoro, bromo and iodo.
  • alkyl used alone or as part of a larger moiety, such as "alkoxy”,
  • alkylcarbonyl means saturated straight-chain or branched aliphatic group. As used herein, a C1 -C6 alkyl group is referred to "lower alkyl.” Similarly, the terms “lower alkoxy”, “lower haloalkyl”, “lower arylalkyl”, “lower alkylamine”, lower dialkyamine”, “lower alkylamino”, “lower dialkyamino” “lower alkylcarbonyl”, “lower alkoxy carbonyl” include straight and branched, saturated chains containing one to six carbon atoms.
  • alkenyl means straight-chain or branched aliphatic group having at least one double bond.
  • alkynyl menas straight-chain or branched aliphatic group having at least one triple bond.
  • alkoxy means -O-alkyl
  • hydroxyalkyl means alkyl substituted with hydroxy
  • aralkyl means alkyl substituted with an aryl group
  • alkoxyalkyl mean alkyl substituted with an alkoxy group
  • alkylamine means amine substituted with an alkyl group
  • cycloalkylalkyl means alkyl substituted with cycloalkyl
  • dialkylamine means amine substituted with two alkyl groups
  • alkylcarbonyl means -C(0)-R, wherein R is alkyl;
  • alkoxycarbonyl means -C(0)-OR, wherein R is alkyl; and where alkyl is as defined above.
  • haloalkyl and “haloalkoxy” means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • halogen means F, CI, Br or I.
  • acyl group means -C(0)R, wherein R is an optionally substituted alkyl group or aryl group (e.g., optionally substituted phenyl). R is preferably an unsubstituted alkyl group or phenyl.
  • aryl means a carbocyclic aromatic ring.
  • aryl may be used interchangeably with the terms “aryl ring” “carbocyclic aromatic ring”, “aryl group” and
  • 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 refers to a monocyclic or polycyclic saturated hydrocarbon ring system.
  • a C 5- 7 cycloalkyl includes, but is not limited to cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted.
  • heteroaryl 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 carbocyclic 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., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl ( e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5- oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4- pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl (e
  • thiazolyl e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • triazolyl e.g., 2-triazolyl, 5- triazolyl
  • tetrazolyl e.g., tetrazol
  • polycyclic aromatic heteroaryl groups examples include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, 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.
  • the term "monocyclic heterocyclic group” includes a non-aromatic ring with 3 to
  • Each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO); oxygen; and sulfur, including sulfoxide and sulfone.
  • Representative monocyclic heterocyclyl groups include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,
  • valerolactamyl oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • a "substituted monocyclic heterocylyl group” is substituted at any one or more substitutable ring atom, which is a ring carbon or ring nitrogen atom bonded to a hydrogen.
  • bridged includes two monocyclic heterocyclyl rings with three adjacent ring atoms in common.
  • heterocyclyloxy group refers to an oxy group attached to a 3- to 10-membered non-aromatic, heterocyclic ring which contains one or more heteroatoms independently selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • Non-aromatic heterocyclyloxy groups include azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, pyrrolyloxy, imidazolyloxy, imidazolinyloxy, pyrazolyloxy, pyrazolinyloxy, oxazolinyloxy, morpholinyloxy, thiomorpholinyloxy, pyridinyloxy, pyrazinyloxy,
  • pyrimidinyloxy pyridazinyloxy, hexamethyleneiminoxy, furyloxy, tetrahydrofuryloxy, thienyloxy, tetrahydrothienyloxy, dioxolanyloxy, oxathiolanyloxy and dioxanyloxy.
  • Such a heterocyclic group may be substituted at any substitutable position on its carbon or nitrogen atom(s).
  • suitable substituents for a substituted aliphatic group, aryl group, heteroaryl group and non-aromatic heteroaryl groups include the groups represented by R a .
  • Other examples include halogen, nitro, cyano, hydroxy, Ci -2 o alkyl, C 2-20 alkenyl, C 2- 2o alkynyl, amino, Ci -20 alkylamino, Ci -20 dialkylamino, Ci -20 alkoxy, (Ci-i 0 alkoxy)Ci -20 alkyl, Ci -20 haloalkoxy, (Ci-i 0 haloalkoxy)Ci -20 alkyl and Ci -20 haloalkyl.
  • Spiro cyclopropyl indolinone compounds of the invention can inhibit various kinases, including the PLK4, Aurora A, Aurora B and FLT-3 (see Examples B-E).
  • the spiro cyclopropyl indolinone compounds of the invention are useful in the treatment of diseases or conditions associated with such kinases.
  • PLK4, Aurora A and Aurora B are believed to be involved in cellular miotic progression.
  • small molecule inhibitors of these enzymes can be potential anti-tumor agents.
  • the compounds of the invention are PLK, Aurora A,
  • Aurora B and/or FLT-3 inhibitors are useful for treating diseases, such as cancer, associated with such a kinase(s).
  • the compounds of the invention are PLK inhibitors and are useful for treating diseases associated with PLK, such as cancer.
  • the PLK is PLK4, PLK2 and PLK 1.
  • the PLK is PLK4.
  • the compounds of the invention are Aurora A and/or B inhibitors and are useful in inhibiting Aurora A and/or B activity for the treatment of various conditions such as cancers.
  • the compounds of the invention are FLT-3 inhibitors and are useful in inhibiting FLT-3 activity for the treatment of various conditions such as cancers.
  • Another aspect of the invention relates to a method of treating a subject with cancer comprising administering to the subject an effective amount of a compound of the invention.
  • the compounds of the invention inhibit the growth of a tumor.
  • the compounds of the invention inhibit the growth of a tumor that over expresses at least one of PLK, Aurora A, Aurora B, and FLT-3. More specifically, the compounds of the invention inhibit the growth of a tumor that over expresses PLK, for example, PLK4. Even more specifically, the compounds of the invention inhibit the growth of a tumor that over expresses
  • the compounds of the invention inhibit the growth of the tumor by inducing apoptosis of the tumor cells or by inhibiting proliferation of the tumor cells.
  • Cancers that can be treated or prevented by the methods of the present invention include lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform, ovarian cancer, lymphoma, leukemia, melanoma, sarcoma, paraneoplasia, osteosarcoma, germinoma, glioma and mesothelioma.
  • lung cancer breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform, ovarian cancer, lymphoma, leukemia, melanoma, sarcoma, paraneoplasia, osteosarcoma, germinoma, glioma and mesothelioma.
  • the cancer is lung cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma mutiform or ovarian cancer.
  • the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform or ovarian cancer.
  • the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiform or ovarian cancer.
  • the cancer is a breast cancer.
  • the cancer is a basal sub-type breast cancer or a luminal B sub-type breast cancer.
  • the basal sub-type breast cancer is ER (estrogen receptor), HER2 and PR (progesterone receptor) negative breast cancer.
  • the cancer is a soft tissue cancer.
  • a "soft tissue cancer” is an art-recognized term that encompasses tumors derived from any soft tissue of the body.
  • soft tissue connects, supports, or surrounds various structures and organs of the body, including, but not limited to, smooth muscle, skeletal muscle, tendons, fibrous tissues, fatty tissue, blood and lymph vessels, perivascular tissue, nerves, mesenchymal cells and synovial tissues.
  • soft tissue cancers can be of fat tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymph vessels, and fibrous tissues.
  • Soft tissue cancers can be benign or malignant. Generally, malignant soft tissue cancers are referred to as sarcomas, or soft tissue sarcomas.
  • soft tissue tumors including lipoma, lipoblastoma, hibernoma, liposarcoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma, schwannoma (neurilemoma), neuroma, malignant schwannoma,
  • neurofibrosarcoma neurogenic sarcoma, nodular tenosynovitis, synovial sarcoma, hemangioma, glomus tumor, hemangiopericytoma, hemangioendothelioma, angiosarcoma, Kaposi sarcoma, lymphangioma, fibroma, elastofibroma, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor, malignant mesenchymomas, alveolar soft- part sarcoma, epithelioid sarcoma, clear cell sarcoma, and desmoplastic small cell tumor.
  • DFSP malignant fibrous histiocytoma
  • myxoma granular cell tumor, mal
  • the soft tissue cancer is a sarcoma selected from the group consisting of a fibrosarcoma, a gastrointestinal sarcoma, a leiomyosarcoma, a dedifferentiated liposarcoma, a pleomorphic liposarcoma, a malignant fibrous histiocytoma, a round cell sarcoma, and a synovial sarcoma.
  • the invention further relates to a method of treating a subject with tumor cells, comprising administering to the subject, an amount of a compound disclosed herein that is effective to reduce effectively PLK activity, such as PLK4 activity, in the subject.
  • an "effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., reduces the likelihood of developing the cancer or inhibits, suppresses or reduces the cancer (e.g., as determined by clinical symptoms or the amount of cancer cells) in a subject as compared to a control.
  • treating a subject with a cancer includes achieving, partially or substantially, one or more of the following: arresting the growth or spread of a cancer, reducing the extent of a cancer (e.g., reducing size of a tumor or reducing the number of affected sites), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components). It also reduces the likelihood of reoccurrence of the cancer.
  • an effective amount of a compound of the invention varies depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • An effective amount of a compound of the present invention may be readily determined by one of ordinary skill by routine methods known in the art.
  • an effective amount of a compound of the invention ranges from about 0.01 to about 1000 mg/kg body weight, alternatively about 0.05 to about 500 mg/kg body weight, alternatively about 0.1 to about 100 mg/kg body weight, alternatively about 0.1 to about 15 mg/kg body weight, alternatively about 1 to about 5 mg/kg body weight, and in another alternative, from about 2 to about 3 mg/kg body weight.
  • the skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject suffering from cancer and these factors include, but are not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject and other diseases present.
  • a "treatment" regime of a subject with an effective amount of the compound of the present invention may consist of a single administration, or alternatively comprise a series of applications.
  • the compound of the present invention may be administered at least once a week.
  • the compound may be administered to the subject from about one time per week to once daily for a given treatment.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration and the activity of the compounds of the present invention, or a combination thereof.
  • the effective dosage of the compound used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime.
  • 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, reducing the likelihood of the spread of the 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. “Treatment” also includes reducing the likelihood of developing the disease or reducing the likelihood of reoccurrence of the disease.
  • 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 method of the present invention is a mono-therapy where the pharmaceutical compositions of the invention are administered alone. Accordingly, in this embodiment, the compound of the invention is the only pharmaceutically active ingredient in the pharmaceutical compositions or the only pharmaceutically active ingredient administered to the subject.
  • the method of the invention is a co-therapy with one or more of other therapeutically active drugs or therapies known in the art for treating the desired diseases or indications.
  • one or more other anti-proliferative or anticancer therapies are combined with the compounds of the invention.
  • the method of the invention is a co-therapy with one or more of other therapeutically active drugs or therapies known in the art for treating the desired diseases or indications.
  • one or more other anti-proliferative or anticancer therapies are combined with the compounds of the invention.
  • the method of the invention is a co-therapy with one or more of other therapeutically active drugs or therapies known in the art for treating the desired diseases or indications.
  • one or more other anti-proliferative or anticancer therapies are combined with the compounds of the invention.
  • the method of the invention is a co-therapy with one or more of other therapeutically active drugs or therapies known in the art for treating the desired diseases or indications.
  • one or more other anti-proliferative or anticancer therapies are combined with the compounds of the invention.
  • Anticancer therapies that may be used in combination with the compound of the invention include surgery, radiotherapy (including, but not limited to, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes) and endocrine therapy.
  • Anticancer agents that may be used in combination with the compounds of the invention include biologic response modifiers
  • contemporaneously means that two substances are administered to a subject such that they are both biologically active in the subject at the same time.
  • the exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering one substance within a period of time of one another, e.g., 24 hours of administration of the other, if the pharmacokinetics are suitable. Designs of suitable dosing regimens are routine for one skilled in the art.
  • two substances will be administered substantially simultaneously, i.e. within minutes of each other, or in a single composition that comprises both substances.
  • the two agents can be administered separately, such that only one is biologically active in the subject at the same time.
  • the compounds of the invention can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithehal, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.
  • the compounds of the invention can be suitably formulated into pharmaceutical compositions for administration to a subject.
  • the pharmaceutical compositions of the invention optionally include one or more pharmaceutically acceptable carriers and/or diluents therefore, such as lactose, starch, cellulose and dextrose.
  • pharmaceutically acceptable carriers and/or diluents therefore, 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
  • a compound of the invention may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • solutions of a compound of the invention can generally be prepared in water suitably mixed with a surfactant such as
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • sterile aqueous solutions or dispersion of, and sterile powders of a compound of the invention are suitable for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the compounds of the invention can be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve, which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, 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 invention can be formulated 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 of the invention can be formulated in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • a pharmaceutical composition of the invention comprises a pharmaceutically acceptable carrier or diluent, a compound disclosed herein or a pharmaceutically acceptable salt thereof and another anti-cancer agent, for example, but not limited to a glucose metabolism inhibitor or taxol.
  • the compounds of the invention can be prepared by processes analogous to those established in the art.
  • compounds of Formula (I), wherein Rings A and B are as defined herein may be prepared by the methods outlined in Scheme 1.
  • Reaction of an appropriately substituted indazolylspirocyclopropaneindolinone and a suitable vinyl compound, wherein Ar is a phenyl and heteroaryl group as defined herein, and P 1 represents suitable indazole protecting group (such as Boc, acetyl or SEM) and X is a halide can be achieved under typical Heck reaction conditions.
  • Ar is a phenyl and heteroaryl group as defined herein
  • P 1 represents suitable indazole protecting group (such as Boc, acetyl or SEM) and X is a halide
  • the reaction is preferably effected under microwave irradiation conditions
  • Removal of the protecting group may be effected by any of the procedures known to effect such a transformation.
  • the transformation can be effected by treatment with tetrabutylammonium fluoride in a polar solvent, such as THF, at reflux, or by stepwise treatment with boron trifluoride etherate and 2N HC1 in ethanol.
  • the aryl linkage Ar is phenyl with substituents as defined herein, P 1 is either H or a suitable indazole protecting group (such as Boc, acetyl or SEM) and X is a halide, can be installed under typical Suzuki reaction conditions, using either a boronic acid or boronate ester.
  • the reaction is preferably effected under microwave irradiation conditions, advantageously in the range, for example of 100 to 150 °C, or generally at about 120 °C. Removal of the protecting group may be effected by any of the procedures known to effect such a transformation.
  • the transformation can be effected by treatment with tetrabutylammonium fluoride in a polar solvent, such as THF, at reflux, or by stepwise treatment with boron trifluoride etherate and aqueous 2N HC1 in ethanol.
  • a polar solvent such as THF
  • Ultra version 1 1.0 The standard R and S nomenclature is used to describe single enantiomers or enantiomerically enriched compounds of greater than 95% e.e.
  • the title compound was synthesized according to the synthesis of (3S,5R)-l-(4- iodophenyl)-3,5-dimethylpiperazine, except reacting 4-bromo-l-iodo-2-methylbenzene (3.0 g, 10 mmol) with N-methylpiperazine (1.7 mL, 15 mmol).
  • the title compound was purified by silica gel chromatography (MeOH/CH 2 Cl 2 , 2:98 to 15:85) to give the desired product as a yellow solid (0.93 g, 34%).
  • the title compound was synthesized according to the synthesis of (3S,5R)-l-(4- iodophenyl)-3,5-dimethylpiperazine, except reacting 4-bromo-l-iodo-2-methoxybenzene (1.0 g, 3.2 mmol) with JV-methylpiperazine (0.53 mL, 4.8 mmol).
  • the title compound was purified by silica gel chromatography (MeOH/CH 2 Cl 2 , 2:98 to 1 :9) to give the desired product as a yellow solid (0.29 g, 32%).
  • Example A8 ( 1 R.2SV 2-(3 -((E)-4-(( ethvK 2-methoxyethyl)amino methyl styryl)- 1 H-indazol-6- yl)spiro[cyclopropane-l '-indolin]-2'-one 2,2,2-trifluoroacetate
  • Example A15 (lR.2S -2-r3-((E)-4-(((2S,6R)-2,6-dimethylmo holino)methvnstyrvn-lH- indazol-6-yl)-5'-methoxy-l , -meth lspiro[cvclopropane-l,3'-indolinl-2'-one 2,2,2-trifluoroacetate
  • Example A ( 1 R.2S 2-(3 -((E)-3 -(((2S.6RV2,6-dimethylmorpholino)methvnstyryl)- 1 H-
  • Example A19 (1 ⁇ .28 ⁇ 5'- ⁇ ⁇ 6 ⁇ 1 ⁇ ⁇ ⁇ -2- 3-(( ⁇ )-4- (38,5 ⁇ -3.4.5- ⁇ 63 ⁇ 4 ⁇ 1 ⁇ 6 ⁇ -1- ⁇ 6 ⁇ 1 ⁇ 1 styryl)-lH-indazol-6-vnspirorcvclopropane-l ,3'-indolin1-2'-one 2,2,2-trifluoroacetate
  • the flask was purged with argon and Pd(PPh 3 ) 4 (10 mg, 0.67 mmol) was added, The mixture was stirred for 16 h at 120°C. The mixture was cooled to room temperature and water (10 mL) was added. The solution was extracted with EtOAc (4 x 10 mL), dried over MgS0 4 and concentrated. The residue was purified by silica gel chromatography (CH 2 Cl 2 /MeOH, 0-10%). The material was then dissolved into THF and added 1M HCI in ether (1.1 eq, diluted to 100 mL of ether) and the solid was filtered. The title compound was isolated as a yellow powder (55 mg, 40%, 99% ee).
  • Active PLK4 was purified from an E. coli expression system as an amino terminal
  • the protein was purified from clarified cell extracts after induction at 15 °C overnight using glutathione sepharose, gel permeation chromatography, and ion exchange (Resource Q). The resulting protein was dephosphorylated with lambda phosphatase (NEB cat# P0753), and resolved from the phosphatase using gluthione sepharose. The dephosphorylated GST-PLK4 was stored in aliquots at -80°C until use. [0129] PLK4 activity was measured using an indirect ELISA detection system.
  • the plate was washed 5 times with Wash Buffer, incubated for 30 minutes in the presence of secondary antibody coupled to horse radish peroxidase (BioRad cat# 1721019, 1 :3000 concentration), washed an additional 5 times with Wash Buffer, and incubated in the presence of TMB substrate (Sigma cat# T0440).
  • the colourimetric reaction was allowed to continue for 5 minutes, followed by addition of stop solution (0.5 N sulphuric acid), and quantified by detection at 450 nm with either a monochromatic or filter based plate reader (Molecular Devices M5 or Beckman DTX880, respectively).
  • XLfit4, IDBS non-linear 4 point logistic curve fit
  • Aurora A inhibition was determined using the Z-Lyte assay kit from Invitrogen.
  • Aurora B inhibition was determined using the Z-Lyte assay kit from Invitrogen.
  • the assay was performed using the recommended manufacturer's instructions with 128 ⁇ ATP and 28 nM Aurora B (Invitrogen cat # PV3970).
  • the % inhibition values were determined according to the manufacturer's directions and IC50 values were obtained using a non-linear 4 point logistic curve fit (XLfit4, IDBS)
  • IC50 values for PLK4, Aurora A and Aurora B Kinases are indicated as “A,” “B,” and “C,” for those less than or equal to 0.1 ⁇ ; those greater than 0.1 ⁇ and less than or equal to 1 ⁇ ; and those greater than 1 ⁇ , respectively.
  • the relative inhibition percentages at a dose of 1 ⁇ are indicated as "X” and "Y” for those equal to or greater than 50% inhibition and those less than 50% inhibition, respectively.
  • numerous compounds of the invention are effective PLK4 inhibitors.
  • a number of compounds of the invention also inhibit Aurora kinases, in particular Aurora B kinase.
  • Invitrogen Invitrogen cat # PV3191. The assay was performed using the recommended manufacturer's instructions with 1 17.5 ⁇ ATP and 1 nM FLT3 (Invitrogen cat # PV3182). The % inhibition values were determined according to the manufacturer's directions and IC 50 values were obtained using a non-linear 4 point logistic curve fit (XLfit4, IDBS). In Table 2, IC 50 values for FLT3 inhibition are indicated as "A,” "B,” and "C,” for those less than or equal to 0.1 ⁇ ; those greater than 0.1 ⁇ and less than or equal to 1 ⁇ ; and those greater than 1 ⁇ , respectively, for selected compounds of the invention.
  • SW620 lung cancer cells
  • A549 lung cancer cells
  • HMEC HMEC
  • Bovine Serum to concentrations ranging from 50 nM to 250 ⁇ . Aliquots (20 ⁇ ) from each concentration were overlaid to 80 ⁇ of the pre-seeded cells in the 96 well plates to make final concentrations of 10 nM to 50 ⁇ . The cells were cultured for 5 days before the Sulforhodamine B assay (SRB) was performed to determine the compound's cell growth inhibition activity.
  • SRB Sulforhodamine B assay
  • Sulforhodamine B (purchased from Sigma, Oakville, ON, Canada) is a water- soluble dye that binds to the basic amino acids of the cellular proteins.
  • colorimetric measurement of the bound dye provides an estimate of the total protein mass that is related to the cell number
  • the cells are fixed in situ by gently aspirating off the culture media and adding 50 ⁇ ice cold 10% Trichloroacetic Acid (TCA) per well and incubate at 4°C for 30-60 min, The plates are washed with water five times and allowed to air dry for 5 min.
  • TCA Trichloroacetic Acid
  • GIso's were determined for compounds with cytotoxic activity.
  • the GI 5 o was calculated using GraphPad PRISM software (GraphPad Software, Inc., San Diego, CA, USA).
  • GI 5 o (growth inhibition) is the compound concentration that causes 50% inhibition of cell growth.
  • GI 50 value ranges for several compound examples against a luminal breast cancer cell line (MCF-7), two basal breast cancer cell line (MDA-MB-468, HCC1954), a lung cancer cell line (A549), a colon cancer cell line (SW-620) and primary breast cells (HMEC) are given.
  • MCF-7 luminal breast cancer cell line
  • MDA-MB-468, HCC1954 basal breast cancer cell line
  • A549 a lung cancer cell line
  • SW-620 colon cancer cell line
  • HMEC primary breast cells
  • the GI 50 ranges are indicated as "A,” “B,” “C,” and “D,” for values less than or equal to 0.1 ⁇ ; those greater than 0.1 ⁇ and less than or equal to 1 ⁇ ; those greater than 1 ⁇ and less than or equal to 10 ⁇ ; and those greater than 10 ⁇ , respectively.

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Abstract

L'invention concerne un composé représenté par les Formules structurales suivantes (I) et (II) et des sels pharmaceutiquement acceptables de celui-ci : (Formule (I)) ; (Formule (IV)). Les composés représentés par ces formules structurales sont des inhibiteurs de kinase et sont, par conséquent, décrits présentement pour le traitement du cancer. Les définitions des variables des formules structurales sont données ici.
PCT/CA2011/001144 2010-10-13 2011-10-13 Inhibiteurs de plk4 et méthode de traitement du cancer à l'aide de ceux-ci WO2012048411A1 (fr)

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CN104098507A (zh) * 2014-07-21 2014-10-15 太原理工大学 一种羟吲哚螺环丙烷衍生物及其合成方法
WO2015054781A1 (fr) 2013-10-18 2015-04-23 University Health Network Traitement du cancer du pancréas
WO2015054793A1 (fr) * 2013-10-18 2015-04-23 University Health Network Sel et formes cristallines d'un inhibiteur de plk-4
US9796703B2 (en) 2010-04-06 2017-10-24 University Health Network Synthesis of chiral 2-(1H-indazol-6-yl)-spiro[cyclopropane-1,3′-indolin]-2′-ones
WO2018145525A1 (fr) 2017-02-08 2018-08-16 中国医药研究开发中心有限公司 Composé hétérocyclique pyrrolo-aromatique, son procédé de préparation et son utilisation médicale
USRE47731E1 (en) 2009-04-06 2019-11-19 University Health Network Kinase inhibitors and method of treating cancer with same
CN111225670A (zh) * 2017-09-08 2020-06-02 大学健康网络 抑制Polo样激酶4的组合疗法
US11197863B2 (en) * 2017-08-29 2021-12-14 Ann And Robert H. Lurie Children's Hospital Of Chicago Inhibitors of polo-like kinase 4 (PLK4) for treating pediatric embryonal tumors
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CN115677682A (zh) * 2021-07-30 2023-02-03 上海齐鲁制药研究中心有限公司 螺环类plk4抑制剂及其用途
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USRE47731E1 (en) 2009-04-06 2019-11-19 University Health Network Kinase inhibitors and method of treating cancer with same
US9796703B2 (en) 2010-04-06 2017-10-24 University Health Network Synthesis of chiral 2-(1H-indazol-6-yl)-spiro[cyclopropane-1,3′-indolin]-2′-ones
US10358436B2 (en) 2010-04-06 2019-07-23 University Health Network Kinase inhibitors and method of treating cancer
US10077255B2 (en) 2010-04-06 2018-09-18 University Health Network Synthesis of chiral 2-(1H-indazol-6-yl)-spiro[cyclopropane-1,3′-indolin]-2′-ones
US9907800B2 (en) 2010-04-06 2018-03-06 University Health Network Kinase inhibitors and method of treating cancer
US9884855B2 (en) 2013-10-18 2018-02-06 University Health Network Salt and crystal forms of PLK-4 inhibitor
US10472353B2 (en) 2013-10-18 2019-11-12 University Health Network Salt and crystal forms of PLK-4 inhibitor
US11667627B2 (en) 2013-10-18 2023-06-06 University Health Network Salt and crystal forms of PLK-4 inhibitor
JP2016537326A (ja) * 2013-10-18 2016-12-01 ユニバーシティー ヘルス ネットワーク Ｐｌｋ４阻害剤の塩および結晶形態
EA030089B1 (ru) * 2013-10-18 2018-06-29 Юниверсити Хелс Нетуорк Лечение рака поджелудочной железы
CN105764899B (zh) * 2013-10-18 2021-06-01 大学健康网络 Plk-4抑制剂的盐和晶型
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EA031569B1 (ru) * 2013-10-18 2019-01-31 Юниверсити Хелс Нетуорк Солевые и кристаллические формы ингибитора plk-4
WO2015054793A1 (fr) * 2013-10-18 2015-04-23 University Health Network Sel et formes cristallines d'un inhibiteur de plk-4
US10392374B2 (en) 2013-10-18 2019-08-27 University Health Network Salt and crystal forms of PLK-4 inhibitor
US9642856B2 (en) 2013-10-18 2017-05-09 University Health Network Treatment for pancreatic cancer
WO2015054781A1 (fr) 2013-10-18 2015-04-23 University Health Network Traitement du cancer du pancréas
US10919886B2 (en) 2013-10-18 2021-02-16 University Health Network Salt and crystal forms of PLK-4 inhibitor
CN104098507A (zh) * 2014-07-21 2014-10-15 太原理工大学 一种羟吲哚螺环丙烷衍生物及其合成方法
WO2018145525A1 (fr) 2017-02-08 2018-08-16 中国医药研究开发中心有限公司 Composé hétérocyclique pyrrolo-aromatique, son procédé de préparation et son utilisation médicale
US11197863B2 (en) * 2017-08-29 2021-12-14 Ann And Robert H. Lurie Children's Hospital Of Chicago Inhibitors of polo-like kinase 4 (PLK4) for treating pediatric embryonal tumors
CN111225670A (zh) * 2017-09-08 2020-06-02 大学健康网络 抑制Polo样激酶4的组合疗法
US20210060026A1 (en) * 2017-09-08 2021-03-04 University Health Network Combination therapies for inhibition of polo-like kinase 4
WO2022240876A1 (fr) * 2021-05-11 2022-11-17 Oric Pharmaceuticals, Inc. Inhibiteurs de kinase de type polo 4
US11858915B2 (en) 2021-05-11 2024-01-02 Oric Pharmaceuticals, Inc. Polo like kinase 4 inhibitors
CN115677682A (zh) * 2021-07-30 2023-02-03 上海齐鲁制药研究中心有限公司 螺环类plk4抑制剂及其用途
WO2024076891A1 (fr) * 2022-10-03 2024-04-11 Oric Pharmaceuticals, Inc. Inhibiteurs de polo kinase 4

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