WO2010007389A1 - 5 -amidothiazole derivatives and their use as checkpoint kinase inhibitors - Google Patents

5 -amidothiazole derivatives and their use as checkpoint kinase inhibitors Download PDF

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Publication number
WO2010007389A1
WO2010007389A1 PCT/GB2009/001786 GB2009001786W WO2010007389A1 WO 2010007389 A1 WO2010007389 A1 WO 2010007389A1 GB 2009001786 W GB2009001786 W GB 2009001786W WO 2010007389 A1 WO2010007389 A1 WO 2010007389A1
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independently
compound according
present
nhr
optionally substituted
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PCT/GB2009/001786
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French (fr)
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Ian Collins
John Charles Reader
Sukhbinder Singh Klair
Glynn Jonathan Addison
Michael Cherry
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Cancer Research Technology Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain thiazole carboxylic acid amide compounds (for convenience, collectively referred to herein as "TCA compounds"), which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function and/or Checkpoint Kinase 2 (CHK2) kinase function.
  • TCA compounds thiazole carboxylic acid amide compounds
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function and/or CHK2 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1 and/or CHK2, that are ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • a DNA topoisomerase I or Il inhibitor a DNA damaging agent
  • an antimetabolite or TS inhibitor an antimetabolite or TS inhibitor
  • microtubule targeted agent ionising radiation.
  • Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about,” it will be understood that the particular value forms another embodiment.
  • Progression through the cell division cycle is a tightly regulated process and is monitored at several positions known as cell cycle checkpoints (see, e.g., Weinert and Hartwell,
  • Cell cycle checkpoints are activated by a number of stimuli, including DNA damage and DNA errors caused by defective replication. When this occurs, the cell cycle will arrest, allowing time for either DNA repair to occur or, if the damage is too severe, for activation of cellular processes leading to controlled cell death.
  • cancers by definition, have some form of aberrant cell division cycle. Frequently, the cancer cells possess one or more defective cell cycle checkpoints, or harbour defects in a particular DNA repair pathway. These cells are therefore often more dependent on the remaining cell cycle checkpoints and repair pathways, compared to non-cancerous cells (where all checkpoints and DNA repair pathways are intact).
  • the response of cancer cells to DNA damage is frequently a critical determinant of whether they continue to proliferate or activate cell death processes and die.
  • tumour cells that contain a mutant form(s) of the tumour suppressor p53 are defective in the G1 DNA damage checkpoint. Thus inhibitors of the G2 or S-phase checkpoints are expected to further impair the ability of the tumour cell to repair damaged DNA.
  • cancer treatments cause DNA damage by either physically modifying the cell's DNA or disrupting vital cellular processes that can affect the fidelity of DNA replication and cell division, such as DNA metabolism, DNA synthesis, DNA transcription and microtubule spindle formation.
  • treatments include for example, radiotherapy, which causes DNA strand breaks, and a variety of chemotherapeutic agents including topoisomerase inhibitors, antimetabolites, DNA-alkylating agents, and platinum- containing cytotoxic drugs.
  • a significant limitation to these genotoxic treatments is drug resistance.
  • One of the most important mechanisms leading to this resistance is attributed to activation of cell cycle checkpoints, giving the tumour cell time to repair damaged DNA. By abrogating a particular cell cycle checkpoint, or inhibiting a particular form of DNA repair, it may therefore be possible to circumvent tumour cell resistance to the genotoxic agents and augment tumour cell death induced by DNA damage, thus increasing the therapeutic index of these cancer treatments.
  • CHK1 and CHK2 Two key regulators of cell cycle checkpoints that are activated in response to DNA damage are the serine/threonine kinases CHK1 and CHK2.
  • CHK1 is activated through phosphorylation at S317 and S345 by the ATR protein, which is a component of the
  • CHK1 RPA/ATR/ATRIP DNA damage sensor complex, associated with DNA (see, e.g., Bucher and Britten, 2008).
  • CHK1 transduces DNA damage signals through phosphorylation of substrates involved in a number of cellular activities including cell cycle arrest and DNA repair.
  • Two key substrates of CHK1 are the Cdc25A and Cdc25C phosphatases that dephosphorylate CDK1 leading to its activation, which is a requirement for exit from G2 into mitosis (M phase) (see, e.g., Sanchez et a/., 1997).
  • CHK1 Phosphorylation of Cdc25C and the related Cdc25A by CHK1 blocks their ability to activate CDK1, thus preventing the cell from exiting G2 into M phase.
  • the role of CHK1 in the DNA damage-induced G2 cell cycle checkpoint has been demonstrated in a number of studies where CHK1 function has been knocked out (see, e.g., Liu et a/., 2000; Zhao et a/., 2002; Zachos et a/., 2003).
  • the reliance of the DNA damage-induced G2 checkpoint upon CHK1 provides one example of a therapeutic strategy for cancer treatment, involving targeted inhibition of CHK1.
  • the p53 tumour suppressor protein Upon DNA damage, the p53 tumour suppressor protein is stabilised and activated to give a p53-dependent G1 arrest, leading to apoptosis or DNA repair (Balaint and Vousden, 2001).
  • IR ionising radiation
  • certain forms of chemotherapy see, e.g., Greenblatt et a/., 1994; Carson and Lois, 1995).
  • CHK1 has also been shown to be involved in the S phase cell cycle checkpoint and DNA repair by homologous recombination.
  • inhibition of CHK1 kinase in those cancers that are reliant on these processes after DNA damage may provide additional therapeutic strategies, including S phase checkpoint abrogation for the treatment of cancers using CHK1 inhibitors (see, e.g., Sorensen et al., 2005).
  • CHK2 is activated in response to DNA damage by phosphorylation at threonine 68, which requires the PI3-Kinase family member, ATM (see, e.g., Matsuoka et al., 1998; Melchionna et al., 2000). This promotes dimerisation of the protein allowing trans- activation through T-loop exchange (see, e.g., Oliver et a/., 2006).
  • CHK2 can phosphorylate a number of substrates that regulate cell cycle arrest, DNA repair and cell death.
  • Key substrates include the cell cycle phosphatases, Cdc25A and Cdc25C, which are inactivated through degradation and relocalisation respectively (see, e.g., Pommier et al., 2005).
  • Another important substrate is the p53 protein that is phosphorylated at serine 20, which promotes activation of this important tumour suppressor (see, e.g., Hirao et al., 2000; Chehab et al., 2000).
  • Others include BRCA1 , E2F, PIkI and PML (see, e.g., Pommier et al., 2005).
  • Inhibition of CHK2 has the potential to offer a number of therapeutic strategies for the treatment of cancer.
  • these agents often have side effects, due to toxicity to normal proliferating tissues.
  • cancer cells are often resistant to apoptosis due to defective cell cycle checkpoints. Consequently the doses of a particular cancer treatment that are effective against the tumour may also kill the proliferating normal cells that have intact cell cycle checkpoints and undergo apoptosis.
  • One of the most important signalling pathways involved in activation of cell cycle checkpoints is the p53 pathway.
  • TP53 gene itself is mutated in 50% of human tumours, whilst other components of this pathway are also found altered in cancer (see, e.g., Gorgoulis et al., 2005; Bartkova et al., 2005).
  • p53-dependent apoptosis is temporarily inhibited in normal cells the toxicity/side effects of cancer treatments may be reduced.
  • pifithrin- ⁇ a pharmacological inhibitor of p53 function, protects mice from lethal and sub-lethal doses of radiation without causing tumour formation (see, e.g., Komarov et al., 1999).
  • CHK2 inhibitors that can abrogate the G2 or S-phase checkpoints (induced by such cancer treatments as ionising radiation or chemotherapeutic anticancer agents) are expected to further cripple the ability of the tumour cell to repair damaged DNA.
  • CHK2 is also activated in response to the physiological stress of hypoxia/reoxygenation (see, e.g., Gibson et a/., 2005). Loss or inhibition of CHK2 sensitises tumour cells to hypoxia/reoxygenation. Therefore inhibition of CHK2 in this context may have particular therapeutic value in the treatment of solid tumours, which are often hypoxic.
  • Inhibition of CHK1 and CHK2 may be an effective therapeutic strategy.
  • a tumour may contain a non-clonal population of cells.
  • individual cells within the tumour may be defective in different cell cycle checkpoints and/or repair mechanisms.
  • inhibition of several cell cycle checkpoints and/or repair mechanisms, using a dual inhibitor of CHK1 and CHK2 could provide an effective strategy for greater eradication of cells within such a tumour, when combined with radiotherapy or the appropriate chemotherapeutic agent.
  • the possibility that CHK2 inhibition may provide radio- or chemo-protection to normal tissue could also offer additional therapeutic benefit in this context.
  • Dual inhibitors of CHK1 and CHK2 may also have therapeutic activity across a wide range of tumour types, due to the ability to target multiple cell cycle checkpoints. Furthermore, since loss or inhibition of CHK2 sensitises tumour cells to hypoxia/reoxygenation, combining this function with CHK1 inhibition may provide an effective treatment for p53 deficient solid tumours.
  • TCA compounds thiazole carboxylic acid amide compounds
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a TCA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • compositions e.g., a pharmaceutical composition
  • a method of preparing a composition comprising the step of admixing a TCA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the present invention pertains to a method of inhibiting CHK1 kinase function and/or CHK2 kinase function, in vitro or in vivo, comprising contacting a CHK1 kinase and/or a CHK2 kinase with an effective amount of a TCA compound, as described herein.
  • Another aspect of the present invention pertains to a method of inhibiting CHK1 kinase function and/or CHK2 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a TCA compound, as described herein.
  • the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a TCA compound, as described herein.
  • the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a TCA compound, as described herein, preferably in the form of a pharmaceutical composition.
  • the method further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to a TCA compound as described herein for use in a method of treatment of the human or animal body by therapy.
  • the method of treatment comprises treatment with both (i) a TCA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to use of a TCA compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the treatment comprises treatment with both (i) a medicament comprising a TCA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • a medicament comprising a TCA compound
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • the treatment is treatment of a disease or condition that is mediated by CHK1 and/or CHK2.
  • the treatment is treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function.
  • the treatment is treatment of a proliferative condition.
  • the treatment is treatment of cancer.
  • the treatment is treatment of: p53 negative cancer.
  • the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
  • a kit comprising (a) a TCA compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • the kit further comprises one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; and (d) a microtubule targeted agent.
  • Another aspect of the present invention pertains to a TCA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to a TCA compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • TCA compounds certain thiazole carboxylic acid amide compounds which are related to 2,4-diamino-thiazole-5-carboxylic acid amide.
  • the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • -R w is independently -R W1 , -R W2 , or -L W -R W2 ;
  • -R W1 is independently saturated aliphatic C 1-6 alkyl, and is optionally substituted;
  • -R W2 is independently -R W2C or -R W2H ;
  • -R W2C is independently C 6- iocarboaryl, and is optionally substituted; -R W2H is independently C 5 -i 4 heteroaryl, and is optionally substituted; and -L w - is independently saturated aliphatic C 1-4 alkylene;
  • -R z is independently -R Z1 , -L Z1 -R Z1 , -R Z2 , -L Z1 -R Z2 , or -L Z2 -R Z3 ,
  • -R Z1 is independently saturated C 4 . 7 heterocyclyl, and is optionally substituted;
  • -R Z2 is independently C 5 . 14 heteroaryl, and is optionally substituted; -L Z1 - is independently saturated aliphatic -L Z2 - is independently saturated aliphatic C 2-6 alkylene; -R Z3 is independently -NH 2 , -NHR ZN1 , -N(R ZN1 ) 2 , or -NR ZN2 R ZN3 ; each -R ZN1 is independently saturated aliphatic C 1-6 alkyl, phenyl, or benzyl; and
  • -NR ZN2 R ZN3 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted.
  • Cs- ⁇ heteroaryl and C ⁇ heterocyclyl refer to the number of ring atoms, whether carbon atoms or heteroatoms.
  • triazolyl is an example of a C 5 heteroaryl group
  • diazepinyl is an example of a C 7 heterocyclyl group.
  • -R w is independently -R W1 , -R W2 , or -L W -R W2 .
  • -R w is independently -R W1 .
  • -R w is independently -R W2 .
  • -R w is independently -L W -R W2 .
  • -R W1 is independently saturated aliphatic C 1-6 alkyl, and is optionally substituted.
  • -R W1 is independently saturated aliphatic C 1-4 alkyl, and is optionally substituted.
  • -R W1 if present, is independently saturated aliphatic C M alkyl.
  • -R W1 if present, is independently -Me.
  • -R W2 if present, is independently -R W2C or -R W2H . In one embodiment, -R W2 , if present, is independently -R W2C . In one embodiment, -R W2 , if present, is independently -R W2H .
  • -R W2C if present, is independently C 6 .iocarboaryl, and is optionally substituted. In one embodiment, -R W2C , if present, is independently phenyl or naphthyl, and is optionally substituted.
  • -R W2C if present, is independently phenyl, and is optionally substituted.
  • -R W2H if present, is independently C 5 .i 4 heteroaryl, and is optionally substituted.
  • -R W2H if present, is independently C 5 . 10 heteroaryl, and is optionally substituted.
  • -R W2H if present, is independently C 5 . 6 heteroaryl, and is optionally substituted.
  • -R W2H is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, or benzopyridazinyl, and is optionally substituted.
  • -R W2H is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
  • -R W2H is independently thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, or pyrimidinyl, and is optionally substituted.
  • -L w - is independently saturated aliphatic C 1-4 alkylene.
  • -L w - is independently saturated linear
  • -L w - is independently -CH 2 - or -CH 2 CH 2 -.
  • -L w - is independently -CH 2 -.
  • -R z is independently -R Z1 , -L Z1 -R Z1 , -R Z2 , -L Z1 -R Z2 , or -L Z2 -R Z3 . In one embodiment, -R z is independently -R Z1 , -L Z1 -R Z1 , -R Z2 , or -L z1 -R Z2 . In one embodiment, -R z is independently -R Z1 or -L Z1 -R Z1 . In one embodiment, -R z is independently -R Z1 . In one embodiment, -R z is independently -L Z1 -R Z1 . In one embodiment, -R z is independently -L Z1 -R Z1 .
  • -R z is independently -R Z2 or -L Z1 -R Z2 . In one embodiment, -R z is independently -R Z2 . In one embodiment, -R z is independently -L Z1 -R Z2 . In one embodiment, -R z is independently -L Z2 -R Z3 .
  • -R Z1 if present, is independently saturated C 4 . 7 heterocyclyl, and is optionally substituted.
  • -R Z1 is independently saturated C 4-7 heterocyclyl having at least one ring nitrogen atom, and is optionally substituted.
  • -R Z1 is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, or diazepinyl, and is optionally substituted.
  • -R Z1 is independently azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or azepinyl, and is optionally substituted.
  • -R Z1 is independently azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, azepin-3-yl, or azepin-4-yl, and is optionally substituted.
  • -R Z1 is independently selected from the following, wherein -R zz is independently -H or saturated aliphatic C 1-4 alkyl:
  • -R Z1 is independently selected from the following, wherein -R 22 is independently -H or saturated aliphatic C 1-4 alkyl:
  • -R Z1 is independently selected from the following, wherein -R 22 is independently -H or saturated aliphatic C 1-4 alkyl:
  • -R Z1 is independently selected from the following, wherein -R 22 is independently -H or saturated aliphatic C 1-4 alkyl:
  • -R 22 is -H.
  • -R 22 is independently C 5-14 heteroaryl, and is optionally substituted.
  • -R 22 if present, is independently C 5 . 10 heteroaryl, and is optionally substituted.
  • -R 22 if present, is independently C 5 . 6 heteroaryl, and is optionally substituted.
  • -R Z2 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, or benzopyridazinyl, and is optionally substituted.
  • -R Z2 is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyrazinyl, pyridazinyl, and is optionally substituted.
  • -R 22 is independently pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
  • -R Z2 is independently pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
  • -R Z2 is independently pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
  • -R Z2 if present, is independently pyridyl, and is optionally substituted. In one embodiment, -R Z2 , if present, is independently pyrid-2-yl, and is optionally substituted. In one embodiment, -R Z2 , if present, is independently pyrid-3-yl, and is optionally substituted.
  • -R Z2 if present, is independently pyrid-4-yl, and is optionally substituted.
  • -L Z1 - is independently saturated aliphatic Ci -4 alkylene. In one embodiment, -L Z1 -, if present, is independently saturated linear C ⁇ alkylene. In one embodiment, -L Z1 -, if present, is independently -CH 2 - or -CH 2 CH 2 -. In one embodiment, -L Z1 -, if present, is independently -CH 2 -.
  • -L Z2 - is independently saturated aliphatic C 2-6 alkylene. In one embodiment, -L Z2 -, if present, is independently saturated aliphatic C 2-4 alkylene.
  • -L Z2 - is independently -(CH 2 ) P -, wherein p is 2, 3, or 4. In one embodiment, -L Z2 -, if present, is independently -(CH 2 ) 2 -. In one embodiment, -L Z2 -, if present, is independently -(CH 2 ) 3 -. In one embodiment, -L Z2 -, if present, is independently -(CH 2 ) 4 -.
  • -R Z3 if present, is independently -NH 2 , -NHR ZN1 , -N(R ZN1 ) 2l or
  • -R Z3 if present, is independently -NH 2 , -NHR ZN1 , or -N(R ZN1 ) 2 . In one embodiment, -R Z3 , if present, is independently -NH 2 . In one embodiment, -R Z3 , if present, is independently -NHR ZN1 . In one embodiment, -R Z3 , if present, is independently -N(R ZN1 ) 2 . In one embodiment, -R Z3 , if present, is independently -NR ZN2 R ZN3 .
  • each -R ZN1 is independently saturated aliphatic Ci. 6 alkyl, phenyl, or benzyl.
  • each -R ZN1 if present, is independently saturated aliphatic C h alky!. In one embodiment, each -R ZN1 , if present, is independently saturated aliphatic C ⁇ alkyl.
  • -NR ZN2 R ZN3 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted.
  • -NR ZN2 R ZN3 is independently pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, or morpholino, and is optionally substituted.
  • -NR ZN2 R ZN3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted.
  • -R W1 if present, is independently unsubstituted.
  • -R W1 is independently optionally substituted with one or more substituents, -R S1 .
  • each -R S1 if present, is independently selected from:
  • each -R S1 is independently selected from:
  • each -R S1 is independently selected from:
  • -R Z1 if present, is independently unsubstituted. In one embodiment, -R Z1 , if present, is independently optionally substituted with one or more substituents, -R S2 .
  • -NR ZN2 R ZN3 if present, is independently unsubstituted.
  • -NR ZN2 R ZN3 is independently optionally substituted with one or more substituents, -R S2 .
  • each -R S2 if present, is independently selected from:
  • each -R S2 is independently selected from:
  • each -R S2 is independently selected from:
  • -R W2C if present, is independently unsubstituted.
  • -R W2C if present, is independently optionally substituted with one or more substituents, -R S3 .
  • -R W2H if present, is independently unsubstituted. In one embodiment, -R W2H , if present, is independently optionally substituted with one or more substituents, -R S3 .
  • -R Z2 if present, is independently unsubstituted. In one embodiment, -R Z2 , if present, is independently optionally substituted with one or more substituents, -R S3 . In one embodiment, each -R S3 , if present, is independently selected from:
  • each -R S3 is independently selected from:
  • each -R S3 is independently selected from:
  • each -R S3 is independently selected from:
  • each -R S3 is independently selected from:
  • each -R T1 is independently saturated aliphatic C 1-4 alkyl, -Ph, Or -CH 2 -Ph, wherein -Ph is independently phenyl optionally substituted with -F, -Cl, -Br, -R T2 -OH, -OR T2 , wherein each -R T2 is independently saturated aliphatic C 1-4 alkyl.
  • each -R JB1 is independently saturated aliphatic C 1-6 alkyl; each -R JB2 is independently aliphatic C 2 - 6 alkenyl; each -R JB3 is independently aliphatic C 2-6 alkynyl; each -R JB4 is independently saturated C 3 .
  • each -R JB5 is independently Cs ⁇ cycloalkenyl
  • each -R JB6 is independently non-aromatic C 4-7 heterocyclyl
  • each -R JB7 is independently C 6-10 carboaryl
  • each -R JB8 is independently C 5-10 heteroaryl
  • each -L JB - is independently saturated aliphatic Ci -3 alkylene; wherein: each -R JB4 , -R JB5 , -R JB6 , -R JB7 , and -R JB8 is optionally substituted, for example, with one or more substituents -R JC1 and/or one or more substituents -R JC2 , each -R JB1 , -R JB2 , -R JB3 , and -L JB - is optionally substituted, for example, with one or more substituents -R JC2 , and wherein: each -R JC1 is
  • each -R JD1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl; each -L JD - is independently saturated aliphatic C ⁇ alkylene; and each -NR JD2 R JD3 , if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from -R J55 , -CF 3 , -F, -OH, -OR J55 , -NH 2 , -NHR J55 , -NR J55 2
  • each -L JA - is independently -(CH 2 ) n2 -, wherein n2 is independently 1 to 4.
  • each -L JA - is independently -CH 2 - or -CH 2 CH 2 -.
  • each -NR JA2 R JA3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -R J44 ; wherein each -R J44 is independently saturated aliphatic C 1-4 alkyl.
  • each -R JA1 is independently:
  • each -R JA1 if present, is independently: , -L JB -R JB ' 7 , R JB6 , or -L JB -R JB8 .
  • each -R JA1 is independently: -R JB1 , -R JB6 , -R JB7 , or -L JB -R JB7 .
  • each -R JB6 is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
  • each -R JB6 if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
  • each -R JB7 if present, is independently phenyl, and is optionally substituted.
  • each -R JB8 if present, is independently C 5 . 6 heteroaryl, and is optionally substituted.
  • each -R JB8 if present, is independently C 9 .i 0 heteroaryl, and is optionally substituted.
  • each -R JB8 is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
  • each -R JB8 is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -L JB - is independently -CH 2 - or -CH 2 CH 2 -. In one embodiment, each -L JB -, if present, is independently -CH 2 -.
  • each -R JC1 if present, is independently saturated aliphatic C ⁇ alkyl.
  • each -R JC2 is independently: -F, -Cl 1 -Br, -I 1 -OH, -OR JD1 , -CN,
  • each -R JD1 if present, is independently saturated aliphatic C 1-4 alkyl.
  • each -L JD - if present, is independently -(CH 2 ) m2 -, wherein m2 is independently 1 to 4.
  • each -L JD - is independently -CH 2 - or -CH 2 CH 2 -.
  • each -NR JD2 R JD3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -R J55 ; wherein each -R J55 is independently saturated aliphatic C 1-4 alkyl.
  • the TCA compound has a molecular weight of from 186 to 1200. In one embodiment, the bottom of range is 200, 225, 250, 275, 300, or 350. In one embodiment, the top of range is 1100, 1000, 900, 800, 700, or 600. In one embodiment, the range is from 225 to 600.
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form.
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds.
  • the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer.
  • the substantially purified form refers to a mixture of enantiomers.
  • the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate).
  • the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • 60% optically pure i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer
  • at least 70% optically pure e.g., at least 80% optically pure, e.g., at least 90% optically pure, e
  • the compound may have a chiral centre.
  • the chiral centre, or each chiral centre, if more than one is present, is independently in the R-configuration or the S-configuration.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • isomers are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • C 1-7 alkyl includes n-propyl and iso-propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • keto-, enol-, and enolate-forms as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • keto enol enolate as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a corresponding salt of the compound for example, a pharmaceutically-acceptable salt.
  • pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL, Vol. 66, pp. 1-19.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al +3 .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 )/.
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • a reference to a particular compound also includes solvate and hydrate forms thereof.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CHa) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as
  • a carboxylic acid group may be protected as an ester for example, as: an Ci. 7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci. 7 haloalkyl ester (e.g., a C 1-7 trihaloalkyl ester); a triC 1-7 alkylsilyl-Ci. 7 alkyl ester; or a C 5 . 20 aryl-Ci. 7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an Ci. 7 alkyl ester e.g., a methyl ester; a t-butyl ester
  • a Ci. 7 haloalkyl ester e.g., a C 1-7 trihaloalkyl ester
  • prodrug refers to a compound which, when metabolised (e.g., in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • TCA thiazole carboxylic acid amide
  • Chloroamides (3) are prepared by treatment of chloroacetyl chloride (1) with the appropriate primary or secondary amine (2), typically in dichloromethane and typically in the presence of a tertiary amine base such as triethylamine or H ⁇ nig's base. Further treatment with the appropriate isothiocyanate (4) and cyanamide (5), typically in combination with a base, such as potassium tert-butoxide, yields compounds of type (6). Where these do not spontaneously cyclise, base-mediated cyclisation can be effected by heating, typically by microwave irradiation, to give the target compounds (7).
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a TCA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing a TCA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function, such as, for example, proliferative conditions, cancer, etc.
  • One aspect of the present invention pertains to a method of inhibiting CHK1 kinase function and/or CHK2 kinase function, in vitro or in vivo, comprising contacting a CHK1 kinase and/or a CHK2 kinase with an effective amount of a TCA compound, as described herein.
  • One aspect of the present invention pertains to a method of inhibiting CHK1 kinase function and/or CHK2 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a TCA compound, as described herein.
  • the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Suitable assays for determining CHK1 kinase function inhibition and/or CHK2 kinase function inhibition are described herein and/or are known in the art.
  • TCA compounds described herein e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these.
  • One aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a TCA compound, as described herein.
  • the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting a cell with an effective amount of a TCA compound, as described herein.
  • the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • the method is performed in vitro. In one embodiment, the method is performed in vivo.
  • the TCA compound is provided in the form of a pharmaceutically acceptable composition.
  • Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
  • gastrointestinal including, e.g., bowel, colon
  • breast mammary
  • ovarian prostate
  • liver hepatic
  • kidney renal
  • bladder pancreas
  • brain and skin.
  • a candidate compound regulates (e.g., inhibits) cell proliferation, etc.
  • assays which may conveniently be used to assess the activity offered by a particular compound are described herein.
  • a sample of cells e.g., from a tumour
  • a compound brought into contact with said cells, and the effect of the compound on those cells observed.
  • effect the morphological status of the cells (e.g., alive or dead, etc.) may be determined.
  • this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.
  • Another aspect of the present invention pertains to a TCA compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
  • the method of treatment comprises treatment with both (i) a TCA compound, as described herein, and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • a TCA compound as described herein
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, for use in a method of treatment of the human or animal body by therapy, wherein the method of treatment comprises treatment with both (i) a TCA compound, as described herein, and (a) the DNA topoisomerase I or Il inhibitor, (b) the DNA damaging agent, (c) the antimetabolite or TS inhibitor, or (d) the microtubule targeted agent.
  • Another aspect of the present invention pertains to use of a TCA compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the medicament comprises the TCA compound.
  • the treatment comprises treatment with both (i) a medicament comprising a TCA compound, as described herein, and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • a medicament comprising a TCA compound, as described herein
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to use of (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, in the manufacture of a medicament for use in a treatment, wherein the treatment comprises treatment with both (i) a TCA compound, as described herein, and (a) the DNA topoisomerase I or Il inhibitor, (b) the DNA damaging agent, (c) the antimetabolite or TS inhibitor, or (d) the microtubule targeted agent.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a TCA compound, as described herein, preferably in the form of a pharmaceutical composition.
  • the method further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • the treatment is treatment of a disease or condition that is mediated by CHK1 and/or CHK2.
  • the treatment is treatment of: a disease or condition that is ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function.
  • the treatment is treatment of: a proliferative condition.
  • proliferative condition pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth.
  • the treatment is treatment of: a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroprolife
  • the treatment is treatment of: cancer.
  • the treatment is treatment of: p53 negative cancer.
  • the treatment is treatment of: lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer (e.g., head cancer, neck cancer), skin cancer, squamous cancer, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.
  • lung cancer small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer
  • rectal cancer colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder
  • the treatment is treatment of: a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma); a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumour of lymph
  • the treatment is treatment of solid tumour cancer.
  • the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis
  • the compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein.
  • treatment refers generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis
  • treatment is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment.”
  • treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.
  • therapeutic ly-effective amount refers to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, cytotoxic agents, anticancer agents, etc.
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.
  • a compound as described herein may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1, 2, 3, 4) agents or therapies that regulates cell growth or survival or differentiation via a different mechanism, thus treating several characteristic features of cancer development.
  • one or more other agents or therapies that regulates cell growth or survival or differentiation via a different mechanism
  • One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.
  • the agents may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes.
  • the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
  • agents i.e., the compound described here, plus one or more other agents
  • the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • the TCA compound is employed in combination with (e.g., in conjunction with) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • both a TCA compound and one or more other agents When both a TCA compound and one or more other agents are employed, they may be used (e.g., contacted, administered, etc.) in any order. Furthermore, they may be used (e.g., contacted, administered, etc.) together, as part of a single formulation, or separately, as separate formulations.
  • treatment with e.g., administration of the TCA compound may be prior to, concurrent with, or may follow, treatment with (e.g., administration of) the one or more other agents, or a combination thereof.
  • treatment with (e.g., administration of) a TCA compound is concurrent with, or follows, treatment with (e.g., administration of) the one or more other agents.
  • the one or more other agents is a DNA topoisomerase I or Il inhibitor; for example, Etoposide, Toptecan, Camptothecin, Irinotecan, SN-38, Doxorubicin, Daunorubicin.
  • a DNA topoisomerase I or Il inhibitor for example, Etoposide, Toptecan, Camptothecin, Irinotecan, SN-38, Doxorubicin, Daunorubicin.
  • the one or more other agents is a DNA damaging agent; for example, alkylating agents, platinating agents, or compounds that generate free radicals; for example, Temozolomide, Cisplatin, Carboplatin, Mitomycin C, Cyclophosphamide, BCNU, CCNU, Bleomycin.
  • the one or more other agents is an antimetabolite or TS inhibitor; for example, 5-fluorouracil, hydroxyurea, Gemcitabine, Arabinosylcytosine, Fludarabine, Tomudex, ZD9331.
  • the one or more other agents is a microtubule targeted agent; for example, Paclitaxel, Docetaxel, Vincristine, Vinblastine.
  • the one or more other agents is ionising radiation (e.g., as part of radiotherapy).
  • TCA compounds described herein may also be used as cell culture additives to inhibit CHK1 kinase function and/or CHK2 kinase function, e.g., to inhibit cell proliferation, etc.
  • TCA compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • TCA compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other CHK1 kinase function, other CHK2 kinase function inhibitors, other anti-proliferative agents, other anti-cancer agents, etc.
  • kits comprising (a) a TCA compound as described herein, or a composition comprising a TCA compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
  • the kit further comprises one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; and (d) a microtubule targeted agent.
  • the written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
  • the TCA compound or pharmaceutical composition comprising the TCA compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular
  • the subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • the TCA compound While it is possible for the TCA compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one TCA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one TCA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences. 18th edition, Mack Publishing
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers
  • the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
  • Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non- aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • solutions e.g., aqueous, non- aqueous
  • suspensions e.g., aqueous, non-aqueous
  • Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
  • the compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients.
  • the compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
  • Formulations suitable for oral administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil- in-water, water-in-oil
  • mouthwashes e.g., gluges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • suppositories e.g., pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs. Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners.
  • binders
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
  • Creams are typically prepared from the compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier also known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
  • Formulations suitable for intranasal administration, where the carrier is a solid include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Formulations suitable for pulmonary administration include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • the concentration of the compound in the liquid is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • TCA compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular TCA compound, the route of administration, the time of administration, the rate of excretion of the TCA compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
  • the amount of TCA compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • a suitable dose of the TCA compound is in the range of about 10 ⁇ g to about 250 mg (more typically about 100 ⁇ g to about 25 mg) per kilogram body weight of the subject per day. Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • Solvent A (Aqueous):
  • Solvent B (Organic):
  • the solid was dissolved in a mixture of acetonitrile (5 mL) and triethylamine (0.2 mL) and irradiated in a microwave reactor at 140°C for 2 x 5 minutes.
  • the mixture was diluted with methanol and the product was simultaneously isolated and deprotected by solid phase extraction on a 1g MP-TsOH cartridge, eluting with 2 M ammonia in methanol.
  • the basic eluent was concentrated and the residue purified by preparative HPLC to give the title compound (21 mg, 0.066 mmol, 6.6%).
  • Rt 2.17 min, 318 (M+H) + .
  • CHK1 kinase function was measured in a DELFIA® assay in order to monitor phosphorylation of a CDC25C peptide using a specific phospho antibody.
  • the enzyme reaction was carried out in polypropylene plates (Greiner) using a reaction mix (25 ⁇ L) containing enzyme and peptide mix (CHK1 , 1 nM; Biotin- KKKVSRSGLYRSPSMPENLNRPR, 1 ⁇ M or 15 ⁇ L), ATP (30 ⁇ M or 5 ⁇ L) and either DMSO (2.5%) or test compound (5 ⁇ L) diluted to a give a range of concentrations (from 0 to 100 ⁇ M in 2.5% DMSO, final concentrations) in assay buffer (40 mM Tris, 40 mM NaCI, 2 mM MgCI 2 , 1 mM DTT and 0.1% Tween 20).
  • reaction mixture was incubated for 30 minutes at room temperature and then stopped by the addition of buffer (125 ⁇ L) containing 40 mM EDTA, 0.05% Tween 20, 0.1% BSA in TBS (10x concentrate, Sigma). An aliquot (100 ⁇ L) of the stopped reaction mixture was transferred to a black neutravidin- coated plate (Perbio) and incubated for 1 hour on a shaker (Titertek, Flow Laboratories) at room temperature.
  • the plates were washed four times with wash buffer (25 mM Tris (pH 8), 150 mM NaCI, and 0.1% Tween 20) (WellWash4, Thermo Life Sciences) and incubated for 1 hour as before with an antibody mixture (100 ⁇ L) consisting of anti- phospho CDC25C (1.25 nM, #9528, Cell Signalling Technology) and europium-labelled anti-rabbit IgG (0.3 ⁇ g/mL, AD0105, PerkinElmer Life Sciences) diluted in DELFIA assay buffer (PerkinElmer Life Sciences). The plates were washed a further four times with wash buffer before the addition of enhancement solution (100 ⁇ L/well, PerkinElmer Life Sciences).
  • the plate was read on a Victor 2 1420 multi-label counter (Perkin Elmer Life Sciences) using a time-resolved measurement mode reading fluorescence at 615 nm.
  • the concentration of test compound required to inhibit enzyme activity by 50% was calculated (IC 50 ).
  • CHK2 kinase activity was measured in a DELFIA® assay that monitors phosphorylation of a CDC25C peptide using a specific phospho antibody.
  • the enzyme reaction was carried out in 96-well polypropylene plates (Greiner).
  • the reaction mix (total volume 25 ⁇ l_) contained enzyme and peptide mix (15 ⁇ l_) (containing CHK2, 1 nM; Biotin-KKKVSRSGLYRSPSMPENLNRPR, 1 ⁇ M), ATP (30 ⁇ M, 5 ⁇ l_) and either DMSO (2.5%) or test compound (5 ⁇ l_) diluted to a give a range of concentrations (0-100 ⁇ M in 2.5% DMSO, final concentrations) in assay buffer (40 mM HEPES (pH7.4), 40 mM KCI, 2 mM MgCI 2 , 10 mM DTT and 0.02% Tween 20).
  • reaction mixture was incubated for 30 minutes at room temperature and stopped by the addition of buffer (125 ⁇ l_) containing 40 mM EDTA, 0.05% Tween 20, 0.1% BSA in TBS (10x concentrate, Sigma). An aliquot (100 ⁇ l_) of the reaction mix was transferred to a black neutravidin- coated 96-well plate (Perbio) and incubated for 1 hour on a shaker (Titertek, Flow
  • HT29 colon carcinoma cells were obtained from ATCC (Rockville, MD, USA). Cells were grown in DMEM supplemented with 10% foetal calf serum and containing L-glutamine 5 mM, glucose, penicillin, and streptomycin. Cells were grown at 37°C in a dry 5% CO 2 atmosphere. Cytotoxicity assays were carried out in 96-well plates using quadruplicate wells for each dose. Cells were seeded at 1.6 x 10 3 per well in 160 ⁇ L medium and were allowed to attach for 36 hours prior to treatment. Test compounds were dissolved in DMSO at 10 mM and serially diluted in culture medium to 5 x final concentration prior to addition in a volume of 40 ⁇ L per well.
  • MIA Mitosis Inhibition Assay
  • HT29 cells were seeded at 10 4 cells per well into 96 well plates in a volume of 160 ⁇ L and left to attach for 36 hours.
  • Etoposide (10 mM stock in DMSO) was diluted in medium to 250 ⁇ M and then 40 ⁇ L was added to appropriate wells to give a final concentration of 50 ⁇ M and incubated for 1 hour. This treatment had previously been optimised to induce a G2 arrest in 80% of cells 16 hours following treatment. After genotoxic drug exposure, the medium was removed and replaced with fresh medium (160 ⁇ L).
  • Cells were either untreated (untreated control or etoposide pre-treatment alone), exposed to nocodazole following etoposide pre-treatment or nocodazole alone (100 ng/mL final concentration), or exposed to increasing concentrations of test compound (200 ⁇ M - 0.01 nM final concentration) in combination with nocodazole (100 ng/mL final concentration). Test compounds were added in 40 ⁇ L using quadruplicate wells for each dose.
  • the following compounds had IC50 values of 50 ⁇ M or less: TCA-001 , TCA-002, TCA-003, TCA-004, TCA-005, TCA-006, TCA-007, TCA-009, TCA-010, TCA-011 , TCA-012, TCA-013, TCA-014, TCA-015, TCA-016, TCA-017, TCA-018, TCA-019, TCA-020, TCA-021 , TCA-022,
  • the following compounds had IC50 values of 10 ⁇ M or less: TCA-001 , TCA-003, TCA-004, TCA-005, TCA-006, TCA-007, TCA-010, TCA-011 , TCA-013, TCA-014, TCA-015, TCA-017, TCA-018, TCA-019, TCA-020.
  • Biological data were obtained using the CHK2 kinase function inhibition assay described above for the following compounds: TCA-001 , TCA-003, TCA-005, TCA-006, TCA-007, TCA-008, TCA-010, TCA-011 , TCA-013, TCA-014, TCA-017, TCA-018, TCA-019, TCA-020.
  • the following compounds had IC50 values of 0.1 ⁇ M or less: TCA-001 , TCA-006, TCA-013, TCA-014, TCA-018, TCA-019.
  • Biological data were obtained using the cytotoxicity assay (SRB) described above for the following compounds: TCA-001 , TCA-013, TCA-014, TCA-017, TCA-019.
  • TCA-001 One compound, compound TCA-001 , had an IC50 value of 38 ⁇ M.
  • Biological data were obtained using the mitosis inhibition assay (MIA) described above for the following compounds: TCA-001 , TCA-013, TCA-014, TCA-017, TCA-019.

Abstract

The present invention pertains to certain thiazole carboxylic acid amide compounds which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function and/or Checkpoint Kinase 2 (CHK2) kinase function, to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHKl kinase function and/or CHK2 kinase function, and in the treatment of diseases and conditions that are mediated by CHKl and/or CHK2, that are ameliorated by the inhibition of CHKl kinase function and/or CHK2 kinase function, such as cancer, optionally in combination with another agent, for example, (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Description

5 -AMIDOTHIAZOLE DERIVATIVES AND THEIR USE AS CHECKPOINT KINASE INHIBITORS
RELATED APPLICATIONS
This application is related to United States provisional patent application number
61/080,718 filed 15 July 2008 and United Kingdom patent application number 0812913.2 filed 15 July 2008, the contents of both of which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain thiazole carboxylic acid amide compounds (for convenience, collectively referred to herein as "TCA compounds"), which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function and/or Checkpoint Kinase 2 (CHK2) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function and/or CHK2 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1 and/or CHK2, that are ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
BACKGROUND
A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Checkpoint Kinase 1 (CHK1) and Checkpoint Kinase 2 (CHK2)
Progression through the cell division cycle is a tightly regulated process and is monitored at several positions known as cell cycle checkpoints (see, e.g., Weinert and Hartwell,
1989; Bartek and Lukas, 2003). These checkpoints are found in all four stages of the cell cycle; G1 , S (DNA replication), G2 and M (Mitosis) and they ensure that key events, which control the fidelity of DNA replication and cell division, are completed correctly.
Cell cycle checkpoints are activated by a number of stimuli, including DNA damage and DNA errors caused by defective replication. When this occurs, the cell cycle will arrest, allowing time for either DNA repair to occur or, if the damage is too severe, for activation of cellular processes leading to controlled cell death.
All cancers, by definition, have some form of aberrant cell division cycle. Frequently, the cancer cells possess one or more defective cell cycle checkpoints, or harbour defects in a particular DNA repair pathway. These cells are therefore often more dependent on the remaining cell cycle checkpoints and repair pathways, compared to non-cancerous cells (where all checkpoints and DNA repair pathways are intact). The response of cancer cells to DNA damage is frequently a critical determinant of whether they continue to proliferate or activate cell death processes and die. For example, tumour cells that contain a mutant form(s) of the tumour suppressor p53 are defective in the G1 DNA damage checkpoint. Thus inhibitors of the G2 or S-phase checkpoints are expected to further impair the ability of the tumour cell to repair damaged DNA.
Many known cancer treatments cause DNA damage by either physically modifying the cell's DNA or disrupting vital cellular processes that can affect the fidelity of DNA replication and cell division, such as DNA metabolism, DNA synthesis, DNA transcription and microtubule spindle formation. Such treatments include for example, radiotherapy, which causes DNA strand breaks, and a variety of chemotherapeutic agents including topoisomerase inhibitors, antimetabolites, DNA-alkylating agents, and platinum- containing cytotoxic drugs. A significant limitation to these genotoxic treatments is drug resistance. One of the most important mechanisms leading to this resistance is attributed to activation of cell cycle checkpoints, giving the tumour cell time to repair damaged DNA. By abrogating a particular cell cycle checkpoint, or inhibiting a particular form of DNA repair, it may therefore be possible to circumvent tumour cell resistance to the genotoxic agents and augment tumour cell death induced by DNA damage, thus increasing the therapeutic index of these cancer treatments.
Two key regulators of cell cycle checkpoints that are activated in response to DNA damage are the serine/threonine kinases CHK1 and CHK2. CHK1 is activated through phosphorylation at S317 and S345 by the ATR protein, which is a component of the
RPA/ATR/ATRIP DNA damage sensor complex, associated with DNA (see, e.g., Bucher and Britten, 2008). Once active, CHK1 transduces DNA damage signals through phosphorylation of substrates involved in a number of cellular activities including cell cycle arrest and DNA repair. Two key substrates of CHK1 are the Cdc25A and Cdc25C phosphatases that dephosphorylate CDK1 leading to its activation, which is a requirement for exit from G2 into mitosis (M phase) (see, e.g., Sanchez et a/., 1997). Phosphorylation of Cdc25C and the related Cdc25A by CHK1 blocks their ability to activate CDK1, thus preventing the cell from exiting G2 into M phase. The role of CHK1 in the DNA damage-induced G2 cell cycle checkpoint has been demonstrated in a number of studies where CHK1 function has been knocked out (see, e.g., Liu et a/., 2000; Zhao et a/., 2002; Zachos et a/., 2003).
The reliance of the DNA damage-induced G2 checkpoint upon CHK1 provides one example of a therapeutic strategy for cancer treatment, involving targeted inhibition of CHK1. Upon DNA damage, the p53 tumour suppressor protein is stabilised and activated to give a p53-dependent G1 arrest, leading to apoptosis or DNA repair (Balaint and Vousden, 2001). Over half of all cancers are functionally defective for p53, which can make them resistant to genotoxic cancer treatments such as ionising radiation (IR) and certain forms of chemotherapy (see, e.g., Greenblatt et a/., 1994; Carson and Lois, 1995). These p53 deficient cells fail to arrest at the G1 checkpoint or undergo apoptosis or DNA repair, and consequently may be more reliant on the G2 checkpoint for viability and replication fidelity. Therefore abrogation of the G2 checkpoint through inhibition of the CHK1 kinase function may selectively sensitise p53 deficient cancer cells to genotoxic cancer therapies, and this has been demonstrated (see, e.g., Wang et al., 1996; Dixon and Norbury, 2002). - A -
CHK1 has also been shown to be involved in the S phase cell cycle checkpoint and DNA repair by homologous recombination. Thus, inhibition of CHK1 kinase in those cancers that are reliant on these processes after DNA damage may provide additional therapeutic strategies, including S phase checkpoint abrogation for the treatment of cancers using CHK1 inhibitors (see, e.g., Sorensen et al., 2005).
CHK2 is activated in response to DNA damage by phosphorylation at threonine 68, which requires the PI3-Kinase family member, ATM (see, e.g., Matsuoka et al., 1998; Melchionna et al., 2000). This promotes dimerisation of the protein allowing trans- activation through T-loop exchange (see, e.g., Oliver et a/., 2006). Once activated, CHK2 can phosphorylate a number of substrates that regulate cell cycle arrest, DNA repair and cell death. Key substrates include the cell cycle phosphatases, Cdc25A and Cdc25C, which are inactivated through degradation and relocalisation respectively (see, e.g., Pommier et al., 2005). Another important substrate is the p53 protein that is phosphorylated at serine 20, which promotes activation of this important tumour suppressor (see, e.g., Hirao et al., 2000; Chehab et al., 2000). Others include BRCA1 , E2F, PIkI and PML (see, e.g., Pommier et al., 2005).
Inhibition of CHK2 has the potential to offer a number of therapeutic strategies for the treatment of cancer. A major effect of cytotoxic cancer treatments, such as ionising radiation or chemotherapeutic agents, is the death of proliferating cancer cells. However, these agents often have side effects, due to toxicity to normal proliferating tissues. One explanation for this is that cancer cells are often resistant to apoptosis due to defective cell cycle checkpoints. Consequently the doses of a particular cancer treatment that are effective against the tumour may also kill the proliferating normal cells that have intact cell cycle checkpoints and undergo apoptosis. One of the most important signalling pathways involved in activation of cell cycle checkpoints is the p53 pathway. The TP53 gene itself is mutated in 50% of human tumours, whilst other components of this pathway are also found altered in cancer (see, e.g., Gorgoulis et al., 2005; Bartkova et al., 2005). Thus, if p53-dependent apoptosis is temporarily inhibited in normal cells the toxicity/side effects of cancer treatments may be reduced. For example, pifithrin-α, a pharmacological inhibitor of p53 function, protects mice from lethal and sub-lethal doses of radiation without causing tumour formation (see, e.g., Komarov et al., 1999). In addition, targeted disruption of CHK2 allows the increased survival of mice exposed to radiation (through resistance to apoptosis) and these animals do not show an increase in spontaneous tumour development compared to the wild-type controls (see, e.g., Takai et al., 2002). Pharmacological inhibition of CHK2 has been shown to have a radioprotective effect on normal human cells (see, e.g., Arienti et al., 2005). As mentioned earlier, tumour cells that contain a mutant form(s) of the tumour suppressor p53 are defective in the G1 DNA damage checkpoint. Thus CHK2 inhibitors that can abrogate the G2 or S-phase checkpoints (induced by such cancer treatments as ionising radiation or chemotherapeutic anticancer agents) are expected to further cripple the ability of the tumour cell to repair damaged DNA.
CHK2 is also activated in response to the physiological stress of hypoxia/reoxygenation (see, e.g., Gibson et a/., 2005). Loss or inhibition of CHK2 sensitises tumour cells to hypoxia/reoxygenation. Therefore inhibition of CHK2 in this context may have particular therapeutic value in the treatment of solid tumours, which are often hypoxic.
Inhibition of CHK1 and CHK2 may be an effective therapeutic strategy. For example, a tumour may contain a non-clonal population of cells. Thus individual cells within the tumour may be defective in different cell cycle checkpoints and/or repair mechanisms. In this scenario, inhibition of several cell cycle checkpoints and/or repair mechanisms, using a dual inhibitor of CHK1 and CHK2 could provide an effective strategy for greater eradication of cells within such a tumour, when combined with radiotherapy or the appropriate chemotherapeutic agent. The possibility that CHK2 inhibition may provide radio- or chemo-protection to normal tissue could also offer additional therapeutic benefit in this context. Dual inhibitors of CHK1 and CHK2 may also have therapeutic activity across a wide range of tumour types, due to the ability to target multiple cell cycle checkpoints. Furthermore, since loss or inhibition of CHK2 sensitises tumour cells to hypoxia/reoxygenation, combining this function with CHK1 inhibition may provide an effective treatment for p53 deficient solid tumours.
SUMMARY OF THE INVENTION
One aspect of the invention pertains to certain thiazole carboxylic acid amide compounds (for convenience, collectively referred to herein as "TCA compounds"), as described herein.
Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a TCA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
Another aspect of the invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of admixing a TCA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
Another aspect of the present invention pertains to a method of inhibiting CHK1 kinase function and/or CHK2 kinase function, in vitro or in vivo, comprising contacting a CHK1 kinase and/or a CHK2 kinase with an effective amount of a TCA compound, as described herein.
Another aspect of the present invention pertains to a method of inhibiting CHK1 kinase function and/or CHK2 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a TCA compound, as described herein.
In one embodiment, the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a TCA compound, as described herein.
In one embodiment, the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation. Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a TCA compound, as described herein, preferably in the form of a pharmaceutical composition.
In one embodiment, the method further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to a TCA compound as described herein for use in a method of treatment of the human or animal body by therapy.
In one embodiment, the method of treatment comprises treatment with both (i) a TCA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to use of a TCA compound, as described herein, in the manufacture of a medicament for use in treatment.
In one embodiment, the treatment comprises treatment with both (i) a medicament comprising a TCA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
In one embodiment, the treatment is treatment of a disease or condition that is mediated by CHK1 and/or CHK2.
In one embodiment, the treatment is treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function.
In one embodiment, the treatment is treatment of a proliferative condition.
In one embodiment, the treatment is treatment of cancer.
In one embodiment, the treatment is treatment of: p53 negative cancer.
In one embodiment, the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma. Another aspect of the present invention pertains to a kit comprising (a) a TCA compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
In one embodiment, the kit further comprises one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; and (d) a microtubule targeted agent.
Another aspect of the present invention pertains to a TCA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
Another aspect of the present invention pertains to a TCA compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Compounds
One aspect of the present invention relates to certain thiazole carboxylic acid amide compounds (for convenience, collectively referred to herein as "TCA compounds") which are related to 2,4-diamino-thiazole-5-carboxylic acid amide.
Figure imgf000010_0001
2,4-Diamino-thiazole-5-carboxylic acid amide
In one embodiment, the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000010_0002
wherein:
-Rw is independently -RW1, -RW2, or -LW-RW2;
wherein:
-RW1 is independently saturated aliphatic C1-6alkyl, and is optionally substituted; -RW2 is independently -RW2C or -RW2H;
-RW2C is independently C6-iocarboaryl, and is optionally substituted; -RW2H is independently C5-i4heteroaryl, and is optionally substituted; and -Lw- is independently saturated aliphatic C1-4alkylene;
and wherein:
-Rz is independently -RZ1, -LZ1-RZ1, -RZ2, -LZ1-RZ2, or -LZ2-RZ3,
wherein: -RZ1 is independently saturated C4.7heterocyclyl, and is optionally substituted;
-RZ2 is independently C5.14heteroaryl, and is optionally substituted; -LZ1- is independently saturated aliphatic
Figure imgf000010_0003
-LZ2- is independently saturated aliphatic C2-6alkylene; -RZ3 is independently -NH2, -NHRZN1, -N(RZN1)2, or -NRZN2RZN3; each -RZN1 is independently saturated aliphatic C1-6alkyl, phenyl, or benzyl; and
-NRZN2RZN3 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted.
For the avoidance of doubt, the indices such as "C5-6" and "C4.7" in terms such as
"Cs-βheteroaryl" and "C^heterocyclyl" refer to the number of ring atoms, whether carbon atoms or heteroatoms. For example, triazolyl is an example of a C5heteroaryl group, and diazepinyl is an example of a C7heterocyclyl group.
For the avoidance of doubt, it is not intended that the groups -Rw and -Rz are linked, other than via the thiazole ring as shown in the above formula.
The Group -Rw
In one embodiment, -Rw is independently -RW1, -RW2, or -LW-RW2.
In one embodiment, -Rw is independently -RW1.
In one embodiment, -Rw is independently -RW2.
In one embodiment, -Rw is independently -LW-RW2.
The Group -RW1
In one embodiment, -RW1, if present, is independently saturated aliphatic C1-6alkyl, and is optionally substituted.
In one embodiment, -RW1, if present, is independently saturated aliphatic C1-4alkyl, and is optionally substituted.
In one embodiment, -RW1, if present, is independently saturated aliphatic CMalkyl.
In one embodiment, -RW1, if present, is independently -Me.
The Group -RW2
In one embodiment, -RW2, if present, is independently -RW2C or -RW2H. In one embodiment, -RW2, if present, is independently -RW2C. In one embodiment, -RW2, if present, is independently -RW2H. The Group -RW2C
In one embodiment, -RW2C, if present, is independently C6.iocarboaryl, and is optionally substituted. In one embodiment, -RW2C, if present, is independently phenyl or naphthyl, and is optionally substituted.
In one embodiment, -RW2C, if present, is independently phenyl, and is optionally substituted.
The Group -RW2H
In one embodiment, -RW2H, if present, is independently C5.i4heteroaryl, and is optionally substituted.
In one embodiment, -RW2H, if present, is independently C5.10heteroaryl, and is optionally substituted.
In one embodiment, -RW2H, if present, is independently C5.6heteroaryl, and is optionally substituted.
In one embodiment, -RW2H, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, or benzopyridazinyl, and is optionally substituted.
In one embodiment, -RW2H, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, -RW2H, if present, is independently thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, or pyrimidinyl, and is optionally substituted.
The Group -Lw-
In one embodiment, -Lw-, if present, is independently saturated aliphatic C1-4alkylene.
In one embodiment, -Lw-, if present, is independently saturated linear
Figure imgf000012_0001
In one embodiment, -Lw-, if present, is independently -CH2- or -CH2CH2-.
In one embodiment, -Lw-, if present, is independently -CH2-. The Group -Rz
In one embodiment, -Rz is independently -RZ1, -LZ1-RZ1, -RZ2, -LZ1-RZ2, or -LZ2-RZ3. In one embodiment, -Rz is independently -RZ1, -LZ1-RZ1, -RZ2, or -Lz1-RZ2. In one embodiment, -Rz is independently -RZ1 or -LZ1-RZ1. In one embodiment, -Rz is independently -RZ1. In one embodiment, -Rz is independently -LZ1-RZ1. In one embodiment, -Rz is independently -RZ2 or -LZ1-RZ2. In one embodiment, -Rz is independently -RZ2. In one embodiment, -Rz is independently -LZ1-RZ2. In one embodiment, -Rz is independently -LZ2-RZ3.
The Group -RZ1
In one embodiment, -RZ1, if present, is independently saturated C4.7heterocyclyl, and is optionally substituted.
In one embodiment, -RZ1, if present, is independently saturated C4-7heterocyclyl having at least one ring nitrogen atom, and is optionally substituted.
In one embodiment, -RZ1, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, or diazepinyl, and is optionally substituted.
In one embodiment, -RZ1, if present, is independently azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or azepinyl, and is optionally substituted.
In one embodiment, -RZ1, if present, is independently azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, azepin-3-yl, or azepin-4-yl, and is optionally substituted.
In one embodiment, -RZ1, if present, is independently selected from the following, wherein -Rzz is independently -H or saturated aliphatic C1-4alkyl:
Figure imgf000013_0001
Figure imgf000014_0001
In one embodiment, -RZ1, if present, is independently selected from the following, wherein -R22 is independently -H or saturated aliphatic C1-4alkyl:
Figure imgf000014_0002
In one embodiment, -RZ1, if present, is independently selected from the following, wherein -R22 is independently -H or saturated aliphatic C1-4alkyl:
Figure imgf000014_0003
In one embodiment, -RZ1, if present, is independently selected from the following, wherein -R22 is independently -H or saturated aliphatic C1-4alkyl:
Figure imgf000014_0004
In one embodiment, -R22 is -H.
The Group -R22
In one embodiment, -R22, if present, is independently C5-14heteroaryl, and is optionally substituted.
In one embodiment, -R22, if present, is independently C5.10heteroaryl, and is optionally substituted.
In one embodiment, -R22, if present, is independently C5.6heteroaryl, and is optionally substituted. In one embodiment, -RZ2, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, or benzopyridazinyl, and is optionally substituted.
In one embodiment, -RZ2, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyrazinyl, pyridazinyl, and is optionally substituted.
In one embodiment, -R22, if present, is independently pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, -RZ2, if present, is independently pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, -RZ2, if present, is independently pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, -RZ2, if present, is independently pyridyl, and is optionally substituted. In one embodiment, -RZ2, if present, is independently pyrid-2-yl, and is optionally substituted. In one embodiment, -RZ2, if present, is independently pyrid-3-yl, and is optionally substituted.
In one embodiment, -RZ2, if present, is independently pyrid-4-yl, and is optionally substituted.
The Group -LZ1-
In one embodiment, -LZ1-, if present, is independently saturated aliphatic Ci-4alkylene. In one embodiment, -LZ1-, if present, is independently saturated linear C^alkylene. In one embodiment, -LZ1-, if present, is independently -CH2- or -CH2CH2-. In one embodiment, -LZ1-, if present, is independently -CH2-.
The Group -LZ2-
In one embodiment, -LZ2-, if present, is independently saturated aliphatic C2-6alkylene. In one embodiment, -LZ2-, if present, is independently saturated aliphatic C2-4alkylene.
In one embodiment, -LZ2-, if present, is independently -(CH2)P-, wherein p is 2, 3, or 4. In one embodiment, -LZ2-, if present, is independently -(CH2)2-. In one embodiment, -LZ2-, if present, is independently -(CH2)3-. In one embodiment, -LZ2-, if present, is independently -(CH2)4-.
The Group -RZ3
In one embodiment, -RZ3, if present, is independently -NH2, -NHRZN1, -N(RZN1)2l or
.NRZN2RZN3
In one embodiment, -RZ3, if present, is independently -NH2, -NHRZN1, or -N(RZN1)2. In one embodiment, -RZ3, if present, is independently -NH2. In one embodiment, -RZ3, if present, is independently -NHRZN1. In one embodiment, -RZ3, if present, is independently -N(RZN1)2. In one embodiment, -RZ3, if present, is independently -NRZN2RZN3.
The Group -RZN1
In one embodiment, each -RZN1, if present, is independently saturated aliphatic Ci.6alkyl, phenyl, or benzyl.
In one embodiment, each -RZN1, if present, is independently saturated aliphatic Chalky!. In one embodiment, each -RZN1, if present, is independently saturated aliphatic C^alkyl.
The Group -NRZN2RZN3
In one embodiment, -NRZN2RZN3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted.
In one embodiment, -NRZN2RZN3, if present, is independently pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, or morpholino, and is optionally substituted.
In one embodiment, -NRZN2RZN3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted.
Optional Substituents on -RW1
In one embodiment, -RW1, if present, is independently unsubstituted.
In one embodiment, -RW1, if present, is independently optionally substituted with one or more substituents, -RS1. In one embodiment, each -RS1, if present, is independently selected from:
-RJA\
-F, -CF3, -OCF3, -SCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH, -NRJA1-LJA-OH,
-0RJA1, -LJA-ORJA1, -O-LJA-ORJA1, -NH-LJA-ORJA1, -NRJA1-LJA-ORJA1,
-SH, -SRJA1,
-CN, -NH2, -NHRJA1 , -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2, -O-LJA-NRJA2RJA3,
-NH-LJA-NH2, -NRJA1-LJA-NH2, -NH-LJA-NHRJA1, -NRJA1-LJA-NHRJA1,
-NH-LJA-NRJA1 2, -NRJA1-LJA-NRJA1 2, -NH-LJA-NRJA2RJA3, -NRJA1-LJA-NRJA2RJA3,
-OC(=O)RJA1,
-C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1,
-C(=O)NH2l -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3, -NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)ORJA1, -NRJA1C(=O)ORJA1,
-OC(=O)NH2, -OC(=O)NHRJA1, -OC(=O)NRJA1 2, -OC(=O)NRJA2RJA3,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3, -NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1,
-NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3,
-S(=O)RJA1, -S(=O)2RJA1, -OS(=O)2RJA1, -S(=O)2OH, -S(=O)2ORJA1; and =0; or two adjacent groups -RS3, if present, together form -0-CH2-O- or -0-CH2CH2-O-.
In one embodiment, each -RS1, if present, is independently selected from:
-RJA1,
-F,
-CF3, -OCF3,
-OH, -LJA-OH, -O-LJA-OH, -0RJA1 , -LJA-ORJA1 , -O-LJA-ORJA1 ,
-CN, -NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1, -C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3,
-NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)NH2l -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3,
-NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1, -NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3,
-S(=O)RJA1, -S(=O)2RJA1, -OS(=O)2RJA1, -S(=O)2OH, -S(=O)2ORJA1; and
=0.
In one embodiment, each -RS1, if present, is independently selected from:
-RJA1,
-F, -CF3,
-OH, -LJA-OH, -O-LJA-OH,
-0RJA1, -LJA-ORJA1, -O-LJA-ORJA1,
-CN,
-NH2, -NHRJA1, -NRJA1 2, -LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2,
-C(=O)OH,
-C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, and -C(=O)NRJA1 2.
Optional Substituents on -RZ1 and -NRZN2RZN3
In one embodiment, -RZ1, if present, is independently unsubstituted. In one embodiment, -RZ1, if present, is independently optionally substituted with one or more substituents, -RS2.
In one embodiment, -NRZN2RZN3, if present, is independently unsubstituted.
In one embodiment, -NRZN2RZN3, if present, is independently optionally substituted with one or more substituents, -RS2. In one embodiment, each -RS2, if present, is independently selected from:
-RJA1,
-F, -CF3, -OCF3, -SCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH, -NRJA1-LJA-OH,
-0RJA1, -LJA-ORJA1, -O-LJA-ORJA1, -NH-LJA-ORJA1, -NRJA1-LJA-ORJA1,
-SH, -SRJA1,
-CN, -NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2) -O-LJA-NRJA2RJA3,
-NH-LJA-NH2, -NRJA1-LJA-NH2, -NH-LJA-NHRJA1, -NRJA1-LJA-NHRJA1,
-NH-LJA-NRJA1 2, -NRJA1-LJA-NRJA1 2, -NH-LJA-NRJA2RJA3, -NRJA1-LJA-NRJA2RJA3,
-OC(=O)RJA1,
-C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3, -NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)ORJA1, -NRJA1C(=O)ORJA1,
-OC(=O)NH2, -OC(=O)NHRJA1, -OC(=O)NRJA1 2, -OC(=O)NRJA2RJA3,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3, -NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1,
-NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3,
-S(=O)RJA1, -S(=O)2RJA1, -OS(=O)2RJA1, -S(=O)2OH, -S(=O)2ORJA1; and =0.
In one embodiment, each -RS2, if present, is independently selected from:
-F,
-CF3, -OCF3,
-OH, -LJA-OH, -O-LJA-OH,
-0RJA1, -LJA-ORJA1, -O-LJA-ORJA1,
-CN, -NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3, -C(=O)OH, -C(=O)ORJA1, -C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2l -C(=O)NRJA2RJA3, -NHC(=O)RJA1, -NRJA1C(=O)RJA1, -NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3, -NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1, -NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3, -NHS(=O)2RJA1, -NRJA1S(=O)2RJA1, -S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3,
-S(=O)RJA1, -S(=O)2RJA1, -OS(=O)2RJA1, -S(=O)2OH, -S(=O)2ORJA1; and =0.
In one embodiment, each -RS2, if present, is independently selected from:
-RJA1,
-F,
-CF3,
-OH, -LJA-OH, -0RJA1, -LJA-ORJA1,
-CN,
-NH2, -NHRJA1, -NRJA1 2,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2,
-C(=O)OH, -C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, and -C(=O)NRJA1 2.
Optional Substituents on -RW2C. -RW2H. and -RZ2
In one embodiment, -RW2C, if present, is independently unsubstituted.
In one embodiment, -RW2C, if present, is independently optionally substituted with one or more substituents, -RS3.
In one embodiment, -RW2H, if present, is independently unsubstituted. In one embodiment, -RW2H, if present, is independently optionally substituted with one or more substituents, -RS3.
In one embodiment, -RZ2, if present, is independently unsubstituted. In one embodiment, -RZ2, if present, is independently optionally substituted with one or more substituents, -RS3. In one embodiment, each -RS3, if present, is independently selected from:
-RJA1,
-F, -Cl, -Br, -I, -CF3, -OCF3, -SCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH, -NRJA1-LJA-OH,
-0RJA1, -LJA-ORJA1, -O-LJA-ORJA1, -NH-LJA-ORJA1, -NRJA1-LJA-ORJA1,
-SH, -SRJA1,
-CN, -NO2,
-NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2, -O-LJA-NRJA2RJA3,
-NH-LJA-NH2, -NRJA1-LJA-NH2, -NH-LJA-NHRJA1, -NRJA1-LJA-NHRJA1, -NH-LJA-NRJA1 2, -NRJA1-LJA-NRJA1 2,
-NH-LJA-NRJA2RJA3, -NRJA1-LJA-NRJA2RJA3,
-OC(=O)RJA1,
-C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1, -C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3,
-NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)ORJA1, -NRJA1C(=O)ORJA1,
-OC(=O)NH2, -OC(=O)NHRJA1, -OC(=O)NRJA1 2, -OC(=O)NRJA2RJA3,
-NHC(=O)NH2, -NHC(=O)NHRJA1, -NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3,
-NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1,
-NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3, -S(=O)RJA1 , -S(=O)2RJA1 , -OS(=O)2RJA1 , -S(=O)2OH, and -S(=O)2ORJA1 ; or two adjacent groups -RS3, if present, together form -0-CH2-O- or -0-CH2CH2-O-.
In one embodiment, each -RS3, if present, is independently selected from:
-RJA1,
-F, -Cl, -Br,
-CF3, -OCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH, -NRJA1-LJA-OH, -0RJA1, -LJA-ORJA1, -O-LJA-ORJA1, -NH-LJA-ORJA1, -NRJA1-LJA-ORJA1,
-SRJA1, -CN,
-NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2, -O-LJA-NRJA2RJA3, -NH-LJA-NH2, -NRJA1-LJA-NH2, -NH-LJA-NHRJA1, -NRJA1-LJA-NHRJA1,
-NH-LJA-NRJA1 2, -NRJA1-LJA-NRJA1 2,
-NH-LJA-NRJA2RJA3, -NRJA1-LJA-NRJA2RJA3,
-OC(=O)RJA1,
-C(=O)OH, -C(=O)ORJA1, -C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3,
-NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3, -NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1,
-NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3, or -S(=O)2RJA1; or two adjacent groups -RS3, if present, together form -0-CH2-O- or -0-CH2CH2-O-.
In one embodiment, each -RS3, if present, is independently selected from:
-RJA1, -F1 -Cl, -Br,
-CF3, -OCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH,
-0RJA1, -LJA-ORJA1, -O-LJA-ORJA1, -NH-LJA-ORJA1,
-CN, -NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2l -LJA-NRJA2RJA3,
-O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2, -O-LJA-NRJA2RJA3,
-NH-LJA-NH2, -NRJA1-LJA-NH2, -NH-LJA-NHRJA1, -NH-LJA-NRJA1 2,
-NH-LJA-NRJA2RJA3, -C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3,
-NHC(=O)RJA1,
-NHC(=O)NH2, -NHC(=O)NHRJA1, -NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3, -S(=O)2RJA1, or two adjacent groups -RS3, if present, together form -0-CH2-O- or -0-CH2CH2-O-.
In one embodiment, each -RS3, if present, is independently selected from:
-RJA1,
-F, -Cl, -Br, -CF31 -OCF3,
-OH,
-0RJA1,
-NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-C(=O)OH, -C(=O)ORJA1, -C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3,
-NHC(=O)RJA1,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3, -NHS(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3, or two adjacent groups -RS3, if present, together form -0-CH2-O- or -0-CH2CH2-O-.
In one embodiment, each -RS3, if present, is independently selected from:
-RT1,
-F, -Cl, -Br,
-OH, -0RT1, -CF3, -OCF3,
-NH2, -NHRT1, -NRT1 2, piperidino, piperizino, N-methyl-piperizino, morpholino,
-C(=O)NH2, -C(=O)NHRT1, -C(=O)NRT1 2,
-C(=O)-piperidino, -C(=O)-piperizino, -C(=O)-N-methyl-piperizino, -C(=O)-morpholino,
-S(=O)2NH2, -S(=O)2NHRT1, -S(=O)2NRT1 2,
-S(=O)2-piperidino, -S(=O)2-piperizino,
-S(=O)2-N-methyl-piperizino, and -S(=0)2-morpholino; or two adjacent groups -RS3, if present, together form -0-CH2-O- or -0-CH2CH2-O-; wherein each -RT1 is independently saturated aliphatic C1-4alkyl, -Ph, Or -CH2-Ph, wherein -Ph is independently phenyl optionally substituted with -F, -Cl, -Br, -RT2 -OH, -ORT2, wherein each -RT2 is independently saturated aliphatic C1-4alkyl.
Elements of the Optional Substituents. -RS1, -RS2, and -RS3
In one embodiment: each -LJA-, if present, is independently saturated aliphatic Ci.5alkylene; each -NRJA2RJA3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from -RJ44, -CF3, -F, -OH, -ORJ44, -NH2, -NHRJ44, -NRJ44 2, and =0; wherein each -RJ44 is independently saturated aliphatic C1-4alkyl; each -RJA1 is independently: -RJB1 -RJB2 -RJB3 -RJB4 -RJB5 -RJB6 -RJB7 -RJB8
_ι JB_pJB4 i JB_pJB5 i JB _pJB6 i JB _pJB7 -_ i JB_pJB8. each -RJB1 is independently saturated aliphatic C1-6alkyl; each -RJB2 is independently aliphatic C2-6alkenyl; each -RJB3 is independently aliphatic C2-6alkynyl; each -RJB4 is independently saturated C3.6cycloalkyl; each -RJB5 is independently Cs^cycloalkenyl; each -RJB6 is independently non-aromatic C4-7heterocyclyl; each -RJB7 is independently C6-10carboaryl; each -RJB8 is independently C5-10heteroaryl; each -LJB- is independently saturated aliphatic Ci-3alkylene; wherein: each -RJB4, -RJB5, -RJB6, -RJB7, and -RJB8 is optionally substituted, for example, with one or more substituents -RJC1 and/or one or more substituents -RJC2, each -RJB1, -RJB2, -RJB3, and -LJB- is optionally substituted, for example, with one or more substituents -RJC2, and wherein: each -RJC1 is independently saturated aliphatic C^alkyl, phenyl, or benzyl; each -RJC2 is independently:
-F, -Cl, -Br, -I, -CF3, -OCF3, -SCF3,
-OH, -LJD-OH, -O-LJD-OH, -0RJD1, -LJD-ORJD1, -O-LJD-ORJD1, -SH, -SRJD1, -CN, -NO2,
-NH2, -NHRJD1, -NRJD1 2l -NRJD2RJD3, -LJD-NH2l -LJD-NHRJD1, -LJD-NRJD1 2, -LJD-NRJD2RJD3, -C(=O)OH, -C(=O)ORJD1,
-C(=O)NH2, -C(=O)NHRJD1, -C(=O)NRJD1 2, or -C(=O)NRJD2RJD3; wherein: each -RJD1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -LJD- is independently saturated aliphatic C^alkylene; and each -NRJD2RJD3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from -RJ55, -CF3, -F, -OH, -ORJ55, -NH2, -NHRJ55, -NRJ55 2, and =0; wherein each -RJ55 is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -LJA-, if present, is independently -(CH2)n2-, wherein n2 is independently 1 to 4.
In one embodiment, each -LJA-, if present, is independently -CH2- or -CH2CH2-.
In one embodiment, each -NRJA2RJA3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -RJ44, -CF3, -F, -OH1 -ORJ44, -NH2, -NHRJ44, -NRJ44 2, and =0; wherein each -RJ44 is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -NRJA2RJA3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -RJ44; wherein each -RJ44 is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -RJA1, if present, is independently:
Figure imgf000025_0001
|_JB RJB4 -I JB_RJB6 _| JB_pJB7 __ I JB_pJB8
In one embodiment, each -RJA1, if present, is independently:
Figure imgf000025_0002
, -LJB-RJB'7, RJB6, or -LJB-RJB8.
In one embodiment, each -RJA1, if present, is independently: -RJB1, -RJB6, -RJB7, or -LJB-RJB7.
In one embodiment, each -RJB6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted. In one embodiment, each -RJB6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
In one embodiment, each -RJB7, if present, is independently phenyl, and is optionally substituted.
In one embodiment, each -RJB8, if present, is independently C5.6heteroaryl, and is optionally substituted.
In one embodiment, each -RJB8, if present, is independently C9.i0heteroaryl, and is optionally substituted.
In one embodiment, each -RJB8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
In one embodiment, each -RJB8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, each -LJB-, if present, is independently -CH2- or -CH2CH2-. In one embodiment, each -LJB-, if present, is independently -CH2-.
In one embodiment, each -RJC1, if present, is independently saturated aliphatic C^alkyl.
In one embodiment, each -RJC2 is independently: -F, -Cl1 -Br, -I1 -OH, -ORJD1, -CN,
-NO2, -NH2, -NHRJD1, -NRJD1 2, or -NRJD2RJD3.
In one embodiment, each -RJD1, if present, is independently saturated aliphatic C1-4alkyl. In one embodiment, each -LJD-, if present, is independently -(CH2)m2-, wherein m2 is independently 1 to 4.
In one embodiment, each -LJD-, if present, is independently -CH2- or -CH2CH2-.
In one embodiment, each -NRJD2RJD3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -RJ55, -CF3, -F, -OH, -ORJ55, -NH2, -NHRJ55, -NRJ55 2, and =0; wherein each -RJ55 is independently saturated aliphatic
Figure imgf000027_0001
In one embodiment, each -NRJD2RJD3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -RJ55; wherein each -RJ55 is independently saturated aliphatic C1-4alkyl.
Molecular Weight
In one embodiment, the TCA compound has a molecular weight of from 186 to 1200. In one embodiment, the bottom of range is 200, 225, 250, 275, 300, or 350. In one embodiment, the top of range is 1100, 1000, 900, 800, 700, or 600. In one embodiment, the range is from 225 to 600.
Combinations
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., ~RW, -Rz-, -RW1, -RW2, -Lw-, -RW2C, -RW2H, -RZ1, -RZ2, -RZ3, -LZ1-, -LZ2-, -RZN1, -NRZN2RZN3, -R22, -RS1, -RS2, -RS3, -RJA1, -LJ\
_HgpJA2pJA3 _pJ44 _pJB1 _RJB2 _pJB3 _pJB4 _pJB5 _pJB6 _pJB7 _pJB8 i JB_ _RJC1 _RJC2
_R JDI _|_JD_ _NR JD2 RJD3 _R j55 etc ^ are specjfjca||y embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterised, and tested for biological activity). In addition, all sub-combinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. Examples of Specific Embodiments
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Substantially Purified Forms
One aspect of the present invention pertains to TCA compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants. In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
Unless specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
Chiralitv
In some embodiments (for example, according to the choice of -Rz), the compound may have a chiral centre.
The chiral centre, or each chiral centre, if more than one is present, is independently in the R-configuration or the S-configuration.
If no configuration is indicated, then both configurations are encompassed. lsomers
Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C1-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
Figure imgf000033_0001
keto enol enolate
Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; and the like.
Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
Salts
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL, Vol. 66, pp. 1-19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO ), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)/.
If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be -NH3 +), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
Unless otherwise specified, a reference to a particular compound also includes salt forms thereof. Solvates and Hydrates
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof.
Chemically Protected Forms
It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.
For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc). For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CHa)2C6H4C6H5, -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O»).
For example, a carboxylic acid group may be protected as an ester for example, as: an Ci.7alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci.7haloalkyl ester (e.g., a C1-7trihaloalkyl ester); a triC1-7alkylsilyl-Ci.7alkyl ester; or a C5.20aryl-Ci.7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).
Prodrugs
It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Chemical Synthesis
Several methods for the chemical synthesis of thiazole carboxylic acid amide (TCA) compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
In one approach, compounds of type (7) are prepared as shown in the following scheme. Chloroamides (3) are prepared by treatment of chloroacetyl chloride (1) with the appropriate primary or secondary amine (2), typically in dichloromethane and typically in the presence of a tertiary amine base such as triethylamine or Hϋnig's base. Further treatment with the appropriate isothiocyanate (4) and cyanamide (5), typically in combination with a base, such as potassium tert-butoxide, yields compounds of type (6). Where these do not spontaneously cyclise, base-mediated cyclisation can be effected by heating, typically by microwave irradiation, to give the target compounds (7).
Scheme 1
Figure imgf000037_0001
Compositions
One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising a TCA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a TCA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. Uses
The compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function, such as, for example, proliferative conditions, cancer, etc.
Use in Methods of Inhibiting CHK1 and/or CHK2
One aspect of the present invention pertains to a method of inhibiting CHK1 kinase function and/or CHK2 kinase function, in vitro or in vivo, comprising contacting a CHK1 kinase and/or a CHK2 kinase with an effective amount of a TCA compound, as described herein.
One aspect of the present invention pertains to a method of inhibiting CHK1 kinase function and/or CHK2 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a TCA compound, as described herein.
In one embodiment, the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Suitable assays for determining CHK1 kinase function inhibition and/or CHK2 kinase function inhibition are described herein and/or are known in the art.
Use in Methods of Inhibiting Cell Proliferation, Etc.
The TCA compounds described herein, e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these.
One aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a TCA compound, as described herein.
In one embodiment, the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting a cell with an effective amount of a TCA compound, as described herein. In one embodiment, the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo.
In one embodiment, the TCA compound is provided in the form of a pharmaceutically acceptable composition.
Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described herein.
For example, a sample of cells (e.g., from a tumour) may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.
Use in Methods of Therapy
Another aspect of the present invention pertains to a TCA compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
In one embodiment, the method of treatment comprises treatment with both (i) a TCA compound, as described herein, and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, for use in a method of treatment of the human or animal body by therapy, wherein the method of treatment comprises treatment with both (i) a TCA compound, as described herein, and (a) the DNA topoisomerase I or Il inhibitor, (b) the DNA damaging agent, (c) the antimetabolite or TS inhibitor, or (d) the microtubule targeted agent.
Use in the Manufacture of Medicaments
Another aspect of the present invention pertains to use of a TCA compound, as described herein, in the manufacture of a medicament for use in treatment.
In one embodiment, the medicament comprises the TCA compound.
In one embodiment, the treatment comprises treatment with both (i) a medicament comprising a TCA compound, as described herein, and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to use of (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, in the manufacture of a medicament for use in a treatment, wherein the treatment comprises treatment with both (i) a TCA compound, as described herein, and (a) the DNA topoisomerase I or Il inhibitor, (b) the DNA damaging agent, (c) the antimetabolite or TS inhibitor, or (d) the microtubule targeted agent.
Methods of Treatment
Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a TCA compound, as described herein, preferably in the form of a pharmaceutical composition.
In one embodiment, the method further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation. Conditions Treated - Conditions Mediated by CHK1 and/or CHK2
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disease or condition that is mediated by CHK1 and/or CHK2.
Conditions Treated - Conditions Ameliorated by the Inhibition of CHK1 Kinase Function and/or CHK2 Kinase Function
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disease or condition that is ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function.
Conditions Treated - Proliferative Conditions and Cancer
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a proliferative condition.
The term "proliferative condition," as used herein, pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth.
In one embodiment, the treatment is treatment of: a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
In one embodiment, the treatment is treatment of: cancer.
In one embodiment, the treatment is treatment of: p53 negative cancer.
In one embodiment, the treatment is treatment of: lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer (e.g., head cancer, neck cancer), skin cancer, squamous cancer, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.
In one embodiment, the treatment is treatment of: a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma); a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia; a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentoum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
In one embodiment, the treatment is treatment of solid tumour cancer.
In one embodiment, the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis
(programmed cell death). The compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein.
Treatment
The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment."
For example, treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.
The term "therapeutical ly-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
Combination Therapies
The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, cytotoxic agents, anticancer agents, etc. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.
For example, it may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1, 2, 3, 4) agents or therapies that regulates cell growth or survival or differentiation via a different mechanism, thus treating several characteristic features of cancer development.
One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.
The particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.
The agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
The agents (i.e., the compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
Combination Therapies Employing DNA Damaging Agents
As discussed herein, in some embodiments, the TCA compound is employed in combination with (e.g., in conjunction with) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
When both a TCA compound and one or more other agents are employed, they may be used (e.g., contacted, administered, etc.) in any order. Furthermore, they may be used (e.g., contacted, administered, etc.) together, as part of a single formulation, or separately, as separate formulations.
For example, in regard to methods of treatment employing both a TCA compound and one or more other agents, treatment with (e.g., administration of) the TCA compound may be prior to, concurrent with, or may follow, treatment with (e.g., administration of) the one or more other agents, or a combination thereof.
In one embodiment, treatment with (e.g., administration of) a TCA compound is concurrent with, or follows, treatment with (e.g., administration of) the one or more other agents.
In one embodiment, the one or more other agents is a DNA topoisomerase I or Il inhibitor; for example, Etoposide, Toptecan, Camptothecin, Irinotecan, SN-38, Doxorubicin, Daunorubicin.
In one embodiment, the one or more other agents is a DNA damaging agent; for example, alkylating agents, platinating agents, or compounds that generate free radicals; for example, Temozolomide, Cisplatin, Carboplatin, Mitomycin C, Cyclophosphamide, BCNU, CCNU, Bleomycin. In one embodiment, the one or more other agents is an antimetabolite or TS inhibitor; for example, 5-fluorouracil, hydroxyurea, Gemcitabine, Arabinosylcytosine, Fludarabine, Tomudex, ZD9331.
In one embodiment, the one or more other agents is a microtubule targeted agent; for example, Paclitaxel, Docetaxel, Vincristine, Vinblastine.
In one embodiment, the one or more other agents is ionising radiation (e.g., as part of radiotherapy).
Other Uses
The TCA compounds described herein may also be used as cell culture additives to inhibit CHK1 kinase function and/or CHK2 kinase function, e.g., to inhibit cell proliferation, etc.
The TCA compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
The TCA compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other CHK1 kinase function, other CHK2 kinase function inhibitors, other anti-proliferative agents, other anti-cancer agents, etc.
Kjts
One aspect of the invention pertains to a kit comprising (a) a TCA compound as described herein, or a composition comprising a TCA compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
In one embodiment, the kit further comprises one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; and (d) a microtubule targeted agent.
The written instructions may also include a list of indications for which the active ingredient is a suitable treatment. Routes of Administration
The TCA compound or pharmaceutical composition comprising the TCA compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
The Subject/Patient
The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.
In one preferred embodiment, the subject/patient is a human.
Formulations
While it is possible for the TCA compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one TCA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one TCA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences. 18th edition, Mack Publishing
Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers
(e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non- aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols. Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
The compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier.
Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs. Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
Typically, the concentration of the compound in the liquid is from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 μg/ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
Dosage
It will be appreciated by one of skill in the art that appropriate dosages of the TCA compounds, and compositions comprising the TCA compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular TCA compound, the route of administration, the time of administration, the rate of excretion of the TCA compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of TCA compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician. In general, a suitable dose of the TCA compound is in the range of about 10 μg to about 250 mg (more typically about 100 μg to about 25 mg) per kilogram body weight of the subject per day. Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
EXAMPLES
The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.
Chemical Synthesis
LCMS Conditions:
Solvent A (Aqueous):
0.02% Ammonia and 0.063% ammonium formate in water.
Solvent B (Organic):
0.02% Ammonia and 5% Buffer A in acetonitrile.
LCMS Method:
Column: Phenomenex Gemini C18, 5 μm, 4.6 x 30 mm. Injection Volume: 5 μl_. UV detection: 220 to 400 nm. Column Temperature: 35°C.
0.00 to 4.25 min: 95% A to 5% A.
4.25 to 5.80 min: 5% A.
5.80 to 5.90 min: 5% A to 95% A. 5.90 to 7.00 min: 95% A.
(all at 2.0 mL/min). Synthesis 1 (S)-4-amino-2-(phenylamino)-N-(piperidin-3-yl)thiazole-5-carboxamide (TCA-001)
Figure imgf000053_0001
Chloroacetyl chloride (0.08 mL, 1 mmol) was added in one portion to (S)-3-amino-1-N- Boc-piperidine (200 mg, 1 mmol) and Hϋnig's base (0.261 mL, 1.5 mmol) in dichloromethane (5 mL). After stirring for 30 minutes, the reaction mixture was diluted with water and dichloromethane. The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to give the crude chloroamide intermediate. In a separate vessel, potassium t-butoxide (112 mg, 1 mmol) was added portionwise to a stirred mixture of cyanamide (42 mg, 1 mmol) and phenylisothiocyanate (0.119 mL, 1mmol) in acetonitrile (0.5 mL). When the mixture had cooled to room temperature, a solution of the crude chloroamide in MeCN (1.5 mL) was added portionwise. The resulting mixture was heated at 50GC for 1 hour and then poured into water (50 mL) and diluted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated to a brown oil which solidified on standing. The solid was dissolved in a mixture of acetonitrile (5 mL) and triethylamine (0.2 mL) and irradiated in a microwave reactor at 140°C for 2 x 5 minutes. The mixture was diluted with methanol and the product was simultaneously isolated and deprotected by solid phase extraction on a 1g MP-TsOH cartridge, eluting with 2 M ammonia in methanol. The basic eluent was concentrated and the residue purified by preparative HPLC to give the title compound (21 mg, 0.066 mmol, 6.6%). Rt = 2.17 min, 318 (M+H)+. 1H NMR: δ (ppm, d-6 DMSO, 400 MHz) 7.71 (s, 1 H), 6.75 (d, 2H, J = 7.8Hz), 6.51 (dd, 2H, J = 7.3, 8.6Hz)1 6.25 (t, 1 H, J = 7.4Hz), 3.26-3.57 (m, 1 H), 2.56-2.63 (m, 1 H), 2.45- 2.53 (m, 1 H, partially obscured by DMSO signal), 2.04-2.13 (m, 1 H), 1.96-2.04 (m, 1 H), 1.15-1.285 (m, 2H), 0.92-1.04 (m, 1H), 0.76-0.88 (m, 1 H).
The following compounds were prepared in a similar manner using the appropriate amine in place of (S)-3-amino-1-N-Boc-piperidine and the appropriate isothiocyanate in place of phenylisothiocyanate.
Figure imgf000054_0001
Compound Name Structure
(S)-4-amino-2-(4- methoxyphenylamino)-N-
TCA-006 (piperidin-3-yl)thiazole-5- carboxamide
Rt = 2.22 min, 348 (M+H)+
(S)-4-amino-2-(3- methoxyphenylamino)-N-
TCA-007 (piperidin-3-yl)thiazole-5- carboxamide
Rt = 2.33 min, 348 (M+H)+
4-amino-N-(2-aminoethyl)-
2-(phenylamino)thiazole-5- carboxamide
Figure imgf000055_0001
TCA-008 1H NMR: δ (ppm, MeOD, 400MHz) 7.57 (d, 2H, J = 8.6Hz), 7.41-7.31
Rt = 1.89 min, 278 (M+H)+ (3H, m), 7.06 (t, 1 H), 3.40-3.30 (m, 2H, partially obscured by methanol signal), 2.79 (t, 2H, J = 6.2Hz)
(R)-4-amino-2-
(phenylamino)-N-
(piperidin-3-yl)thiazole-5- carboxamide
Figure imgf000055_0002
1H NMR: δ (ppm, CDCI3, 400MHz)
7.40-7.33 (m, 4H); 7.17-7.12 (m,
TCA-009
1H); 5.97 (S, 2H); 5.37 (s, 1H);
4.06-3.98 (m, 1 H); 3.47 (s, 1 H);
Rt = 2.24 min, 318 (M+H)+
3.05 (dd, 1 H1 J = 3.0,14.5Hz);
2.82-2.69 (m, 2H); 2.64-2.59 (m,
1 H); 1.83-1.76 (m, 2H); 1.73-1.65
(m, 2H); 1.61-1.45 (m, 3H).
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Biological Methods
Measurement of Inhibition of CHK1 Kinase Function
CHK1 kinase function was measured in a DELFIA® assay in order to monitor phosphorylation of a CDC25C peptide using a specific phospho antibody.
The enzyme reaction was carried out in polypropylene plates (Greiner) using a reaction mix (25 μL) containing enzyme and peptide mix (CHK1 , 1 nM; Biotin- KKKVSRSGLYRSPSMPENLNRPR, 1 μM or 15 μL), ATP (30 μM or 5 μL) and either DMSO (2.5%) or test compound (5 μL) diluted to a give a range of concentrations (from 0 to 100 μM in 2.5% DMSO, final concentrations) in assay buffer (40 mM Tris, 40 mM NaCI, 2 mM MgCI2, 1 mM DTT and 0.1% Tween 20). The reaction mixture was incubated for 30 minutes at room temperature and then stopped by the addition of buffer (125 μL) containing 40 mM EDTA, 0.05% Tween 20, 0.1% BSA in TBS (10x concentrate, Sigma). An aliquot (100 μL) of the stopped reaction mixture was transferred to a black neutravidin- coated plate (Perbio) and incubated for 1 hour on a shaker (Titertek, Flow Laboratories) at room temperature. The plates were washed four times with wash buffer (25 mM Tris (pH 8), 150 mM NaCI, and 0.1% Tween 20) (WellWash4, Thermo Life Sciences) and incubated for 1 hour as before with an antibody mixture (100 μL) consisting of anti- phospho CDC25C (1.25 nM, #9528, Cell Signalling Technology) and europium-labelled anti-rabbit IgG (0.3 μg/mL, AD0105, PerkinElmer Life Sciences) diluted in DELFIA assay buffer (PerkinElmer Life Sciences). The plates were washed a further four times with wash buffer before the addition of enhancement solution (100 μL/well, PerkinElmer Life Sciences). The plate was read on a Victor2 1420 multi-label counter (Perkin Elmer Life Sciences) using a time-resolved measurement mode reading fluorescence at 615 nm. The concentration of test compound required to inhibit enzyme activity by 50% was calculated (IC50). Measurement of Inhibition of CHK2 Kinase Function
CHK2 kinase activity was measured in a DELFIA® assay that monitors phosphorylation of a CDC25C peptide using a specific phospho antibody.
The enzyme reaction was carried out in 96-well polypropylene plates (Greiner). The reaction mix (total volume 25 μl_) contained enzyme and peptide mix (15 μl_) (containing CHK2, 1 nM; Biotin-KKKVSRSGLYRSPSMPENLNRPR, 1 μM), ATP (30 μM, 5 μl_) and either DMSO (2.5%) or test compound (5 μl_) diluted to a give a range of concentrations (0-100 μM in 2.5% DMSO, final concentrations) in assay buffer (40 mM HEPES (pH7.4), 40 mM KCI, 2 mM MgCI2, 10 mM DTT and 0.02% Tween 20). The reaction mixture was incubated for 30 minutes at room temperature and stopped by the addition of buffer (125 μl_) containing 40 mM EDTA, 0.05% Tween 20, 0.1% BSA in TBS (10x concentrate, Sigma). An aliquot (100 μl_) of the reaction mix was transferred to a black neutravidin- coated 96-well plate (Perbio) and incubated for 1 hour on a shaker (Titertek, Flow
Laboratories) at room temperature. The plates were washed four times with wash buffer (25 mM Tris (pH 8), 150 mM NaCI and 0.1% Tween 20) (WellWash4, Thermo Life Sciences) and incubated for 1 hour as before with antibody mix (100 μL) consisting of anti-phospho CDC25C (diluted 1/4000 equivalent to 0.35 nM-1.25 nM, #9528, Cell Signalling Technology) and europium-labelled anti-rabbit IgG, (0.3 μg/mL, AD0105,
PerkinElmer Life Sciences) diluted in DELFIA assay buffer (PerkinElmer Life Sciences). The plates were washed a further four times with wash buffer before the addition of enhancement solution (100 μL/well, PerkinElmer Life Sciences). The plate was read on a Victor2 1420 multilabel counter (PerkinElmer Life Sciences) using a time-resolved measurement mode reading fluorescence at 615 nM. The concentration of test compound required to inhibit enzyme activity by 50% was calculated (IC50).
Cytotoxicity Assay (SRB)
HT29 colon carcinoma cells were obtained from ATCC (Rockville, MD, USA). Cells were grown in DMEM supplemented with 10% foetal calf serum and containing L-glutamine 5 mM, glucose, penicillin, and streptomycin. Cells were grown at 37°C in a dry 5% CO2 atmosphere. Cytotoxicity assays were carried out in 96-well plates using quadruplicate wells for each dose. Cells were seeded at 1.6 x 103 per well in 160 μL medium and were allowed to attach for 36 hours prior to treatment. Test compounds were dissolved in DMSO at 10 mM and serially diluted in culture medium to 5 x final concentration prior to addition in a volume of 40 μL per well. Cells were left for 4 doublings (96 hours) in the presence of the test compounds and then fixed in 10% trichloroacetic acid for 30 minutes, washed in water, and dried. The fixed cells were stained with Sulfurhodamine B (SRB, 0.4% in 1 % acetic acid, Sigma, Dorset, UK) for 30 minutes, washed in 1% acetic acid, and dried. SRB was resolubilised in 10 mM Tris base and the optical density (OD) was measured at 490 nm. Results were expressed relative to untreated controls and the concentration of compound required to inhibit growth by 50% (SRB IC50) was calculated.
Mitosis Inhibition Assay (MIA)
Checkpoint abrogation by CHK1 kinase function inhibitors in combination with genotoxic agents was assessed using a europium based ELISA assay designed to quantify the number of cells trapped in mitosis after treatment with a genotoxic agent (to induce G2 arrest) followed by a test compound in combination with nocodazole to abrogate this arrest.
HT29 cells were seeded at 104 cells per well into 96 well plates in a volume of 160 μL and left to attach for 36 hours. Etoposide (10 mM stock in DMSO) was diluted in medium to 250 μM and then 40 μL was added to appropriate wells to give a final concentration of 50 μM and incubated for 1 hour. This treatment had previously been optimised to induce a G2 arrest in 80% of cells 16 hours following treatment. After genotoxic drug exposure, the medium was removed and replaced with fresh medium (160 μL). Cells were either untreated (untreated control or etoposide pre-treatment alone), exposed to nocodazole following etoposide pre-treatment or nocodazole alone (100 ng/mL final concentration), or exposed to increasing concentrations of test compound (200 μM - 0.01 nM final concentration) in combination with nocodazole (100 ng/mL final concentration). Test compounds were added in 40 μL using quadruplicate wells for each dose. After 21 hours exposure, the medium was removed and cells were fixed in 4% formaldehyde in phosphate buffered saline (PBS, pH 7.4, pre-cooled to 4°C) for 30 minutes at 40C, followed by 100% methanol (pre-cooled to -200C) for 10 minutes at ambient temperature. Wells were washed with PBS and blocked with 5% dried milk (Marvel) in Tris-buffered saline (TBS, pH 7.4) at 370C for 30 minutes. Each well was washed three times with water containing 0.1% Tween 20. Primary antibody (MPM-2, Upstate cat# 05-368, 1 μg/mL in 5% milk in TBS) was added to each well and incubated overnight with shaking at 40C. Primary antibody was removed and wells were washed with water containing 0.1 % Tween 20. The secondary antibody (europium labelled anti-mouse, Perkin-Elmer Catalog Number AD0124, 333 ng/mL in assay buffer Perkin-Elmer Catalog Number 1244- 111) was added to each well and incubated at 37°C for 1 hour. Each well was washed with water 0.1% containing Tween 20 and treated with enhancement solution (Perkin- Elmer Catalog Number 1244-105). Europium emissions were counted on a Wallac,
Victor2 counter (Perkin-Elmer, Bucks UK). Appropriate controls were included and results were expressed as the concentration of test compound required to allow 50% of cells to enter mitosis (MIA IC50). Biological Data
Biological data were obtained using the CHK1 kinase function inhibition assay described above for the following compounds: TCA-001 through TCA-022.
For the CHK1 kinase function inhibition assay, all of the compounds had IC50 values of less than 100 μM.
For the CHK1 kinase function inhibition assay, the following compounds had IC50 values of 50 μM or less: TCA-001 , TCA-002, TCA-003, TCA-004, TCA-005, TCA-006, TCA-007, TCA-009, TCA-010, TCA-011 , TCA-012, TCA-013, TCA-014, TCA-015, TCA-016, TCA-017, TCA-018, TCA-019, TCA-020, TCA-021 , TCA-022,
For the CHK1 kinase function inhibition assay, the following compounds had IC50 values of 10 μM or less: TCA-001 , TCA-003, TCA-004, TCA-005, TCA-006, TCA-007, TCA-010, TCA-011 , TCA-013, TCA-014, TCA-015, TCA-017, TCA-018, TCA-019, TCA-020.
One compound, compound TCA-001 , had an IC50 value of 1.2 μM.
Biological data were obtained using the CHK2 kinase function inhibition assay described above for the following compounds: TCA-001 , TCA-003, TCA-005, TCA-006, TCA-007, TCA-008, TCA-010, TCA-011 , TCA-013, TCA-014, TCA-017, TCA-018, TCA-019, TCA-020.
For the CHK2 kinase function inhibition assay, all of the compounds had IC50 values of less than 1 μM.
For the CHK2 kinase function inhibition assay, the following compounds had IC50 values of 0.1 μM or less: TCA-001 , TCA-006, TCA-013, TCA-014, TCA-018, TCA-019.
One compound, compound TCA-001 , had an IC50 value of 0.09 μM.
Biological data were obtained using the cytotoxicity assay (SRB) described above for the following compounds: TCA-001 , TCA-013, TCA-014, TCA-017, TCA-019.
One compound, compound TCA-001 , had an IC50 value of 38 μM. Biological data were obtained using the mitosis inhibition assay (MIA) described above for the following compounds: TCA-001 , TCA-013, TCA-014, TCA-017, TCA-019.
One compound, compound TCA-001 , had an IC50 value of 5 μM.
The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.
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Claims

1. A compound selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000067_0001
wherein:
-Rw is independently -RW1, -RW2, or -LW-RW2;
wherein: -RW1 is independently saturated aliphatic Ci-6alkyl, and is optionally substituted;
-RW2 is independently -RW2C or -RW2H;
-RW2C is independently C6-i0carboaryl, and is optionally substituted;
-RW2H is independently C5.i4heteroaryl, and is optionally substituted; and
-Lw- is independently saturated aliphatic C1-4alkylene;
and wherein:
-Rz is independently -RZ1, -LZ1-RZ1, -RZ2, -LZ1-RZ2, or -LZ2-RZ3,
wherein: -RZ1 is independently saturated C4.7heterocyclyl, and is optionally substituted;
-RZ2 is independently C5.14heteroaryl, and is optionally substituted;
-LZ1- is independently saturated aliphatic C^alkylene;
-LZ2- is independently saturated aliphatic C2.6alkylene;
-RZ3 is independently -NH2, -NHRZN1, -N(RZN1)2, or -NRZN2RZN3; each -RZN1 is independently saturated aliphatic C1-6alkyl, phenyl, or benzyl; and
-NRZN2RZN3 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted.
2. A compound according to claim 1, wherein -Rw is independently -RW1.
3. A compound according to claim 1 , wherein -Rw is independently -RW2.
4. A compound according to claim 1 , wherein -Rw is independently -LW-RW2.
5. A compound according to any one of claims 1 to 4, wherein -RW1, if present, is independently saturated aliphatic
Figure imgf000068_0001
and is optionally substituted.
6. A compound according to any one of claims 1 to 4, wherein -RW1, if present, is independently saturated aliphatic
Figure imgf000068_0002
7. A compound according to any one of claims 1 to 4, wherein -RW1, if present, is independently -Me.
8. A compound according to any one of claims 1 to 7, wherein -RW2, if present, is independently -RW2C.
9. A compound according to any one of claims 1 to 7, wherein -RW2, if present, is independently -RW2H.
10. A compound according to any one of claims 1 to 9, wherein -RW2C, if present, is independently phenyl or naphthyl, and is optionally substituted.
11. A compound according to any one of claims 1 to 9, wherein -RW2C, if present, is independently phenyl, and is optionally substituted.
12. A compound according to any one of claims 1 to 11 , wherein -RW2H, if present, is independently C5.10heteroaryl, and is optionally substituted.
13. A compound according to any one of claims 1 to 11 , wherein -RW2H, if present, is independently C5.6heteroaryl, and is optionally substituted.
14. A compound according to any one of claims 1 to 11 , wherein -RW2H, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, or benzopyridazinyl, and is optionally substituted.
15. A compound according to any one of claims 1 to 11 , wherein -RW2H, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,. pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
16. A compound according to any one of claims 1 to 11 , wherein -RW2H, if present, is independently thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, or pyrimidinyl, and is optionally substituted.
17. A compound according to any one of claims 1 to 16, wherein -Lw-, if present, is independently saturated linear C1-4alkylene.
18. A compound according to any one of claims 1 to 16, wherein -Lw-, if present, is independently -CH2- or -CH2CH2-.
19. A compound according to any one of claims 1 to 16, wherein -Lw-, if present, is independently -CH2-.
20. A compound according to any one of claims 1 to 19, wherein -Rz is independently -Rz1, -Lz1-Rz1, -RZ2, or -Lz1-RZ2.
21. A compound according to any one of claims 1 to 19, wherein -Rz is independently -Rz1 or -Lz1-Rz1.
22. A compound according to any one of claims 1 to 19, wherein -Rz is independently -RZ1.
23. A compound according to any one of claims 1 to 19, wherein -Rz is independently -LZ1-RZ1.
24. A compound according to any one of claims 1 to 19, wherein -Rz is independently -RZ2 or -Lz1-RZ2.
25. A compound according to any one of claims 1 to 19, wherein -Rz is independently -RZ2.
26. A compound according to any one of claims 1 to 19, wherein -Rz is independently -L21-RZ2.
27. A compound according to any one of claims 1 to 19, wherein -Rz is independently -LZ2-RZ3.
28. A compound according to any one of claims 1 to 27, wherein -RZ1, if present, is independently saturated C^heterocyclyl having at least one ring nitrogen atom, and is optionally substituted.
29. A compound according to any one of claims 1 to 27, wherein -RZ1, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, or diazepinyl, and is optionally substituted.
30. A compound according to any one of claims 1 to 27, wherein -RZ1, if present, is independently azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or azepinyl, and is optionally substituted.
31. A compound according to any one of claims 1 to 27, wherein -RZ1, if present, is independently azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, azepin-3-yl, or azepin-4-yl, and is optionally substituted.
32. A compound according to any one of claims 1 to 27, wherein -RZ1, if present, is independently selected from the following, wherein -R22 is independently -H or saturated aliphatic C1-4alkyl:
Figure imgf000070_0001
33. A compound according to any one of claims 1 to 27, wherein -RZ1, if present, is independently selected from the following, wherein -Rzz is independently -H or saturated aliphatic d^alkyl:
Figure imgf000071_0001
34. A compound according to any one of claims 1 to 27, wherein -RZ1, if present, is independently selected from the following, wherein -R22 is independently -H or saturated aliphatic C1-4alkyl:
Figure imgf000071_0002
35. A compound according to any one of claims 1 to 27, wherein -RZ1, if present, is independently selected from the following, wherein -R22 is independently -H or saturated aliphatic C^alkyl:
Figure imgf000071_0003
36. A compound according to any one of claims 32 to 35, wherein -R22 is -H.
37. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently C5-i0heteroaryl, and is optionally substituted.
38. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently Cs^heteroaryl, and is optionally substituted.
39. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, or benzopyridazinyl, and is optionally substituted.
40. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyrazinyl, pyridazinyl, and is optionally substituted.
41. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
42. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
43. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
44. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently pyridyl, and is optionally substituted.
45. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently pyrid-2-yl, and is optionally substituted.
46. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently pyrid-3-yl, and is optionally substituted.
47. A compound according to any one of claims 1 to 36, wherein -RZ2, if present, is independently pyrid-4-yl, and is optionally substituted.
48. A compound according to any one of claims 1 to 47, wherein -LZ1-, if present, is independently saturated linear C1-4alkylene.
49. A compound according to any one of claims 1 to 47, wherein -LZ1-, if present, is independently -CH2- or -CH2CH2-.
50. A compound according to any one of claims 1 to 47, wherein -LZ1-, if present, is independently -CH2-.
51. A compound according to any one of claims 1 to 50, wherein -LZ2-, if present, is independently saturated aliphatic C2-4alkylene.
52. A compound according to any one of claims 1 to 50, wherein -LZ2-, if present, is independently -(CH2)P-, wherein p is 2, 3, or 4.
53. A compound according to any one of claims 1 to 50, wherein -LZ2-, if present, is independently -(CH2)2-.
54. A compound according to any one of claims 1 to 50, wherein -LZ2-, if present, is independently -(CH2)3-.
55. A compound according to any one of claims 1 to 50, wherein -LZ2-, if present, is independently -(CH2J4-.
56. A compound according to any one of claims 1 to 55, wherein -RZ3, if present, is independently -NH2, -NHRZN1, or -N(RZN1)2.
57. A compound according to any one of claims 1 to 55, wherein -RZ3, if present, is independently -NH2.
58. A compound according to any one of claims 1 to 55, wherein -RZ3, if present, is independently -NHRZN1.
59. A compound according to any one of claims 1 to 55, wherein -RZ3, if present, is independently -N(RZN1)2.
60. A compound according to any one of claims 1 to 55, wherein -RZ3, if present, is independently -NRZN2RZN3.
61. A compound according to any one of claims 1 to 60, wherein each -RZN1, if present, is independently saturated aliphatic Ci.βalkyl.
62. A compound according to any one of claims 1 to 60, wherein each -RZN1, if present, is independently saturated aliphatic C1-4alkyl.
63. A compound according to any one of claims 1 to 62, wherein -NRZN2RZN3, if present, is independently pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, or morpholino, and is optionally substituted.
64. A compound according to any one of claims 1 to 62, wherein -NRZN2RZN3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted.
65. A compound according to any one of claims 1 to 64, wherein:
-RW1, if present, is optionally substituted with one or more substituents, -RS1, wherein each -RS1 is independently selected from:
-RJA1, -F,
-CF3, -OCF3, -SCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH, -NRJA1-LJA-OH,
-ORJA1, -LJA-ORJA1, -O-LJA-ORJA1, -NH-LJA-ORJA1, -NRJA1-LJA-ORJA1,
-SH, -SRJA1, -CN,
-NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2l -O-LJA-NRJA2RJA3,
-NH-LJA-NH2, -NRJA1-LJA-NH2, -NH-LJA-NHRJA1, -NRJA1-LJA-NHRJA1, -NH-LJA-NRJA1 2, -NRJA1-LJA-NRJA12,
-NH-LJA-NRJA2RJA3, -NRJA1-LJA-NRJA2RJA3, -OC(=O)RJA1,
-C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3, -NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)ORJA1, -NRJA1C(=O)ORJA1,
-OC(=O)NH2, -OC(=O)NHRJA1, -OC(=O)NRJA1 2, -OC(=O)NRJA2RJA3,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2l -NHC(=O)NRJA2RJA3, -NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1,
-NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3,
-S(=O)RJA1, -S(=O)2RJA1, -OS(=O)2RJA1, -S(=O)2OH, -S(=O)2ORJA1; and =0; or two adjacent groups -RS3, if present, together form -0-CH2-O- or
-0-CH2CH2-O-I;
each of -RZ1, if present, and -NRZN2RZN3, if present, is independently optionally substituted with one or more substituents, -RS2, wherein each -RS2 is independently selected from:
-RJA1,
-F, -CF3, -OCF3, -SCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH, -NRJA1-LJA-OH,
-0RJA1, -LJA-ORJA1, -O-LJA-ORJA1, -NH-LJA-ORJA1, -NRJA1-LJA-ORJA1,
-SH, -SRJA1,
-CN, -NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2, -O-LJA-NRJA2RJA3,
-NH-LJA-NH2, -NRJA1-LJA-NH2l -NH-LJA-NHRJA1, -NRJA1-LJA-NHRJA1,
-NH-LJA-NRJA1 2, -NRJA1-LJA-NRJA1 2, -NH-LJA-NRJA2RJA3, -NRJA1-LJA-NRJA2RJA3,
-OC(=O)RJA1,
-C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3, -NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)ORJA1, -NRJA1C(=O)ORJA1, -OC(=O)NH2, -OC(=O)NHRJA1, -OC(=O)NRJA1 2, -OC(=O)NRJA2RJA3, -NHC(=O)NH2, -NHC(=O)NHRJA1, -NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3, -NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1, -NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3, -S(=O)RJA1, -S(=O)2RJA1, -OS(=O)2RJA1, -S(=O)2OH, -S(=O)2ORJA1; and =0;
each of -RW2C, if present, -RW2H, if present, and -RZ2, if present, is independently optionally substituted with one or more substituents, -RS3, wherein each -RS3 is independently selected from:
-RJA1,
-F, -Cl, -Br, -I,
-CF3, -OCF3, -SCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH, -NRJA1-LJA-OH,
.ORJAI .LJA -0RJAi 1 .0-LJA-ORJA1, -NH-LJA-ORJA1, -NRJA1-LJA-ORJA1, -SH, -SRJA1,
-CN,
-NO2,
-NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3, -O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2, -O-LJA-NRJA2RJA3,
-NH-LJA-NH2, -NRJA1-LJA-NH2, -NH-LJA-NHRJA1, -NRJA1-LJA-NHRJA1,
-NH-LJA-NRJA1 2, -NRJA1-LJA-NRJA1 2,
-NH-LJA-NRJA2RJA3, -NRJA1-LJA-NRJA2RJA3,
-OC(=O)RJA1, -C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3,
-NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)ORJA1, -NRJA1C(=O)ORJA1, -OC(=O)NH2, -OC(=O)NHRJA1, -OC(=O)NRJA1 2, -OC(=O)NRJA2RJA3,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3,
-NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1,
-NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3, -NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3, -S(=O)RJA1, -S(=O)2RJA1, -OS(=O)2RJA1, -S(=O)2OH, and -S(=O)2ORJA1; or two adjacent groups -RS3, if present, together form -0-CH2-O- or -0-CH2CH2-O-;
5 wherein:
each -LJA-, if present, is independently saturated aliphatic C1-5alkylene; each -NRJA2RJA3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is 10 optionally substituted, for example, with one or more groups selected from -RJ44,
-CF3, -F, -OH, -ORJ44, -NH2, -NHRJ44, -NRJ44 2, and =0; wherein each -RJ44 is independently saturated aliphatic C1-4alkyl; each -RJA1 is independently:
_pJB1 _DJB2 _pJB3 _pJB4 _pJB5 _pJB6 _DJB7 _pJB8 Λ c I JB pJB4 I JB pJB5 i JB pJB6 i JB pJB7 Qf. ι JB_pJB8. each -RJB1 is independently saturated aliphatic d.6alkyl; each -RJB2 is independently aliphatic C2.6alkenyl; each -RJB3 is independently aliphatic C2-6alkynyl; each -RJB4 is independently saturated C3-6cycloalkyl; 20 each -RJB5 is independently C3.6cycloalkenyl; each -RJB6 is independently non-aromatic C4-7heterocyclyl; each -RJB7 is independently C6.i0carboaryl; each -RJB8 is independently C5.10heteroaryl; each -LJB- is independently saturated aliphatic C1-3alkylene; 25 wherein: each -RJB4, -RJB5, -RJB6, -RJB7, and -RJB8 is optionally substituted, for example, with one or more substituents -RJC1 and/or one or more substituents -RJC2, each -RJB1, -RJB2, -RJB3, and -LJB- is optionally substituted, for example, with one or more substituents -RJC2, and 30 wherein: each -RJC1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -RJC2 is independently:
-F, -Cl, -Br, -I1
-CF3, -OCF3, -SCF3, 35 -OH, -LJD-OH, -O-LJD-OH,
-ORJD1, -LJD-ORJD1, -O-LJD-ORJD1,
-SH, -SRJD1,
-CN,
-NO2, 40 -NH2, -NHRJD1, -NRJD1 2, -NRJD2RJD3,
-LJD-NH2, -LJD-NHRJD1, -LJD-NRJD1 2, -LJD-NRJD2RJD3, -C(=O)OH, -C(=O)ORJD1,
-C(=O)NH2, -C(=O)NHRJD1, -C(=O)NRJD1 2, or -C(=O)NRJD2RJD3; wherein: each -RJD1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -LJD- is independently saturated aliphatic C1-5alkylene; and each -NRJD2RJD3, if present, is independently azetidino, pyrrolidine imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from -RJ55, -CF3, -F, -OH, -ORJ55, -NH2, -NHRJ55, -NRJ55 2, and =0; wherein each -RJ55 is independently saturated aliphatic C^alkyl.
66. A compound according to claim 65, wherein each -RS1, if present, is independently selected from:
-RJA1,
-F,
-CF3, -OCF3,
-OH, -LJA-OH, -O-LJA-OH,
-0RJA1, -LJA-ORJA1, -O-LJA-ORJA1, -CN,
-NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2l -LJA-NRJA2RJA3,
-C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1, -C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3,
-NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3,
-NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1, -NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3,
-S(=O)RJA1, -S(=O)2RJA1, -OS(=O)2RJA1, -S(=O)2OH, -S(=O)2ORJA1; and
=0.
67. A compound according to claim 65, wherein each -RS1, if present, is independently selected from:
-RJA1, -F,
-CF3,
-OH, -LJA-OH, -O-LJA-OH,
-ORJA1, -LJA-ORJA1, -O-LJA-ORJA1,
-CN, -NH2, -NHRJA1, -NRJA1 2,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2l
-C(=O)OH,
-C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, and -C(=O)NRJA1 2.
68. A compound according to any one of claims 65 to 67, wherein each -RS2, if present, is independently selected from:
-RJA1, -F,
-CF3, -OCF3,
-OH, -LJA-OH, -O-LJA-OH,
-ORJA1, -LJA-ORJA1, -O-LJA-ORJA1,
-CN, -NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3, -NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3,
-NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1,
-NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3, -NHS(=O)2RJA1, -NRJA1S(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3,
-S(=O)RJA1, -S(=O)2RJA1, -OS(=O)2RJA1, -S(S=O)2OH, -S(=O)2ORJA1; and
=0.
69. A compound according to any one of claims 65 to 67, wherein each -RS2, if present, is independently selected from:
-RJA1, -F,
-CF3,
-OH, -LJA-OH,
-ORJA1, -LJA-ORJA1,
-CN, -NH2, -NHRJA1, -NRJA1 2,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2,
-C(=O)OH,
-C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, and -C(=O)NRJA1 2.
70. A compound according to any one of claims 65 to 69, wherein each -RS3, if present, is independently selected from:
-RJA1, -F, -Cl, -Br,
-CF3, -OCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH, -NRJA1-LJA-OH,
-ORJA1, -LJA-ORJA1, -O-LJA-ORJA1, -NH-LJA-ORJA1, -NRJA1-LJA-ORJA1,
-SRJA1, -CN,
-NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3,
-LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2, -O-LJA-NRJA2RJA3,
-NH-LJA-NH2, -NRJA1-LJA-NH2, -NH-LJA-NHRJA1, -NRJA1-LJA-NHRJA1, -NH-LJA-NRJA1 2, -NRJA1-LJA-NRJA1 2,
-NH-LJA-NRJA2RJA3, -NRJA1-LJA-NRJA2RJA3,
-OC(=O)RJA1,
-C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1, -C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3,
-NHC(=O)RJA1, -NRJA1C(=O)RJA1,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3,
-NRJA1C(=O)NH2, -NRJA1C(=O)NHRJA1, -NRJA1C(=O)NRJA1 2, -NRJA1C(=O)NRJA2RJA3,
-NHS(=O)2RJA1, -NRJA1S(=O)2RJA1, -S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3, or -S(=0)2RJA1; or two adjacent groups -RS3, if present, together form -0-CH2-O- or -0-CH2CH2-O-.
71. A compound according to any one of claims 65 to 69, wherein each -RS3, if present, is independently selected from:
-F, -Cl, -Br, -CF31 -OCF3,
-OH, -LJA-OH, -O-LJA-OH, -NH-LJA-OH,
-0RJA1, -LJA-ORJA1, -O-LJA-ORJA1, -NH-LJA-ORJA1,
-CN,
-NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3, -LJA-NH2, -LJA-NHRJA1, -LJA-NRJA1 2, -LJA-NRJA2RJA3,
-O-LJA-NH2, -O-LJA-NHRJA1, -O-LJA-NRJA1 2, -O-LJA-NRJA2RJA3,
-NH-LJA-NH2, -NRJA1-LJA-NH2, -NH-LJA-NHRJA1, -NH-LJA-NRJA1 2,
-NH-LJA-NRJA2RJA3,
-C(=O)OH, -C(=O)ORJA1, -C(=O)RJA1,
-C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3,
-NHC(=O)RJA1,
-NHC(=O)NH2, -NHC(=O)NHRJA1,
-NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3, -NHS(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3,
-S(=O)2RJA1, or two adjacent groups -RS3, if present, together form -0-CH2-O- or
-0-CH2CH2-O-.
72. A compound according to any one of claims 65 to 69, wherein each -RS3, if present, is independently selected from:
-RJA1, -F, -Cl, -Br,
-CF3, -OCF3,
-OH,
-0RJA1,
-NH2, -NHRJA1, -NRJA1 2, -NRJA2RJA3, -C(=O)OH, -C(=O)ORJA1,
-C(=O)RJA1, -C(=O)NH2, -C(=O)NHRJA1, -C(=O)NRJA1 2, -C(=O)NRJA2RJA3, -NHC(=O)RJA1,
-NHC(=O)NH2, -NHC(=O)NHRJA1, -NHC(=O)NRJA1 2, -NHC(=O)NRJA2RJA3, -NHS(=O)2RJA1,
-S(=O)2NH2, -S(=O)2NHRJA1, -S(=O)2NRJA1 2, -S(=O)2NRJA2RJA3, or two adjacent groups -RS3, if present, together form -0-CH2-O- or -0-CH2CH2-O-.
73. A compound according to any one of claims 65 to 69, wherein each -RS3, if present, is independently selected from:
-RT1,
-F, -Cl, -Br, -OH, -0RT1,
-CF3, -OCF3,
-NH2, -NHRT1, -NRT1 2, piperidino, piperizino, N-methyl-piperizino, morpholino,
-C(=O)NH2, -C(=O)NHRT1, -C(=O)NRT1 2, -C(=O)-piperidino, -C(=O)-piperizino,
-C(=0)-N-methyl-piperizino, -C(=O)-morpholino,
-S(=O)2NH2, -S(=O)2NHRT1, -S(=O)2NRT1 2,
-S(=O)2-piperidino, -S(=O)2-piperizino,
-S(=O)2-N-methyl-piperizino, and -S(=O)2-morpholino; or two adjacent groups -RS3, if present, together form -0-CH2-O- or
-0-CH2CH2-O-; wherein each -RT1 is independently saturated aliphatic C1-4alkyl, -Ph, Or -CH2-Ph, wherein -Ph is independently phenyl optionally substituted with -F, -Cl, -Br, -RT2
-OH, -0RT2, wherein each -RT2 is independently saturated aliphatic C^alkyl.
74. A compound according to any one of claims 65 to 73, wherein each -LJA-, if present, is independently -(CH2)n2-, wherein n2 is independently 1 to 4.
75. A compound according to any one of claims 65 to 73, wherein each -LJA-, if present, is independently -CH2- or -CH2CH2-.
76. A compound according to any one of claims 65 to 75, wherein each -NRJA2RJΛ3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -RJ44, -CF3, -F, -OH, -ORJ44, -NH2, -NHRJ44, -NRJ44 2, and =0; wherein each -RJ44 is independently saturated aliphatic C1-4alkyl.
77. A compound according to any one of claims 65 to 75, wherein each -NRJA2RJA3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -RJ44; wherein each -RJ44 is independently saturated aliphatic
Figure imgf000083_0001
78. A compound according to any one of claims 65 to 77, wherein each -RJA1, if present, is independently:
Figure imgf000083_0002
.I JB-RJB4 .I JB-RJB6 -I JB-RJB7 or -I JB-RJB8
79. A compound according to any one of claims 65 to 77, wherein each -RJA1, if present, is independently: pJB1 _pJB6 _DJB7 _pJB8 -LJB-RJB6, -LJB-RJB7, -LJB-RJB6, or -|_JB-RJB8.
80. A compound according to any one of claims 65 to 77, wherein each -RJA1, if present, is independently:
-RJB1, -RJB6, -RJB7, or -LJB-RJB7.
81. A compound according to any one of claims 65 to 80, wherein each -RJB6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
82. A compound according to any one of claims 65 to 80, wherein each -RJB6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
83. A compound according to any one of claims 65 to 82, wherein each -RJB7, if present, is independently phenyl, and is optionally substituted.
84. A compound according to any one of claims 65 to 83, wherein each -RJB8, if present, is independently C5.6heteroaryl, and is optionally substituted.
85. A compound according to any one of claims 65 to 83, wherein each -RJB8, if present, is independently C9.10heteroaryl, and is optionally substituted.
86. A compound according to any one of claims 65 to 83, wherein each -RJB8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
87. A compound according to any one of claims 65 to 83, wherein each -RJB8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
88. A compound according to any one of claims 65 to 87, wherein each -LJB-, if present, is independently -CH2- or -CH2CH2-.
89. A compound according to any one of claims 65 to 87, wherein each -LJB-, if present, is independently -CH2-.
90. A compound according to any one of claims 65 to 89, wherein each -RJC1, if present, is independently saturated aliphatic Ci_4alkyl.
91. A compound according to any one of claims 65 to 90, wherein each -RJC2 is independently:
-F, -Cl, -Br1 -I1
-OH1
-ORJD1, -CN,
-NO2,
-NH2, -NHRJD1, -NRJD1 2l or -NRJD2RJD3.
92. A compound according to any one of claims 65 to 91 , wherein each -RJD1, if present, is independently saturated aliphatic C^alkyl.
93. A compound according to any one of claims 65 to 92, wherein each -LJD-, if present, is independently -(CH2)m2-, wherein m2 is independently 1 to 4.
94. A compound according to any one of claims 65 to 92, wherein each -LJD-, if present, is independently -CH2- or -CH2CH2-.
95. A compound according to any one of claims 65 to 94, wherein each -NRJD2RJD3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -RJ55, -CF3, -F, -OH, -ORJ55, -NH2, -NHRJ55, -NRJ55 2, and =0; wherein each -RJ55 is independently saturated aliphatic C^alkyl.
96. A compound according to any one of claims 65 to 94, wherein each -NRJD2RJD3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from -RJ55; wherein each -RJ55 is independently saturated aliphatic C1-4alkyl.
97. A compound according to claim 1 , selected from the following compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof: Compound Nos. TCA-001 through TCA-022.
98. A pharmaceutical composition comprising a compound according to any one of claims 1 to 97, and a pharmaceutically acceptable carrier or diluent.
99. A method of preparing a pharmaceutical composition comprising the step of admixing a compound according to any one of claims 1 to 98, and a pharmaceutically acceptable carrier or diluent.
100. A compound according to any one of claims 1 to 98, for use in a method of treatment of the human or animal body by therapy.
101. A compound according to any one of claims 1 to 98, for use in a method of treatment of a disease or condition that is mediated by CHK1 and/or CHK2.
102. A compound according to any one of claims 1 to 98, for use in a method of treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function.
103. A compound according to any one of claims 1 to 98, for use in a method of treatment of a proliferative condition.
104. A compound according to any one of claims 1 to 98, for use in a method of treatment of cancer.
105. A compound according to any one of claims 1 to 98, for use in a method of treatment of p53 cancer.
106. A compound according to any one of claims 1 to 98, for use in a method of treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
107. A compound according to any one of claims 101 to to 106, wherein the treatment further comprises treatment with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
108. Use of a compound according to any one of claims 1 to 98, in the manufacture of a medicament for the treatment of a disease or condition that is mediated by CHK1 and/or CHK2.
109. Use of a compound according to any one of claims 1 to 98, in the manufacture of a medicament for the treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function.
110. Use of a compound according to any one of claims 1 to 98, in the manufacture of a medicament for the treatment of a proliferative condition.
111. Use of a compound according to any one of claims 1 to 98, in the manufacture of a medicament for the treatment of cancer.
112. Use of a compound according to any one of claims 1 to 98, in the manufacture of a medicament for the treatment of p53 cancer.
113. Use of a compound according to any one of claims 1 to 98, in the manufacture of a medicament for the treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
114. Use according to any one of claims 108 to 113, wherein the treatment further comprises treatment with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
115. A method of treatment of a disease or condition that is mediated by CHK1 and/or CHK2 comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 98.
116. A method of treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function and/or CHK2 kinase function comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 98.
117. A method of treatment of a proliferative condition comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 98.
118. A method of treatment of cancer comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 98.
119. A method of treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 98.
120. A method according to any one of claims 115 to 119, wherein the treatment further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
121. A method of inhibiting CHK1 kinase function and/or CHK2 kinase function, in vitro or in vivo, comprising contacting a CHK1 kinase and/or a CHK2 kinase with an effective amount of a compound according to any one of claims 1 to 98.
122. A method of inhibiting CHK1 kinase function and/or CHK2 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 98.
123. A method of inhibiting cell proliferation, inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 98.
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Publication number Priority date Publication date Assignee Title
CN103333132A (en) * 2012-12-03 2013-10-02 湖南大学 N-(4-tertbutyl-5-benzyl thiazole-2-yl)amide and preparation method and application thereof
CN103601697A (en) * 2012-12-03 2014-02-26 湖南大学 4-tertiary butyl-5-(2-nitroethyl)-2-acylamino thiazole and preparation method and application thereof
CN103333132B (en) * 2012-12-03 2015-03-25 湖南大学 N-(4-tertbutyl-5-benzyl thiazole-2-yl)amide and preparation method and application thereof
CN111440127A (en) * 2019-01-17 2020-07-24 青岛农业大学 Thiazole amide compound and preparation and application thereof
CN111440127B (en) * 2019-01-17 2022-07-26 青岛农业大学 Thiazole amide compound and preparation and application thereof
WO2021225980A1 (en) * 2020-05-04 2021-11-11 Dna-Seq, Inc. Methods and systems for determination of an effective therapeutic regimen and drug discovery

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