[go: up one dir, main page]

WO2008075007A1 - Composé bicyclohétéroarylés substitué par morpholino et leur utilisation en tant qu'agents anti-cancer - Google Patents

Composé bicyclohétéroarylés substitué par morpholino et leur utilisation en tant qu'agents anti-cancer Download PDF

Info

Publication number
WO2008075007A1
WO2008075007A1 PCT/GB2007/004819 GB2007004819W WO2008075007A1 WO 2008075007 A1 WO2008075007 A1 WO 2008075007A1 GB 2007004819 W GB2007004819 W GB 2007004819W WO 2008075007 A1 WO2008075007 A1 WO 2008075007A1
Authority
WO
WIPO (PCT)
Prior art keywords
independently
compound according
present
substituted
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2007/004819
Other languages
English (en)
Inventor
Ian Collins
John Charles Reader
Kwai Ming Cheung
Thomas Peter Matthews
Nicolas Proisy
Sukhbinder Singh Klair
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cancer Research Technology Ltd
Original Assignee
Cancer Research Technology Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0625633A external-priority patent/GB0625633D0/en
Application filed by Cancer Research Technology Ltd filed Critical Cancer Research Technology Ltd
Publication of WO2008075007A1 publication Critical patent/WO2008075007A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain morpholino-substituted bicycloheteroaryl compounds (referred to herein as MBHA compounds), and especially certain morpholino-substituted 7H- pyrrolo[2,3-d]pyrimidine and morpholino-substituted 1 H-pyrazolo[3,4-b]pyridine compounds, which, inter alia, inhibit Checkpoint Kinase 1 (CHK1 ) kinase function.
  • CHK1 Checkpoint Kinase 1
  • 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 in the treatment of diseases and conditions that are mediated by CHK1 , that are ameliorated by the inhibition of CHK1 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.
  • 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,
  • 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 is a serine/threonine kinase involved in regulating cell cycle checkpoint signals that are activated in response to DNA damage and errors in DNA caused by defective replication (see, e.g., Bartek and Lukas, 2003). CHK1 transduces these 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 al., 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 al., 2000; Zhao et a/., 2002; Zachos et al., 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 ).
  • 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 al., 1994; Carson and Lois, 1995).
  • CHK1 has also been shown to be involved in S phase cell cycle checkpoints and DNA repair by homologous recombination.
  • CHK1 inhibitors may provide additional therapeutic strategies for the treatment of cancers using CHK1 inhibitors (see, e.g., Sorensen et al., 2005).
  • CHK1 selective siRNA supports the selective inhibition of CHK1 as a relevant therapeutic approach, and suggests that combined inhibition with certain other checkpoint kinases provides no additional benefit and may be non-productive (see, e.g., Xiao et al., 2006).
  • Small-molecule selective inhibitors of CHK1 kinase function from various chemical classes have been described (see, e.g., Tao and Lin, 2006).
  • One aspect of the invention pertains to certain morpholino-substituted bicycloheteroaryl compounds compounds (referred to herein as MBHA compounds), as described herein.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising an MBHA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising the step of admixing an MBHA 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 in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an MBHA compound, as described herein.
  • the method further comprises contacting the cells 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 cells (or the cell) with an effective amount of an MBHA compound, as described herein.
  • the method further comprises contacting the cells 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 for treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an MBHA 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 an MBHA 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) the MBHA 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 MHBA compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the treatment comprises treatment with both (i) a medicament comprising the MBHA 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 the MBHA 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 CHKL
  • the treatment is treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function.
  • the treatment is treatment of a proliferative condition.
  • the treatment is treatment of cancer.
  • the treatment is treatment of a hyperproliferative skin disorder, for example, psoriasis, actinic keratosis, and/or non-melanoma skin cancer.
  • a hyperproliferative skin disorder for example, psoriasis, actinic keratosis, and/or non-melanoma skin cancer.
  • the treatment is treatment of a disease or condition that is characterised by inappropriate, excessive, and/or undesirable angiogenesis, for example, macular degeneration, cancer (solid tumours), psoriasis, and obesity.
  • the treatment is treatment of an inflammatory disease.
  • the treatment is treatment a disease or disorder associated with heart remodelling, myocyte hypertrophy of the heart, impaired contractility of the heart, pump failure of the heart, pathologic cardiac hypertrophy, and/or heart failure.
  • a kit comprising (a) an MBHA 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 an MBHA 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 an MBHA 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.
  • One aspect of the present invention pertains to compounds selected from compounds of the following formula:
  • the compounds may be described as having three core rings: a 6-membered Ring A fused to a 5-membered Ring B (and forming an bicyclic fused ring system), with a morpholino ring (denoted Ring C) linked to a ring carbon atom of Ring A, as illustrated below:
  • Ring A be fused to any other rings, other than Ring B; and it is not intended that Ring B be fused to any other rings, other than Ring A.
  • Ring C be linked to Ring A, other than by the single covalent bond shown; it is not intended that Ring C be linked to Ring B; and it is not intended that Ring C be fused to any other rings.
  • the Bicvclic Fused Ring System is not intended that Ring C be linked to Ring A, other than by the single covalent bond shown; it is not intended that Ring C be linked to Ring B; and it is not intended that Ring C be fused to any other rings.
  • the group X is independently N or C(R ).
  • X is N, as in, for example:
  • X is C(R ), as in, for example:
  • bicyclic fused ring system of the compounds described herein may exist in different tautomeric forms, to various extents, when the 5-membered Ring B contains an NH group.
  • a reference to any one tautomer is intended to be a reference to all tautomers.
  • a reference to the compound labelled "Tautomer 1" below is intended to be a reference to that compound and all tautomers thereof, including, for example, Tautomers 2, 3 and 4.
  • the compounds bear a morpholino group, as shown below, attached via its nitrogen ring atom to the bicyclic fused ring system:
  • the morpholino group bears at least one substituent, R 1M .
  • R 1M is attached at the 2- or 6-position of the morpholino group. In one embodiment, R 1M is attached at the 3- or 5-position of the morpholino group.
  • At least the ring carbon atom to which the group R 1M is attached is a chiral centre, and therefore the compounds are expected to be optically active.
  • Some examples of the stereoisomers are shown below.
  • R AM the ring carbon atoms to which they are attached will also be chiral centres.
  • the chiral centre, or each chiral centre, if more than one is present, is independently in the R-configuration or the S-configuration.
  • the ring carbon atom to which the group R 1M is attached is in the R- configuration.
  • the ring carbon atom to which the group R 1M is attached is in the S- configuration.
  • the group R 1M is independently selected from:
  • each L M is independently d. 3 alkylene; and . each R ⁇ is independently C 1-3 alkyl.
  • R 1M is independently selected from:
  • R 1M is independently selected from: -L M -NH 2 ;
  • R 1M is independently selected from: -L M -NH 2 ; -L M -NHR K ; and -L M -NR K 2 .
  • R 1M is independently selected from: -CONH 2 ;
  • R 1M is independently selected from: -L M -CN.
  • R 1M is independently selected from: -L M -OH; or -L M -OR K .
  • each L M is independently -(CH 2 )-, -(CH 2 ) 2 -, or -(CH 2 ) 3 -. In one embodiment, each L M is independently -(CH 2 )-. In one embodiment, each L M is independently -(CH 2 ) 2 . In one embodiment, each L M is independently -(CH 2 ) 3 -.
  • each R ⁇ is independently -Me or Et.
  • R 1M is independently selected from:
  • R 1M is independently selected from: -(CH 2 )-NH 2 , -(CHa) 2 -NH 2 , -(CHa) 3 -NH 2 ;
  • R 1M is independently selected from:
  • R 1M is independently -(CH 2 )-NH 2 .
  • R 1M is -(CH 2 ) P -NH 2 (wherein p is independently 1, 2, or 3); R 1M is attached at the 2- or 6-position; and n is O, as in, for example, the following group:
  • R 1M is -CH 2 -NH 2 ; R 1M is attached at the 2- or 6-position; and n is O, as in, for example, the following group:
  • the morpholino group optionally bears 1 or 2 additional subsitutents, R AM .
  • n is independently 0, 1 or 2.
  • n is independently 0. In one embodiment, n is independently 1. In one embodiment, n is independently 2.
  • An additional subsitutent, R AM may be attached at the same position as the group R 1M , or at a different position than the group R 1M .
  • an additional subsitutent, R AM is attached at the same position as the group R 1M , as in, for example:
  • any additional subsitutents, R AM are attached at different positions than the group R 1M (i.e., are not attached at the same position as the group R 1M ), as in, for example:
  • Each group R AM is independently C ⁇ alkyl or -CF 3 . In one embodiment, each R AM , if present, is independently C 1-3 alkyl. In one embodiment, each R AM , if present, is independently -Me, -Et, or -CF 3 . In one embodiment, each R AM , if present, is independently -Me.
  • the morpholino group is selected from the following groups (wherein n is 1 or 2, each R AM is -Me):
  • the morphoino group is selected from the following groups (wherein n is 1 or 2, each R AM is -Me, and R 1M is -CH 2 -NH 2 ):
  • a A is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted;
  • a B is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;
  • a c is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;
  • a D is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted;
  • a E is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted;
  • q1 is independently 1 , 2, or 3;
  • q2 is independently 1 , 2, or 3;
  • R N1 is independently -H or C 1-3 alkyl
  • R N2 is independently -H or C 1-3 alkyl
  • R N3 is independently -H or C 1-3 alkyl
  • R N4 is independently -H or C 1-3 alkyi; each of R N5 and R m is independently -H, C 1-6 alkyl, or C 1-6 cycloalkyl;
  • R N1R and R N2R taken together with the nitrogen atom to which they are attached, independently form a non-aromatic heterocyclic ring having from 4 to 7 ring atoms, and having exactly one ring heteroatom, wherein said one ring heteroatom is nitrogen, or having exactly two ring heteroatoms, wherein one of said two ring heteroatoms is nitrogen and the other of said two ring heteroatoms is independently selected from nitrogen, oxygen, and sulfur; and wherein said non-aromatic heterocyclic ring is independently unsubstituted or substituted;
  • R ⁇ is independently -H or C 1-4 alkyl
  • G 0 ⁇ is independently halogen.
  • non-aromatic heterocyclic ring has exactly one ring heteroatom, then that ring heteroatom is the nitrogen atom to which R N1 R and R N2R are attached. If the non- aromatic heterocyclic ring has exactly two ring heteroatoms, then one ring heteroatom is the nitrogen atom to which R N1R and R N2R are attached, and the other ring heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • Q A is independently -A A .
  • Q A is independently -NR N1 2 . In one embodiment, Q A is independently -NH 2 .
  • Q A is independently -NR N1 -A B .
  • R N1 is independently -H or -Me. In one embodiment, R N1 is independently -H.
  • Q A is independently -NR N2 -(CH 2 ) q1 -A c .
  • R N2 is independently -H or -Me. In one embodiment, R N2 is independently -H.
  • q1 is independently 1 or 2. In one embodiment, q1 is independently 1.
  • R m is independently -H or -Me. In one embodiment, R m is independently -H.
  • R N4 is independently -H or -Me. In one embodiment, R N4 is independently -H.
  • q2 is independently 1 or 2. In one embodiment, q2 is independently 1.
  • R N5 is independently -H or C 1-3 alkyl; and R N6 is independently -H, C 1 . 6 alkyl, or Ci- ⁇ cycloalkyl.
  • each of R N5 and R m is independently -H or C-, -6 alkyl. In one embodiment, each of R N5 and R N6 is independently -H or Ci -3 alkyl.
  • -NR N1R R N2R is independently selected from: azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperizino, morpholino, azepino, and diazepino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).
  • -NR N1R R N2R is independently selected from: pyrrolidino, piperidino, piperizino, and morpholino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).
  • R E is independently C 1-4 alkyl. In one embodiment, R E is independently -H, -Me, -Et, -nPr, or -iPr. In one embodiment, R E is independently -Me, -Et, -nPr, or -iPr. In one embodiment, R ⁇ is independently -Me or -Et.
  • Q A is independently -G 0 ⁇ .
  • G ⁇ is independently -F, -Cl, -Br 1 or -I.
  • GTM is independently -Cl, -Br, or -I.
  • G 0 ⁇ is independently -Cl or -Br.
  • G 0 ⁇ is independently -Cl. In one embodiment, G ⁇ is independently -Br.
  • Q A is independently selected from those groups exemplified for Q A under the heading "Some Preferred Embodiments.”
  • the group Q B if present, is independently C ⁇ alkyl or -CF 3 . In one embodiment, Q B , if present, is independently C ⁇ alkyl.
  • Q B if present, is independently -Me, -Et, or -CF 3 .
  • Q B if present, is independently -Me.
  • R 5G is independently -H or C 1-3 alkyl. In one embodiment, R 5G , if present, is independently -H or -Me. In one embodiment, R 5G , if present, is independently -H.
  • the substituent R 6G1 is independently selected from: -H;
  • G 6C1 is independently halogen
  • D 6G1 is independently Ci -3 alkyl
  • a F is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;
  • R N3R and R N4R taken together with the nitrogen atom to which they are attached, independently form a non-aromatic heterocyclic ring having from 4 to 7 ring atoms, and having exactly one ring heteroatom, wherein said one ring heteroatom is nitrogen, or having exactly two ring heteroatoms, wherein one of said two ring heteroatoms is nitrogen and the other of said two ring heteroatoms is independently selected from nitrogen, oxygen, and sulfur; and wherein said non-aromatic heterocyclic ring is independently unsubstituted or substituted;
  • R N7 is independently -H or C 1-3 alkyl; either:
  • L 1 is -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -, and
  • L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and
  • J 1 is -H, -CN, -OH, ⁇ OR J1 , -NH 2 , -NHR J1 , or -NR Ji 2 ; each R J1 is independently C 1-3 alkyl;
  • R Na is independently -H or C-
  • B 6C1 is independently C 5-7 cycloalkyl or C 5- rheterocyclyl, optionally substituted with one or more C 1-3 alkyl groups
  • a G is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;
  • R N9 is independently -H or C 1-3 alkyl; q3 is independently 1 , 2, or 3; and
  • a H is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted.
  • R 6C1 is independently selected from: -G 6C1 ;
  • R 6C1 is independently selected from: -A F ;
  • R 6C1 is independently -H.
  • R 6C1 is independently -G 6C1 .
  • G 6C1 is independently -F, -Cl, -Br, or -I. In one embodiment, G 6G1 is independently -Cl, -Br, or -I. In one embodiment, G 6C1 is independently -Cl or -Br. In one embodiment, G 6C1 is independently -Cl. In one embodiment, G 6C1 is independently -Br.
  • R 6C1 is independently -D 6C1 .
  • D 6C1 is independently -Me, -Et, -nPr, or -iPr.
  • R 6C1 is independently -A F .
  • -NR N3R R N4R is independently selected from: azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperizino, morpholino, azepino, and diazepino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).
  • -NR N3R R N4R is independently selected from: pyrrolidino, piperidino, piperizino, and morpholino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).
  • R N7 is independently -H or -Me. In one embodiment, R N7 is independently -H.
  • L 1 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or - CH 2 CH 2 CH 2 -, and J 1 is -H.
  • L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and J 1 is -CN.
  • L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and J 1 is -OH or -OR J1 .
  • L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and J 1 Js -NH 2 , -NHR J1 , or -NR J1 2 .
  • L 1 is -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 - > and
  • L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, and J 1 is -H, -CN 1 -OH, -OR J1 , -NH 2 , -NHR J1 , or -NR J1 2 .
  • L 1 is -CH 2 CH 2 CH 2 -
  • J 1 is -H, -CN, -OH, -OR J1 , -NH 2 , -NHR J1 , or -NR J1 2 .
  • each R J1 is independently -Me or -Et.
  • the group -L 1 -J 1 is independently selected from: -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ; -(CH 2 ) J rCN 1 -(CHz) 3 -CN;
  • R N8 is independently -H or -Me. In one embodiment, R N8 is independently -H.
  • B 6C1 is independently cylcopentyl, cyclohexyl, cylcoheptyl, pyrrolidine, imidazolidinyl, pyrazolidinyl, piperidinyl, piperizinyl, morpholinyl, azepinyl, or diazepinyl; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 a!kyl groups, e.g., -Me).
  • B 6C1 is independently cyclohexyl, piperidinyl, piperizinyl, or morpholinyl; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).
  • R NS is independently -H or -Me. In one embodiment, R N8 is independently -H.
  • R N9 is independently -H or -Me. In one embodiment, R N9 is independently -H.
  • q3 is independently 1 or 2. In one embodiment, q3 is independently 1.
  • R 6C1 is independently selected from those groups exemplified for R 6G1 and R 6C2 under the heading "Some Preferred Embodiments.”
  • R 6C1 is independently selected from those groups exemplified for R 6C1 under the heading "Some Preferred Embodiments.”
  • the substituent R 6C2 is independently selected from: -H; -A J ;
  • G 6C2 is independently halogen
  • D 6C2 is independently C 1-3 alkyl
  • a J is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted;
  • R N5R and R N6R taken together with the nitrogen atom to which they are attached, independently form a non-aromatic heterocyclic ring having from 4 to 7 ring atoms, and having exactly one ring heteroatom, wherein said one ring heteroatom is nitrogen, or having exactly two ring heteroatoms, wherein one of said two ring heteroatoms is nitrogen and the other of said two ring heteroatoms is independently selected from nitrogen, oxygen, and sulfur; and wherein said non-aromatic heterocyclic ring is independently unsubstituted or substituted;
  • R N1 ° is independently -H or C 1-3 alkyl; either: L 2 is -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -, and
  • L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and
  • J 2 is -H, -CN, -OH, -OR J2 , -NH 2 , -NHR J2 , or -NR J2 2 ; each R J2 is independently C 1-3 alkyl;
  • R N11 is independently -H or C 1-3 alkyl
  • B 6C2 is independently C 5-7 cycloalkyl or C 5-7 heterocyclyl, optionally substituted with one or more C 1-3 alkyl groups;
  • a ⁇ is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;
  • R N12 is independently -H or C 1-3 alkyl; q4 is independently 1 , 2, or 3;. and
  • a L is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted.
  • R 6C2 is independently -H.
  • R 6C2 is independently -G 6C2 .
  • G 6C2 is independently -F, -Cl, -Br, or -I.
  • G 6C2 is independently -Cl, -Br, or -I.
  • G 6C2 is independently -Cl or -Br.
  • G 6C2 is independently -Cl.
  • G 6C2 is independently -Br.
  • R 6C2 is independently -D 6C2 .
  • D 6C2 is independently -Me, -Et, -nPr, or -iPr.
  • R 6C2 is independently -A J .
  • -NR N5R R N6R is independently selected from: azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperizino, morpholino, azepino, and diazepino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).
  • -NR N5R R N6R is independently selected from: pyrrolidino, piperidino, piperizino, and morpholino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).
  • R N1 ° is independently -H or -Me. In one embodiment, R N1 ° is independently -H.
  • L 2 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 J 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and J 2 is -H.
  • L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and
  • J 2 is -CN.
  • L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and
  • J 2 is -OH or -OR J2 .
  • L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and J 2 is -NH 2 , -NHR J2 , or -NR J2 2 .
  • L 2 is -CH 2 -, -CH(CH 3 )- or -C(CHg) 2 -, and
  • J 2 is -H.
  • L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, and
  • J 2 is -H, -CN, -OH, -OR J2 , -NH 2 , -NHR J2 , or -NR J2 2 .
  • L 2 is -CH 2 CH 2 CH 2 -
  • J 2 is -H, -CN, -OH, -OR J2 , -NH 2 , -NHR J2 , or -NR J2 2 .
  • each R J2 is independently -Me or -Et.
  • the group -L 2 -J 2 is independently selected from:
  • R N11 is independently -H or -Me. In one embodiment, R N11 is independently -H.
  • B 6C2 is independently cylcopentyl, cyclohexyl, cylcoheptyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperizinyl, morpholinyl, azepinyl, or diazepinyl; and is independently unsubstituted or substituted (e.g., with one or more C ⁇ alkyl groups, e.g., -Me).
  • B 602 is independently cyclohexyl, piperidinyl, piperizinyl, or morpholinyl; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).
  • R N12 is independently -H or -Me. In one embodiment, R N12 is independently -H.
  • q4 is independently 1 or 2. In one embodiment, q4 is independently 1.
  • R 6C2 is independently selected from those groups exemplified for R 6C1 and R 6C2 under the heading "Some Preferred Embodiments.”
  • R 6C2 is independently selected from those groups exemplified for R 602 under the heading "Some Preferred Embodiments.”
  • the substituent R 6N is independently selected from:
  • a M is independently phenyl or C 5 - 6 heteroaryl, and is independently unsubstituted or substituted; q5 is independently 1 , 2, or 3;
  • a N is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted; either:
  • L 3 is -CH 2 -, -CH(CH 3 )- or -C(CHg) 2 -, and
  • J 3 is -H; or: L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and
  • J 3 is -H, -CN, -OH, -OR J3 , -NH 2 , -NHR J3 , or -NR J3 2 ; each R J3 is independently C 1-3 alkyl.
  • R 6N is independently selected from: -A M ;
  • R 6N is independently -H.
  • R 6N is independently -A M .
  • R 6N is independently -(CH 2 )q 5 -A N .
  • q5 is independently 1 or 2. In one embodiment, q5 is independently 1.
  • R 6N is independently -L 3 -J 3 .
  • L 3 is -CH 2 -, -CH(CH 3 )-, -C(CHs) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or
  • L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and
  • J 3 is -CN.
  • L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and J 3 is -OH or -OR J3 .
  • L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and
  • L 3 is -CH 2 -, -CH(CH 3 )- or -C(CHs) 2 -, and
  • L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, and J 3 is -H, -CN, -OH, -OR J3 , -NH 2 , -NHR J3 , or -NR j3 2 .
  • L 3 is -CH 2 CH 2 CH 2 -
  • each R J3 is independently -Me or -Et.
  • the group -L 3 -J 3 is independently selected from: -CH 3 , -CH 2 CH 3 , -CH 2 CH Z CH 3 ;
  • each of the groups A A , A B , A c , A D , A E , A F , A G , A H , A J , A ⁇ , A L , A M , and A N is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.
  • the or each C 5 . 6 heteroaryl is independently selected from: furanyl (C 5 ), thienyl (C 5 ), pyrrolyl (C 5 ), imidazolyl (C 5 ), pyrazolyl (C 5 ), oxazolyl (C 5 ), isoxazolyi (C 5 ), thiazolyl (C 5 ), isothiazolyl (C 5 ), furazanyl (C 5 ), [1 ,3,4]oxadiazolyl (C 5 ), [1 ,2,4]oxadiazolyl (C 5 ), [1 ,2,5]thiadiazolyl (C 5 ), [1 ,3,4]thiadiazolyl (C 5 ), [1 ,2,4]thiadiazolyl (C 5 ), [1 ,2,4]thiadiazolyl (C 5 ), [1 ,2,3]triazolyl (C 5 ), [1 ,2,4]triazolyl (C 5 ),
  • a A is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.
  • the or each C 5-6 heteroaryl is independently selected from: thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.
  • a A is independently phenyl, and is independently unsubstituted or substituted.
  • a A is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.
  • a A is independently selected from: phenyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, and pyridyl; and is independently unsubstituted or substituted.
  • a A is independently thienyl, and is independently unsubstituted or substituted.
  • a B is independently phenyl, and is independently unsubstituted or substituted.
  • a B is independently C 5 - 6 heteroaryl, and is independently unsubstituted or substituted. In one embodiment, A B is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, or pyrimidinyl; and is independently unsubstituted or substituted.
  • a c is independently phenyl, and is independently unsubstituted or substituted.
  • a c is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.
  • a c is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.
  • a D is independently phenyl, and is independently unsubstituted or substituted.
  • a D is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.
  • a D is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.
  • a E is independently phenyl, and is independently unsubstituted or substituted.
  • a E is independently C 5-6 heteroaryl, and is independently unsubstituted or substituted.
  • a E is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.
  • a F is independently phenyl, and is independently unsubstituted or substituted.
  • a F is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted. In one embodiment, A F is independently selected from: phenyl, thienyl, pyrazolyl,
  • a F is independently selected from: phenyl, thienyl, pyridyl, pyrazolyl, [1 ,2,3]triazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.
  • a F is independently selected from: phenyl, pyridyl, pyrazolyl, [1 ,2,3]triazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.
  • a F is independently selected from: phenyl, thienyl, pyridyl, pyrazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.
  • a F is independently selected from: phenyl, pyridyl, pyrazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.
  • a G is independently phenyl, and is independently unsubstituted or substituted.
  • a G is independently C 5-6 heteroaryl, and is independently unsubstituted or substituted.
  • a G is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.
  • a H is independently phenyl, and is independently unsubstituted or substituted.
  • a H is independently C 5-6 heteroaryl, and is independently unsubstituted or substituted.
  • a H is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.
  • a J is independently phenyl, and is independently unsubstituted or substituted.
  • a J is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.
  • a J is independently selected from: phenyl, thienyl, pyrazolyl, [1,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.
  • a ⁇ is independently phenyl, and is independently unsubstituted or substituted.
  • a ⁇ is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.
  • a ⁇ is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.
  • a L is independently phenyl, and is independently unsubstituted or substituted.
  • a L is independently C 5 _ 6 heteroaryl, and is independently unsubstituted or substituted.
  • a L is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.
  • a M is independently phenyl, and is independently unsubstituted or substituted.
  • a M is independently C 5-6 heteroaryl, and is independently unsubstituted or substituted.
  • a M is independently selected from: phenyl, thienyl, pyrazolyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.
  • a N is independently phenyl, and is independently unsubstituted or substituted.
  • a N is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted. In one embodiment, A N is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.
  • each of A F , A J , and A M is independently phenyl, pyridyl, [1 ,2,3]triazolyl, or pyrazolyl; and is independently unsubstituted or substituted.
  • each of A F , A J , and A M is independently phenyl, pyridyl, or pyrazolyl; and is independently unsubstituted or substituted.
  • each of A F , A J , and A M is independently the following group, wherein R f is independently a substituent as defined under the heading Optional Substituents on Phenyl and Cs-eHeteroaryl":
  • each of A F , A J , and A M is independently selected from the following groups, wherein R f is independently a substituent as defined under the heading "Optional Substituents on Phenyl and C 5 . 6 Heteroaryl":
  • each of A F , A J , and A M is independently selected from the following groups, wherein R f is independently a substituent as defined under the heading "Optional Substituents on Phenyl and C 5 . 6 Heteroaryl":
  • certain groups are, for example, phenyl or C 5 . 6 heteroaryl, and are unsubstituted or substituted, for example, substituted with one or more (e.g., 1 , 2, etc.) substituents.
  • Substituents, if present, may be on a ring carbon atom or a ring heteroatom. For example, when a C 5 .
  • 6 heteroaryl group includes -NH- in the aromatic ring (e.g., as in pyrrolyl, imidazolyl, pyrazolyl), this group may be N-substituted, for example N-(C 1-3 alkyl)- substituted, for example N-(methyl)-substituted, as in, for example, N-methyl-pyrazolyl.
  • each substituent e.g., each optional substituent on A ⁇ , A B , A c , A D ,
  • a E , A F , A G , A H , A J , A ⁇ , A L , A M , and/or A N is independently selected from:
  • R d and each R a is independently selected from:
  • each Ci -7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3- 14 heterocyclyl, C 6-14 carboaryl, and C 5- i 4 heteroaryl is independently unsubstituted or substituted with one or more (e.g., 1 , 2, etc.) substituents selected from (H-1) through (H- 22);
  • R b and R c taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms.
  • each substituent e.g., each optional substituent on A A , A B , A c , A D , A E , A F , A G , A H , A J , A ⁇ , A L , A M , and/or A N ) is independently selected from:
  • R d' and each R a' is independently selected from:
  • substituents selected from (H'-2), (H'-3), (H'-5), (H'-6), (H'-8), (H'-9), (H'-14), (H'-15), (H'-17), (H'-18), (H"-20), and (H'-22).
  • R b' and R 0' taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms.
  • each substituent e.g., each optional substituent on A A , A B , A c , A D , A E , A F , A G , A H , A J , A ⁇ , A L , A M , and/or A N ) is independently selected from:
  • each L 4 is independently a covalent bond or C 1-4 alkylenyl; and each L 5 is independently C 2 . 4 alkylenyl; each R e is independently C 1-4 alkyl, -Ph, Or -CH 2 Ph; and each NR f R 9 is independently pyrrolidino, piperidino, piperizino, N-(C 1-3 alkyl)-piperizino, or morpholino.
  • each substituent e.g., each optional substituent on A A , A B , A c , A D , A E , A F , A G , A H , A J , A ⁇ , A L , A M , and/or A N ) is independently selected from:
  • each L 4 is independently a covalent bond or C 1-4 alkylenyl; and each L 5 is independently C 2-4 alkylenyl; each R e is independently C 1-4 alkyl, -Ph, or -CH 2 Ph; and each NR f R 9 is independently pyrrolidino, piperidino, piperizino,
  • N-(Ci -3 alkyl)-piperizino, or morpholino N-(Ci -3 alkyl)-piperizino, or morpholino.
  • each L 4 is independently a covalent bond or C 1-4 alkylenyl; and each L 5 is independently C 2-4 alkylenyl; each R e is independently Ci. 4 alkyl; and each NR f R 9 is independently pyrrolidino, piperidino, piperizino,
  • N-(C 1-3 alkyl)-piperizino, or morpholino is N-(C 1-3 alkyl)-piperizino, or morpholino.
  • each L 4 is independently a covalent bond, -CH 2 -, -CH 2 CH 2 -, Or -CH 2 CH 2 CH 2 -; each L 5 is independently -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -; each R e is independently -Me, -Et, -Ph, or -CH 2 Ph. each NR f R 9 is independently pyrrolidino, piperidino, piperizino, N-(C 1-3 alkyl)-piperizino, or morpholino.
  • each L 4 is independently a covalent bond, -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -; each L 5 is independently -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -; each R e is independently -Me or -Et. each NR f R 9 is independently pyrrolidino, piperidino, piperizino, N-(Ci -3 alkyl)-piperizino, or morpholino.
  • the substituents are independently selected from those substituents exemplified under the heading "Some Preferred Embodiments.”
  • certain groups may be, for example, a non-aromatic heterocyclic ring (as defined herein), and are unsubstituted or substituted, for example, substituted with one or more (e.g., 1 , 2, etc.) substituents.
  • Substituents may be on a ring carbon atom or a ring heteroatom.
  • a non-aromatic heterocyclic ring includes -NH- (e.g., as in imidazolidino, pyrazolidino, piperidino, diazepino)
  • this group may be N-substituted, for example N-(Ci- 3 alkyl)-substituted, for example N-(methyl)-substituted, as in, for example, N-methyl- piperidino.
  • the substituents are as defined for substituents under the heading Optional Substituents on Phenyl and C 5 - 6 Heteroaryl.
  • the substituents are independently selected from those substituents exemplified under the heading "Some Preferred Embodiments.”
  • the compound has a molecular weight of 250 to 1200.
  • the bottom of range is 275; 300; 325; 350; 375; 400.
  • the top of range is 1100; 1000, 900, 800, 700.
  • the range is 300 to 700.
  • alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated aliphatic hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified).
  • each C 1-7 alkyl is independently selected from: -Me, -Et, -nPr, -iPr, - nBu, -iBu, -sBu, -tBu, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, n-heptyl; and is independently unsubstituted or substituted. In one embodiment, each C- ⁇ -7 alkyl is independently unsubstitued.
  • alkylenyl refers to a divalent bidentate moiety obtained by removing two hydrogen atoms from one carbon atom or two different carbon atoms of a saturated aliphatic hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified).
  • each C 1-7 alkylenyl is independently selected from: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -CH(CH 3 )CH 2 -,
  • each C 1-7 alkylenyl is independently unsubstitued.
  • alkenyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an unsaturated aliphatic hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified) and having one or more (e.g., 1 , 2, etc.) carbon-carbon double bonds.
  • alkynyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an unsaturated aliphatic hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified) and having one or more (e.g., 1 , 2, etc.) carbon-carbon triple bonds.
  • cycloalkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring carbon atom of a saturated hydrocarbon compound having at least one carbocyclic ring, and having from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms (unless otherwise specified).
  • each C 3-7 cycloalkyl is independently selected from: cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), cyclohexyl (C 6 ), cycloheptyl (C 7 ), methylcyclopropyl (C 4 ), dimethylcyclopropyl (C 5 ), methylcyclobutyl (C 5 ), dimethylcyclobutyl (C 6 ), methylcyclopentyl (C 6 ), dimethylcyclopentyl (C 7 ), methylcyclohexyl (C 7 ); and is independently unsubstituted or substituted. In one embodiment, each C 3-7 cycloalkyl is independently unsubstitued.
  • cycloalkenyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring carbon atom of an unsaturated hydrocarbon compound having at least one carbocyclic ring that has at least one carbon-carbon double bond as part of that ring, and having from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms (unless otherwise specified).
  • each C 3-7 cycloalkenyl is independently selected from: cyclopropenyl (C 3 ), cyclobutenyl (C 4 ), cyclopentenyl (C 5 ), cyclohexenyl (C 6 ), methylcyclopropenyl (C 4 ), dimethylcyclopropenyl (C 5 ), methylcyclobutenyl (C 5 ), dimethylcyclobutenyl (C 6 ), methylcyclopentenyl (C 6 ), dimethylcyclopentenyl (C 7 ), methylcyclohexenyl (C 7 ); and is independently unsubstituted or substituted. In one embodiment, each C 3-7 cycloalkenyl is independently unsubstitued.
  • heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a non-aromatic ring atom of a compound having at least one non-aromatic heterocyclic ring, and having from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms (unless otherwise specified).
  • each ring of the compound has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • the ring heteroatoms are selected from N, O, and S.
  • the prefixes e.g., C 3- i 4 , C 3-7 , C 5-6 , etc.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • C 5-6 heterocyclyl as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms.
  • each C 3- i 4 heterocyclyl is independently selected from: C 3 heterocyclyl groups including: Ni : aziridinyl (C 3 ); O 1 : oxiranyl (C 3 ); and S 1 : thiiranyl (C 3 );
  • C 4 heterocyclyl groups including: N 1 : azetidinyl (C 4 ); O 1 : oxetanyl (C 4 ); and S 1 : thietanyl (C 4 ); C 5 heterocyclyl groups including:
  • N 1 pyrrolidinyl (C 5 ), pyrrolinyl (C 5 ), 2H-pyrrolyl or 3H-pyrrolyl (C 5 );
  • ⁇ O 1 tetrahydrofuranyl (C 5 ), dihydrofuranyl (C 5 );
  • N 2 imidazolinyl (C 5 ), pyrazo ⁇ nyl (C 5 ); N 1 O 1 : tetrahydrooxazolyl (C 5 ), dihydrooxazolyl (C 5 ), tetrahydroisoxazolyl (C 5 ), dihydroisoxazolyl (C 5 );
  • N 1 S 1 thiazolinyl (C 5 ), thiazolidinyl (C 5 );
  • O 1 S 1 oxathiolyl (C 5 );
  • C 6 heterocyclyl groups including: N 1 : piperidinyl (C 6 ), dihydropyridinyl (C 6 ), tetrahydr ⁇ pyridinyl (C 6 );
  • N 1 O 1 morpholinyl (C 6 ), tetrahydrooxazinyl (C 6 ), dihydrooxazinyl (C 6 ), oxazinyl (C 6 );
  • N 1 S 1 thiomorpholinyl (C 6 );
  • N 2 O 1 oxadiazinyl (C 6 ); O 1 S 1 : oxathianyl (thioxanyl) (C 6 ); and,
  • NiO 1 S 1 oxathiazinyl (C 6 ); and Cyheterocyclyl groups including:
  • Ni azepinyl (C 7 );
  • aryl refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified).
  • each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.
  • the ring atoms may be all carbon atoms, as in “carboaryl” groups.
  • the ring atoms may include one or more heteroatoms, as in “heteroaryl” groups.
  • the ring heteroatoms are selected from N, O, and S.
  • the prefixes e.g., C 3 . 14l C 5-7 , C 5-6 , etc.
  • the term "C 5-6 heteroaryl,” as used herein, pertains to a heteroaryl group having 5 or 6 ring atoms, including at least one heteroatom.
  • each C 6- i 4 carboaryl is independently selected from: phenyl (C 6 ), indanyl (C 9 ), indenyl (C 9 ), isoindenyl (C 9 ), naphthyl (Ci 0 ), azulenyl (C 10 ), tetralinyl (1 ,2,3,4-tetrahydronaphthalene) (C 10 ), acenaphthenyl (C 12 ), fluorenyl (C 13 ), phenalenyl (C 13 ), anthracenyl (C 14 ), and phenanthreny! (C 14 ).
  • each C 5-14 heteroaryl is independently selected from: C 5 heteroaryl groups including: N 1 : pyrrolyl (C 5 ); O 1 : furanyl (C 5 ); Sv thienyl (C 5 );
  • N 3 triazolyl (C 5 ); and, N 4 : tetrazolyl (C 5 ); Ceheteroaryl groups including:
  • N 1 pyridinyl (C 6 ); N 1 O 1 : isoxazinyl (C 6 );
  • N 1 indolyl (C 9 ), isoindolyl (C 9 ), indolizinyl (C 9 ), indolinyl (C 9 ), isoindolinyl (C 9 );
  • O 1 benzofuranyl (C 9 ), isobenzofuranyl (C 9 );
  • N 2 O 1 benzofurazanyl (C 9 ); N 2 Si: benzothiadiazoly! (C 9 ); N 3 : benzotriazolyl (C 9 ); and N 4 : purinyl (C 9 ); C 10 heteroaryl groups including:
  • O 1 chromenyl (C 10 ), isochromenyl (C 10 ), chromanyl (C 10 ), isochromanyl (C 10 );
  • O 2 benzodioxanyl (C 10 );
  • N 1 quinolinyl (Ci 0 ), isoquinolinyl (N-i), quinolizinyl (N 1 );
  • N 1 Oi benzoxazinyl (Ci 0 );
  • N 2 benzodiazinyl (Ci 0 ), pyridopyridinyl (Ci 0 ), quinoxalinyl (Ci 0 ), quinazolinyl (Ci 0 ), cinnolinyl (C 10 ), phthalazinyl C 10 ), naphthyridinyl (Ci 0 ); and
  • N 4 : pteridinyl (C 10 ); C-nheteroaryl groups (with 2 fused rings) including:
  • C 13 heteroaryl groups (with 3 fused rings) including: N 1 : carbazolyl (C 13 );
  • N 2 carbolinyl (C 13 ), pyridoindolyl (C 13 ); and C 14 heteroaryl groups (with 3 fused rings) including: N 1 : acridinyl (C 14 ), phenanthridine (C 14 );
  • N 2 phenazinyl (C 14 ), phenanthroline (C 14 ), phenazine (C 14 );
  • Another aspect of the present invention pertains to compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
  • 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 an 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
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, 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 (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • keto enol enol ate (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 (wholly or partially) racemic and other 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 a/., 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 + ).
  • 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 ) 4 + .
  • 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, ethanesuifonic, 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, trifluoroacetic, and valeric.
  • a reference to a particular compound also includes salt forms thereof.
  • 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 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(CHs) 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 C 1-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C 1-7 haloalkyl ester (e.g., a
  • C 1-7 trihaloalkyl ester a triC 1-7 alkylsilyl-C 1-7 alkyl ester; or a C 5-20 aryl-C 1-7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • prodrug refers to a compound which, when metabolised (e.g., in vivo), yields the desired compound.
  • the prodrug is inactive, or less active than the compound, but may provide advantageous handling, administration, or metabolic properties.
  • a reference to a particular compound also includes prodrugs thereof.
  • prodrugs are activated enzymatically to yield the compound, or a compound which, upon further chemical reaction, yields the 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.
  • 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, such as, for example, proliferative conditions, cancer, etc.
  • One aspect of the present invention pertains to a method of inhibiting CHK1 kinase function, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound, as described herein.
  • One aspect of the present invention pertains to a method of inhibiting CHK1 kinase function in a cell, in vitro or in vivo, comprising contacting the ceil with an effective amount of a compound, as described herein.
  • the method further comprises contacting the cells 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 are described herein and/or are known in the art.
  • the 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 cells (or the cell) with an effective amount of a 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 cells (or the cell) with an effective amount of a compound, as described herein.
  • the method further comprises contacting the cells 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.
  • the method is performed in vitro. In one embodiment, the method is performed in vivo.
  • the compound is provided in the form of a pharmaceutically acceptable composition.
  • 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.
  • 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 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) the MBHA 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 (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) an MBHA 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 compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the medicament comprises the compound, as described herein.
  • the treatment comprises treatment with both (i) a medicament comprising the MBHA 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) 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) an MBHA 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 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.
  • the treatment is treatment of a disease or condition that is mediated by CHK1.
  • the treatment is treatment of: a disease or condition that is ameliorated by the inhibition of CHK1 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: 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 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.
  • terapéutica ⁇ y-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 MBHA compound is employed in combination with (e.g., in conjunction with) 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 an MBHA compound and one or more other agents 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 MBHA 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) the MBHA 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.
  • 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.
  • 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).
  • the compounds described herein may also be used as cell culture additives to inhibit CHK1 kinase function, e.g., to inhibit cell proliferation, etc.
  • the 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 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 inhibitors, other anti-proliferative agents, other anti-cancer agents, etc.
  • kits comprising (a) a compound as described herein, or a composition comprising a 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 compound or pharmaceutical composition comprising the 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.
  • composition, preparation, medicament comprising at least one 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 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 Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, . 1994.
  • 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.
  • carriers e.g., liquid carriers, finely divided solid carrier, etc.
  • 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, nonaqueous), 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, nonaqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions
  • 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
  • suppositories 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
  • 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 hydroxy! 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).
  • sterile liquids e.g., solutions, suspensions
  • 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.
  • 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.
  • 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.
  • appropriate dosages of the compounds, and compositions comprising the 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 compound, the route of administration, the time of administration, the rate of excretion of the 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 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 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.
  • 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 0.1% Ammonia in acetonitrile.
  • Solvent B 0.1% Ammonia, 5% acetonitrile and 0.063% ammonium formate in water. 0.00 - 4.25 minutes: 5% A / 95% B to 95% A / 5% B. 4.25 - 5.80 minutes: 95% A / 5% B. 5.80 - 5.90 minutes: 95% A / 5% B to 5% A / 95% B. 5.90 - 7.00 minutes: 5% A / 95% B.
  • UV detection was at 220-400 nm using a Waters 996 photodiode array UV detector and ionisation was by positive or negative ion electrospray. Molecular weight scan range was 80-1000 amu.
  • Solvent B 0.1 % Formic acid in water . 0.0 - 0.3 minutes: 10% A/ 90% B.
  • UV detection was at 254 nm and ionisation was by positive or negative ion electrospray. Molecular weight scan range was 50-1000 amu.
  • the crude material was dissolved in DMF (2 mL) and tetra-N-butylammonium fluoride (1 M in THF, 0.25 mL, 0.25 mmol) and ethylenediamine (0.01 mL, 0.16 mmol) were added. The solution was stirred at 60 0 C under nitrogen for 4 hours. Further TBAF (1 M in THF, 0.25 mL, 0.25 mmol) was added and stirring was continued for an additional 3 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried (Na 2 SO 4 ), filtered, and concentrated.
  • Chlorotitanium triisopropoxide (0.28 mL, 1.3 mmol) was added to a suspension of 6-chloro-7deazaguanine (0.10 mg, 0.59 mmol) and benzaldehyde (0.057 g, 0.53 mmol) in a mixture of anhydrous THF (0.75 mL) and dichloromethane (0.75 mL) under argon.
  • the reactants initially dissolved to form an orange solution, followed by formation of a white precipitate.
  • freshly ground sodium triacetoxyborohydride (0.507 g, 2.65 mmol) was added in portions followed by acetic acid (3 drops).
  • Triethylamine (0.14 ml_, 1.0 mmol) was added to N-benzyl-4-chloro-7H-pyrrolo[2,3- d]pyrimidin-2-amine (0.110 g, 0.43 mmol) and ferf-butyl morpholin-2-ylmethylcarbamate (0.097 mg, 0.45 mmol) in butan-1-ol (1.8 ml_) and the mixture was heated overnight at 100 0 C. The mixture was cooled and concentrated. Preparative TLC, eluting with 10% methanol-dichloromethane, gave the title compound (0.061 g, 0.138 mmol, 32%).
  • N-Bromosuccinimide (0.044 g, 0.25 mmol) was added in portions at room temperature to a solution of ethyl 4-(2-((ferf-butoxycarbonylamino)methyl)-morpholino)-1 H-pyrazolo[3,4- b]pyridine-5-carboxylate (0.083 g, 0.20 mmol) in DMF (2 ml_). After stirring for 2 hours, saturated brine was added and the precipitate was collected by filtration, washed with water, and dried, to yield the title compound as a pale yellow powder (0.076 g, 77%).
  • n-BuLi (4 mL, 1.5M, 6 mmol) was added to a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3- d]pyrimidine (0.95 g, 4.09 mmol) in THF (15 mL) at -78°C. The mixture was stirred at - 78°C for 1 hour followed by addition of solid CO 2 . The resulting suspension was stirred at -78 0 C for 2 hours, and then warmed gradually to room temperature. 1 M HCI was added until the solution became acidic and the precipitate was collected by filtration, washed with water, and dried, to give the title compound as a white solid (0.53 g, 66%).
  • ⁇ /-Bromosuccinimide (10 mg, 0.058 mmol) was added to (4-(5-phenyl-1tf-pyrazolo[3,4- b]pyridin-4-yl)morpholin-2-yl)methanamine, prepared as described in Synthesis 11-1 , (15 mg, 0.048 mmol) in DMF (0.5 ml_) and the reaction was stirred at rt for 16 hours. Further ⁇ /-bromosuccinimide (5 mg, 0.029 mmol) was added and reaction was stirred for 2 hours before being diluted with MeOH and added to a conditioned 2 g lsolute SCX-II acidic resin column.
  • Triethylamine (4.0 mL, 28.9 mmol) was added at -10 0 C to a solution of (S)-3-amino-1 ,2- propanediol (2.2 g, 24.1 mmol) in a mixture of MeCN/MeOH (80 mL/13 mL).
  • Chloroacetyl chloride (2.1 mL, 26.5 mmol) was added dropwise under nitrogen at -10 0 C over 30 minutes.
  • the reaction mixture was allowed to warm to room temperature and was stirred for 16 hours.
  • the mixture was concentrated and purified by flash chromatography on silica gel, eluting with MeOH-EtOAc (8:92), to give the title compound as a white solid (3.63 g, 90%).
  • reaction mixture was stirred for 16 hours at room temperature and then cooled to 0 0 C before the addition of water (0.5 mL) followed by potassium hydroxide solution (4M,
  • the reaction mixture was stirred at room temperature for 4 hours, then diluted with water (4 mL) and washed with an aqueous HCI solution (0.2 M, 8 mL). The organic phase was dried (MgSO 4 ) and the solvent was removed in vacuo. The crude mixture was purified by flash column chromatography on silica, eluting with ethyl acetate-hexane (1:1), to give the title compound as a colourless solid (0.316 g, 87%).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention appartient d'une manière générale au domaine des composés thérapeutiques, et, plus spécifiquement, à certains composés bicyclohétéroarylés substitués par morpholino (désignés ci-après comme étant des composés MBHA), de la formule suivante : et notamment certains composés de 7H-pyrrolo[2,3-d]pyrimidine substitués par morpholino et 1H-pyrazolo[3,4-b]pyridine substitués par morpholino, qui, entre autres, inhibent la fonction kinase de la Kinase 1 de point de contrôle (CHK1). La présente invention concerne également des compositions pharmaceutiques comprenant de tels composés, et l'utilisation de tels composés et de telles compositions, à la fois in vitro et in vivo pour inhiber la fonction de kinase CHK1, et dans le traitement de maladies et d'états médiés par CHK1 améliorés par l'inhibition de la fonction de kinase CHK1, etc., comprenant des états prolifératifs tels que le cancer, etc., facultativement en combinaison avec un autre agent, par exemple, (a) un inhibiteur de l'ADN topoisomérase I ou II, (b) un agent endommageant l'ADN ; (c) un antimétabolite ou inhibiteur de TS ; (d) un agent ciblé sur les microtubules ; et (e) un rayonnement ionisant
PCT/GB2007/004819 2006-12-21 2007-12-14 Composé bicyclohétéroarylés substitué par morpholino et leur utilisation en tant qu'agents anti-cancer Ceased WO2008075007A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US87613706P 2006-12-21 2006-12-21
GB0625633A GB0625633D0 (en) 2006-12-21 2006-12-21 Therapeutic compounds and their use
US60/876,137 2006-12-21
GB0625633.3 2006-12-21

Publications (1)

Publication Number Publication Date
WO2008075007A1 true WO2008075007A1 (fr) 2008-06-26

Family

ID=39133780

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/004819 Ceased WO2008075007A1 (fr) 2006-12-21 2007-12-14 Composé bicyclohétéroarylés substitué par morpholino et leur utilisation en tant qu'agents anti-cancer

Country Status (1)

Country Link
WO (1) WO2008075007A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2056822A4 (fr) * 2007-05-29 2009-09-16 Sgx Pharmaceuticals Inc Pyrrolopyridines et pyrazolopyridines substituées en tant que modulateurs de kinase
US7989469B2 (en) * 2008-02-04 2011-08-02 Cytokinetics, Incorporated Certain chemical entities, compositions, and methods
US8178131B2 (en) 2008-05-13 2012-05-15 Array Biopharma Inc. Pyrrolopyridines as kinase inhibitors
US8227603B2 (en) 2006-08-01 2012-07-24 Cytokinetics, Inc. Modulating skeletal muscle
US8293761B2 (en) 2006-08-02 2012-10-23 Cytokinetics, Inc. Certain chemical entities, compositions and methods
US8299248B2 (en) 2006-08-02 2012-10-30 Cytokinetics, Incorporated Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols and methods for their use
US8372842B2 (en) 2008-01-09 2013-02-12 Array Biopharma Inc. Pyrazolopyridines as kinase inhibitors
WO2014001973A1 (fr) * 2012-06-29 2014-01-03 Pfizer Inc. Nouvelles 7h-pyrrolo[2,3-d]pyrimidines substituées par un groupe amino en position 4, utilisées comme inhibiteurs de lrrk2
CN103923081A (zh) * 2014-04-14 2014-07-16 武汉光谷人福生物医药有限公司 化合物及其制备方法和应用
US8841304B2 (en) 2008-01-08 2014-09-23 Array Biopharma, Inc. Pyrrolopyridines as kinase inhibitors
US9630968B1 (en) 2015-12-23 2017-04-25 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
US10039753B2 (en) 2015-09-14 2018-08-07 Pfizer Inc. Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors
US10272082B2 (en) 2011-07-13 2019-04-30 Cytokinetics, Inc. Combination ALS therapy
WO2020040591A1 (fr) * 2018-08-23 2020-02-27 재단법인 대구경북첨단의료산업진흥재단 Nouvelle utilisation d'un dérivé de pyrimidine comprenant un inhibiteur de kinase lrrk en tant que principe actif
US11020398B2 (en) 2016-08-24 2021-06-01 Arqule, Inc. Amino-pyrrolopyrimidinone compounds and methods of use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999065909A1 (fr) * 1998-06-19 1999-12-23 Pfizer Products Inc. COMPOSES DE PYRROLO[2,3-d]PYRIMIDINE
EP1277738A1 (fr) * 2000-04-27 2003-01-22 Yamanouchi Pharmaceutical Co. Ltd. Derives d'heteroaryle condenses
FR2880626A1 (fr) * 2005-01-13 2006-07-14 Aventis Pharma Sa Derives de la purine, compositions les contenant et utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999065909A1 (fr) * 1998-06-19 1999-12-23 Pfizer Products Inc. COMPOSES DE PYRROLO[2,3-d]PYRIMIDINE
EP1277738A1 (fr) * 2000-04-27 2003-01-22 Yamanouchi Pharmaceutical Co. Ltd. Derives d'heteroaryle condenses
FR2880626A1 (fr) * 2005-01-13 2006-07-14 Aventis Pharma Sa Derives de la purine, compositions les contenant et utilisation

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8227603B2 (en) 2006-08-01 2012-07-24 Cytokinetics, Inc. Modulating skeletal muscle
US10766899B2 (en) 2006-08-02 2020-09-08 Cytokinetics, Incorporated Methods for preparing substituted imidazo[4,5-b]pyrazines
US8716291B2 (en) 2006-08-02 2014-05-06 Cytokinetics, Inc. Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols and methods for their use
US8299248B2 (en) 2006-08-02 2012-10-30 Cytokinetics, Incorporated Certain 1H-imidazo[4,5-b]pyrazin-2(3H)-ones and 1H-imidazo[4,5-b]pyrazin-2-ols and methods for their use
US8293761B2 (en) 2006-08-02 2012-10-23 Cytokinetics, Inc. Certain chemical entities, compositions and methods
EP2056822A4 (fr) * 2007-05-29 2009-09-16 Sgx Pharmaceuticals Inc Pyrrolopyridines et pyrazolopyridines substituées en tant que modulateurs de kinase
US8158647B2 (en) 2007-05-29 2012-04-17 Sgx Pharmaceuticals, Inc. Substituted pyrrolopyridines and pyrazolopyridines as kinase modulators
US8841304B2 (en) 2008-01-08 2014-09-23 Array Biopharma, Inc. Pyrrolopyridines as kinase inhibitors
US8372842B2 (en) 2008-01-09 2013-02-12 Array Biopharma Inc. Pyrazolopyridines as kinase inhibitors
US7989469B2 (en) * 2008-02-04 2011-08-02 Cytokinetics, Incorporated Certain chemical entities, compositions, and methods
US9969727B2 (en) 2008-05-13 2018-05-15 Array Biopharma Inc. Pyrrolopyridines as kinase inhibitors
US8758830B2 (en) 2008-05-13 2014-06-24 Array Biopharma, Inc. Pyrrolopyridines as kinase inhibitors
EP2990407A1 (fr) 2008-05-13 2016-03-02 Array Biopharma, Inc. Pyrrolopyridines en tant qu'inhibiteurs de kinase
US8545897B2 (en) 2008-05-13 2013-10-01 Array Biopharma Inc. Pyrrolopyridines as kinase inhibitors
US8981085B2 (en) 2008-05-13 2015-03-17 Array Biopharma Inc. Pyrrolopyridines as kinase inhibitors
US8178131B2 (en) 2008-05-13 2012-05-15 Array Biopharma Inc. Pyrrolopyridines as kinase inhibitors
US9365568B2 (en) 2008-05-13 2016-06-14 Array Biopharma Inc. Pyrrolopyridines as kinase inhibitors
US10272082B2 (en) 2011-07-13 2019-04-30 Cytokinetics, Inc. Combination ALS therapy
WO2014001973A1 (fr) * 2012-06-29 2014-01-03 Pfizer Inc. Nouvelles 7h-pyrrolo[2,3-d]pyrimidines substituées par un groupe amino en position 4, utilisées comme inhibiteurs de lrrk2
JP2019073522A (ja) * 2012-06-29 2019-05-16 ファイザー・インク ＬＲＲＫ２阻害薬としての新規な４−（置換アミノ）−７Ｈ−ピロロ［２，３−ｄ］ピリミジン
US9156845B2 (en) 2012-06-29 2015-10-13 Pfizer Inc. 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors
JP2015522002A (ja) * 2012-06-29 2015-08-03 ファイザー・インク ＬＲＲＫ２阻害薬としての新規な４−（置換アミノ）−７Ｈ−ピロロ［２，３−ｄ］ピリミジン
EA025186B1 (ru) * 2012-06-29 2016-11-30 Пфайзер Инк. НОВЫЕ 4-(ЗАМЕЩЕННЫЙ АМИНО)-7Н-ПИРРОЛО[2,3-d]ПИРИМИДИНЫ В КАЧЕСТВЕ ИНГИБИТОРОВ LRRK2
AU2013282869B2 (en) * 2012-06-29 2015-12-24 Pfizer Inc. Novel 4-(substituted-amino)-7H-pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors
US9642855B2 (en) 2012-06-29 2017-05-09 Pfizer Inc. Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors
CN104395315A (zh) * 2012-06-29 2015-03-04 辉瑞大药厂 作为LRRK2抑制剂的新的4-(取代的氨基)-7H-吡咯并〔2,3-d〕嘧啶类
EP3255049A1 (fr) * 2012-06-29 2017-12-13 Pfizer Inc Nouvelles 7h-pyrrolo[2,3-d]pyrimidines substituées par un groupe amino en position 4, utilisées comme inhibiteurs de lrrk2
TWI482774B (zh) * 2012-06-29 2015-05-01 Pfizer 作爲ＬＲＲＫ２抑制劑之新穎４－（經取代胺基）－７Ｈ－吡咯并［２，３－ｄ］嘧啶類
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
CN103923081A (zh) * 2014-04-14 2014-07-16 武汉光谷人福生物医药有限公司 化合物及其制备方法和应用
US10039753B2 (en) 2015-09-14 2018-08-07 Pfizer Inc. Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors
US10245263B2 (en) 2015-12-23 2019-04-02 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US9630968B1 (en) 2015-12-23 2017-04-25 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US10933065B2 (en) 2015-12-23 2021-03-02 Arqule Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US11020400B2 (en) 2015-12-23 2021-06-01 Arqule, Inc. Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof
US11020398B2 (en) 2016-08-24 2021-06-01 Arqule, Inc. Amino-pyrrolopyrimidinone compounds and methods of use thereof
WO2020040591A1 (fr) * 2018-08-23 2020-02-27 재단법인 대구경북첨단의료산업진흥재단 Nouvelle utilisation d'un dérivé de pyrimidine comprenant un inhibiteur de kinase lrrk en tant que principe actif

Similar Documents

Publication Publication Date Title
WO2008075007A1 (fr) Composé bicyclohétéroarylés substitué par morpholino et leur utilisation en tant qu'agents anti-cancer
EP2288601B1 (fr) Composés de type bicyclylaryl-aryl-amine et leur utilisation
CN114269735B (zh) 二氢或四氢喹唑啉类化合物及其中间体、制备方法和应用
US8618121B2 (en) 9H-pyrimido[4,5-B]indoles, 9H-pyrido[4',3':4,5]pyrrolo[2,3-D]pyridines, and 9H 1,3,6,9 tetraaza-fluorenes as CHK1 kinase function inhibitors
KR102565546B1 (ko) 신규 옥소이소퀴놀린 유도체
KR20250070059A (ko) 신규한 테트라헤테로사이클 화합물
KR20200131246A (ko) 키나제 억제제로서의 헤테로시클릭 화합물
MX2011003447A (es) Inhibidores heterociclicos de jak quinasa.
AU2014338549A1 (en) Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors
HK1223100A1 (zh) 杂环化合物
KR20170023156A (ko) 단백질 키나제 저해제로서의 아미노피리다지논 화합물
KR20090101281A (ko) 퓨린 유도체
CN111205310A (zh) 杂环稠合嘧啶衍生物、其药物组合物及应用
AU2014320149A1 (en) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
AU2019296085A1 (en) Heterocyclic compound as TRK inhibitor
CN114929708B (zh) 4-[[(7-氨基吡唑并[1,5-a]嘧啶-5-基)氨基]甲基]哌啶-3-醇化合物以及它们的治疗用途
ES3036245T3 (en) Substituted pyrazine-2-carboxamides as hpk1 inhibitors for the treatment of cancer
ES2709003T3 (es) Compuestos de 5-(piridin-2-il-amino)-pirazina-2-carbonitrilo y su uso terapéutico
WO2024184550A1 (fr) Dérivés de biarylamide et leur utilisation en tant qu'inhibiteurs de pkmyt1
WO2024184520A1 (fr) Dérivés de biarylamide et leur utilisation dans le traitement de troubles prolifératifs
CN112209934B (zh) 含有氮杂螺庚烷的btk抑制剂
KR102920599B1 (ko) 항종양 활성을 갖는 화합물 및 이의 용도
RU2772226C2 (ru) Новые производные оксоизохинолина
TWI690528B (zh) 稠環雙環吡啶基衍生物
HK40009542B (zh) 氧代异喹啉衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07848559

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07848559

Country of ref document: EP

Kind code of ref document: A1