[go: up one dir, main page]

WO2009103966A1 - Bicyclylaryl-aryl-amine compounds and their use - Google Patents

Bicyclylaryl-aryl-amine compounds and their use Download PDF

Info

Publication number
WO2009103966A1
WO2009103966A1 PCT/GB2009/000438 GB2009000438W WO2009103966A1 WO 2009103966 A1 WO2009103966 A1 WO 2009103966A1 GB 2009000438 W GB2009000438 W GB 2009000438W WO 2009103966 A1 WO2009103966 A1 WO 2009103966A1
Authority
WO
WIPO (PCT)
Prior art keywords
independently
compound according
present
nhr
nhc
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/GB2009/000438
Other languages
French (fr)
Inventor
Ian Collins
John Charles Reader
David Hugh Williams
Sukhbinder Singh Klair
Jane Elizabeth Scanlon
Nelly Piton
Michael Cherry
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
Application filed by Cancer Research Technology Ltd filed Critical Cancer Research Technology Ltd
Priority to EP09712330.1A priority Critical patent/EP2288601B1/en
Priority to US12/918,266 priority patent/US8530468B2/en
Priority to ES09712330.1T priority patent/ES2527519T3/en
Publication of WO2009103966A1 publication Critical patent/WO2009103966A1/en
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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain bicyclylaryl-aryl-amine compounds (referred to herein as BCAA compounds), which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function.
  • BCAA compounds bicyclylaryl-aryl-amine compounds
  • 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.
  • Cell cycle checkpoints are found in all four stages of the cell cycle; G1 , S (DNA replication), G2 and M (Mitosis) and they ensure that key events which control the fidelity of DNA replication and cell division are completed correctly.
  • Cell cycle checkpoints are activated by a number of stimuli, including DNA damage and DNA errors caused by defective replication. When this occurs, the cell cycle will arrest, allowing time for either DNA repair to occur or, if the damage is too severe, for activation of cellular processes leading to controlled cell death.
  • 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 a/., 1997).
  • CHK1 Phosphorylation of Cdc25C and the related Cdc25A by CHK1 blocks their ability to activate CDK1 , thus preventing the cell from exiting G2 into M phase.
  • the role of CHK1 in the DNA damage-induced G2 cell cycle checkpoint has been demonstrated in a number of studies where CHK1 function has been knocked out (see, e.g., Liu et ai, 2000; Zhao et a/., 2002; Zachos et a/., 2003).
  • the reliance of the DNA damage-induced G2 checkpoint upon CHK1 provides one example of a therapeutic strategy for cancer treatment, involving targeted inhibition of CHK1.
  • the p53 tumour suppressor protein Upon DNA damage, the p53 tumour suppressor protein is stabilised and activated to give a p53-dependent G1 arrest, leading to apoptosis or DNA repair (Balaint and Vousden, 2001).
  • IR ionising radiation
  • certain forms of chemotherapy see, e.g., Greenblatt et 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.
  • inhibition of CHK1 kinase in those cancers that are reliant on these processes after DNA damage may provide additional therapeutic strategies for the treatment of cancers using CHK1 inhibitors (see, e.g., Sorensen et al., 2005).
  • Recent data using 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 ai, 2006).
  • Small-molecule selective inhibitors of CHK1 kinase function from various chemical classes have been described (see, e.g., Tao and Lin, 2006).
  • BCAA compounds bicyclylaryl-aryl-amine compounds
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a BCAA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising the step of admixing a BCAA 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 a BCAA compound, as described herein.
  • the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a BCAA compound, as described herein.
  • the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a BCAA 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 method of treatment comprises treatment with both (i) a BCAA 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 BCAA compound as described herein for use in a method of treatment of the human or animal body by therapy.
  • the method of treatment comprises treatment with both (i) a BCAA 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 BCAA compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the treatment comprises treatment with both (i) a medicament comprising a BCAA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • a medicament comprising a BCAA 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: p53 negative cancer.
  • the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
  • kits comprising (a) a
  • BCAA compound as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • the kit further comprises one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; and (d) a microtubule targeted agent.
  • Another aspect of the present invention pertains to a BCAA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to a BCAA 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.
  • bicyclylaryl-aryl-amines for convenience, collectively referred to herein as "bicyclylaryl-aryl compounds” or "BCAA compounds" which are related to pyrazin-2-yl-pyridin-2-yl-amines.
  • the compounds are related to the following compounds:
  • the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • each of -R C1 , -R C2 , -R C3 , and -R C4 is independently -H or -Q c ;
  • -R D1 is independently -H or -Q D ; each of -R E1 and -R E2 is independently -H or -Q E ;
  • the compounds are optionally as defined herein, but with one or more optional provisos, as defined herein.
  • the proviso is that the compound is not the following compound, which is shown on page 117 (No 197) in WO 2007/000240 and is allegedly useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase.
  • the proviso is that the compound is not [6-(piperidin-4-yloxy)- isoquinolin-3-yl]-pyrazin-2-yl-amine hydrochloride salt.
  • the proviso is that the compound is not [6-(piperidin-4-yloxy)- isoquinolin-3-yl]-pyrazin-2-yl-amine, or a salt, hydrate, or solvate thereof.
  • the compounds are optionally as defined herein, but without the above proviso.
  • a reference to a particular group of compounds "without the recited proviso" is intended to be a reference to the compounds as defined, but wherein the definition no longer includes the indicated proviso.
  • the definition no longer includes the indicated proviso.
  • the ring denoted A is independently:
  • the ring denoted A is independently selected from: as in, for example:
  • the ring denoted A is independently: In one embodiment, the ring denoted A is independently:
  • the ring denoted A is independently selected from: as in, for example: In one embodiment, the ring denoted A is independently:
  • the ring denoted A is independently:
  • -R A3 is independently -H or -Q A3 . In one embodiment, -R A3 is independently -H. In one embodiment, -R A3 is independently -Q A3 .
  • -R A ⁇ is independently -H or -Q A6 . In one embodiment, -R A6 is independently -H. In one embodiment, -R A6 is independently -Q A6 .
  • -R B3 is independently -H or -Q B3 . In one embodiment, -R B3 is independently -H. In one embodiment, -R B3 is independently -Q B3 .
  • -R B5 is independently -H or -Q B5 . In one embodiment, -R B5 is independently -H. In one embodiment, -R B5 is independently -Q B5 .
  • -R B6 is independently -H or -Q B6 . In one embodiment, -R B6 is independently -H. In one embodiment, -R B6 is independently -Q B6 .
  • each of -R C1 , -R C2 , -R C3 , and -R C4 if present, is independently -H or -Q c .
  • -R C1 if present, is independently -Q c ; and each of -R C2 , -R C3 , and -R C4 , if present, is independently -H or -Q c .
  • -R C1 if present, is independently -Q c ; and each of -R C2 , -R C3 , and -R C4 , if present, is independently -H;
  • -R C3 if present, is independently -Q c ; and each of -R C1 , -R C2 , and -R C4 , if present, is independently -H or -Q c
  • -R C3 if present, is independently -H; and each of -R C1 , -R C2 , and -R C4 , if present, is independently -H or -Q c
  • -R C3 if present, is independently -Q c ; and each of -R C1 , -R C2 , and -R C4 , if present, is independently -H.
  • -R 03 if present, is independently -H; and each of -R C1 , -R C2 , and -R C4 , if present, is independently -H.
  • each of -R C1 and -R C3 if present, is independently -Q c ; and each of -R C2 and -R C4 , if present, is independently -H or -Q c .
  • each of -R C1 and -R C3 if present, is independently -Q c ; and each of -R C2 and -R 04 , if present, is independently -H. In one embodiment:
  • -R C3 if present, is independently -H; and -R C1 , if present, is independently -Q c .
  • each of -R C2 and -R C4 if present, is independently -H or -Q c .
  • -R D1 if present, is independently -H or -Q D . In one embodiment, -R D1 , if present, is independently -H. In one embodiment, -R D1 , if present, is independently -Q D .
  • each of -R E1 and -R E2 if present, is independently -H or -Q E .
  • -R E1 if present, is independently -H or -Q E . In one embodiment, -R E1 , if present, is independently -H. In one embodiment, -R E1 , if present, is independently -Q E .
  • -R E2 if present, is independently -H or -Q E . In one embodiment, -R E2 , if present, is independently -H. In one embodiment, -R E2 , if present, is independently -Q E .
  • -Q A3 is independently:
  • each -R QA3 is independently saturated aliphatic C h alky!; and _ NR QA3A R Q A 3B js j nc j e p enc i en tiy azetidjno, pyrrolidino, ⁇ midazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from saturated aliphatic C 1-3 alkyl, -F, and -CF 3 .
  • -Q A3 is independently: -F, -Cl, -Br, -I 1 -Me, -Et, -nPr, -iPr, -CF 3 , -OCF 3 , -OH, -OMe, -OEt, -SH 1 -SMe, -NH 2 , -NHMe, or -NMe 2 .
  • -Q A6 is independently:
  • each -R QA6 is independently saturated aliphatic C 1-6 alkyl; and _ NR QA6 A R Q A 6B js j nc
  • -Q A6 is independently: -Me 1 -Et, -nPr, -iPr,
  • -Q B3 if present, is independently:
  • each -R QB3 is independently saturated aliphatic Ci -6 alkyl
  • R QB3B is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from saturated aliphatic C 1-3 alkyl, -F, and -CF 3 .
  • -Q B3 if present, is independently:
  • -Q B5 if present, is independently: -R 1A1 ,
  • each -L 1A - is independently saturated aliphatic C 1-5 alkylene; in each group -NR 1A2 R 1A3 , R 1A2 and R 1A3 , taken together with the nitrogen atom to which they are attached, form a A-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R 1A1 is independently: -R 1B1 -R 1B2 -R 1B3 -R 1B4 -R 1B5 -R 1B6 -R 1B7 -R 1B8
  • each -R 1B1 is independently saturated aliphatic C 1-6 alkyl; each -R 1B2 is independently aliphatic C 2-6 alkenyl; each -R 1B3 is independently aliphatic C 2-6 alkynyl; each -R 1B4 is independently saturated C 3-6 cycloalkyl; each -R 1B5 is independently C ⁇ cycloalkenyl; each -R 1B6 is independently non-aromatic C 3- gheterocyclyl; each -R 1B7 is independently C 6-10 carboaryI; each -R 1B8 is independently C 5 .i 0 heteroaryl; each -L 1B - is independently saturated aliphatic C 1-3 alkylene; where
  • each -R 1D1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl; each -L 1D - is independently saturated aliphatic C 1-5 alkylene; and in each group -NR 102 R 103 , R 102 and R 103 , taken together with the nitrogen atom
  • -Q B5 if present, is independently:
  • -Q B5 if present, is independently:
  • -Q B5 if present, is independently:
  • -Q B5 if present, is independently -CN.
  • -Q B5 if present, is independently -R 1B1 .
  • -Q B5 if present, is independently -Me.
  • -Q B5 if present, is independently -R 188 .
  • -Q B5 if present, is independently -OR 1A1 .
  • -Q B5 if present, is independently -OMe.
  • each -L 1A - is independently -(CH 2 ) n1 -, wherein n1 is independently 1 to 4.
  • each -L 1A - is independently -CH 2 - or -CH 2 CH 2 -.
  • each -NR 1A2 R 1A3 if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -NR 1A2 R 1A3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -R 1A1 is independently:
  • each -R 1A1 is independently:
  • each -R 1A1 if present, is independently: -R 1B1 , -R 1B7 , or -L 1B -R 1B7 .
  • each -R 1A1 is independently: -R 1B7 , -R 1B8 , -L 1B -R 1B7 , or -L 1B -R 1B8 .
  • each -R 1B6 is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
  • each -R 1B6 is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
  • each -R 1B7 is independently phenyl, and is optionally substituted.
  • each -R 1B8 is independently C 5-6 heteroaryl, and is optionally substituted.
  • each -R 1B8 is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -R 1B8 is independently C 9-10 heteroaryl, and is optionally substituted.
  • each -R 1B8 if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
  • each -L 1B - is independently -CH 2 - Or -CH 2 CH 2 -. In one embodiment, each -L 1B -, if present, is independently -CH 2 -.
  • each -R 1C1 if present, is independently saturated aliphatic C 1-4 alkyl.
  • each -R 1C2 is independently: -F, -Cl, -Br, -I, -OH, -OR 1D1 ,
  • each -R 101 is independently saturated aliphatic C 1-4 alkyl.
  • each -L 10 - is independently -(CH 2 ) m1 - > wherein ml is independently 1 to 4.
  • each -L 10 - is independently -CH 2 - or -CH 2 CH 2 -.
  • each -NR 102 R 103 is independently azetidino, pyrrolidine, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -NR 102 R 103 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • -Q B5 if present, is independently:
  • each R X4 is independently saturated aliphatic C 1-4 alkyl.
  • -Q B6 is independently -0-R QB6 , -S-R QB6 , or -NR BN -R QB6 . In one embodiment, -Q B6 is independently -O-R QB6 . In one embodiment, -Q B6 is independently -S-R QB6 . In one embodiment, -Q B6 is independently -NR BN -R QB6 .
  • -R BN if present, is independently -H or saturated aliphatic C 1-4 alkyl. In one embodiment, -R BN , if present, is independently -H or -Me. In one embodiment, -R BN , if present, is independently -H.
  • -R QB6 if present, is independently: -R 4A1 ,
  • each -L 4A - is independently saturated aliphatic C 2-6 alkylene; in each group -NR 4A2 R 4A3 , R 4A2 and R 4A3 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R 4A1 is independently: p4B1 p4B2 p4B3 p4B4 p4B5 p4B6 p4B7 p4B8 -I N , - ⁇ , -
  • each -R 4D1 is independently saturated aliphatic d ⁇ alkyl, phenyl, or benzyl; each -L 4D - is independently saturated aliphatic C 1-5 alkylene; and in each group -NR 402 R 403 , R 402 and R 403 , taken together with the nitrogen atom to which they are attached, form a A-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O.
  • -R QB6 is independently:
  • -R QB6 if present, is independently: -L 4A -OH or -L 4A -OR 4A1 .
  • -R QB6 is independently:
  • -R QB6 if present, is independently -R 4A1 .
  • each -L 4A - is independently -(CH 2 ) n4 -, wherein n4 is independently 2 to 6.
  • each -L 4A - is independently -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • each -NR 4A2 R 4A3 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, diazepino, or oxazepino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -NR 4A2 R 4A3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -R 4A1 if present, is independently:
  • each -R 4A1 is independently:
  • each -R 4A1 if present, is independently: -R 4B1 , -R 4B7 , or -L 4B -R 4B7 .
  • each -R 4A1 is independently:
  • each -R 4A1 if present, is independently -R 4B6 or -L 4B -R 4B ⁇ .
  • -R QB6 if present, is independently -R 4A1 , wherein -R 4A1 is -R 4B6 or -L 4B -R 4B6 .
  • each -R 4B6 is independently a C 3-8 heterocyclyl group that is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring or a 7-, 8-, or 9-membered non-aromatic bicyclic ring, said ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ring heteroatoms is independently N, O, or S; and is optionally substituted.
  • each -R 4B ⁇ is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, oxazepanyl, 3-aza-bicyclo[3.2.1]octanyl, 8-aza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3-aza-bicyclo[3.1.1]heptanyl, 6-aza-bicyclo[3.1.1]heptanyl,
  • each -R 4B6 is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, 8-aza-bicyclo[3.2.1]octanyl, or quinuclidinyl, and is optionally substituted.
  • each -R 4B6 is independently pyrrolidinyl, piperidinyl, or morpholinyl; and is optionally substituted.
  • each -R 4B7 is independently phenyl, and is optionally substituted.
  • each -R 4B8 is independently C 5-6 heteroaryl, and is optionally substituted.
  • each -R 4B8 is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -R 4B8 is independently C 9-10 heteroaryl, and is optionally substituted.
  • each -R 4B8 is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
  • each -L 4B - is independently -CH 2 - or -CH 2 CH 2 -. In one embodiment, each -L 4B -, if present, is independently -CH 2 -.
  • each -R 4C1 if present, is independently saturated aliphatic C 1-4 alkyl.
  • each -R 4C2 is independently: -F, -Cl, -Br, -I,
  • each -R 4D1 is independently saturated aliphatic C 1-4 alkyl.
  • each -L 4D - is independently -(CH 2 ) m i- > wherein ml is independently 1 to 4.
  • each -L 4D - is independently -CH 2 - or -CH 2 CH 2 -.
  • each -NR 4D2 R 4D3 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -NR 4D2 R 4D3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • -R QB6 is independently selected from groups of the following formulae, wherein p1 is independently 1 , 2, 3, or 4; p2 is independently 1 , 2, 3, or 4; p3 is independently 0, 1 , or 2; and p4 is independently 1 , 2, 3, or 4:
  • -R QB6 if present, is independently a group of formula (B6-1).
  • -R QB6 if present, is independently a group of formula (B6-1 B). In one embodiment, -R QB6 , if present, is independently a group of formula (B6-2).
  • -R QB6 if present, is independently a group of formula (B6-3).
  • -R QB6 if present, is independently a group of formula (B6-4).
  • -R QB6 if present, is independently a group of formula (B6-5).
  • -R QB6 if present, is independently a group of formula (B6-6). In one embodiment, -R QB6 , if present, is independently a group of formula (B6-7).
  • -R QB6 if present, is independently a group of formula (B6-8).
  • -R QB6 if present, is independently a group of formula (B6-9).
  • -R QB6 if present, is independently a group of formula (B6-10).
  • -R QB ⁇ if present, is independently a group of formula (B6-11). In one embodiment, -R QB6 , if present, is independently a group of formula (B6-12).
  • p1 if present, is independently 1.
  • p3, if present, is independently 0. In one embodiment, p3, if present, is independently 1 or 2.
  • p4 if present, is independently 1.
  • each -R NN1 is independently -H, saturated aliphatic C 1-4 alkyl, phenyl, or benzyl; or, the group -NR NN1 R NN1 , if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -R NN1 is independently -H, saturated aliphatic C 1-4 alkyl, phenyl, or benzyl; or, the group -NR NN1 R NN1 , if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -R NN1 if present, is independently -H, saturated aliphatic
  • each -R NN1 if present, is independently -H or saturated aliphatic
  • each -R NN1 if present, is independently -H or -Me. In one embodiment, each -R NN1 , if present, is independently -H. In one embodiment, each -R NN2 , if present, is independently -H or saturated aliphatic C 1-4 alkyl.
  • each -R NN2 if present, is independently -H or -Me. In one embodiment, each -R NN2 , if present, is independently -H.
  • each -R NN3 is independently -H, saturated aliphatic C 1-4 alkyl, phenyl, or benzyl.
  • each -R NN3 if present, is independently -H or saturated aliphatic C 1-4 alkyl.
  • each -R NN3 if present, is independently -H or -Me. In one embodiment, each -R NN3 , if present, is independently -H. In one embodiment, each -R NN3 , if present, is independently -Me.
  • -R NN4 if present, is independently saturated aliphatic C 1-6 alkyl. In one embodiment, -R NN4 , if present, is independently saturated aliphatic C 1-4 alkyl.
  • each -13- is independently saturated aliphatic C 1-5 alkylene; in each group -NR 2A2 R 2A3 , R 2 * 2 and R 2 * 3 , taken together with the nitrogen atom to which they are attached, form a A-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R 2 * 1 is independently: -R 2B1 -R 2B2 -R 2B3 -R 2B4 -R 2B5 -R 2B6 -R 2B7 -R 2B8
  • each -R 2B1 is independently saturated aliphatic C 1-6 alkyl; each -R 2B2 is independently aliphatic C 2-6 alkenyl; each -R 2B3 is independently aliphatic C 2 - 6 alkynyl; each -R 2B4 is independently saturated C 3-6 cycloalkyl; each -R 2B5 is independently C 3-6 cycloalkenyl; each -R 2B6 is independently non-aromatic C ⁇ heterocyclyl; each -R 2B7 is independently C 6-10 carboaryl; each -R 2B8 is independently C 5 .
  • each -L 2B - is independently saturated aliphatic C 1-3 alkylene; wherein: each -R 2B4 , -R 2B5 , -R 2B6 , -R 2B7 , and -R 2B8 is optionally substituted, for example, with one or more substituents -R 2C1 and/or one or more substituents -R 2C2 , each -R 2B1 , -R 2B2 , -R 2B3 , and -L 2B - is optionally substituted, for example, with one or more substituents -R 2C2 , and wherein: each -R 2C1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl; each -R 2C2 is independently:
  • each -R 2D1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl; each -L 2D - is independently saturated aliphatic C 1-5 alkylene; and in each group -NR 202 R 203 , R 202 and R 203 , taken together with the
  • each -Q c , if present, and each -Q E , if present, is independently selected from: -R 2A1 ,
  • each -Q c is independently selected from:
  • each -Q c is independently selected from: -R 2A1 , -F, -Cl, -Br, -I, -CF 3 , -OCF 3 , -OH, -L 2A -OH, -O-L 2A -OH, -NH-L 2A -OH, -OR 2 * 1 , -L 2A -OR 2 * 1 , -O-L 2A -OR 2 * 1 , -NH-L 2A -OR 2 * 1 ,
  • each -Q c is independently selected from: -R 2 * 1 , -F, -Cl, -Br, -I, -CF 3 , -OCF 3 ,
  • each -Q c is independently selected from:
  • each -Q E is independently selected from: -R 2A1 , -CF 3 ,
  • each -Q E is independently selected from: -R 2A1 ,
  • each -Q E is independently selected from:
  • each -L 2 *- if present, is independently -(CH 2 )n 2 -, wherein n2 is independently 1 to 4.
  • each -L 2 " 1 - if present, is independently -CH 2 - or -CH 2 CH 2 -.
  • each -NR 2A2 R 2A3 I if present, is independently azetidino, pyrrolidine, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -NR 2A2 R 2A3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -R 2A B4 _D2B6 _p2B7 1 1 if present, is independently:
  • each -R 2A1 is independently:
  • each -RTM if present, is independently: -R 2B1 , -R 2B7 , or -L 2B -R 2B7 .
  • each -R 2A1 1 if present, is independently:
  • each -R 2B6 is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholihyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
  • each -R 2B6 is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
  • each -R 2B7 if present, is independently phenyl, and is optionally substituted.
  • each -R 2B8 is independently C 5-6 heteroaryl, and is optionally substituted.
  • each -R 2B8 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -R 2B8 if present, is independently C 9-1 oheteroaryl, and is optionally substituted.
  • each -R 2B8 is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
  • each -L 2B - is independently -CH 2 - or -CH 2 CH 2 -. In one embodiment, each -L 2B -, if present, is independently -CH 2 -.
  • each -R 2C1 if present, is independently saturated aliphatic C 1-4 alkyl.
  • each -R 2C2 is independently: -F 1 -Cl 1 -Br 1 -I,
  • each -R 2D1 if present, is independently saturated aliphatic C 1-4 alkyl.
  • each -L 2D - is independently -(CH 2 ) m2 -, wherein m2 is independently 1 to 4.
  • each -L 2D - is independently -CH 2 - or -CH 2 CH 2 -.
  • each -NR 202 R 203 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -NR 202 R 203 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -Q c is independently selected from:
  • each -Q c is independently selected from:
  • each -R X1 is independently saturated aliphatic C 1-4 alkyl.
  • each -Q c is independently selected from:
  • each -R X1 is independently saturated aliphatic C 1-4 alkyl
  • each -R M1 is independently piperidino, piperizino, or morpholino, and is optionally substituted with one or more saturated aliphatic C 1-4 alkyl groups.
  • each -Q c is independently selected from: -Me, -F, -Cl, -Br, -I, and -CF 3 .
  • each -Q E is independently selected from:
  • each -Q E is independently selected from:
  • each -R X2 is independently saturated aliphatic C 1-4 alkyl.
  • -Q D if present, is independently selected from: -R 3A1 ,
  • each -L 3A - is independently saturated aliphatic C 2 - 5 alkylene; in each group -NR 3A2 R 3A3 , R 3A2 and R 3A3 , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R 3A1 is independently:
  • each -R 3D1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl; each -L 3D - is independently saturated aliphatic C 1-5 alkylene; and in each group -NR 302 R 303 , R 302 and R 303 ,.
  • -Q D is independently selected from:
  • -Q° is independently selected from:
  • -Q D is independently selected from:
  • -Q D if present, is independently selected from: -L 3A -OH and -L 3A -OR 3A1 .
  • each -L 3A - is independently -(CH 2 ),*-, wherein n3 is independently 1 to 4.
  • each -L 3A - is independently -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • each -NR 3A2 R 3A3 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -NR 3A2 R 3A3 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -R 3A1 is independently: p3B1 p3B4 p3B6 p3B7 p3B8 -r ⁇ , -r ⁇ , -r ⁇ , ⁇ r ⁇ , -rx ,
  • I 3B_p3B4 I 3B_p3B6 ⁇ 3B_p3B7 _. i 3B_p3B8
  • each -R 3A1 is independently:
  • each -R 3A1 is independently: -R 3B1 , -R 3B7 , -R 3B8 , ⁇ 3B_p3B7 Qr ⁇ 3B_p3B8
  • each -R 3A1 is independently:
  • each -R 3A1 is independently:
  • each -R 3B6 is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
  • each -R 3B6 if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
  • each -R 3B7 is independently phenyl, and is optionally substituted.
  • each -R 3B ⁇ is independently C 5-6 heteroaryl, and is optionally substituted.
  • each -R 3BS if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -R 3B8 is independently C 9-10 heteroaryl, and is optionally substituted.
  • each -R 3B8 is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
  • each -L 3B - is independently -CH 2 - or -CH 3C H 2 -. In one embodiment, each -L 3B -, if present, is independently -CH 2 -.
  • each -R 3C1 if present, is independently saturated aliphatic C 1-4 alkyl.
  • each -R 3C2 is independently:
  • each -R 301 is independently saturated aliphatic C 1-4 alkyl.
  • each -L 30 - is independently -(CH 2 ) m3 -, wherein m3 is independently 1 to 4.
  • each -L 30 - is independently -CH 2 - or -CH 30 H 2 -.
  • each -NR 302 R 303 is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -NR 302 R 303 is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C 1-3 alkyl, -CF 3 , and -F.
  • each -Q D is independently selected from:
  • each -R X3 is independently saturated aliphatic C 1-4 alkyl.
  • the BA compound has a molecular weight of from 212 to 1200.
  • the bottom of range is 225, 250, 275, 300, or 350.
  • the top of range is 1100, 1000, 900, 800, 700, or 600. In one embodiment, the range is from 225 to 600.
  • the compounds are selected from compounds of the following formula and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formula and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formula and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • One aspect of the present invention pertains to BCAA 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 stereoisomer ⁇ or enantiomeric form.
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds.
  • the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer.
  • the substantially purified form refers to a mixture of enantiomers.
  • the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate).
  • the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5%. by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • 60% optically pure i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer
  • at least 70% optically pure e.g., at least 80% optically pure, e.g., at least 90% optically pure, e
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • isomers are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • C 1-7 alkyl includes n-propyl and iso-propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a corresponding salt of the compound for example, a pharmaceutically-acceptable salt.
  • pharmaceutically acceptable salts are discussed in Berge et 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 + ).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 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, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • 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 and hydrate forms thereof.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(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 active compound.
  • the prodrug is inactive, or less active than the desired active 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 active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • compounds of type (vi) and (vii) are prepared as shown in the following scheme.
  • 2-Bromo-4-chloro-5-nitropyridine (i) is treated with 4-methoxybenzylamine (PMB-NH 2 ), typically in acetonitrile and in the presence of a tertiary base to afford the intermediate (ii).
  • PMB-NH 2 4-methoxybenzylamine
  • Reduction of the nitro group using tin (II) chloride or a metal/acid mixture followed by treatment with formamide or a mixture of acetic anhydride and triethylorthoformate gives the fused bicyclic intermediate (iv).
  • 2-alkoxy-5-amino pyrazines are prepared as shown in the following scheme. 2,6-Dichloropyrazine (viii) is treated with ammonia to give 2-chloro-6- aminopyrazine (ix) which is then treated with suitable alcohols (ROH), typically with heating in acetonitrile and in the presence of a base such as sodium hydride, to give the required intermediates (x).
  • ROH suitable alcohols
  • 2-alkoxy-3-cyano-5-amino pyrazines are prepared as shown in the following scheme.
  • 2-Chloro-6-aminopyrazine (ix) is brom.inated, typically with NBS, to give intermediate (xiii).
  • a cyanide source such as potassium cyanide under palladium-mediated reaction conditions
  • ROH suitable alcohols
  • a base such as sodium hydride
  • compounds of type (xxvii) are prepared according to the following scheme.
  • 2-Amino-5-cyanopyrazine and an appropriate 3-chloro, or 3-bromo, or 3-(trifluoromethansulfonyloxy)isoquinoline (xxvi) are coupled under palladium-mediated amination conditions typically with heating and in the presence of a base and a suitable phosphine ligand, followed by removal of any protecting groups, to give the target compunds (xxvii).
  • compounds of type (xxviii) are prepared according to the following scheme.
  • a 2-amino-6-alkoxypyrazine (x) and an appropriate 3-chloro, or 3-bromo, or 3-(trifluoromethansulfonyloxy)isoquinoIine (xxvi) are coupled under palladium-mediated amination conditions typically with heating and in the presence of a base and a suitable phosphine ligand, followed by removal of any protecting groups, to give the target compounds (xxvii).
  • compounds of type (xxix) are prepared according to the following scheme.
  • a 2-amino-5-cyano-6-alkoxypyrazine (xv) and an appropriate 3-chloro, or 3-bromo, or 3-(trifluoromethansulfonyloxy)isoquinoline (xxvi) are coupled under palladium-mediated amination conditions typically with heating and in the presence of base of a suitable phosphine ligand, followed by removal of any protecting groups, to give the target compounds (xxix).
  • compounds of type (xxxii) are prepared according to the following scheme.
  • a 2-amino-5-cyano-6-alkoxypyrazine (xv) and 5-chloro- or 5-bromo-3- (trifluoromethanesulfonyloxy)isoquinoline (xxx) are selectively coupled under palladium- mediated amination conditions, typically with heating and in the presence of base of a suitable phosphine ligand, to give the corresponding 5-haloisoquinoline compounds (xxxi).
  • the 5-haloisoquinolines (xxxi) are further reacted under palladium catalysis with either a boronic acid, typically in the presence of a suitable base and phosphine ligand and with heating, or with an amine, typically in the presence of a suitable base and phosphine ligand and with heating.
  • the 5-haloisoquinolines (xxxi) are reacted with an alkoxide in the presence of a suitable copper (I) compound, typically with heating. The removal of any protecting groups gives the target compounds (xxxii).
  • compounds of type (xxxiii) are prepared according to the following scheme.
  • 2-Amino-5-cyanopyrazine and an appropriate tert-butyl 5-chloro-1 H-pyrrolo[2,3- c]pyridine-1-carboxylate (xxxiv) are coupled under palladium-mediated amination conditions typically with heating and in the presence of a base and a suitable phosphine ligand, with concomitant removal of the nitrogen protecting group, to give the target compounds (xxxiii).
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a BCAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing a BCAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of CHK1 kinase function, 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 a CHK1 kinase with an effective amount of a BCAA 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 cell with an effective amount of a BCAA compound, as described herein.
  • the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Suitable assays for determining CHK1 kinase function inhibition are described herein and/or are known in the art.
  • BCAA compounds described herein e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these.
  • One aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a BCAA compound, as described herein.
  • the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting a cell with an effective amount of a BCAA compound, as described herein.
  • the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • the method is performed in vitro. In one embodiment, the method is performed in vivo.
  • the BCAA compound is provided in the form of a pharmaceutically acceptable composition.
  • Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
  • gastrointestinal including, e.g., bowel, colon
  • breast mammary
  • ovarian prostate
  • liver hepatic
  • kidney renal
  • bladder pancreas
  • brain and skin.
  • a candidate compound regulates (e.g., inhibits) cell proliferation, etc.
  • assays which may conveniently be used to assess the activity offered by a particular compound are described herein.
  • a sample of cells e.g., from a tumour
  • a compound brought into contact with said cells, and the effect of the compound on those cells observed.
  • effect the morphological status of the cells (e.g., alive or dead, etc.) may be determined.
  • this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.
  • Another aspect of the present invention pertains to a BCAA compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
  • the method of treatment comprises treatment with both (i) a BCAA compound, as described herein, and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • a BCAA compound as described herein
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, for use in a method of treatment of the human or animal body by therapy, wherein the method of treatment comprises treatment with both (i) a BCAA 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 BCAA compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the medicament comprises the BCAA compound.
  • the treatment comprises treatment with both (i) a medicament comprising a BCAA compound, as described herein, and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • a medicament comprising a BCAA compound, as described herein
  • one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  • Another aspect of the present invention pertains to use of (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, in the manufacture of a medicament for use in a treatment, wherein the treatment comprises treatment with both (i) a BCAA 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 BCAA 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: cancer characterised by, or further characterised by, cancer cells which overexpress Checkpoint Kinase 1 (CHK1).
  • CHK1 Checkpoint Kinase 1
  • the treatment is treatment of: p53 negative cancer.
  • the treatment is treatment of: lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer (e.g., head cancer, neck cancer), skin cancer, squamous cancer, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.
  • lung cancer small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer
  • rectal cancer colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder
  • the treatment is treatment of: a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma); a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumour of lymph
  • the treatment is treatment of solid tumour cancer.
  • the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
  • the cancer is characterised by, or further characterised by, cancer stem cells.
  • 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.
  • terapéuticaally-effective amount pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • 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 BCAA 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.
  • a BCAA compound and one or more other agents may be used (e.g., contacted, administered, etc.) in any order.
  • 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 BCAA compound may be prior to, concurrent with, or may follow, treatment with (e.g., administration of) the one or more other agents, or a combination thereof.
  • treatment with (e.g., administration of) a BCAA 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).
  • BCAA compounds described herein may also be used as cell culture additives to inhibit CHK1 kinase function, e.g., to inhibit cell proliferation, etc.
  • the BCAA 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 BCAA 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 BCAA compound as described herein, or a composition comprising a BCAA 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 BCAA compound or pharmaceutical composition comprising the BCAA compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular
  • the subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • the BCAA compound While it is possible for the BCAA compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one BCAA 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 BCAA 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, 5th edition, 2005.
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • 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 (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • suppositories e.g., pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
  • Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
  • Creams are typically prepared from the compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier also known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • 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.
  • 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 BCAA compounds, and compositions comprising the BCAA 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 BCAA compound, the route of administration, the time of administration, the rate of excretion of the BCAA 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 BCAA 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 BCAA 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 (Aqueous): 0.02% Ammonia and 0.063% ammonium formate in water.
  • Solvent B (Organic):
  • Tin(ll)chloride dihydrate (1.59 g, 7.04 mmol) was added portionwise to 5-(4-(4- methoxybenzylamino)-5-nitropyridin-2-ylamino)pyrazine-2-carbonitrile (531 mg, 1.41 mmol) in absolute EtOH (10 ml_) at room temperature. The mixture was heated at 70°C for 2 hours before being concentrated in vacuo. The residue was suspended in a mixture of ethyl acetate and saturated sodium bicarbonate solution, then filtered to remove insoluble material. The solids were then washed with EtOAc.
  • N-(1-Bromo-8-chloroisoquinolin-3-yl)acetamide (1.00 g, 3.33 mmol), potassium carbonate (0.508 mg, 3.67 mmol), triphenylphosphine (35 mg, 0.134 mmol) and palladium acetate (7.49 mg, 0.033 mmol) were stirred in 1-butanol (10 mL) with nitrogen bubbling through it for 10 minutes.
  • Butanol (5 mL) was added to the reaction mixture, which was then heated overnight at 100°C in a sealed vial. The reaction mixture was cooled, diluted with water and extracted twice with ethyl acetate.
  • Tin (II) chloride dihydrate (4.37 g, 19.4 mmol) was added portionwise to N-(4- methoxybenzyl)-2-bromo-5-nitropyridin-4-amine (1.31 g, 3.87 mmol) in absolute EtOH (10 ml.) at room temperature. The mixture was then heated at 70°C for 2 hours before being concentrated in vacuo. The residue was suspended in a mixture of ethyl acetate and saturated sodium bicarbonate solution and filtered. The insoluble solids were washed with EtOAc.
  • Acetic anhydride (1.28 ml_, 13.6 mmol) was added to a solution of N 4 -(4-methoxybenzyl)- 6-bromopyridine-3,4-diamine (1.05 g, 3.41 mmol) in triethylorthoformate (13 mL). The mixture was heated at 100°C for 18 hours and then concentrated to give the title compound as a brown oil (1.18 g, quantitative).
  • the title compound was prepared using methods analogous to those described in Synthesis 10-1 , replacing 5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2- carbonitrile with tert-butyl 4-((6-amino-3-cyanopyrazin-2-yloxy)methyI)piperidine-1- carboxylate and replacing 1-(4-methoxybenzyl)-6-bromo-1 H-imidazo[4,5-c]pyridine with 6-bromo-1-methyl-1 H-imidazo[4,5-c]pyridine.
  • the title compound was prepared using a method analogous to that described in Durola et al., 2007.
  • the title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3- yloxy)pyrazine-2-carbonitrile and 8-bromoisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline.
  • the title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3- yloxy)pyrazine-2-carbonitrile and 6-chloroisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline. 6-Chloroisoquinolin-3-yl trifluoromethanesulfonate was prepared using methods analogous to those described in Synthesis 11-1 for 8- bromoisoquinolin-3-yl trifluoromethanesulfonate.
  • the title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3- yloxy)pyrazine-2-carbonitrile, and using 5-bromo-8-chloroisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline.
  • 5-Bromo-8- chloroisoquinolin-3-yl trifluoromethanesulfonate was prepared using methods analogous to those described in Synthesis 11-1 for 8-bromoisoquinolin-3-yl trifluoromethanesulfonate.
  • the aqueous layer was further extracted with ethyl acetate and the combined organics were washed with water and brine, dried (Na 2 SO 4 ), and passed sequentially through two PS-Thiol cartridges.
  • the eluent was concentrated to a yellow solid which was dissolved in methanol and purified by SPE on a MP-TsOH cartridge, eluting with 2 M ammonia in methanol. Concentration of the eluent gave the required product as a light yellow solid (18 mg, 0.06 mmol, 29%).
  • the title compound was prepared using methods analogous to those described in Synthesis 5-1 , replacing 3,8-dichloroisoquinoline with 5-(8-bromoisoquinolin-3- ylamino)pyrazine-2-carbonitrile and replacing (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine- 2-carbonitrile with N-(2-aminoethyl)morpholine, and conducting the reaction at 14O°C.
  • Acetyl chloride 13 mg, 0.16 mmol was added to a solution of 5-(8-aminoisoquinolin-3- ylamino)pyrazine-2-carbonitrile (36 mg, 0.14 mmol) and diisopropylethylamine (39 mg, 0.30 mmol) in DCE (1.5 mL). The reaction mixture stirred at room temperature for

Landscapes

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

Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain bicyclylaryl-aryl-amines compounds of the following formula (referred to herein as BCAA compounds), which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and 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 II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation: (I).

Description

BICYCLYLARYL-ARYL-AMINE COMPOUNDS AND THEIR USE
RELATED APPLICATIONS
This application is related to United States provisional patent application number 61/029,621 filed 19 February 2008 and United Kingdom patent application number 0803018.1 filed 19 February 2008, the contents of both of which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain bicyclylaryl-aryl-amine compounds (referred to herein as BCAA compounds), which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and 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.
BACKGROUND
A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Checkpoint Kinase 1 (CHKD
Progression through the cell division cycle is a tightly regulated process and is monitored at several positions known as cell cycle checkpoints (see, e.g., Weinert and Hartwell, 1989; Bartek and Lukas, 2003). These checkpoints are found in all four stages of the cell cycle; G1 , S (DNA replication), G2 and M (Mitosis) and they ensure that key events which control the fidelity of DNA replication and cell division are completed correctly. Cell cycle checkpoints are activated by a number of stimuli, including DNA damage and DNA errors caused by defective replication. When this occurs, the cell cycle will arrest, allowing time for either DNA repair to occur or, if the damage is too severe, for activation of cellular processes leading to controlled cell death.
All cancers, by definition, have some form of aberrant cell division cycle. Frequently, the cancer cells possess one or more defective cell cycle checkpoints, or harbour defects in a particular DNA repair pathway. These cells are therefore often more dependent on the remaining cell cycle checkpoints and repair pathways, compared to non-cancerous cells (where all checkpoints and DNA repair pathways are intact). The response of cancer cells to DNA damage is frequently a critical determinant of whether they continue to proliferate or activate cell death processes and die. For example, tumour cells that contain a mutant form(s) of the tumour suppressor p53 are defective in the G1 DNA damage checkpoint. Thus inhibitors of the G2 or S-phase checkpoints are expected to further impair the ability of the tumour cell to repair damaged DNA.
Many known cancer treatments cause DNA damage by either physically modifying the cell's DNA or disrupting vital cellular processes that can affect the fidelity of DNA replication and cell division, such as DNA metabolism, DNA synthesis, DNA transcription and microtubule spindle formation. Such treatments include for example, radiotherapy, which causes DNA strand breaks, and a variety of chemotherapeutic agents including topoisomerase inhibitors, antimetabolites, DNA-alkylating agents, and platinum- containing cytotoxic drugs. A significant limitation to these genotoxic treatments is drug resistance. One of the most important mechanisms leading to this resistance is attributed to activation of cell cycle checkpoints, giving the tumour cell time to repair damaged DNA. By abrogating a particular cell cycle checkpoint, or inhibiting a particular form of DNA repair, it may therefore be possible to circumvent tumour cell resistance to the genotoxic agents and augment tumour cell death induced by DNA damage, thus increasing the therapeutic index of these cancer treatments.
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 a/., 1997). Phosphorylation of Cdc25C and the related Cdc25A by CHK1 blocks their ability to activate CDK1 , thus preventing the cell from exiting G2 into M phase. The role of CHK1 in the DNA damage-induced G2 cell cycle checkpoint has been demonstrated in a number of studies where CHK1 function has been knocked out (see, e.g., Liu et ai, 2000; Zhao et a/., 2002; Zachos et a/., 2003).
The reliance of the DNA damage-induced G2 checkpoint upon CHK1 provides one example of a therapeutic strategy for cancer treatment, involving targeted inhibition of CHK1. Upon DNA damage, the p53 tumour suppressor protein is stabilised and activated to give a p53-dependent G1 arrest, leading to apoptosis or DNA repair (Balaint and Vousden, 2001). Over half of all cancers are functionally defective for p53, which can make them resistant to genotoxic cancer treatments such as ionising radiation (IR) and certain forms of chemotherapy (see, e.g., Greenblatt et al., 1994; Carson and Lois, 1995). These p53 deficient cells fail to arrest at the G1 checkpoint or undergo apoptosis or DNA repair, and consequently may be more reliant on the G2 checkpoint for viability and replication fidelity. Therefore abrogation of the G2 checkpoint through inhibition of the CHK1 kinase function may selectively sensitise p53 deficient. cancer cells to genotoxic cancer therapies, and this has been demonstrated (see, e.g., Wang et al., 1996; Dixon and Norbury, 2002).
In addition, CHK1 has also been shown to be involved in S phase cell cycle checkpoints and DNA repair by homologous recombination. Thus, inhibition of CHK1 kinase in those cancers that are reliant on these processes after DNA damage, may provide additional therapeutic strategies for the treatment of cancers using CHK1 inhibitors (see, e.g., Sorensen et al., 2005). Recent data using 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 ai, 2006). Small-molecule selective inhibitors of CHK1 kinase function from various chemical classes have been described (see, e.g., Tao and Lin, 2006). SUMMARY OF THE INVENTION
One aspect of the invention pertains to certain bicyclylaryl-aryl-amine compounds (referred to herein as BCAA compounds), as described herein.
Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a BCAA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
Another aspect of the invention pertains to method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of admixing a BCAA 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 a BCAA compound, as described herein.
In one embodiment, the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a BCAA compound, as described herein.
In one embodiment, the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a BCAA compound, as described herein, preferably in the form of a pharmaceutical composition.
In one embodiment, the method further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to a BCAA compound as described herein for use in a method of treatment of the human or animal body by therapy. In one embodiment, the method of treatment comprises treatment with both (i) a BCAA 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 BCAA compound, as described herein, in the manufacture of a medicament for use in treatment.
In one embodiment, the treatment comprises treatment with both (i) a medicament comprising a BCAA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
In one embodiment, the treatment is treatment of a disease or condition that is mediated by CHKl
In one embodiment, the treatment is treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function.
In one embodiment, the treatment is treatment of a proliferative condition.
In one embodiment, the treatment is treatment of cancer.
In one embodiment, the treatment is treatment of: p53 negative cancer.
In one embodiment, the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
Another aspect of the present invention pertains to a kit comprising (a) a
BCAA compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
In one embodiment, the kit further comprises one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; and (d) a microtubule targeted agent.
Another aspect of the present invention pertains to a BCAA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. Another aspect of the present invention pertains to a BCAA compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.
DETAlLED DESCRIPTION OF THE INVENTION
Compounds
One aspect of the present invention relates to certain bicyclylaryl-aryl-amines (for convenience, collectively referred to herein as "bicyclylaryl-aryl compounds" or "BCAA compounds") which are related to pyrazin-2-yl-pyridin-2-yl-amines.
Figure imgf000009_0001
Pyrazin-2-yl-pyridin-2-yl-amine
More particularly, the compounds are related to the following compounds:
Figure imgf000009_0002
In one embodiment, the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000010_0001
wherein the ring denoted A is independently selected from:
Figure imgf000010_0002
and wherein: each of -RC1, -RC2, -RC3, and -RC4 is independently -H or -Qc;
-RD1 is independently -H or -QD; each of -RE1 and -RE2 is independently -H or -QE;
and wherein:
-RA3 is independently -H or -QA3; -RA6 is independently -H or -QA6; -RB3 is independently -H or -Q83; -RB5 is independently -H or -Q85; -RB6 is independently -H or -QB6.
Optional Provisos
In one or more aspects of the present invention (e.g., compounds, compositions, compounds for use in therapy, use of compounds in the manufacture of a medicament, methods, methods of treatment, etc.), the compounds are optionally as defined herein, but with one or more optional provisos, as defined herein.
In one embodiment, the proviso is that the compound is not the following compound, which is shown on page 117 (No 197) in WO 2007/000240 and is allegedly useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase.
Figure imgf000011_0002
In one embodiment, the proviso is that the compound is not [6-(piperidin-4-yloxy)- isoquinolin-3-yl]-pyrazin-2-yl-amine hydrochloride salt.
In one embodiment, the proviso is that the compound is not [6-(piperidin-4-yloxy)- isoquinolin-3-yl]-pyrazin-2-yl-amine, or a salt, hydrate, or solvate thereof.
In one or more aspects of the present invention (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.), the compounds are optionally as defined herein, but without the above proviso.
For example, a reference to a particular group of compounds "without the recited proviso" (e.g., for use in therapy) is intended to be a reference to the compounds as defined, but wherein the definition no longer includes the indicated proviso. In such cases, it is as if the indicated proviso has been deleted from the definition of compounds, and the definition has been expanded to encompass those compounds which otherwise would have been excluded by the indicated proviso.
The Fused Ring
In one embodiment, the ring denoted A is independently:
,C3
,C4
R'
R
as in, for example:
B6
Figure imgf000011_0001
In one embodiment, the ring denoted A is independently selected from:
Figure imgf000012_0001
as in, for example:
Figure imgf000012_0002
In one embodiment, the ring denoted A is independently:
Figure imgf000012_0003
In one embodiment, the ring denoted A is independently:
Figure imgf000012_0004
In one embodiment, the ring denoted A is independently selected from:
Figure imgf000012_0005
as in, for example:
Figure imgf000012_0006
In one embodiment, the ring denoted A is independently:
Figure imgf000013_0001
In one embodiment, the ring denoted A is independently:
Figure imgf000013_0002
The Group -RA3
In one embodiment, -RA3 is independently -H or -QA3. In one embodiment, -RA3 is independently -H. In one embodiment, -RA3 is independently -QA3.
The Group -RA6
In one embodiment, -RAδ is independently -H or -QA6. In one embodiment, -RA6 is independently -H. In one embodiment, -RA6 is independently -QA6.
The Group -RB3
In one embodiment, -RB3 is independently -H or -QB3. In one embodiment, -RB3 is independently -H. In one embodiment, -RB3 is independently -QB3.
The Group -RB5
In one embodiment, -RB5 is independently -H or -QB5. In one embodiment, -RB5 is independently -H. In one embodiment, -RB5 is independently -QB5.
The Group -RB6
In one embodiment, -RB6 is independently -H or -QB6. In one embodiment, -RB6 is independently -H. In one embodiment, -RB6 is independently -QB6. The Groups -RC1. -RC2. -RC3. and -RC4
In one embodiment: each of -RC1, -RC2, -RC3, and -RC4, if present, is independently -H or -Qc.
In one embodiment:
-RC1, if present, is independently -Qc; and each of -RC2, -RC3, and -RC4, if present, is independently -H or -Qc.
In one embodiment:
-RC1, if present, is independently -Qc; and each of -RC2, -RC3, and -RC4, if present, is independently -H;
as in, for example:
Figure imgf000014_0001
In one embodiment:
-RC3, if present, is independently -Qc; and each of -RC1, -RC2, and -RC4, if present, is independently -H or -Qc
In one embodiment:
-RC3, if present, is independently -H; and each of -RC1, -RC2, and -RC4, if present, is independently -H or -Qc
In one embodiment:
-RC3, if present, is independently -Qc; and each of -RC1, -RC2, and -RC4, if present, is independently -H.
In one embodiment: -R03, if present, is independently -H; and each of -RC1, -RC2, and -RC4, if present, is independently -H.
In one embodiment: each of -RC1 and -RC3, if present, is independently -Qc; and each of -RC2 and -RC4, if present, is independently -H or -Qc.
In one embodiment: each of -RC1 and -RC3, if present, is independently -Qc; and each of -RC2 and -R04, if present, is independently -H. In one embodiment:
-RC3, if present, is independently -H; and -RC1, if present, is independently -Qc. each of -RC2 and -RC4, if present, is independently -H or -Qc.
The Group -RD1
In one embodiment, -RD1, if present, is independently -H or -QD. In one embodiment, -RD1, if present, is independently -H. In one embodiment, -RD1, if present, is independently -QD.
The Groups -RE1 and -RE2
In one embodiment, each of -RE1 and -RE2, if present, is independently -H or -QE.
In one embodiment, -RE1, if present, is independently -H or -QE. In one embodiment, -RE1, if present, is independently -H. In one embodiment, -RE1, if present, is independently -QE.
In one embodiment, -RE2, if present, is independently -H or -QE. In one embodiment, -RE2, if present, is independently -H. In one embodiment, -RE2, if present, is independently -QE.
The Group -QA3
In one embodiment, -QA3, if present, is independently:
-F, -Cl, -Br, -I,
-CF3, -OCF3,
-RQA3, -OH, -ORQA3,
-SH, -SRQA3,
-NH2, -NHR^3, -NR0^2, or -NR^R0*36; wherein: each -RQA3 is independently saturated aliphatic Chalky!; and _NR QA3A R QA3B js jncjepencientiy azetidjno, pyrrolidino, ϊmidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from saturated aliphatic C1-3alkyl, -F, and -CF3.
In one embodiment, -QA3, if present, is independently: -F, -Cl, -Br, -I1 -Me, -Et, -nPr, -iPr, -CF3, -OCF3, -OH, -OMe, -OEt, -SH1 -SMe, -NH2, -NHMe, or -NMe2.
The Group -QA6
In one embodiment, -QA6, if present, is independently:
-CF3, -OCF3,
_RQA6I
-OH, -OR0*6, -SH, -SR^6,
-NH2, -NHRQA6, -NRQA6 2, or -NR^R^66; wherein: each -RQA6 is independently saturated aliphatic C1-6alkyl; and _NR QA6AR QA6B js jnc|epencjentiy azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from saturated aliphatic C1-3alkyl, -F, and -CF3.
In one embodiment, -QA6, if present, is independently: -Me1 -Et, -nPr, -iPr,
-CF3, -OCF3, -OH1 -OMe, -OEt1 -SH, -SMe,
-NH2, -NHMe, or -NMe2.
The Group -QB3
iln one embodiment, -QB3, if present, is independently:
-CF3, -OCF3, -RQB3,
-OH1 -ORQB3,
-SH, -SRQB3,
-NH2, -NHRQB3, ~NRQB3 2, or -NRQB3ARQB3B; wherein: each -RQB3 is independently saturated aliphatic Ci-6alkyl; and
-NRQB3ARQB3B is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from saturated aliphatic C1-3alkyl, -F, and -CF3.
In one embodiment, -QB3, if present, is independently:
-OCF3,
-Me1 -Et,
-OH, -OMe, -OEt, -SH, -SMe,
-NH2, -NHMe, or -NMe2.
The Group -QB5
In one embodiment, -QB5, if present, is independently: -R1A1,
-F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L1A-OH, -O-L1A-OH,
-0R1A1, -L1A-OR1A1, -O-L1A-OR1A1, -SH, -SR1A1, -CN, -NO2, -NH2, -NHR1A1, -NR1A1 2, -NR1A2R1A3,
-L1A-NH2, -L1A-NHR1A1, -L1A-NR1A1 2, -L1A-NR1A2R1A3, -O-L1A-NH2, -O-L1A-NHR1A1, -O-L1A-NR1A1 2, -O-L1A-NR1A2R1A3, -OC(=O)R1A1, -C(=O)OH, -C(=O)OR1A1, -C(=O)R1A1,
-C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3, -NHC(=O)R1A1, -NR1A1C(=O)R1A1, -NHC(=O)OR1A1, -NR1A1C(=O)OR1A1,
-OC(=O)NH2, -OC(=O)NHR1A1, -OC(=O)NR1A1 2, -OC(=O)NR1A2R1A3, -NHC(=O)NH2, -NHC(=O)NHR1A1,
-NHC(=O)NR1A1 2, -NHC(=O)NR1A2R1A3, -NR1A1C(=O)NH2, -NR1A1C(=O)NHR1A1, -NR1A1C(=O)NR1A1 2, -NR1A1C(=O)NR1A2R1A3, -NHS(=O)2R1A1, -NR1A1S(=O)2R1A1, -S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, -S(=O)2NR1A2R1A3,
-S(=O)R1A1, -S(=O)2R1A1, -OS(=O)2R1A1, or -S(=0)2OR1A1; wherein: each -L1A- is independently saturated aliphatic C1-5alkylene; in each group -NR1A2R1A3, R1A2 and R1A3, taken together with the nitrogen atom to which they are attached, form a A-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R1A1 is independently: -R1B1 -R1B2 -R1B3 -R1B4 -R1B5 -R1B6 -R1B7 -R1B8
-L1B-R1B4, -L1B-R1B5, -L1B'-R1B6, -L1B-R>1B7, or'-L1B-R1B8; each -R1B1 is independently saturated aliphatic C1-6alkyl; each -R1B2 is independently aliphatic C2-6alkenyl; each -R1B3 is independently aliphatic C2-6alkynyl; each -R1B4 is independently saturated C3-6cycloalkyl; each -R1B5 is independently C^cycloalkenyl; each -R1B6 is independently non-aromatic C3-gheterocyclyl; each -R1B7 is independently C6-10carboaryI; each -R1B8 is independently C5.i0heteroaryl; each -L1B- is independently saturated aliphatic C1-3alkylene; wherein: each -R1B4, -R1B5, -R1B6, -R1B7, and -R1B8 is optionally substituted, for example, with one or more substituents -R1C1 and/or one or more substituents -R1C2, each -R1B1, -R1B2, -R1B3, and -L1B- is optionally substituted, for example, with one or more substituents -R1C2, and wherein: each -R1C1 is independently saturated aliphatic C^alkyl, phenyl, or benzyl; each -R1C2 is independently: -F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH, -L1D-OH, -O-L1D-OH, -OR1D1, -L1D-OR1D1, -O-L1D-OR1D1, -SH1 -SR1D1, -CN,
-NO2,
-NH2, -NHR1D1, -NR1D1 2, -NR1D2R1D3, -L1D-NH2, -L1D-NHR1D1, -L1D-NR1D1 2, -L1D-NR1D2R1D3, -C(=O)OH, -C(=O)OR1D1, -C(=O)NH2, -C(=O)NHR1D1, -C(=O)NR1D1 2, or -C(O)NR102R103; wherein: each -R1D1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -L1D- is independently saturated aliphatic C1-5alkylene; and in each group -NR102R103, R102 and R103, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O.
In one embodiment, -QB5, if present, is independently:
-R1A1,
-CF3, -OCF3,
-OH, -L1A-OH, -O-L1A-OH,
-0R1A1, -L1A-OR1A1, -O-L1A~OR1A1, -CN,
-NO2,
-NH2, -NHR1A1, -NR1A1 2, -NR1A2R1A3,
-L1A-NH2, -L1A-NHR1A1, -L1A-NR1A1 2, -L1A-NR1A2R1A3,
-O-L1A-NH2, -O-L1A-NHR1A1, -O-L1A-NR1A1 2, -O-L1A-NR1A2R1A3, -OC(=O)R1A1, -C(=O)OH, -C(=O)OR1A1,
-C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3, -NHC(=O)R1A1, or -NR1A1C(=O)R1A1.
In one embodiment, -QB5, if present, is independently:
-R1B1,
-CF3, -OH, -L1A-OH, -O-L1A-OH,
-0R1A1, -L1A-OR1A1, -O-L1A-OR1A1,
-CN,
-OC(=O)R1A1,
-C(=O)OH, -C(=O)OR1A1, -C(O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3,
-NHC(=O)R1A1, or -NR1A1C(=O)R1A1.
In one embodiment, -QB5, if present, is independently:
-R1B1, -0R1A1,
-CN, -C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, or -C(=O)NR1A2R1A3.
In one embodiment, -QB5, if present, is independently -CN.
In one embodiment, -QB5, if present, is independently -C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, or -C(=0)NR1A2R1A3.
In one embodiment, -QB5, if present, is independently -C(=O)NH2.
In one embodiment, -QB5, if present, is independently -R1B1.
In one embodiment, -QB5, if present, is independently -Me.
In one embodiment, -QB5, if present, is independently -R188.
In one embodiment, -QB5, if present, is independently -OR1A1.
In one embodiment, -QB5, if present, is independently -OMe.
In one embodiment, each -L1A-, if present, is independently -(CH2)n1-, wherein n1 is independently 1 to 4.
In one embodiment, each -L1A-, if present, is independently -CH2- or -CH2CH2-. In one embodiment, each -NR1A2R1A3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -NR1A2R1A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -R1A1, if present, is independently:
-R1B1 -R1B4 -R1B6 -R1B7 -R1B8
-L1B-R1B4, -L1B-R1B6, -L1B'-R1B7, or -L1B-R1B8.
In one embodiment, each -R1A1, if present, is independently:
_p1B1 _p1B7 _p1B8
-L1B-R1B7, or -L1B-R1B8.
In one embodiment, each -R1A1, if present, is independently: -R1B1, -R1B7, or -L1B-R1B7.
In one embodiment, each -R1A1, if present, is independently: -R1B7, -R1B8, -L1B-R1B7, or -L1B-R1B8.
In one embodiment, each -R1B6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
In one embodiment, each -R1B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
In one embodiment, each -R1B7, if present, is independently phenyl, and is optionally substituted.
In one embodiment, each -R1B8, if present, is independently C5-6heteroaryl, and is optionally substituted.
In one embodiment, each -R1B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, each -R1B8, if present, is independently C9-10heteroaryl, and is optionally substituted. In one embodiment, each -R1B8, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
In one embodiment, each -L1B-, if present, is independently -CH2- Or -CH2CH2-. In one embodiment, each -L1B-, if present, is independently -CH2-.
In one embodiment, each -R1C1, if present, is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -R1C2 is independently: -F, -Cl, -Br, -I, -OH, -OR1D1,
-CN, -NO2, -NH2, -NHR1D1, -NR1D1 2, or -NR102R103.
In one embodiment, each -R101, if present, is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -L10-, if present, is independently -(CH2)m1-> wherein ml is independently 1 to 4.
In one embodiment, each -L10-, if present, is independently -CH2- or -CH2CH2-.
In one embodiment, each -NR102R103, if present, is independently azetidino, pyrrolidine, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -NR102R103, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, -QB5, if present, is independently:
-CN, -ORX4, -RX4, -C(=O)NH2, -C(=O)NHRX4, or -C(=O)NRX4 2; wherein each RX4 is independently saturated aliphatic C1-4alkyl.
In one embodiment, -QB5, if present, is independently -CN, -OMe, -Me, or -C(=O)NH2.
The Group -QB6
In one embodiment, -QB6 is independently -0-RQB6, -S-RQB6, or -NRBN-RQB6. In one embodiment, -QB6 is independently -O-RQB6. In one embodiment, -QB6 is independently -S-RQB6. In one embodiment, -QB6 is independently -NRBN-RQB6.
In one embodiment, -RBN, if present, is independently -H or saturated aliphatic C1-4alkyl. In one embodiment, -RBN, if present, is independently -H or -Me. In one embodiment, -RBN, if present, is independently -H.
The Group -RQB6
In one embodiment, -RQB6, if present, is independently: -R4A1,
-L4A-OH, -L4A-OR4A1,
-L4A-NH2, -L4A-NHR4A1, -L4A-NR4A1 2, or -L4A-NR4A2R4A3, wherein: each -L4A- is independently saturated aliphatic C2-6alkylene; in each group -NR4A2R4A3, R4A2 and R4A3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R4A1 is independently: p4B1 p4B2 p4B3 p4B4 p4B5 p4B6 p4B7 p4B8 -I N , -ΓΛ , -r\ , -r\ , -r\ , -r\ , -r\ , ~r\ ,
-L4B-R4B4, -L4B-R4B5, -L4B-R4B6, -L4B-R4B7, or -L4B-R4B8; each -R4B1 is independently saturated aliphatic C1-6alkyl; each -R4B2 is independently aliphatic C2-6alkenyl; each -R4B3 is independently aliphatic C2-6alkynyl; each -R4B4 is independently saturated C3-6cycloalkyl; each -R4B5 is independently C3-6cycloalkenyl; each -R4B6 is independently non-aromatic C3-sheterocyclyl; each -R4B7 is independently C6-1ocarboaryl; each -R4B8 is independently C5-10heteroaryl; each -L4B- is independently saturated aliphatic C1-3alkylene; wherein: each -R4B4, -R4B5, -R4B6, -R4B7, and -R4B8 is optionally substituted, for example, with one or more substituents -R4C1 and/or one or more substituents -R4C2, each -R4B1, -R4B2, -R4B3, and -L4B- is optionally substituted, for example, with one or more substituents -R4C2, and wherein: each -R4C1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -R402 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L4D-OH, -O-L4D-OH, -OR4D1 , -L4D-OR4D1 , -O-L4D-OR4D1 , -SH, -SR4D1, -CN, -NO2, -NH2, -NHR4D1, -NR4D1 2, -NR4D2R4D3,
-L4D-NH2, -L4D-NHR4D1, -L4D-NR4D1 2, -L4D-NR4D2R4D3, -C(=O)OH, -C(=O)OR4D1,
-C(=O)NH2, -C(=O)NHR4D1, -C(=O)NR4D1 2, or -C(=O)NR4D2R4D3; wherein: each -R4D1 is independently saturated aliphatic d^alkyl, phenyl, or benzyl; each -L4D- is independently saturated aliphatic C1-5alkylene; and in each group -NR402R403, R402 and R403, taken together with the nitrogen atom to which they are attached, form a A-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O.
In one embodiment, -RQB6, if present, is independently:
-L4A-OH, -L4A-OR4A1, -L4A-NH2, -L4A-NHR4A1 , -L4A-NR4A1 2, or -L4A-NR4A2R4A3.
In one embodiment, -RQB6, if present, is independently: -L4A-OH or -L4A-OR4A1.
In one embodiment, -RQB6, if present, is independently:
-L4A-NH2, -L4A-NHR4A1, -L4A-NR4A1 2, or -L4A-NR4A2R4A3.
In one embodiment, -RQB6, if present, is independently -R4A1.
In one embodiment, each -L4A-, if present, is independently -(CH2)n4-, wherein n4 is independently 2 to 6.
In one embodiment, each -L4A-, if present, is independently -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.
In one embodiment, each -NR4A2R4A3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, diazepino, or oxazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -NR4A2R4A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F. In one embodiment, each -R4A1, if present, is independently:
_p4B1 _o4B4 _p4B6 _p4B7 _p4B8
-L4B-R4B4, -L4B-R4B6, -L4B'-R4B7, or -L4B-R4B8.
In one embodiment, each -R4A1, if present, is independently:
R4B1 D4B7 D4B8 , -K , -K ,
-L4B-R4B7, or -L4B-R4B8.
In one embodiment, each -R4A1, if present, is independently: -R4B1, -R4B7, or -L4B-R4B7.
In one embodiment, each -R4A1, if present, is independently:
_R4B7_ _R4B8j _L4B_R4B7| Q(. _,_4B_R4B8
In one embodiment, each -R4A1, if present, is independently -R4B6 or -L4B-R4Bβ.
For example, in one embodiment, -RQB6, if present, is independently -R4A1, wherein -R4A1 is -R4B6 or -L4B-R4B6.
In one embodiment, each -R4B6, if present, is independently a C3-8heterocyclyl group that is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring or a 7-, 8-, or 9-membered non-aromatic bicyclic ring, said ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ring heteroatoms is independently N, O, or S; and is optionally substituted.
In one embodiment, each -R4Bδ, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, oxazepanyl, 3-aza-bicyclo[3.2.1]octanyl, 8-aza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3-aza-bicyclo[3.1.1]heptanyl, 6-aza-bicyclo[3.1.1]heptanyl,
3,6-diaza-bicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.2]octanyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl, or 9-azabicyclo[3.3.1]nonanyl; and is optionally substituted.
For convenience, the structures of the following groups are illustrated:
Figure imgf000024_0001
8-Aza-bicyclo[3.2.1]octane 6-Aza-bicyclo[3.1.1]heptane 2-Aza-bicyclo[2.2.2]octane
Figure imgf000024_0002
3,8-Diaza-bicyclot3.2.1]octane 3,6-Diaza-bicyclo[3.1.1]heptane 1 -Aza-bicyclo[2.2.1]heptane
Figure imgf000025_0001
In one embodiment, each -R4B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, 8-aza-bicyclo[3.2.1]octanyl, or quinuclidinyl, and is optionally substituted.
In one embodiment, each -R4B6, if present, is independently pyrrolidinyl, piperidinyl, or morpholinyl; and is optionally substituted.
In one embodiment, each -R4B7, if present, is independently phenyl, and is optionally substituted.
In one embodiment, each -R4B8, if present, is independently C5-6heteroaryl, and is optionally substituted.
In one embodiment, each -R4B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, each -R4B8, if present, is independently C9-10heteroaryl, and is optionally substituted.
In one embodiment, each -R4B8, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
In one embodiment, each -L4B-, if present, is independently -CH2- or -CH2CH2-. In one embodiment, each -L4B-, if present, is independently -CH2-.
In one embodiment, each -R4C1, if present, is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -R4C2 is independently: -F, -Cl, -Br, -I,
-OH, -OR4D1, -CN, -NO2, -NH2, -NHR4D1, -NR4D1 2, or -NR4D2R4D3.
In one embodiment, each -R4D1, if present, is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -L4D-, if present, is independently -(CH2)mi-> wherein ml is independently 1 to 4.
In one embodiment, each -L4D-, if present, is independently -CH2- or -CH2CH2-.
In one embodiment, each -NR4D2R4D3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -NR4D2R4D3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, -RQB6, if present, is independently selected from groups of the following formulae, wherein p1 is independently 1 , 2, 3, or 4; p2 is independently 1 , 2, 3, or 4; p3 is independently 0, 1 , or 2; and p4 is independently 1 , 2, 3, or 4:
Figure imgf000026_0001
Figure imgf000027_0001
In one embodiment, -RQB6, if present, is independently a group of formula (B6-1).
In one embodiment, -RQB6, if present, is independently a group of formula (B6-1 B). In one embodiment, -RQB6, if present, is independently a group of formula (B6-2).
In one embodiment, -RQB6, if present, is independently a group of formula (B6-3).
In one embodiment, -RQB6, if present, is independently a group of formula (B6-4).
In one embodiment, -RQB6, if present, is independently a group of formula (B6-5).
In one embodiment, -RQB6, if present, is independently a group of formula (B6-6). In one embodiment, -RQB6, if present, is independently a group of formula (B6-7).
In one embodiment, -RQB6, if present, is independently a group of formula (B6-8).
In one embodiment, -RQB6, if present, is independently a group of formula (B6-9).
In one embodiment, -RQB6, if present, is independently a group of formula (B6-10).
In one embodiment, -RQBδ, if present, is independently a group of formula (B6-11). In one embodiment, -RQB6, if present, is independently a group of formula (B6-12).
In one embodiment, p1 , if present, is independently 1.
In one embodiment, p3, if present, is independently 0. In one embodiment, p3, if present, is independently 1 or 2.
In one embodiment, p4, if present, is independently 1.
In one embodiment, each -RNN1, if present, is independently -H, saturated aliphatic C1-4alkyl, phenyl, or benzyl; or, the group -NRNN1RNN1, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -RNN1, if present, is independently -H, saturated aliphatic C1-4alkyl, phenyl, or benzyl; or, the group -NRNN1RNN1, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -RNN1, if present, is independently -H, saturated aliphatic
C1-4alkyl, phenyl, or benzyl.
In one embodiment, each -RNN1, if present, is independently -H or saturated aliphatic
C1-4alkyl.
In one embodiment, each -RNN1, if present, is independently -H or -Me. In one embodiment, each -RNN1, if present, is independently -H. In one embodiment, each -RNN2, if present, is independently -H or saturated aliphatic C1-4alkyl.
In one embodiment, each -RNN2, if present, is independently -H or -Me. In one embodiment, each -RNN2, if present, is independently -H.
In one embodiment, each -RNN3, if present, is independently -H, saturated aliphatic C1-4alkyl, phenyl, or benzyl.
In one embodiment, each -RNN3, if present, is independently -H or saturated aliphatic C1-4alkyl.
In one embodiment, each -RNN3, if present, is independently -H or -Me. In one embodiment, each -RNN3, if present, is independently -H. In one embodiment, each -RNN3, if present, is independently -Me.
In one embodiment, -RNN4, if present, is independently saturated aliphatic C1-6alkyl. In one embodiment, -RNN4, if present, is independently saturated aliphatic C1-4alkyl.
The Groups -Qc and -QE
In one embodiment, each -Qc, if present, and each -QE, if present, is independently selected from:
-R2A1,
-F, -Cl, -Br, -I1
-CF3, -OCF3, -OH, -L2A-OH1 -O-L2A-OH, -NH-L2A-OH, -NR^-L2A-OH,
.QR2 Ai 1 .LZA -0R2 Ai 1 .o-L2A-OR2A1, -NH-L2^OR2*1, -NR^-L2A-OR2*1,
-SH, -SR2*1,
-CN,
-NO2, -NH2, -NHR2*1, -NR2A1;,, -NR2A2R2*3,
-L2^NH2, -L2^NHR2A1, -L2A-NR2*1^ -L2A-N R2A2R2*3,
-0-L2A-NH2, -O-L2A-NHR2A1, -O-L2A-NR2A1;,, -O-L2A-NR2*^2*3,
-NH-L2A-NH2, -NR^-L2A-NHz, -NH-L2^-NHR2*1, -NR^-L2A-NHR2*1,
-NH-L2A-NR2*^, -NR^-L2A-NR2A1,, -NH-L2A-NR^R2*3, -NR^-L2A-NR2*^2*3,
-OC(=O)R2*1,
-C(=O)OH, -C(=O)OR2*1,
-C(=O)R2*1,
-C(=O)NH2, -C(=O)NHR2A1 , -C(=O)NR2A1;,, -C(=O)NR2A2R2*3, -C(=O)NH-L2A-OH, -C(=O)NH-L2A-OR2A1,
-C(=O)NH-L2A-NH2, -C(=O)NH-L2A-NHR2*1,
-C(=O)NH-L2A-NR2*1;,, -C(=O)NH-L2*-NR2A2R2*3,
-NHC(=O)R2A1, -NR2A1C(=O)R2*1,
-NHC(=O)-L2A-OH, -NHC(=O)-L2A-OR2*1, -NHC(=O)-L2A-NH2, -NHC(=O)-L2^NHR2*1, -NHC(=O)-L2A-NR2A1 2, -NHCC^-L2A-NR^R2A3, -NHC(=O)OR2*1, -NR2A1C(=O)OR2A1,
-OC(=O)NH2, -OC(=O)NHR2*1, -OC(=O)NR^2, -OC(=O)NR2A2R2*3, -NHC(=O)NH2, -NHC(=O)NHR2*1,
-NHC(=O)NR^2, -NHC(=O)NR2A2R2A3, -NR2A1C(=O)NH2, -NR2A1C(=O)NHR2A1, -NR2A1C(=O)NR2A1 2, -NR2A1C(=O)NR2A2R2A3, -NHS(=O)2R2*1, -NR2*1 S(=O)2R2*1, -S(=O)2NH2, -S(=O)2NHR2*1, -S(=O)2NR2A1 2, -S(=O)2NR2A2R2A3,
-S(=O)R2*1, -S(=O)2R2*1, -OS(=O)2R2*1, and -S(=O)2OR2*1; wherein: each -13- is independently saturated aliphatic C1-5alkylene; in each group -NR2A2R2A3, R2*2 and R2*3, taken together with the nitrogen atom to which they are attached, form a A-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R2*1 is independently: -R2B1 -R2B2 -R2B3 -R2B4 -R2B5 -R2B6 -R2B7 -R2B8
-L2B-R2B4, -L2B-R2B5, -L2B'-R2B6, -L2B-R2B7, or'-L2B-R2B8; each -R2B1 is independently saturated aliphatic C1-6alkyl; each -R2B2 is independently aliphatic C2-6alkenyl; each -R2B3 is independently aliphatic C2-6alkynyl; each -R2B4 is independently saturated C3-6cycloalkyl; each -R2B5 is independently C3-6cycloalkenyl; each -R2B6 is independently non-aromatic C^heterocyclyl; each -R2B7 is independently C6-10carboaryl; each -R2B8 is independently C5.10heteroaryl; each -L2B- is independently saturated aliphatic C1-3alkylene; wherein: each -R2B4, -R2B5, -R2B6, -R2B7, and -R2B8 is optionally substituted, for example, with one or more substituents -R2C1 and/or one or more substituents -R2C2, each -R2B1, -R2B2, -R2B3, and -L2B- is optionally substituted, for example, with one or more substituents -R2C2, and wherein: each -R2C1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -R2C2 is independently:
-F, -Cl, -Br, -I1 -CF3, -OCF3,
-OH, -L2D-OH, -O-L2D-OH, -OR2D1, -L2D-OR2D1, -O-L2D-OR2D1, -SH, -SR2D1, -CN, -NO2,
-NH2, -NHR2D1, -NR2D1 2, -NR2D2R2D3, -L2D-NH2, -L2D-NHR2D1, -L2D-NR2D1 2, -L2D-NR2D2R2D3, -C(=O)OH, -C(=O)OR2D1, -C(=O)NH2, -C(=O)NHR2D1, -C(=O)NR2D1 2, or -C(=O)NR2D2R2D3; wherein: each -R2D1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -L2D- is independently saturated aliphatic C1-5alkylene; and in each group -NR202R203, R202 and R203, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O.
In one embodiment, each -Qc, if present, and each -QE, if present, is independently selected from:
-R2A1,
-F, -Cl, -Br, -I,
-CF3, -OCF3, -OH, -L2A-OH, -O-L2A-OH, -NH-L2A-OH, -NR^-L2A-OH,
_OR 2A1_ .,,2A -0R2 Ai 1 .Q-L2A-OR2A1, -NH-L2A-OR2A1 , -NR2A1-L2A-OR2*1,
-CN,
-NH2, -NHR2*1, -NR2*1,, -NR2^R2*3,
-L2^NH2, -L2A-NHR2A1, -L2A-NR2A1,, -L2A-NR^R2*3, -0-L2A-NH2, -O-L2A-NHR2A1, -0-L2A-NR2A1;,, -0-L2^N R2A2R2*3,
-NH-L2^NH2, -NR2A1-L2A-NH2, -NH-L2A-NHR2A1 , -NR^-L2A-NHR2A1,
-NH-L2A-NR2A1,, -NR^-L2A-NR2A1,,
-NH-L2A-NR^R2*3, -NR^-L2A-NR2A2R2*3,
-OC(=O)R2A1, -C(=O)OH, -C(=O)OR2A1,
-C(=0)NH2, -C(=O)NHR2*1, -C(=O)NR2A1 2, -C(=O)NR2A2R2*3,
-C(=O)NH-L2A-OH1 -C(=O)NH-L2A-OR2*1,
-C(=O)NH-L2A-NH2, -C(=O)NH-L2A-NHR2A1,
-C(=O)NH-L2^NR2A1;,, -CC^NH-L2A-NR^R2*3, -NHC(=O)R2A1, -NR2A1C(=O)R2*1,
-NHC(=O)-L2A-OH, -NHC(=O)-L2A-OR2*1,
-NHC(=O)-L2A-NH2, -NHC(=O)-L2A-NHR2*1,
-NHC(=O)-L2A-NR2A1 2, -NHC(=O)-L2A-NR2A2R2*3,
-NHC(=O)NH2, -NHC(=O)NHR2*1, -NHC(=O)NR2A1 2, -NHC(=O)NR2A2R2*3,
-NR2A1C(=O)NH2, -NR2A1C(=O)NHR2A1,
-NR2A1C(=O)NR2*1,, -NR2A1C(=O)NR2A2R2A3,
-NHS(=O)2R2A1, -NR2A1S(=O)2R2A1,
-S(=O)2NH2, -S(=O)2NHR2A1, -S(=O)2NR2A1 Z, -S(=O)2NR2A2R2*3, -S(=O)R2A1, -S(=O)2R2A1 1 -OS(=O)2R2A1, and -S(=O)2OR2A1.
In one embodiment, each -Qc, if present, and each -QE, if present, is independently selected from: -R2A1,
-F, -Cl, -Br, -I, -CF3, -OCF3,
-OH, -L2A-OH, -0-L2A-OH, -NH-L2A-OH, -OR2A1, -L2A-OR2A1, -0-L2A-OR2A1, .MH.^-OR2A1, -CN,
-NH2, -NHR2A1, _NR2A12) _NR2A2R2A3i
-L2A-NH2, -L2A-NHR2A1, -L2A-NR2^, -L2A-NR2A2R2A3,
-0-L2A-NH2, -0-L2A-NHR2A1, -O-L2A-NR2^, -0-L2A-NR2A2R2A3,
-NH-L2A-NH2, -NH-L2A-NHR2A1, -NH-L2A-NR2^, -NH-L2A-NR2A2R2A3, -OC(=O)R2A1,
-C(=O)OH, -C(=O)OR2A1,
-C(=O)NH2, -C(=O)NHR2A1, -C(=O)NR2A1;,, -C(=O)NR2A2R2A3,
-C(=O)NH-L2A-OH, -C(=O)NH-L2A-OR2A1 ,
-C(=O)NH-L2A-NH2, -C(=O)NH-L2A-NHR2A1 , -C(=O)NH-L2A-NR2A1 2, -C(=O)NH-L2A-NR2A2R2A3,
-NHC(=O)R2A1, -NR2A1C(=O)R2A1,
-NHC(=O)-L2A-OH1 -NHC(=O)-L2A-OR2A1,
-NHC(=O)-L2A-NH21 -NHC(=O)-L2A-NHR2A1,
-NHC(=O)-L2A-NR2A1 2, and -NHC(=O)-L2A-NR2A2R2A3.
In one embodiment, each -Qc, if present, is independently selected from:
-R2A1,
-F, -Cl, -Br, -I,
-CF3, -OCF3, -OH, -L2A-OH, -0-L2A-OH, -NH-L2A-OH,
-OR2A1, -L2A-OR2A1, -0-L2A-OR2A1, -NH-L2A-OR™,
-CN,
-NO2,
-NH2, -NHR2A1, _NR2A12i _NR2A2R2A3i -L2A-NH2, -L2A-NHR2A1, -L2A-NR2^, -L2A-NR2A2R2A3,
-0-L2A-NH2, -0-L2A-NHR2A1, -O-L2A-NR2A1 2, -0-L2A-NR2A2R2A3,
-NH-L2A-NH2, -NH-L2A-NHR2A1, -NH-L2A-NR2A1 2, -NH-L2A-NR2A2R2A3,
-OC(=O)R2A1,
-C(=O)OH, -C(=O)OR2A1, -C(=O)NH2, -C(=O)NHR2A1, -C(=O)NR2A1;,, -C(=O)NR2A3R2A3,
-C(=O)NH-L2A-OH, -C(=O)NH-L2A-OR2A1 ,
-C(=O)NH-L2A-NH21 -C(=O)NH-L2A-NHR2A1,
-C(=O)NH-L2A-NR2A1Z1 -C(=O)NH-L2A-NR2A2R2A3,
-NHC(=O)R2A1, -NR2A1C(=O)R2A1, -NHC(=O)-L2^OH, -NHC(=O)-L2A-OR2A1, -NHC(=O)-L2A-NH2, -NHC(=O)-L2A-NHR2A1, -NHC(=O)-L2A-NR2A1 2l -NHC(=O)-L2A-NR2A2R2A3, -NHC(=O)NH2, -NHC(=O)NHR2*1, -NHC(=O)NR^2, -NHC(=O)NR2A2R2A3,
-NR2A1C(=O)NH2, -NR2A1C(=O)NHR2A1, -NR2A1C(=O)NR2A1 2, -NR2A1C(=O)NR2A2R2A3, -NHS(=O)2R2A1, -NR2A1S(=O)2R2A1,
-S(=O)2NH2, -S(=O)2NHR2*1, -S(=O)2NR2*1,, -S(=O)2NR2A2R2*3, -S(=O)R2A1 , -S(=O)2R2*1 , -OS(=O)2R2A1 , and -S(=O)2OR2*1.
In one embodiment, each -Qc, if present, is independently selected from: -R2A1, -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L2A-OH, -O-L2A-OH, -NH-L2A-OH, -OR2*1, -L2A-OR2*1 , -O-L2A-OR2*1, -NH-L2A-OR2*1,
-NH2, -NHR2*1, -NR2*1,, -NR2A2R2*3, -L2A-NH2, -L2A-NHR2A1, -L2A-NR2*1,, -L2A-NR^R2*3, -0-L2A-NH2, -O-L2A-NHR2*1, -O-L2A-NR2*1,, -O-L2A-N R2A2R2*3, -NH-L2A-NH2, -NH-L2A-NHR2A1, -NH-L2A-NR2A1,, -N H-L2A-N R2A2R2*3, -C(=O)NH2, -C(=O)NHR2*1, -C(=O)NR2*1;,, -C(=O)NR2A2R2*3,
-C(=O)NH-L2A-OH, -C(=O)NH-L2A-OR2A1, -C(=O)NH-L2A-NH2, -C(=O)NH-L2A-NHR2A1, -C(=O)NH-L2A-NR2*1,, -C(=O)NH-L2A-NR2A2R2*3, -NHC(=O)R2*1, -NR2A1C(=O)R2*1, -NHC(=O)-L2A-OH, -NHC(=O)-L2A-OR2*1,
-NHC(=O)-L2A-NH2, -NHC(=O)-L2A-NHR2A1, -NHC(=O)-L2A-NR2A1,, and -NHC(=O)-L2*-NR2A2R2*3.
In one embodiment, each -Qc, if present, is independently selected from: -R2*1, -F, -Cl, -Br, -I, -CF3, -OCF3,
-OH, -L2A-OH, -O-L2A-OH, -NH-L2A-OH,
-OR2*1, -L2A-OR2*1, -O-L2A-OR2*1, -NH-L2A-OR2A1,
-NH2, -NHR2*1, -NR2*^, -NR2A2R2*3,
-L2A-NH2, -L2A-NHR2A1, -L2A-NR2*1,, -L2A-NR^R2*3, -0-L2A-NH2, -O-L2A-NHR2*1, -O-L2A-NR2*1,, -O-L2A-N R2A2R2*3,
-NH-L2A-NH2, -NH-L2A-NHR2A1, -NH-L2A-NR2*^, and -N H-L2A-N R2A2R2*3.
In one embodiment, each -Qc, if present, is independently selected from:
-R2*1, -F, -Cl, -Br, -I, -CF3, -OCF3, -NH-L2A-OH, -NH-L2A-OR2*1,
-NH-L2A-NH2, -NH-L2A-NHR2*1, -NH-L2A-NR2*^, and -N H-L2A-N R2A2R2*3.
In one embodiment, each -QE, if present, is independently selected from: -R2A1, -CF3,
-OH, -L2A-OH, -O-L2A-OH,
-OR;*1, .IJA.ORSAI, -O-L2A-OR2*1,
-CN, -NH2, -NHR=*1, -NR2*1,, -NR2A2R2*3,
-L2A-NH2, -L2^-NHR2A1, -L2A-NR2*1^ -L2^N R2A2R2*3,
-C(=O)OH, -C(=O)OR2A1,
-C(O)R2*1,
-C(=O)NH2, -C(=O)NHR2*1, -C(=O)NR2*1;,, -C(=O)NR2A2R2A3, -NHC(=O)R2A1, -NR2A1C(=O)R2A1,
-NHC(=O)NH2, -NHC(=O)NHR2*1,
-NHC(=O)NR^2, -NHC(=O)NR2A2R2A3,
-NR2A1C(=O)NH2, -NR2A1C(=O)NHR2A1,
-NR^CC^NR^a, -NR2A1C(=O)NR2A2R2A3 I -NHS(=O)2R2A1, -NR2A1S(=O)2R2A1,
-S(=O)2NH2, -S(=O)2NHR2A1, -S(=O)2NR2A1 2, -S(=O)2NR2A2R2A3,
-S(=O)R2A1, -S(=O)2R2A1, -OS(=O)2R2A1, and -S(=O)2OR2A1.
In one embodiment, each -QE, if present, is independently selected from: -R2A1,
-CF3,
-OH, -L2A-OH, -O-L2A-OH,
-OR2A1 , -L2A-OR2*1, -O-L2A-OR2*1,
-CN, -NH2, -NHR2*1, -NR2*1,, -NR2A2R2*3,
-L2A-NH2, -L2A-NHR2*1, -L2A-NR2*1,, -L2A-N R2A2R2*3,
-C(=O)OH, -C(=O)OR2*1,
-C(=O)NH2, -C(=O)NHR2*1, -C(=O)NR2A1;,, and -C(=O)NR2A2R2*3.
-NHC(=O)R2*1, and -NR2A1C(=O)R2*1.
In one embodiment, each -QE, if present, is independently selected from:
-R2A1,
-CF3,
-OH, -L2A-OH, -O-L2A-OH, -OR2A1, -L2A-OR2*1, -O-L2A-OR2*1,
-CN,
-NH2, -NHR2*1, -NR2*1,, -NR2A2R2*3,
-L2A-NH2, -L2A-NHR2*1, -L2A-NR2*1,, -L2A-N R2A2R2*3,
-C(=O)OH, -C(=O)OR2*1, -C(=O)NH2, -C(=O)NHR2A1, -C(=O)NR2*1,, and -C(=O)NR2A2R2*3.
In one embodiment, each -L2*-, if present, is independently -(CH2)n2-, wherein n2 is independently 1 to 4. In one embodiment, each -L2"1-, if present, is independently -CH2- or -CH2CH2-.
In one embodiment, each -NR2A2R2A3 I if present, is independently azetidino, pyrrolidine, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -NR2A2R2A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -R2A B4 _D2B6 _p2B71 1 if present, is independently:
_p2B1 _D2 _p2B8
-L2B-R2B4, -L2B-R2B6, -L2B'-R2B7, or -L2B-R2Bδ.
In one embodiment, each -R2A1, if present, is independently:
_p2B1 _p2B7 _p2B8
-L2B-R2B7, or -L2B-R2B8.
In one embodiment, each -R™, if present, is independently: -R2B1, -R2B7, or -L2B-R2B7.
In one embodiment, each -R2A1 1 if present, is independently:
-R2B7, -R2B8, -L2B-R2B7, or -L2B-R2B8.
In one embodiment, each -R2B6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholihyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
In one embodiment, each -R2B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
In one embodiment, each -R2B7, if present, is independently phenyl, and is optionally substituted.
In one embodiment, each -R2B8, if present, is independently C5-6heteroaryl, and is optionally substituted.
In one embodiment, each -R2B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted. In one embodiment, each -R2B8, if present, is independently C9-1oheteroaryl, and is optionally substituted.
In one embodiment, each -R2B8, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
In one embodiment, each -L2B-, if present, is independently -CH2- or -CH2CH2-. In one embodiment, each -L2B-, if present, is independently -CH2-.
In one embodiment, each -R2C1, if present, is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -R2C2 is independently: -F1 -Cl1 -Br1 -I,
-OH1
-OR2D1,
-CN1
-NO2, -NH2, -NHR2D1, -NR2D1 2l or -NR2D2R2D3.
In one embodiment, each -R2D1, if present, is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -L2D-, if present, is independently -(CH2)m2-, wherein m2 is independently 1 to 4.
In one embodiment, each -L2D-, if present, is independently -CH2- or -CH2CH2-.
In one embodiment, each -NR202R203, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -NR202R203, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -Qc, if present, is independently selected from:
-RX1, -F, -Cl, -Br, -I,
-CF3, -OCF3, -OH, -ORX1,
-NH2, -NHRX1, -NRX1 2, -RM1, -O-(CH2)Z-OH, -O-(CH2)2-ORX1, -O-(CH2)Z-NH2, -O-(CH2)Z-NHRX1, -0-(C H2J2-N RX1 2, -O-(CH2)Z-RM1,
-NH-(CH2)2-OH, -NH-(CH2)Z-ORX1,
-NH-(CH2)Z-NH2, -NH-(CH2)Z-NHRX1, -NH-(CH2)Z-NRX1 2, -NH-(CH2)Z-RM1,
-C(=O)NH-(CH2)Z-OH, -C(=O)NH-(CH2)Z-ORX1, -C(=O)NH-(CH2)2-NH2, -C(=O)NH-(CH2)2-NHRX1,
-C(=O)NH-(CH2)2-NRX1 2, -C(=O)NH-(CH2)Z-RM1,
-NHC(=O)-(CH2)Z-OH, -NHC(=O)-(CH2)Z-ORX1 ,
-NHC(=O)-(CH2)Z-NH2, -NHC(=O)-(CH2)Z-NHRX1 ,
-NHC(=O)-(CH2)Z-NRX1 2, and -NHC(=O)-(CH2)2-RM1, wherein: each z is independently 2 or 3; each -RX1 is independently saturated aliphatic C1-4alkyl; and each -RM1 is independently piperidino, piperizino, or morpholino, and is optionally substituted with one or more saturated aliphatic C-i^alkyl groups.
In one embodiment, each -Qc, if present, is independently selected from:
-RX1,
-F, -Cl, -Br, -I,
-OH, -ORX1, -NH2, -NHRX1, -NRX1 2,
-0-CH2CH2-OH, -O-CH2CH2-ORX1,
-0-CH2CH2CH2-OH1 -O-CH2CH2CH2-OR^,
-0-CH2CH2-NH2, -O-CH2CH2-NHRX1, -O-CH2CH2-NRX1 2,
-0-CH2CH2CH2-NH2, -0-CH2CH2CH2-NHR^, -O-CH2CH2CH2-NRx1 2, -NH-CH2CH2-OH, -NH-CH2CH2-ORX1,
-NH-CH2CH2CH2-OH1 -NH-CH2CH2CH2-OR^,
-NH-CH2CH2-NH2, -NH-CH2CH2-NHRX1, -NH-CH2CH2-NRX1 2,
-NH-CH2CH2CH2-NH2, -NH-CH2CH2CH2-NHR^, and -NH-CH2CH2CH2-NRX1 2; wherein each -RX1 is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -Qc, if present, is independently selected from:
-RX1, -F, -Cl, -Br, -I, -CF3, -OCF3,
-NH-(CH2)Z-OH, -NH-(CH2)Z-ORX1,
-NH-(CH2)Z-NH2, -NH-(CH2)Z-NHRX1, -NH-(CH2)Z-NRX1 2, and -NH-(CH2)2-RM1; wherein: each -RX1 is independently saturated aliphatic C1-4alkyl; and each -RM1 is independently piperidino, piperizino, or morpholino, and is optionally substituted with one or more saturated aliphatic C1-4alkyl groups.
In one embodiment, each -Qc, if present, is independently selected from: -Me, -F, -Cl, -Br, -I, and -CF3. In one embodiment, each -QE, if present, is independently selected from:
-RX2,
-RX2A, -CH2-RX2A, -CH2CH2-RX2A,
-OH, -0RX2, -NH2, -NHRX2, -NRX2 2, -RM2,
-0-(CHz)2-OH, -O-(CH2)Z-ORX2,
-(CH2)ZrOH1 -(CH2)Z-ORX2,
-(CH2)Z-NH2, -(CH2)Z-NHRX2, -(CH2)Z-NRX2 2, and -(CH2)Z-RM2; wherein: each z is independently 2 or 3; each -RX2A is independently phenyl, pyridyl, thienyl, piperidinyl, or C3-6cycloalkyl, and is optionally substituted with one or more groups selected from -RX2, -OH1 -0RX2, -NH2, -NHRX2, -NRX2 2, or -RM2; each -RX2 is independently saturated aliphatic C1-4alkyl; and each -RM2 is independently piperidino, piperizino, or morpholino, and is optionally substituted with one or more saturated aliphatic C-i-4alkyl groups.
In one embodiment, each -QE, if present, is independently selected from:
-RX2, -OH, -OR*2,
-NH2, -NHRX2, -NRX2 2,
-0-CH2CH2-OH, -O-CH2CH2-ORX2,
-0-CH2CH2CH2-OH, -0-CH2CH2CH2-OR^,
-CH2CH2-OH, -CH2CH2-ORX2, -CH2CH2-NH2, -CH2CH2-NHRX2, and -CH2CH2-NRX2 2; wherein each -RX2 is independently saturated aliphatic C1-4alkyl.
The Group -QD
In one embodiment, -QD, if present, is independently selected from: -R3A1,
-L3A-OH, -L3A-OR3A1,
-L3A-NH2, -L3A-NHR3A1, -L3A-NR3A1 2, and -|_3A-NR3A2R3A3; wherein: each -L3A- is independently saturated aliphatic C2-5alkylene; in each group -NR3A2R3A3, R3A2 and R3A3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R3A1 is independently:
R3B1 D3B2 i->3B3 D3B4 r-)3B5 D3B6 r>3B7 rj3B8 , -K , -K , -f\ , -rv , -r\ , -K , -r\ , i 3B p3B4 I 3B p3B5 i 3B _p3B6 ι 3B_p3B7 __ _ι 3B_p3B8. each -R3B1 is independently saturated aliphatic C1-6alkyl; each -R3B2 is independently aliphatic C2-6alkenyl; each -R3B3 is independently aliphatic C2-6alkynyl; each -R3B4 is independently saturated C3-6cycloalkyl; each -R3B5 is independently C3^cycloalkenyl; each -R3B6 is independently non-aromatic C^heterocyclyl; each -R3B7 is independently C6-10carboaryl; each -R3B8 is independently C5-10heteroaryl; each -L3B- is independently saturated aliphatic C1-3alkylene; wherein: each -R3B4, -R3B5, -R3B6, -R3B7, and -R3BS is optionally substituted, for example, with one or more substituents -R3C1 and/or one or more substituents -R3C2, each -R3B1, -R3B2, -R3B3, and -L3B- is optionally substituted, for example, with one or more substituents -R3C2, and wherein: each -R3C1 is independently saturated aliphatic C1.4alkyl, phenyl, or benzyl; each -R3C2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3,
-OH, -L3D-OH, -O-L3D-OH, -OR3D1 , -L3D-OR3D1 , -O-L3D-OR3D1 ,
-SH, -SR3D1, -CN, -NO2,
-NH2, -NHR3D1, -NR3D1 2, -NR3D2R3D3, -L3D-NH2, -L3D-NHR3D1, -L3D-NR3D1 2, -L3D-NR3D2R3D3,
-C(=O)OH, -C(=O)OR3D1,
-C(=O)NH2, -C(=O)NHR3D1, -C(=O)NR3D1 2, or -C(=O)NR3D2R3D3; wherein: each -R3D1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -L3D- is independently saturated aliphatic C1-5alkylene; and in each group -NR302R303, R302 and R303,. taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O.
In one embodiment, -QD, if present, is independently selected from:
-R3A1,
-L3A-NH2, -L3A-NHR3A1, -L3A-NR3A1 2, and -L3A-NR3A2R3A3.
In one embodiment, -Q°, if present, is independently selected from:
-L3A-NH2, -L3A-NHR3A1, -L3A-NR3A1 2, and -L3A-NR3A2R3A3. In one embodiment, -QD, if present, is independently selected from:
_p3A1
-L3A-OH, and -L3A-OR3A1.
In one embodiment, -QD, if present, is independently selected from: -L3A-OH and -L3A-OR3A1.
In one embodiment, each -L3A-, if present, is independently -(CH2),*-, wherein n3 is independently 1 to 4.
In one embodiment, each -L3A-, if present, is independently -CH2CH2- or -CH2CH2CH2-.
In one embodiment, each -NR3A2R3A3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -NR3A2R3A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -R3A1, if present, is independently: p3B1 p3B4 p3B6 p3B7 p3B8 -r\ , -r\ , -r\ , ~r\ , -rx ,
I 3B_p3B4 I 3B_p3B6 ι 3B_p3B7 _. i 3B_p3B8
In one embodiment, each -R3A1, if present, is independently:
_R3B1 _R3B6i Or .L3B.R3B6
In one embodiment, each -R3A1, if present, is independently: -R3B1, -R3B7, -R3B8, ι 3B_p3B7 Qr ι 3B_p3B8
In one embodiment, each -R3A1, if present, is independently:
-R3B1, -R3B7, or -L3B-R3B7.
In one embodiment, each -R3A1, if present, is independently:
_p3B7 _p3B8 I 3B_p3B7 __ _ι 3B_p3B8
In one embodiment, each -R3B6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted. In one embodiment, each -R3B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
In one embodiment, each -R3B7, if present, is independently phenyl, and is optionally substituted.
In one embodiment, each -R3Bδ, if present, is independently C5-6heteroaryl, and is optionally substituted.
In one embodiment, each -R3BS, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, each -R3B8, if present, is independently C9-10heteroaryl, and is optionally substituted.
In one embodiment, each -R3B8, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
In one embodiment, each -L3B-, if present, is independently -CH2- or -CH3CH2-. In one embodiment, each -L3B-, if present, is independently -CH2-.
In one embodiment, each -R3C1, if present, is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -R3C2 is independently:
-F, -Cl, -Br, -I, -OH,
-OR3D1, -CN, -NO2,
-NH2, -NHR3D1, -NR3D1 2, or -NR302R303.
In one embodiment, each -R301, if present, is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -L30-, if present, is independently -(CH2)m3-, wherein m3 is independently 1 to 4.
In one embodiment, each -L30-, if present, is independently -CH2- or -CH30H2-.
In one embodiment, each -NR302R303, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -NR302R303, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F.
In one embodiment, each -QD, if present, is independently selected from:
-RX3, -CH2CH2-OH1 -CH2CH2-OR*3,
-CH2CH2CH2-OH, -CH2CH2CH2-ORX3, -CH2CH2-NH2, -CH2CH2-NHRX3, -CH2CH2-NRX3 2, -CH2CH2CH2-NH2, -CH2CH2CH2-NHRX3, and -CH2CH2CH2-NR^2; wherein each -RX3 is independently saturated aliphatic C1-4alkyl.
Molecular Weight
In one embodiment, the BA compound has a molecular weight of from 212 to 1200. In one embodiment, the bottom of range is 225, 250, 275, 300, or 350. In one embodiment, the top of range is 1100, 1000, 900, 800, 700, or 600. In one embodiment, the range is from 225 to 600.
Combinations
Each and every compatible combination and subcombination of the embodiments described above is explicitly disclosed herein, as if each and every combination and subcombination was individually and explicitly recited.
Some Preferrred Embodiments
In one preferred embodiment, the compounds are selected from compounds of the following formula and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000041_0001
In one preferred embodiment, the compounds are selected from compounds of the following formula and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000042_0001
In one preferred embodiment, the compounds are selected from compounds of the following formula and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000042_0002
Examples of Specific Embodiments
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000042_0003
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0002
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000058_0001
Substantially Purified Forms
One aspect of the present invention pertains to BCAA compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
Unless specified, the substantially purified form refers to the compound in any stereoisomer^ or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5%. by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight. Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
Isomers
Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C1-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
Figure imgf000059_0001
Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; and the like.
Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
Salts
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et a/., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL Vol. 66, pp. 1-19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO-), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 +.
If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be -NH3 +), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.
Solvates and Hydrates
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof.
Chemically Protected Forms
It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
Unless otherwise specified, a reference to a particular compound also includes chemically protected forms thereof.
A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.
For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc).
For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CHs)2C6H4C6H5, -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O»).
For example, a carboxylic acid group may be protected as an ester for example, as: an C1-7alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1-7haloalkyl ester (e.g., a
C1-7trihaloalkyl ester); a triC1-7alkylsilyl-C1.7alkyl ester; or a C5-20aryl-C1-7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).
Prodrugs
It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
Unless otherwise specified, a reference to a particular compound also includes prodrugs thereof.
For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Chemical Synthesis
Several methods for the chemical synthesis of fused bicyclic diarylamine compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
In one approach, compounds of type (vi) and (vii) are prepared as shown in the following scheme. 2-Bromo-4-chloro-5-nitropyridine (i) is treated with 4-methoxybenzylamine (PMB-NH2), typically in acetonitrile and in the presence of a tertiary base to afford the intermediate (ii). Reduction of the nitro group using tin (II) chloride or a metal/acid mixture followed by treatment with formamide or a mixture of acetic anhydride and triethylorthoformate gives the fused bicyclic intermediate (iv). Palladium-mediated amination of (iv) with 2-amino-5-cyanopyrazine, typically with heating and in the presence of a base and a suitable phosphine ligand, gives intermediate (v). Removal of the 4- methoxybenzyl group is effected by treatment with trifluoroacetic acid (TFA) or by hydrogenolysis to give intermediate (vi). Alternatively, prolonged treatment with TFA gives the target compound (vii).
Figure imgf000064_0001
In another approach, 2-alkoxy-5-amino pyrazines (x) are prepared as shown in the following scheme. 2,6-Dichloropyrazine (viii) is treated with ammonia to give 2-chloro-6- aminopyrazine (ix) which is then treated with suitable alcohols (ROH), typically with heating in acetonitrile and in the presence of a base such as sodium hydride, to give the required intermediates (x).
Figure imgf000064_0002
Compounds of type (xii) are prepared as shown in the following scheme. Intermediate (iv) is subjected to palladium-mediated amination with aminopyrazines (x), typically with heating and in the presence of a base and a suitable phosphine ligand, to give intermediates (xi). Removal of the 4-methoxybenzyl group and any protecting groups on the pyrazine component then gives the target compounds (xii). Scheme 3
Figure imgf000065_0001
In another approach, 2-alkoxy-3-cyano-5-amino pyrazines (xv) are prepared as shown in the following scheme. 2-Chloro-6-aminopyrazine (ix) is brom.inated, typically with NBS, to give intermediate (xiii). Treatment of this intermediate with a cyanide source such as potassium cyanide under palladium-mediated reaction conditions then gives intermediate (xiv) which upon treatment with suitable alcohols (ROH), usually with heating in acetonitrile and in the presence of a base such as sodium hydride, gives the required intermediates (xv).
Scheme 4
Figure imgf000065_0002
Figure imgf000065_0003
Compounds of type (xvii) are prepared as shown in the following scheme. Intermediate (iv) is subjected to palladium-mediated amination with aminopyrazines (xv), typically with heating and in the presence of a base and a suitable phosphine ligand to give (xvi). Removal of the 4-methoxybenzyl group and any protecting groups on the pyrazine component then gives the target compounds (xvii).
Figure imgf000066_0001
In another approach, compounds of type (xxi) are prepared according to the following scheme. Intermediate (ii) is subjected to palladium-mediated amination with 2-amino-5- cyanopyrazine, typically with heating and in the presence of a base and a suitable phosphine ligand to give intermediate (xviii). Reduction of the nitro group using tin (II) chloride or a metal/acid mixture gives intermediate (xix) which is treated with a suitable aldehyde (RCHO) under oxidative cyclisation conditions, typically sodium metabisulphite in DMF with heating, to give the fused bicyclic diarylamines (xx). Removal of the
4-methoxybenzyl group and any protecting groups on the aldehyde component then gives the target compounds (xxi).
Figure imgf000066_0002
In another approach, compounds of type (xxv) are prepared according to the following scheme. 2-Bromo-4-chloro-5-nitropyridine (i) is treated with an appropriate amine (R- NH2), typically in acetonitrile and in the presence of a tertiary base to afford intermediate (xxii). Reduction of the nitro group using tin (II) chloride or a metal/acid mixture followed by treatment with formamide or a mixture of acetic anhydride and triethylorthoformate gives the fused bicyclic intermediate (xxiv). Palladium-mediated amination of intermediate (iv) with 2-amino-5-cyanopyrazine, typically with heating and in the presence of a base and a suitable phosphine ligand, followed by removal of any protecting groups on the amine component gives the target compounds (xxv).
Figure imgf000067_0001
In another approach, compounds of type (xxvii) are prepared according to the following scheme. 2-Amino-5-cyanopyrazine and an appropriate 3-chloro, or 3-bromo, or 3-(trifluoromethansulfonyloxy)isoquinoline (xxvi) are coupled under palladium-mediated amination conditions typically with heating and in the presence of a base and a suitable phosphine ligand, followed by removal of any protecting groups, to give the target compunds (xxvii).
Figure imgf000067_0002
In another approach, compounds of type (xxviii) are prepared according to the following scheme. A 2-amino-6-alkoxypyrazine (x) and an appropriate 3-chloro, or 3-bromo, or 3-(trifluoromethansulfonyloxy)isoquinoIine (xxvi) are coupled under palladium-mediated amination conditions typically with heating and in the presence of a base and a suitable phosphine ligand, followed by removal of any protecting groups, to give the target compounds (xxvii).
Figure imgf000067_0003
In another approach, compounds of type (xxix) are prepared according to the following scheme. A 2-amino-5-cyano-6-alkoxypyrazine (xv) and an appropriate 3-chloro, or 3-bromo, or 3-(trifluoromethansulfonyloxy)isoquinoline (xxvi) are coupled under palladium-mediated amination conditions typically with heating and in the presence of base of a suitable phosphine ligand, followed by removal of any protecting groups, to give the target compounds (xxix).
Figure imgf000068_0001
In another approach, compounds of type (xxxii) are prepared according to the following scheme. A 2-amino-5-cyano-6-alkoxypyrazine (xv) and 5-chloro- or 5-bromo-3- (trifluoromethanesulfonyloxy)isoquinoline (xxx) are selectively coupled under palladium- mediated amination conditions, typically with heating and in the presence of base of a suitable phosphine ligand, to give the corresponding 5-haloisoquinoline compounds (xxxi). The 5-haloisoquinolines (xxxi) are further reacted under palladium catalysis with either a boronic acid, typically in the presence of a suitable base and phosphine ligand and with heating, or with an amine, typically in the presence of a suitable base and phosphine ligand and with heating. Alternatively, the 5-haloisoquinolines (xxxi) are reacted with an alkoxide in the presence of a suitable copper (I) compound, typically with heating. The removal of any protecting groups gives the target compounds (xxxii).
Scheme 11
Figure imgf000069_0001
In another approach, compounds of type (xxxiii) are prepared according to the following scheme. 2-Amino-5-cyanopyrazine and an appropriate tert-butyl 5-chloro-1 H-pyrrolo[2,3- c]pyridine-1-carboxylate (xxxiv) are coupled under palladium-mediated amination conditions typically with heating and in the presence of a base and a suitable phosphine ligand, with concomitant removal of the nitrogen protecting group, to give the target compounds (xxxiii).
Figure imgf000069_0002
Compositions
One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising a BCAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a BCAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. Uses
The compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of CHK1 kinase function, such as, for example, proliferative conditions, cancer, etc.
Use in Methods of Inhibiting CHK1
One aspect of the present invention pertains to a method of inhibiting CHK1 kinase function, in vitro or in vivo, comprising contacting a CHK1 kinase with an effective amount of a BCAA 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 cell with an effective amount of a BCAA compound, as described herein.
In one embodiment, the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Suitable assays for determining CHK1 kinase function inhibition are described herein and/or are known in the art.
Use in Methods of Inhibiting Cell Proliferation, Etc.
The BCAA compounds described herein, e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these.
One aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a BCAA compound, as described herein.
In one embodiment, the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting a cell with an effective amount of a BCAA compound, as described herein.
In one embodiment, the method further comprises contacting the cell with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation. In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo.
In one embodiment, the BCAA compound is provided in the form of a pharmaceutically acceptable composition.
Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described herein.
For example, a sample of cells (e.g., from a tumour) may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.
Use in Methods of Therapy
Another aspect of the present invention pertains to a BCAA compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
In one embodiment, the method of treatment comprises treatment with both (i) a BCAA compound, as described herein, and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, for use in a method of treatment of the human or animal body by therapy, wherein the method of treatment comprises treatment with both (i) a BCAA compound, as described herein, and (a) the DNA topoisomerase I or Il inhibitor, (b) the DNA damaging agent, (c) the antimetabolite or TS inhibitor, or (d) the microtubule targeted agent.
Use in the Manufacture of Medicaments
Another aspect of the present invention pertains to use of a BCAA compound, as described herein, in the manufacture of a medicament for use in treatment. In one embodiment, the medicament comprises the BCAA compound.
In one embodiment, the treatment comprises treatment with both (i) a medicament comprising a BCAA compound, as described herein, and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Another aspect of the present invention pertains to use of (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, in the manufacture of a medicament for use in a treatment, wherein the treatment comprises treatment with both (i) a BCAA compound, as described herein, and (a) the DNA topoisomerase I or Il inhibitor, (b) the DNA damaging agent, (c) the antimetabolite or TS inhibitor, or (d) the microtubule targeted agent.
Methods of Treatment
Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a BCAA compound, as described herein, preferably in the form of a pharmaceutical composition.
In one embodiment, the method further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
Conditions Treated - Conditions Mediated by CHK1
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disease or condition that is mediated by CHK1.
Conditions Treated - Conditions Ameliorated by the Inhibition of CHK1 Kinase Function
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disease or condition that is ameliorated by the inhibition of CHK1 kinase function. Conditions Treated - Proliferative Conditions and Cancer
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a proliferative condition.
The term "proliferative condition," as used herein, pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth.
In one embodiment, the treatment is treatment of: a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
In one embodiment, the treatment is treatment of: cancer.
In one embodiment, the treatment is treatment of: cancer characterised by, or further characterised by, cancer cells which overexpress Checkpoint Kinase 1 (CHK1).
In one embodiment, the treatment is treatment of: p53 negative cancer.
In one embodiment, the treatment is treatment of: lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer (e.g., head cancer, neck cancer), skin cancer, squamous cancer, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.
In one embodiment, the treatment is treatment of: a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma); a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplasia syndrome, or promyelocytic leukemia; a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentoum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
In one embodiment, the treatment is treatment of solid tumour cancer.
In one embodiment, the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
In one embodiment, the cancer is characterised by, or further characterised by, cancer stem cells.
The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death). The compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein.
Treatment
The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment."
For example, treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.
The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen. Combination Therapies
The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, cytotoxic agents, anticancer agents, etc. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.
For example, it may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1, 2, 3, 4) agents or therapies that regulates cell growth or survival or differentiation via a different mechanism, thus treating several characteristic features of cancer development.
One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.
The particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.
The agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
The agents (i.e., the compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
Combination Therapies Employing DNA Damaging Agents
As discussed herein, in some embodiments, the BCAA 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. When both a BCAA compound and one or more other agents are employed, they may be used (e.g., contacted, administered, etc.) in any order. Furthermore, they may be used (e.g., contacted, administered, etc.) together, as part of a single formulation, or separately, as separate formulations.
For example, in regard to methods of treatment employing both a BCAA compound and one or more other agents, treatment with (e.g., administration of) the BCAA compound may be prior to, concurrent with, or may follow, treatment with (e.g., administration of) the one or more other agents, or a combination thereof.
In one embodiment, treatment with (e.g., administration of) a BCAA compound is concurrent with, or follows, treatment with (e.g., administration of) the one or more other agents.
In one embodiment, the one or more other agents is a DNA topoisomerase I or Il inhibitor; for example, Etoposide, Toptecan, Camptothecin, Irinotecan, SN-38, Doxorubicin, Daunorubicin.
In one embodiment, the one or more other agents is a DNA damaging agent; for example, alkylating agents, platinating agents, or compounds that generate free radicals; for example, Temozolomide, Cisplatin, Carboplatin, Mitomycin C, Cyclophosphamide, BCNU, CCNU, Bleomycin.
In one embodiment, the one or more other agents is an antimetabolite or TS inhibitor; for example, 5-fluorouracil, hydroxyurea, Gemcitabine, Arabinosylcytosine, Fludarabine, Tomudex, ZD9331.
In one embodiment, the one or more other agents is a microtubule targeted agent; for example, Paclitaxel, Docetaxel, Vincristine, Vinblastine.
In one embodiment, the one or more other agents is ionising radiation (e.g., as part of radiotherapy).
Other Uses
The BCAA compounds described herein may also be used as cell culture additives to inhibit CHK1 kinase function, e.g., to inhibit cell proliferation, etc.
The BCAA 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 BCAA 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.
Kjts
One aspect of the invention pertains to a kit comprising (a) a BCAA compound as described herein, or a composition comprising a BCAA compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
In one embodiment, the kit further comprises one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; and (d) a microtubule targeted agent.
The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
Routes of Administration
The BCAA compound or pharmaceutical composition comprising the BCAA compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
The Subject/Patient
The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.
In one preferred embodiment, the subject/patient is a human.
Formulations
While it is possible for the BCAA compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one BCAA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one BCAA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences. 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, 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.
Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
The compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier.
Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or . dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound in the liquid is from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 μg/ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
Dosage
It will be appreciated by one of skill in the art that appropriate dosages of the BCAA compounds, and compositions comprising the BCAA 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 BCAA compound, the route of administration, the time of administration, the rate of excretion of the BCAA 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 BCAA compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
In general, a suitable dose of the BCAA compound is in the range of about 10 μg to about 250 mg (more typically about 100 μg to about 25 mg) per kilogram body weight of the subject per day. Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
EXAMPLES
The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.
Chemical Synthesis
General Conditions for LC-MS Analyses
Solvent A (Aqueous): 0.02% Ammonia and 0.063% ammonium formate in water.
Solvent B (Organic):
0.02% Ammonia and 5% Buffer A in acetonitrile.
Method: LCMS (1)
Column: Phenomenex Gemini C18, 3 μm, 3.0 x 30 mm. Injection Volume: 5 μl_. UV detection: 220 to 400 nm. Column Temperature: 35°C.
0.00 to 2.50 min: 95% A to 5%A (1.2 mL/min). 2.50 to 2.75 min: 5% A (1.2 mL/min). 2.75 to 3.50 min: 5% A (2.0 mL/min). 3.50 to 3.65 min: 5% A to 95%A (2.0 mL/min). 3.65 to 4.00 min: 95% A (1.2 mL/min).
Method: LCMS (2)
Column: Phenomenex Gemini C18, 5 μm, 4.6 x 30 mm. Injection Volume: 5 μL. UV detection: 220 to 400 nm. Column Temperature: 35°C. 0.00 to 4.25 min: 95% A to 5% A (2.0 mL/min). 4.25 to 5.80 min: 5% A (2.0 mL/min).. 5.80 to 5.90 min: 5% A to 95% A (2.0 mL/min). 5.90 to 7.00 min: 95% A (2.0 mL/min).
Method: LCMS (3)
Column: Waters X-Bridge C18, 2.5 μM, 3.0 x 30 mm. Injection Volume: 5 μL. UV detection: 220 to 400 nm. Column Temperature: 35°C.
0.00 to 2.50 min 95% A to 5% A (1.0 mL/min). 2.50 to 2.75 min 5% A (1.0 mL/min). 2.75 to 3.55 min 5% A (1.66 mL/min).
3.55 to 3.65 min 5% A to 95%A (1.66 mL/min). 3.65 to 4.00 min 95% A (1.0 mL/min).
Synthesis 1-1 -A N-(4-Methoxybenzyl)-2-bromo-5-nitropyridin-4-amine
Figure imgf000084_0001
A solution of 4-methoxybenzylamine (0.756 g, 5.51 mmol) in acetonitrile (2 mL) was added to a mixture of 2-bromo-4-chloro-5-nitropyridine (1.19 g, 5.01 mmol) and triethylamine (0.768 mL, 5.51 mmol) in acetonitrile (8 mL). After stirring for 1.5 hours, the solution was diluted with ethyl acetate (100 mL) which was then washed successively with water and brine before being concentrated in vacuo to a light brown oil which solidified on standing to give the title compound (1.31 g, 3.87 mmol, 77%). 1H NMR (d6- DMSO, 400 MHz) δ 9.00 (br t, 1 H, J = 6.3 Hz), 8.80 (s, 1 H)1 7.35 (d, 2H, J = 8.7 Hz), 7.10 (s, 1 H), 6.95 (d, 2H, J = 8.8 Hz), 4.60 (d, 2H, J = 6.0 Hz), 3.70 (s, 3H). LCMS (1) Rt = 2.13 min; m/z (ESI-) 336, 338 (M-H). Svnthesis 1-1 -B
5-(4-(4~Methoxybenzylamino)-5-nitropyridin-2-ylamino)pyrazine-2-carbonitrile
Figure imgf000085_0001
A mixture of palladium (II) acetate (38 mg, 0.17 mmol) and (±)-2,2"- bis(diphenylphosphino)-1 ,1"-binaphthalene (318 mg, 0.51 mmol) a mixture of toluene and DMF (1 :1, 10 ml_) was degassed under a stream of nitrogen gas with stirring for 30 minutes. After addition of 2-amino-5-cyanopyrazine (245 mg, 2.04 mmol), sodium tert- butoxide (196 mg, 2.04 mmol) and N-(4-methoxybenzyl)-2-bromo-5-nitropyridin-4-amine (575 mg, 1.70 mmol), the mixture was degassed for a further 5 minutes and then heated at 140°C for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using 3 x 2.5 g MP-TsOH cartridges, washing with methanol and then eluting with 2 M ammonia in methanol. The basic fractions were concentrated in vacuo to give the title compound (470 mg, 1.25 mmol, 73%) which was used without further purification. LCMS (2) Rt = 2.18min; m/z (ESI-) 376 (M-H); (ESI+) 378 (MH+).
Synthesis 1-1 -C
5-(4-(4-Methoxybenzylamino)-5-aminopyridin-2-ylamino)pyrazine-2-carbonitrile
Figure imgf000085_0002
Tin(ll)chloride dihydrate (1.59 g, 7.04 mmol) was added portionwise to 5-(4-(4- methoxybenzylamino)-5-nitropyridin-2-ylamino)pyrazine-2-carbonitrile (531 mg, 1.41 mmol) in absolute EtOH (10 ml_) at room temperature. The mixture was heated at 70°C for 2 hours before being concentrated in vacuo. The residue was suspended in a mixture of ethyl acetate and saturated sodium bicarbonate solution, then filtered to remove insoluble material. The solids were then washed with EtOAc. The aqueous phase was re-extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give crude title compound (415 mg) as a brown solid. The product was 50% pure by LCMS analysis and was used without further purification. LCMS (2) Rt = 1.73 min; m/z (ESI-) 346 (M-H); (ESI+) 348 (MH+). Synthesis 1-1 -D
5-(2-Cyclopropyl-1H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile (BB-001)
Figure imgf000086_0001
A mixture of crude 5-(4-(4-methoxybenzylamino)-5-aminopyridin-2-ylamino)pyrazine-2- carbonitrile (0.083 mmol), cyclopropane carboxaldehyde (5.9 mg, 0.083 mmol) and sodium metabisulfite (16 mg, 0.083 mmol) in DMF (1 mL) was heated at 100°C for 4 hours. Upon cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated to a light brown solid. The solid was stirred at 65°C with trifluoroacetic acid. Upon completion of the reaction, the mixture was concentrated. Preparative HPLC gave the title compound (3.7 mg, 16%). 1H NMR (d6-DMSO, 400 MHz) δ 12.60 (br s, 1 H), 10.75 (br s, 1 H), 8.80 (s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 8.10 (s, 1 H), 2.10-2.20 (m, 1 H), 1.00-1.20 (m, 4H). LCMS (2) Rt = 1.68min; m/z (ESI-) 276 (M-H); (ESI+) 278 (MH+).
The following compounds were prepared using methods analogous to those described in Synthesis 1-1, using the appropriate aldehydes in place of cyclopropane carboxaldehyde in Synthesis 1-1 -D.
Figure imgf000086_0002
Synthesis 1-3
Compound BB-003
\ N—
Structure
H
1H NMR (d6-DMSO, 400 MHz) δ 12.90 (s, 1 H), 10.85 (s, 1 H), 8.80
NMR (s, 1H), 8.75 (s, 1H), 8.65 (s, 1H), 8.20 (s, 1H), 8.00 (d, 2H, J = 9.2 Hz), 6.85 (d, 2H, J = 9.2 Hz), 3.00 (s, 6H).
LCMS LCMS (2) Rt = 2.20min; m/z (ESI-) 355 (M-H) (ESI+) 357 (MH+).
Figure imgf000087_0001
Figure imgf000087_0002
Figure imgf000088_0001
Figure imgf000088_0002
Figure imgf000088_0003
Figure imgf000089_0001
Svnthesis 2-1-A 6-Chloropyrazin-2-amine
Figure imgf000090_0001
2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous ammonia (28%, 10 mL) and heated to 100°C overnight in a sealed tube. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave the title compound as a white solid (2.28 g, 17.6 mmol, 91%). 1H NMR (d6-DMSO, 400 MHz) δ 7.80 (d, 1 H1 J = 0.4 Hz), 7.70 (d, 1 H, J = 0.4 Hz), 6.9 (br s, 2H). LC-MS (2) rt 1.05 min; m/z (ESI+) 130/132.
Synthesis 2-1 -B 5-bromo-6-chloropyrazin-2-amine
Figure imgf000090_0002
6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in dichloromethane (60 mL) and cooled to O°C. N-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0°C for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25% ethyl acetate-hexane, gave the title compound as a yellow solid (1.69 g, 8.16 mmol, 42%). 1HMR (d6-DMSO, 400 MHz) δ 7.65 (s, 1H), 7.1 (br s, 2H). LC-MS (1) rt 1.46 min; m/z (ESI-) 205 (M-H).
Synthesis 2-1 -C
5-amino-3-chloropyrazine-2-carbonitrile
Figure imgf000090_0003
A mixture of 5-bromo-6-chloropyrazin-2-amine (1.00 g, 4.8 mmol), copper (I) iodide (914 mg, 4.8 mmol), 18-crown-6 (95 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium (0) (83 mg, 0.072 mmol) was suspended in dry DMF (20 mL) and a stream of nitrogen was passed through it for 5 minutes. Potassium cyanide (312 mg, 4.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, then refluxed at 200°C for 3 hours. The mixture was cooled and diluted with EtOAc and absorbed onto silica gel (10 g). DMF was removed by evaporation in a Genevac evaporator. The product was purified by flash chromatography, eluting with 1 :1 ethyl acetate-hexane, to yield the title compound as a yellow solid (607 mg, 3.93 mmol, 82%). 1H NMR (d6-DMSO, 400 MHz) δ 8.1 (br s, 2H), 7.87 (s, 1H). LC-MS (1) Rt = 1.20 min; m/z (ESI-) 153 (M-H). Svnthesis 2-1-D
5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile
Figure imgf000091_0001
1-(Dimethylamino)propan-2-ol (187 mg, 1.81 .mmol) was added to a stirred suspension of sodium hydride (123 mg, 60% in mineral oil, 1.81 mmol) in 1 ,4-dioxane. After 30 minutes, 5-amino-3-chloropyrazine-2-carbonitrile (140 mg, 0.906 mmol) was added. The vial was capped and the reaction mixture was heated to 100°C overnight. The reaction mixture was concentrated, diluted with methanol and adsorbed onto an SPE (TsOH) cartridge (pre-conditioned with methanol). The cartridge was rinsed with methanol and the product was eluted with 2 M NH3 in methanol. The basic fractions were concentrated to give the title compound as an orange oil which was used without further purification (79.2 mg, 0.358 mmol, 40%). LC-MS (1) Rt = 1.33 m/z (ESI+) 222 (MH+).
The following intermediates were prepared using methods analogous to those described in Synthesis 2-1 , replacing 1-(dimethylamino)propan-2-ol with the appropriate alcohols in Synthesis 2-1 -D. For the N-Boc protected compounds, the SPE step was replaced by an aqueous workup, extracting into ethyl acetate.
Figure imgf000091_0002
Figure imgf000092_0002
The following intermediate was prepared using a method analogous to that described in Synthesis 2-1 -D, replacing 5-amino-3-chloropyrazine-2-carbonitrile with 2-amino-6- chloropyrazine and replacing 1-(dimethylamino)propan-2-ol with tert-butyl 4- (hydroxymethyl)piperidine-1-carboxylate.
Figure imgf000092_0003
Synthesis 2-13
5-Amino-3-methoxypyrazine-2-carbonitrile
Figure imgf000092_0001
Sodium methoxide (70 mg, 1.29 mmol) was added to a stirred solution of 5-amino-3- chloropyrazine-2-carbonitrile (100 mg, 0.647 mmol) in dioxane (1 ml_). The reaction mixture was heated in a sealed tube at 90°C overnight. The solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give the title compound (32 mg, 0.213 mmol, 33%). LC-MS (3) Rt = 0.96 min; m/z (ESI+) 151 (M+H+).
Synthesis 2-14 5-Amino-3-(cyclopropylmethoxy)pyrazine-2-carbonitrile
Figure imgf000093_0001
To a solution of sodium hydride (93 mg, 3.882 mmol) in dioxane (4 ml.) was added cyclopropylmethanol (280 mg, 3.882 mmol) dropwise. The solution was stirred for 30 minutes and then δ-amino-S-chloropyrazine^-carbonitrile (300 mg, 1.941 mmol) was added and the reaction mixture heated at 90°C for 14 hours. The reaction mixture was poured into aqueous HCI (1 M) and extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to dryness to give the title compound (305 mg, 1.605 mmol, 83%) which was used in subsequent steps without further purification. LC-MS (3) Rt = 1.49 min; m/z (ESI+) 191 (M+H+).
The following intermediates were prepared using a method analogous to that described in Synthesis 2-14, replacing cyclopropylmethanol with the appropriate alcohol.
Figure imgf000093_0003
Synthesis 3-A 2-Chloro-6-(cyanomethyl)benzonitrile
Figure imgf000093_0002
Sodium hydride (60% in mineral oil, 5.00 g, 129 mmol) was stirred in DMF (30 ml_) and cooled to 0°C. Methyl cyanoacetate (12.7 g, 129 mmol) in DMF (10 ml_) was added dropwise and the reaction mixture was allowed to warm to room temperature for 1 hour. 2-Chloro-6-fluorobenzonitrile (10.00 g, 64.3 mmol) was added portionwise. The reaction mixture was heated to 50°C for 4 hours. The mixture was diluted with 2 M HCI and extracted with ethyl acetate (x 3). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated to give an orange oil. LC-MS (1) Rt = 1.29 min; m/z (ESI-) 233 (M-H).
The intermediate was immediately stirred in DMSO (18 ml.) and water (2 ml_) and heated to reflux for 6 hours. Water was added to the cooled reaction mixture and the resulting yellow solid was collected. The solid was triturated in ether and filtered to give the title compound as an off-white solid (6.46 g, 36.6 mmol, 60%). 1H NMR (d6-DMSO, 400 MHz) δ 7.81-7.75 (m, 2H), 7.65-7.62 (m, 1 H), 4.35 (s, 2H). LC-MS (1) Rt = 1.74 min; m/z (ESI-) 175 (M-H).
Synthesis 3-B
N-(1-Bromo-8-chloroisoquinolin-3-yl)acetamide
Figure imgf000094_0001
2-Chloro-6-(cyanomethyl)benzonitrile (3.12 g, 17.7 mmol) was added to a solution of HBr in acetic acid (20 mL) and stirred at room temperature overnight. The reaction mixture was added drop wise to a saturated solution of NaHCO3. The resulting precipitate was collected by filtration to give a yellow solid, which was stirred in dichloromethane (100 mL). Triethylamine (3.7 mL, 26.5 mmol) and acetyl chloride (1.9 mL, 26.7 mmol) were added and the reaction mixture was stirred overnight at room temperature. Solvents were evaporated and residue was triturated with water, then ether, to the title compound as a pale yellow solid (2.67 g, 8.91 mmol, 51%). 1H NMR (d6-DMSO, 400 MHz) δ 8.47 (s, 1 H), 8.00 (dd, 1 H, J = 8.6, 1.3 Hz), 7.74-7.72 (m, 1 H), 7.67-7.64 (m, 1 H), 2.14 (s, 3H). LC-MS (1) Rt = 2.05 min; m/z (ESI+) 299 (MH+).
Synthesis 3-C 8-Chloroisoquinolin-3-amine
Figure imgf000094_0002
N-(1-Bromo-8-chloroisoquinolin-3-yl)acetamide (1.00 g, 3.33 mmol), potassium carbonate (0.508 mg, 3.67 mmol), triphenylphosphine (35 mg, 0.134 mmol) and palladium acetate (7.49 mg, 0.033 mmol) were stirred in 1-butanol (10 mL) with nitrogen bubbling through it for 10 minutes. Butanol (5 mL) was added to the reaction mixture, which was then heated overnight at 100°C in a sealed vial. The reaction mixture was cooled, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give an orange solid. Flash chromatography on silica (20 g), eluting with 15-60% ethyl acetate-hexane, gave the title compound as a yellow solid (333mg, 1.51 mmol, 45%). LC-MS (1) Rt = 1.68 min; m/z (ES+) 221/223.
The intermediate was suspended in 2 M HCI and heated at 100°C for 2 hours. The reaction mixture was neutralised with saturated sodium bicarbonate solution and the aqueous solution was extracted twice with ethyl acetate. The organic extracts were dried and concentrated to give 8-chloroisoquinolin-3-amine (247 mg, 1.38 mmol, 92%) as a yellow solid. 1H NMR (d6-DMSO, 400 MHz) δ 9.02 (br s, 1 H), 7.51 (d, 1H, J = 8.4 Hz), 7.39 (dd, 1 H, J = 8.3, 7.2 Hz), 7.23 (dd, 1H1 J = 7.1 , 1.0 Hz), 6.65 (s, 1 H), 6.22 (br s. 2H). LC-MS (1) Rt = 1.63 min; m/z (ESI-) 179 (M-H).
Synthesis 3-D
3,8-Dichloroisoquinoline
Figure imgf000095_0001
8-Chloroisoquinolin-3-amine (724 mg, 4.05 mmol) was suspended in 10 M HCI and cooled to O°C. Sodium nitrite (336 mg, 4.86 mmol) was added in portions over 10 minutes. The reaction mixture was stirred for 2 hours, slowly warming to room temperature over an additional 1 hour. After 3 hours, the mixture was poured cautiously into saturated sodium bicarbonate solution, and extracted into ethyl acetate. The organic extract was washed with brine, dried (Na2SO4) and concentrated. Flash chromatography on silica, eluting with dichloromethane, gave the title compound as a white solid (362 mg, 1.83 mmol, 45%). 1H NMR (d6-DMSO, 400 MHz) δ 9.40 (br t, 1 H, J = 0.8 Hz), 8.20 (br s, 1 H), 8.00-7.98 (m, 1H), 7.88-7.81 (m, 2H). LCMS (3) Rt = 2.49 min; m/z (ESI+) 198 (MH+).
Synthesis 4-1 -A 3-Chloroisoquinoline
Figure imgf000095_0002
3-Aminoisoquinoline (1.44 g, 10 mmol) was suspended in 10M HCI (5 mL) and cooled to 0°C. Sodium nitrite (689 mg, 10 mmol) was added in portions over 5 minutes. The reaction mixture was stirred at 0°C for 2 hours and allowed to warm to room temperature over 1 hour. The reaction mixture was added carefully to saturated NaHCO3 solution (200 mL) and extracted into ethyl acetate. The insoluble byproduct was removed by filtration and the aqueous layer was re-extracted into ethyl acetate. The combined organics were washed with water and brine, dried (Na2SO4) and concentrated to a brown oil which solidified on standing. Flash chromatography on silica, eluting with dichloromethane, gave the title compound as a white solid (827 mg, 5.05 mmol, 51%). 1H NMR (Cl6-DMSO, 400 MHz) δ 9.12 (s, 1 H), 8.41 (s, 1 H), 8.12 (dd, 1 H, J = 7.5, 1.0 Hz), 7.93-7.90 (m, 1 H), 7.84-7.80 (m, 1 H), 7.74-7.70 (m, 1 H). LCMS (1) Rt = 1.79min; m/z (ESI+) 164 (MH+).
Synthesis 4-1 -B
3-(1-(Dimethylamino)propan-2-yloxy)-5-(isoquinolin-3-ylamino)pyrazine-2-carbonitrile
(AA-001)
Figure imgf000096_0001
A mixture of palladium (II) acetate (24 mg, O.Hmmol) and (±)-2,2"- bis(diphenylphosphino)-1 ,1"-binaphthalene (140 mg, 0.22 mmol) in toluene (2 ml_) was degassed under a stream of nitrogen gas with stirring for 10 minutes. After addition of 3- chloroisoquinoline (59 mg, 0.36 mmol), 5-amino-3-(1-(dimethylamino)propan-2- yloxy)pyrazine-2-carbonitrile (80 mg, 0.36 mmol) in DMF (0.5 ml_), and sodium tert- butoxide (42 mg, 0.43 mmol), the mixture was degassed for a further 5 minutes and then heated at 140°C for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using a MP-TsOH cartridge, washing with methanol and then eluting with 2 M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. Preparative HPLC gave the title compound (8.9 mg, 0.026 mmol, 7%). 1H NMR (d6-DMSO, 400 MHz) δ 9.22 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1 H), 8.09 (d, 1H1 J = 9.1 Hz), 7.84 (d, 1 H1 J = 8.1 Hz), 7.77-7.73 (m, 1 H), 7.58-7.54 (m, 1 H), 5.53-5.49 (m, 1H), 2.67-2.63 (m, 1 H), 2.34-2.32 (m, 1 H), 2.21 (s, 6H), 1.46 (d, 3H, J = 6.3 Hz). LC-MS (2) Rt = 2.93 min m/z (ESI-) 347 (M-H).
The following compounds were prepared using methods analogous to those described in Synthesis 4-1 -B replacing 3-chloroisoquinoline with the appropriate aryl halide, and replacing 5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile with the appropriate aminopyrazine.
Figure imgf000096_0002
Figure imgf000097_0001
Figure imgf000097_0002
Figure imgf000097_0003
Figure imgf000098_0001
Figure imgf000098_0002
Figure imgf000098_0003
Figure imgf000099_0002
Figure imgf000099_0003
Synthesis 5-1
(R)-5-(8-Chloroisoquinolin-3-ylamino)-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile
(AA-008)
Figure imgf000099_0001
A mixture of tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol) and 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (29 mg, 0.05 mmol) in toluene (1.5 mL) was degassed under a stream of nitrogen gas with stirring for 10 minutes. 3,8-Dichloroisoquinoline (50 mg, 0.252 mmol), (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine- 2-carbonitrile (85 mg, 0.278 mmol) in DMF (0.5 mL) and caesium carbonate (165 mg, 0.505 mmol) weer added and the mixture was degassed for a further 5 minutes, then heated at 130°C for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using a MP-TsOH cartridge, washing with methanol and then eluting with 2 M ammonia in methanol. The combined basic fractions were concentrated in vacuo. Preparative HPLC gave (R)-5-(8-chloroisoquinolin-3- ylamino)-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile (3.8 mg, 0.01 mmol, 4%). 1H NMR (d4-Me0D) δ 9.42 (d, 1 H, J = 0.9 Hz), 8.52 (s, 1H), 8.32 (d, 1 H, J = 5.3 Hz), 7.85 (d, 1 H, J = 8.3 Hz), 7.66-7.62 (m, 1H), 7.59-7.57 (m, 1H), 5.89-5.86 (m, 1H), 3.67-3.65 (m, 2H), 3.50-3.46 (m, 2H), 2.52-2.47 (m, 2H). LC-MS (2) Rt = 2.65 min; m/z (ESI-) 365 (M-H).
The following compounds were prepared using methods analogous to those described in Synthesis 5-1 , replacing 3,8-dichloroisoquinoline with the appropriate aryl halide and replacing (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile with the appropriate aminopyrazine.
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000102_0002
Figure imgf000102_0003
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000104_0001
Figure imgf000104_0002
Synthesis 6
5-(6,8-Dimethoxyisoquinolin-3-ylamino)pyrazine-2-carbonitrile (AA-011)
Figure imgf000104_0003
The title compound was prepared according to the method described in Synthesis 4-1 -B from 2-amino-5-cyanopyrazine and 3-bromo-6,8-dimethoxyisoquinoline. The 3-bromo- 6,8-dimethoxyisoquinoline was prepared as described in White et al., 1967. 1H NMR (d6- DMSO, 400 MHz) δ 10.98 (s, 1 H), 9.12 (s, 1 H), 8.80 (s, 1 H), 8.72 (s, 1 H), 8.34 (s, 1 H), 6.86 (s, 1 H), 6.57 (s, 1 H), 3.98 (s, 3H), 3.92 (s, 3H). LCMS (2) Rt = 2.88min; m/z (ESI-) 306 (M-H); (ESI+) 308 (MH+). Svnthesis 7-1-A
N4-(4-methoxybenzyl)-6-bromopyridine-3,4-diamine
Figure imgf000105_0001
Tin (II) chloride dihydrate (4.37 g, 19.4 mmol) was added portionwise to N-(4- methoxybenzyl)-2-bromo-5-nitropyridin-4-amine (1.31 g, 3.87 mmol) in absolute EtOH (10 ml.) at room temperature. The mixture was then heated at 70°C for 2 hours before being concentrated in vacuo. The residue was suspended in a mixture of ethyl acetate and saturated sodium bicarbonate solution and filtered. The insoluble solids were washed with EtOAc. The aqueous phase was re-extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give the title compound as a brown solid (1.05g, 3.41 mmol, 88%). 1H NMR (d6-DMSO, 400 MHz) δ 7.40 (s, 1 H), 7.30 (d, 2H, 8.6 Hz), 6.90 (d, 2H, 8.6 Hz), 6.45 (s, 1H), 6.3 (br t, 1H, 5.5 Hz), 4.85 (br s, 2H), 4.3 (d, 2H, 5.5 Hz), 3.75 (s, 3H). LCMS (1) Rt = 1.77min; m/z (ESI-) 306, 308; (ESI+) 308, 310.
Synthesis 7-1 -B
1 -(4-methoxybenzyl)-6-bromo-1 H-imidazo[4,5-c]pyridine
Figure imgf000105_0002
Acetic anhydride (1.28 ml_, 13.6 mmol) was added to a solution of N4-(4-methoxybenzyl)- 6-bromopyridine-3,4-diamine (1.05 g, 3.41 mmol) in triethylorthoformate (13 mL). The mixture was heated at 100°C for 18 hours and then concentrated to give the title compound as a brown oil (1.18 g, quantitative). 1H NMR (d6-DMSO, 400 MHz) δ 8.75 (s, 1 H), 8.60 (s, 1 H), 8.00 (s, 1 H), 7.35 (d, 2H, J = 8.8 Hz), 6.90 (d, 2H, J = 8.8 Hz), 5.45 (s, 2H), 3.70 (s, 3H). LCMS (2) Rt = 2.27 min; m/z (ESI+) 318, 320 (MH+). Svnthesis 7-1-C
5-(1-(4-methoxybenzyl)-1 H-imida2θ[4,5-c]pyridin-6-ylamino)pyra2ine-2-carbonitrile
Figure imgf000106_0001
Palladium (II) acetate (3.5 mg, 16 μmol) was added to (±)-2,2"-bis(diphenylphosphino)- 1 ,1"-binaphthalene (59 mg, 94 μmol) in DMF/toluene (1 :2) and the resulting mixture was degassed under a stream of nitrogen gas for 10 minutes. 2-Amino-5-cyanopyrazine (19 mg, 0.16 mmol), sodium tert-butoxide (45 mg, 0.47 mmol) and 1-(4-methoxybenzyl)-6- bromo-1 H-imidazo[4,5-c]pyridine (50 mg, 0.16 mmol) were added and the mixture was degassed for a further 5 minutes before heating at 15O°C for 30 minutes using microwave irradiation. The reaction mixture was partitioned between water and dichloromethane. The aqueous phase extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The residue was dissolved in methanol, passed through a PS-Thiol column and concentrated. The product was purified using preparative HPLC to give the title compound (22.4 mg, 40%). 1H NMR (d6-DMSO, 400 MHz) δ 10.84 (br s, 1 H), 8.77 (d, 1 H, J = 1.3 Hz), 8.74 (m, 2H), 8.49 (s, 1 H), 8.17 (s, 1 H), 7.34 (m, 2H), 5.41 (s, 2H), 3.72 (s, 3H). LCMS (2) Rt = 2.32 min; m/z (ESI+) 358 (MH+), (ESP) 356 (M- H).
Synthesis 7-1 -D
5-(1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile (BB-012)
Figure imgf000106_0002
5-(1 -(4-Methoxybenzyl)-1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile (10.6 mg, 30 μmol) was treated with TFA at 80°C over 30 minutes. Isolation by SPE on a MP- TsOH cartridge, eluting with 2N ammonia in methanol, followed by concentration, gave the title compound as a white solid (7.02 mg, 100%). 1H NMR (d6-DMSO, 400 MHz) δ 12.79 (br s, 1 H), 10.85 (br s, 1H), 8.76 (s, 2H), 8.75 (s, 1 H), 8.35 (s, 1H), 8.26 (s, 1 H). LCMS (2) Rt = 1.36 min; m/z (ESI+) 238 (MH+), (ESI-) 236 (M-H). The following compounds were prepared using methods analogous to those described in Synthesis 7-1 -C and 7-1 -D, replacing 2-amino-5-cyanopyrazine with the appropriate 2-aminopyrazine in Synthesis 7-1 -C.
Figure imgf000107_0002
Figure imgf000107_0003
Synthesis 8
5-(1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carboxamide (BB-015)
Figure imgf000107_0001
5-(1-(4-Methoxybenzyl)-1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbo-nitrile (0.16 mmol) was treated overnight with trifluoroacetic acid at 80°C. The solution was evaporated to dryness and the residue was purified using preparative HPLC to give the title compound (3.23 mg, 8%). 1H NMR (d6-DMSO, 400 MHz) δ 12.68 (br s, 1 H), 10.46 (br s, 1 H), 8.76 (d, 1 H, J = 1.2 Hz), 8.72 (d, 2H, =1.2 Hz), 8.28 (br s, 2H), 7.90 (s, 1H), 7.51 (s, 1 H). LCMS (2) Rt = 1.02 min; m/z (ESI+) 256 (MH+), (ESI-) 254 (M-H).
Synthesis 9-1 -A
2-(6-bromo-1 H-imidazo[4,5-c]pyridin-1-yl)-N,N-dimethylethanamine
Figure imgf000108_0001
The title compound was prepared using methods analogous to those described in Synthesis 1-1-A, 7-1-A, and 7-1-B, replacing 4-methoxybenzylamine with N1, N1- dimethylethane-1,2-diamine in Synthesis 1-1-A. 1H NMR (d6-DMSO, 400 MHz) δ 8.75 (s, 1 H), 8.40 (s, 1 H), 8.05 (s, 1 H), 4.35 (t, 2H, J = 6.0 Hz), 2.60 (t, 2H, J = 6.0 Hz), 2.15 (s, 6H). LC-MS (1) Rt = 1.24 min; m/z (ESI+) 269 & 271 (MH+).
Synthesis 9-1 -B 5-(1-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile
(BB-016)
Figure imgf000108_0002
The title compound was prepared using the methods analogous to those described in Synthesis 7-1 -C. 1H NMR (d6-DMSO, 400 MHz) δ 10.88 (br s, 1 H), 8.78 (s, 1 H), 8.73- 8.75 (m, 2H), 8.31 (s, 1 H), 8.21 (s, 1 H), 8.16 (s, 1 H), 4.31 (t, 2H, J = 6.1 Hz), 2.65 (t, 2H, J = 6.1 Hz), 2.19 (s, 6H). LCMS (2) Rt = 1.71 min; m/z (ESI-).307 (M-H); (ESI+) 309 (MH+).
Synthesis 9-2-A 6-Bromo-1-methyl-1 H-imidazo[4,5-c]pyridine
Figure imgf000108_0003
The title compound was prepared using methods analogous to those described in Synthesis 1-1-A, 7-1-A, and 7-1-B, replacing 4-methoxybenzylamine with methylamine in Synthesis 1-1-A. LC-MS (1) Rt = 1.08 min; m/z (ESI+) 212 & 214 (MH+). Svnthesis 9-2-B
5-(1-MethyI-1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile (BB-017)
Figure imgf000109_0001
The title compound was prepared using methods analogous to those described in Synthesis 7-1 -C. 1H NMR (d6-DMSO, 400 MHz) δ 10.83 (br s, 1 H), 8.70 (m, 2H), 8.69 (s, 1 H), 8.22 (S, 1 H), 8.11 (s, 1 H), 3.77 (s, 3H). LCMS (2) Rt = 1.53 min; m/z (ESI+) 252 (MH+), (ESI-) 250 (M-H).
Synthesis 9-3-A tert-Butyl 4-((6-bromo-1H-imidazo[4,5-c]pyridin-1-yl)methyl)piperidine-1-carboxylate
Figure imgf000109_0002
The title compound was prepared using methods analogous to those described in Synthesis 1-1 -A, 7-1 -A, and 7-1 -B, replacing 4-methoxybenzylamine with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate in Synthesis 1-1 -A. LC-MS (1) Rt = 1.91 min; m/z (ESI+) 395 & 397 (MH+).
Synthesis 9-3-B
5-(1-(piperidin-4-ylmethyl)-1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile
(BB-018)
Figure imgf000109_0003
The title compound was prepared using methods analogous to those described in Synthesis 7-1 -C and 7-1 -D. 1H NMR (d6-DMSO, 400 MHz) δ 10.87 (br s, 1 H), 8.80 (d, 1 H, J = 1.2 Hz), 8.77 (d, 1 H, =1.2 Hz), 8.40 (s, 1 H), 8.34 (s, 1 H), 8.16 (s, 1H), 4.16 (m, 1 H), 3.11-3.04 (m, 2H), 2.61-2.54 (m, 3H), 2.02 (m, 1 H), 1.59-1.52 (m, 2H), 1.41-1.21 (m, 2H). LCMS (2) Rt = 1.47 min; m/z (ESI+) 335 (MH+), (ESO 333 (M-H). Svnthesis 9-4-A tert-Butyl 2-(6-bromo-1 H-imidazo[4,5-c]pyridin-1 -yl)ethylcarbamate
Figure imgf000110_0001
The title compound was prepared using methods analogous to those described in Synthesis 1-1 -A, 7-1 -A and 7-1 -B, replacing 4-methoxybenzylamine with tert-butyl 2-aminoethylcarbamate in Synthesis 1-1 -A. LC-MS (1) Rt = 1.55 min; m/z (ESI+) 341 & 343 (MH+).
Synthesis 9-4-B
5-(1-(2-Aminoethyl)-1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile (BB-019)
Figure imgf000110_0002
The title compound was prepared using methods analogous to those described in Synthesis 7-1 -C and 7-1 -D. 1H NMR (d6-DMSO, 400 MHz) δ 10.87 (br s, 1H), 8.79 (d, 1 H, 1.2Hz), 8.76 (d, 1 H, J = 1.2 Hz), 8.31 (s, 1 H), 8.30 (s, 1 H), 8.17 (s, 1H), 4.21 (t, 2H, J = 6 Hz), 2.99 (t, 2H, J = 6 Hz). LCMS (2) Rt = 1.29 min; m/z (ESI+) 281 (MH+), (ESI-) 279 (M-H).
Synthesis 9-5-A tert-Butyl 3-((6-bromo-1H-imidazo[4,5-c]pyridin-1-yl)methyl)piperidine-1-carboxylate
Figure imgf000110_0003
The title compound was prepared using methods analogous to those described in Synthesis 1-1 -A, 7-1 -A and 7-1 -B, replacing 4-methoxybenzylamine with tert-butyl 3- (aminomethyl)piperidine-1-carboxylate in Synthesis 1-1 -A. LC-MS (1) Rt = 2.57 min; m/z (ESI+) 395 & 397 (MH+). Svnthesis 9-5-B
5-(1-(Piperidin-3-ylmethyl)-1H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile
(BB-020)
Figure imgf000111_0001
The title compound was prepared using methods analogous to those described in
Synthesis 7-1-C and 7-1-D. 1H NMR (d6-DMSO, 400 MHz) δ 10.88 (br s, 1 H), 8.80-8.77 (m, 3H), 8.34 (s, 1 H), 8.32 (s, 1 H), 8.17 (s, 1 H), 4.20-4.16 (m, 2H), 2.99-2.86 (m, 3H), 2.61-2.42 (m, 2H), 2.10 9s, 1H), 1.66 (m, 2H), 1.48-1.36 (m, 1 H), 1.41-1.26 (m, 1 H). LCMS (2) Rt = 1.73 min; m/z (ESI+) 335 (MH+), (ESY) 333 (M-H).
Synthesis 9-6-A (S)-tert-Butyl 3-(6-bromo~1 H-imidazo[4,5-c]pyridin-1 -yl)piperidine-1 -carboxylate
Figure imgf000111_0002
The title compound was prepared using methods analogous to those described in Synthesis 1-1 -A, 7-1 -A and 7-1 -B, replacing 4-methoxybenzylamine with (S)-tert-butyl 3- aminopiperidine-1 -carboxylate in Synthesis 1-1-A. LC-MS (1) Rt = 1.88 min; m/z (ESI+) 381 & 383 (MH+).
Synthesis 9-6-B (S)-5-(1-(Piperidin-3-yl)-1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile
(BB-021)
Figure imgf000111_0003
The title compound was prepared using methods analogous to those described in Synthesis 7-1-C and 7-1-D. 1H NMR (d6-DMSO, 400 MHz) δ 10.86 (br s, 1H), 8.81-8.76 (m, 3H), 8.52 (s, 1 H), 8.21 (m, 2H)1 4.38-4.30 (m, 1 H), 3.22-3.16 (m, 1 H), 2.98-2.86 (m, 2H), 2.63-2.54 (m, 1 H), 2.17-1.98 (m, 2H), 1.81-1.74 (m, 1H), 1.67-1.56 (m, 1H). LCMS (2) Rt = 1.62 min; m/z (ESI+) 321 (MH+), (ESI-) 319 (M-H).
Synthesis 9-7-A tert-Butyl 4-(6-bromo-1 H-imidazo[4,5-c]pyridin-1 -yl)piperidine-1 -carboxylate
Figure imgf000112_0001
The title compound was prepared using methods analogous to those described in Synthesis 1-1 -A, 7-1 -A and 7-1 -B, replacing 4-methoxybenzylamine with tert-butyl 4- aminopiperidine-1 -carboxylate in Synthesis 1-1 -A. LC-MS (1) Rt = 1.87 min; m/z (ESI+) 381 & 383 (MH+).
Synthesis 9-7-B 5-(1 -(Piperidin-4-yl)-1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile (BB-022)
Figure imgf000112_0002
The title compound was prepared using methods analogous to those described in
Synthesis 7-1 -C and 7-1 -D. 1H NMR (d6-DMSO, 400 MHz) δ 10.84 (br s, 1H), 8.81 (m, 1 H), 8.78-8.76 (m, 2H), 8.45 (s, 1 H), 8.25 (s, 1 H), 8.22 (s, 1 H), 4.48-4.39 (m, 1 H), 3.20- 3.13 (m, 2H), 2.79-2.70 (m, 2H), 2.06-1.93 (m, 4H). LCMS (2) Rt = 1.65 min; m/z (ESI+) 321 (MH+), (ESI-) 319 (M-H).
Synthesis 9-8-A (R)-tert-Butyl 3-(6-bromo-1 H-imidazo[4,5-c]pyridin-1-yl)piperidine-1 -carboxylate
Figure imgf000112_0003
The title compound was prepared using methods analogous to those described in
Synthesis 1-1 -A, 7-1 -A and 7-1 -B, replacing 4-methoxybenzylamine with (R)-tert-butyl 3- aminopiperidine-1 -carboxylate in Synthesis 1-1 -A. LC-MS (1) Rt = 1.92 min; m/z (ESI+) 381 & 383 (MH+). Svnthesis 9-8-B
(R)-5-(1-(Piperidin-3-yl)-1 H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile
(BB-023)
Figure imgf000113_0001
The title compound was prepared using methods analogous to those described in
Synthesis 7-1 -C and 7-1-D. 1H NMR (d6-DMSO, 400 MHz) δ 10.86 (br s, 1H), 8.81 (m, 1 H), 8.78-8.76 (m, 2H), 8.51 (s, 1 H), 8.26 (s, 1H), 8.21 (br s, 1 H), 4.37-4.30 (m, 1 H), 3.20-3.15 (m, 2H), 2.98-2.88 (m, 2H), 2.16-2.00 (m, 2H), 1.80-1.73 (m, 1 H), 1.65-1.55 (m, 1 H). LCMS (2) Rt = 1.57 min; m/z (ESI+) 321 (MH+), (ESI-) 319 (M-H).
Synthesis 10-1
5-(3H-lmidazo[4,5-c]pyridin-6-ylamino)-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2- carbonitrile (BB-024)
Figure imgf000113_0002
A mixture of tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.016 mmol) and 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (18 mg, 0.031 mmol) in toluene (1.5 ml_) was degassed under a stream of nitrogen gas with stirring for 10 minutes. After addition of 1-(4-methoxybenzyl)-6-bromo-1 H-imidazo[4,5-c]pyridine (50 mg, 0.157 mmol), 5- amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile in DMF (0.5 ml.) (38 mg, 0.173 mmol) and caesium carbonate (102 mg, 0.314 mmol), the mixture was degassed for a further 5 minutes and then heated at 120X for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using a MP-TsOH cartridge, washing with methanol and then eluting with 2 M ammonia in methanol. The combined basic fractions were concentrated in vacuo. Preparative HPLC gave the title compound (10.8 mg, 0.032 mmol, 20%). 1H NMR (de-DMSO, 400 MHz) δ 10.82 (br s, 1 H), 8.75 (d, 1 H, J = 1.0 Hz), 8.36 (br s, 1 H), 8.28 (br s, 1 H), 8.21 (s, 1 H), 8.15 (br s, 1 H), 5.48-5.41 (m, 1 H), 2.62 (dd, 1 H, J = 13.1 , 7.1 Hz), 2.5-2.46 (m, partly obscured by DMSO, 1 H), 2.19 (s, 6H), 1.41 (d, 3H, J = 6.3 Hz). LC-MS (2) Rt = 1.78 min; m/z (ESI-) 337 (M-H).
The following compounds were prepared using methods analogous to those described in Synthesis 10-1 , replacing 5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2- carbonitrile with the appropriate 2-aminopyrazine.
Figure imgf000114_0001
Figure imgf000114_0002
Figure imgf000114_0003
Svnthesis 10-5
5-(3H-lmidazo[4,5-c]pyridin-6-ylamino)-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2- carbonitrile (BB-028)
Figure imgf000115_0001
The title compound was prepared using methods analogous to those described in Synthesis 10-1 , replacing 5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2- carbonitrile with tert-butyl 4-((6-amino-3-cyanopyrazin-2-yloxy)methyI)piperidine-1- carboxylate and replacing 1-(4-methoxybenzyl)-6-bromo-1 H-imidazo[4,5-c]pyridine with 6-bromo-1-methyl-1 H-imidazo[4,5-c]pyridine. 1H NMR (d6-DMSO, 400 MHz) δ 8.76 (d, 1 H1 J = 0.8 Hz), 8.35 (br s, 1 H), 8.29 (br s, 1 H), 4.39 (d, 2H, J = 6.8), 3.84 (s, 3H), 3.01 (d, 2H, J = 12.9 Hz), 2.58-2.52 (m, 2H), 1.96-1.94 (m, 1 H), 1.75 (d, 2H, J = 12.6 Hz), 1.26-1.22 (m, 2H). LC-MS (2) Rt = 1.79 min; m/z (ESI+) 365 (MH+).
Synthesis 11-1 -A N-(2-Bromobenzyl)-2,2-diethoxyacetamide
Figure imgf000115_0002
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (1.15 g, 6.00 mmol) was added to a mixture of 2-bromobenzylamine (0.744 g, 4.00 mmol), sodium 2,2-diethoxyacetate (0.816 g, 4.80 mmol), 1 -hydroxybenzotriazole hydrate (0.919 g, 6.00 mmol) and Hunig's base (1.53 mL, 8.80 mmol) in DMF (10 ml.) with stirring. After 18 hours at room temperature, the mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with 2 M HCI, saturated sodium bicarbonate solution and brine, then dried (Na2SO4) and concentrated to a viscous colourless oil (1.02 g, 81%). LC-MS (1) Rt = 2.23 min; m/z (ESI+) 316 & 318 (M+H+).
Synthesis 11-1 -B
8-Bromoisoquinolin-3-yl trifluoromethanesulfonate
Figure imgf000115_0003
The title compound was prepared using a method analogous to that described in Durola et al., 2007.
Synthesis 11-1 -C 5-(8-Bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (AA-017)
Figure imgf000116_0001
The title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3- yloxy)pyrazine-2-carbonitrile and 8-bromoisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline. 1H NMR (DMSO, 400MHz) δ 11.30 (br s, 1 H), 9.40 (s, H), 8.95 (s, H), 8.80 (s, H), 8.60 (s, H), 8.05 (d, 1 H, J = 8.5Hz), 7.95 (d, 1 H, J = 7.5Hz), 7.75 (dd, 1H, J = 8.5Hz, 7.5Hz). LC-MS (2) Rt = 3.21 min, m/z (ESI+) 326 & 328 (MH+).
The following compounds were prepared using methods analogous to those described in Synthesis 11-1 -C, replacing 2-amino-5-cyanopyrazine with the appropriate 3-alkoxy substituted 5-aminopyrazine-2-carbonitrile and reacting with the appropriate 8-substituted isoquinolin-3-yl trifluoromethanesulfonate.
Figure imgf000116_0002
Figure imgf000117_0001
Figure imgf000117_0002
Figure imgf000117_0003
Figure imgf000118_0001
Figure imgf000118_0002
Figure imgf000118_0003
Figure imgf000119_0003
Synthesis 11-10
5-(6-Chloroisoquinolin-3-ylamino)pyrazine-2-carbonitrile (AA-018)
Figure imgf000119_0001
The title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3- yloxy)pyrazine-2-carbonitrile and 6-chloroisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline. 6-Chloroisoquinolin-3-yl trifluoromethanesulfonate was prepared using methods analogous to those described in Synthesis 11-1 for 8- bromoisoquinolin-3-yl trifluoromethanesulfonate. 1H NMR (DMSO1 400MHz) δ 11.11 (s, 1H), 9.24 (s, 1H)1 8.82 (d, 1H1 J = 1.3 Hz), 8.74 (d, 1H, J = 1.3 Hz)1 8.47 (s, 1H), 8.13 (d, 1 H1 J = 8.6 Hz), 8.09 (d, 1 H1 J = 1.8 Hz)1 7.55 (dd, 1 H, J = 8.8, 2.0 Hz). LCMS (2) Rt = 3.04 min, m/z (ESI+) 282 & 284 (MH+).
Synthesis 11-11
5-(5-Bromo-8-chIoroisoquinolin-3-ylamino)pyrazine-2-carbonitrile (AA-070)
Figure imgf000119_0002
The title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3- yloxy)pyrazine-2-carbonitrile, and using 5-bromo-8-chloroisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline. 5-Bromo-8- chloroisoquinolin-3-yl trifluoromethanesulfonate was prepared using methods analogous to those described in Synthesis 11-1 for 8-bromoisoquinolin-3-yl trifluoromethanesulfonate. 1H NMR (DMSO, 400MHz) δ 11.3 (br s, 1 H), 9.42 (s, 1 H, J = 0.8 Hz), 8.85 (d, 1 H, J = 1.3 Hz), 8.81 (d, 1 H, J = 1.3 Hz), 8.79 (d, 1 H, J = 0.8 Hz), 8.07 (d, 1 H, J = 8.1 Hz), 7.58 (d, 1 H, J = 8.1 Hz). LCMS (2) Rt = 3.58 min; m/z (ESI+) 360 & 362 (M+H).
Synthesis 12 5-(8-(1 H-pyrazol-3-yl)isoquinolin-3-ylamino)pyrazine-2-carbonitrile (AA-019)
Figure imgf000120_0001
A mixture of 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (65 mg, 0.20 mmol), 1 H-pyrazol-3-yl boronic acid (33 mg, 0.30 mmol) and aqueous sodium carbonate (0.5M, 0.60 ml_, 0.30 mmol) in DMF (2 ml_) was degassed for 15 minutes before the addition of tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.10 mmol). The mixture was further degassed for 5 minuted and then heated to 140°C for 20 minutes in a microwave reactor. The cooled mixture was partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate and the combined organics were washed with water and brine, dried (Na2SO4), and passed sequentially through two PS-Thiol cartridges. The eluent was concentrated to a yellow solid which was dissolved in methanol and purified by SPE on a MP-TsOH cartridge, eluting with 2 M ammonia in methanol. Concentration of the eluent gave the required product as a light yellow solid (18 mg, 0.06 mmol, 29%). 1H NMR (DMSO, 400MHz) δ 13.25 (br s, 1 H), 11.10 (br s, 1 H), 10.00 (s, 1 H), 8.84 (s, 1 H), 8.72 (s, 1H), 8.55 (s, 1 H), 7.80-8.00 (m, 2H), 7.70-7.80 (m, 2H), 6.80 (s, 1 H). LCMS (2) Rt = 2.46 min, m/z (ESI+) 314 (MH+).
Synthesis 13-1 5-(8-(2-morpholinoethylamino)isoquinolin-3-ylamino)pyrazine-2-carbonitrile (AA-020)
Figure imgf000120_0002
The title compound was prepared using methods analogous to those described in Synthesis 5-1 , replacing 3,8-dichloroisoquinoline with 5-(8-bromoisoquinolin-3- ylamino)pyrazine-2-carbonitrile and replacing (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine- 2-carbonitrile with N-(2-aminoethyl)morpholine, and conducting the reaction at 14O°C.
1H NMR (DMSO, 400MHz) δ 10.93 (br s, 1H), 9.38 (s, 1 H), 8.80 (s, 1 H), 8.71 (s, 1 H), 8.28 (s, 1H), 7.48-7.43 (m, 1 H), 7.00 (d, 1 H, J = 8.1 Hz), 6.71-6.67 (m, 1H), 6.51 (d, 1 H, J = 7.8 Hz), 3.63-3.59 (m, 3H), 3.39-3.24 (m, 2H), 2.67-2.62 (m, partially obscured by residual water peak), 2.52-2.46 (m, partially obscured by residual solvent peak). LCMS (2) Rt = 2.62 min; m/z (ESI+) 376 (MH+). The following compounds were prepared using methods analogous to those described in Synthesis 13, using the appropriately substituted 5-(8-bromoisoquinolin-3- ylamino)pyrazine-2-carbonitrile prepared using methods analogous to those described in Synthesis 11-3 and the appropriate N-aminoalkylmorpholine.
Figure imgf000121_0001
Figure imgf000121_0002
Figure imgf000121_0003
Figure imgf000122_0003
Synthesis 14-1 5-(8-methoxyisoquinolin-3-ylamino)pyrazine-2-carbonitrile (AA-021)
Figure imgf000122_0001
Sodium methoxide (55 mg, 0.10 mmol) was added to a pre-stirred mixture of 5-(8- bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (33 mg, 0.10 mmol) and copper iodide (19 mg, 0.10 mmol) in DMF in triplicate. The three reaction mixtures were heated at 140°C for 30 minutes, 110°C for 18 hours, and 120°C for 10 minutes, respectively. The combined reaction mixtures were partitioned between ethyl acetate and water and the aqueous layer re-extracted with more ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by preparative HPLC gave the title compound (1.7 mg, 0.006 mmol, 2%). 1H NMR (DMSO, 400MHz) δ 9.33 (s, 1 H), 8.81 (d, 1 H, J = 1.3 Hz), 8.71 (d, 1 H, J = 1.3 Hz), 8.43 (s, 1H), 7.64 (t, 1 H, J = 8.1 Hz), 7.43 (d, 1 H, J = 8.3 Hz), 6.97 (d, 1 H, J = 7.6 Hz), 4.01 (s, 3H). LCMS (2) Rt = 2.87 min, m/z (ESI+) 278 (MH+).
Synthesis 15-1 5-(8-(2-Hydroxyethylamino)isoquinolin-3-ylamino)pyrazine-2-carbonitrile (AA-031)
Figure imgf000122_0002
A mixture of tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.020 mmol) and 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (23 mg, 0.040 mmol) in toluene (1 mL) and DMF (1 mL) was degassed under a stream of nitrogen gas with stirring for 15 minutes. 5-(8-Bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (65 mg, 0.20 mmol), ethanolamine (61 mg, 1.00 mmol) and caesium carbonate (130 mg, 0.40 mmol) were added and the mixture was degassed for a further 5 minutes, then heated at 140°C for 40 minutes in a microwave reactor. Upon cooling the reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%) and filtered through celite. The aqueous phase was re-extracted with ethyl acetate and then the combined organic phases were washed sequentially with aqueous sodium hydrogencarbonate and brine. The organic phase was dried (Na2SO4) and passed sequentially through two PS-Thiol cartridges and concentrated to dryness. Preparative HPLC gave the title compound (8.14 mg, 0.034 mmol, 17%). 1H NMR (d6-DMSO, 400MHz) δ 10.94 (br s, 1 H)1 9.41 (s, 1 H), 8.80 (s, 1H), 8.70 (s, 1 H), 8.29 (s, 1H), 7.43- 7.46 (m, 1 H), 6.98 (d, 1 H, J = 8.4 Hz), 6.70 (br t, 1H), 6.50 (d, 1 H, J = 7.6 Hz), 4.82 (t, 1 H, J = 5.8 Hz), 3.65-3.70 (m, 2H), 3.25-3.30 (m, 2H, partially obscured by water signal). LC-MS (2) Rt = 2.27 min; m/z (ESI+) 308 (M+H).
The following compounds were prepared using methods analogous to those described in Synthesis 15-1 , using the appropriately substituted 5-(8-bromoisoquinolin-3- ylamino)pyrazine-2-carbonitrile prepared using methods analogous to those described in Synthesis 11-3, and the appropriate hydroxy or alkoxy substituted alkyl amine.
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000125_0001
Figure imgf000125_0002
Figure imgf000126_0001
Figure imgf000126_0002
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000128_0001
Figure imgf000128_0002
Figure imgf000129_0001
Figure imgf000129_0002
Figure imgf000130_0002
Figure imgf000130_0001
Figure imgf000130_0003
Figure imgf000131_0001
Figure imgf000131_0002
Figure imgf000131_0003
Svnthesis 16-1 5-(8-Aminoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (AA-061)
Figure imgf000132_0001
A mixture of tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.020 mmol) and 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (23 mg, 0.040 mmol) in toluene (1 mL) and DMF (1 mL) was degassed under a stream of nitrogen gas with stirring for 15 minutes. 5-(8-Bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (65 mg, 0.20 mmol), benzophenone imine (36 mg, 0.20 mmol) and caesium carbonate (130 mg, 0.40 mmol) were added and the mixture was degassed for a further 5 minutes, then heated at 140°C for 40 minutes in a microwave reactor. Upon cooling the reaction mixture was diluted with ethyl acetate and filtered through celite, washed sequentially with water and brine then dried (Na2SO4) and concentrated to dryness to afford a brown oil. The residue was dissolved in THF (2 mL) and treated with aqueous hydrogen chloride (2 mL, 2M) for 30 minutes and then concentrated to dryness. Preparative HPLC gave the title compound (5.64 mg, 0.022 mmol, 11%). 1H NMR (d6-DMSO, 400MHz) δ 10.90 (br s, 1 H), 9.35 (s, 1 H), 8.80 (s, 1H), 8.70 (s, 1 H), 8.25 (s, 1H), 7.40 (t, 1 H, J = 7.8, 6.8 Hz), 6.95 (d, 1 H, J = 7.8 Hz), 6.60 (d, 1H1 J = 6.8 Hz), 6.25 (s, 1H). LC-MS (2) Rt = 2.32 min; m/z (ESI+) 263 (M+H).
Synthesis 17-1
N-(3-(5-Cyanopyrazin-2-ylamino)isoquinolin-8-yl)acetamide (AA-062)
Figure imgf000132_0002
Acetyl chloride (13 mg, 0.16 mmol) was added to a solution of 5-(8-aminoisoquinolin-3- ylamino)pyrazine-2-carbonitrile (36 mg, 0.14 mmol) and diisopropylethylamine (39 mg, 0.30 mmol) in DCE (1.5 mL). The reaction mixture stirred at room temperature for
16 hours and another portion of acetyl chloride (6.5 mg, 0.08 mmol) was added. Stirring was continued for a further 24 hours. The reaction mixture was washed once with water and the organic phase was dried (Na2SO4) and concentrated to dryness. Preparative HPLC gave N-(3-(5-cyanopyrazin-2-ylamino)isoquinolin-8-yl)acetamide (13.4 mg, 0.044 mmol, 32%). 1H NMR (d6-DMSO, 400MHz) δ 11.05 (br s, 1 H), 10.20 (s, 1 H), 9.36 (s, 1 H), 8.82 (d, 1H, J = 1.2 Hz), 8.72 (d, 1H, J = 1.2 Hz), 8.48 (s, 1H), 7.65 - 7.75 (m, 3H), 2.22 (s, 3H). LC-MS (2) Rt = 1.96 min; m/z (ESI+) 305 (M+H).
The following compound was prepared using methods analogous to those described in Synthesis 17-1 , using the appropriately substituted 5-(8-aminoisoquinolin-3- yIamino)pyrazine-2-carbonitrile prepared using methods analogous to those described in Synthesis 16-1.
Figure imgf000133_0002
Synthesis 18-1 N-(3-(5-Cyanopyrazin-2-ylamino)isoquinolin-8-yl)-3-methoxypropanamide (AA-063)
Figure imgf000133_0001
To a solution of 5-(8-aminoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (36 mg, 0.14 mmol), 3-methoxypropionic acid (34 mg, 0.32 mmol), N-hydroxybenzotriazole hydrate (64 mg, 0.42 mmol) and diisopropylethylamine (78 mg, 0.60 mmol) in DMF
(1 mL), was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.42 mmol). The reaction mixture was stirred at 40°C for 48 hours and then concentrated to dryness. Preparative HPLC gave the title compound (5.7 mg, 0.016 mmol, 12%). 1H NMR (de-DMSO, 400MHz) δ 11.05 (br s, 1 H), 10.20 (s, 1 H), 9.32 (s, 1 H), 8.82 (d, 1H, J = 1.2 Hz), 8.71 (d, 1 H, J = 1.2 Hz), 8.49 (s, 1H), 7.65 - 7.75 (m, 3H), 3.71 (t, 2H, J = 6.1 Hz), 3.32 (s, 3H, obscured by water signal), 2.75 (t, 2H, J = 6.1 Hz). LC-MS (2) Rt = 2.10 min; m/z (ESI+) 349 (M+H). Svnthesis 19-1
3-(5-Cyanopyrazin-2-ylamino)-N-(2-morpholinoethyl)isoquinoline-8-carboxamide
(AA-065)
Figure imgf000134_0001
A mixture of 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (33 mg, 0.10 mmol), N-(2-aminoethyl)morpholine (26 mg, 0.20 mmol), triphenylphosphine (8 mg, 0.030 mmol), and sodium acetate (3.3 mg, 0.040 mmol) in DMF (1 mL) was degassed by bubbling N2 through the solution for 5 mins. Palladium (II) acetate (6.8 mg, 0.030 mmol) was added and the mixture degassed for a further 5 minutes. Carbon monoxide was then bubbled through the solution for 5 minutes, before the reaction vessel was sealed. The solution was stirred at 80°C under a balloon of carbon monoxide for 90 minutes and then partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%). The phases were separated and the aqueous phase washed with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate (2.5%) before being dried (Na2SO4) and then passed sequentially through two PS-Thiol cartridges and concentrated to dryness. Preparative HPLC gave the title compound (5.1 mg, 0.013 mmol, 12%). 1H NMR (d6-DMSO, 400MHz) δ 11.05 (s, 1H), 9.58 (s, 1 H), 8.83 (d, 1 H, J = 1.2 Hz), 8.73 (d, 1 H, J = 1.2 Hz), 8.63 (br t, 1 H, J = 5.8 Hz), 8.56 (s, 1 H), 8.00 (d, 1H, J = 8.4 Hz), 7.75 (dd, 1H, J = 7.1 , 8.3 Hz), 7.57 (d, 1H, J = 6.8 Hz), 3.62 - 3.68 (m, 4H), 3.46 - 3.52 (m, 2H), 2.52 - 2.58 (m, 2H), 2.46 - 2.52 (m, 4H, partially obscured by DMSO). LC-MS (2) Rt = 1.95 min; m/z (ESI+) 404 (M+H).
The following compound was prepared using methods analogous to those described in Synthesis 19-1 , using the appropriately substituted 5-(8-bromoisoquinolin-3- ylamino)pyrazine-2-carbonitrile prepared using methods analogous to those described in Synthesis 11.
Figure imgf000135_0003
Synthesis 20-1 -A
2,2-Diethoxy-N-(2-fluorobenzyl)acetamide
Figure imgf000135_0001
2-Fluorobenzylamine (2.00 g, 16.0 mmol), sodium 2,2-diethoxyacetate (3.26 g, 19.2 mmol), N-hydroxybenzotriazole hydrate (3.67 g, 24.0 mmol) and diisopropylethylamine (4.18 mL, 24.0 mmol) were stirred in DMF (20 mL) at room temperature. 1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (4.6 g, 24.0 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted water and ethyl acetate. The organic phase was washed sequentially with HCI(aq) (1 M), saturated sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated to dryness. The crude material was used directly in the following reaction.
Synthesis 20-1 -B 8-Fluoroisoquinolin-3-ol
Figure imgf000135_0002
2,2-Diethoxy-N-(2-fluorobenzyl)acetamide (4.1 g, 16.0 mmol) was stirred in concentrated sulfuric acid (10 mL) for 16 hours. The reaction mixture was poured onto ice and neutralized by the addition of ammonium hydroxide forming a precipitate which was removed by filtration. The filtrate was extracted with ethyl acetate three times, and the combined organic phases were rinsed with brine then dried (Na2SO4) and concentrated to dryness affording an oily solid. Trituration with ether afforded the title compound (1.56 g, 9.6 mmol, 60% over 2 steps). LC-MS (3) Rt = 1.00 min; m/z (ESI+) 164 (M+H).
Synthesis 20-1 -C 8-Methoxyisoquinolin-3-ol
Figure imgf000136_0001
8-Fluoroisoquinolin-3-oI (561 mg, 3.43 mmol) was dissolved in DMF (3 ml.) and sodium methoxide (828 mg, 15.33 mmol) added. The reaction mixture was heated at 9O°C for 14 hours, then diluted with methanol and absorbed onto an SPE (TsOH) cartridge. The column was rinsed with methanol and the compound was then eluted with 7 M ammonia in methanol to afford the title compound (140 mg, 0.798 mmol, 23.2%). LC-MS (2) Rt = 1.23 min; m/z (ESI+) 176 (M+H).
Synthesis 20-1 -D 8-Methoxyisoquinolin-3-yl trifluoromethanesulfonate
Figure imgf000136_0002
8-Methoxyisoquinolin-3-ol (140 mg, 0.798 mmol) was dissolved in DCM (5 mL) and N1N- diisopropylethylamine (309 mg, 2.394 mmol) and cooled to O°C. Triflic anhydride (293 mg, 1.037 mmol) was added dropwise and the reaction was warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted into DCM. The aqueous layer was re- extracted with DCM and the combined organic phases washed with brine, dried (Na2SO4) and concentrated to dryness. The product was purified by flash chromatography to afford the title compound (26.6 mg, 0.087 mmol, 11 %). LC-MS (3) Rt = 2.23 min; m/z (ESI+) 308 (M+H).
Synthesis 20-1 -E
(R)-3-(1-(Dimethylamino)propan-2-yloxy)-5-(8-methoxyisoquinolin-3-ylamino)pyrazine-2- carbonitrile (AA-067)
Figure imgf000136_0003
A mixture of tris(dibenzylideneacetone)dipalladium (0) (7.9 mg, 0.009 mmol) and 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (10 mg, 0.017 mmol) in toluene (1 mL) and DMF (1 mL) was degassed under a stream of nitrogen gas with stirring for 15 minutes. 8-Methoxyisoquinolin-3-yl trifluoromethanesulfonate (26.6 mg, 0.087 mmol), cesium carbonate (28 mg, 0.087 mmol) and (R)-5-amino-3-(1-(dimethylamino)propan-2- yloxy)pyrazine-2-carbonitriIe (19 mg, 0.087 mmol) were added and the mixture degassed for a further 5 minutes. The mixture was heated at 130°C for 30 minutes in a microwave reactor and then partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%). The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with aqueous sodium hydrogen carbonate (2.5%) and brine, then dried (Na2SO4) and passed sequentially through 2 PS-Thiol cartridges and concentrated to dryness. Preparative HPLC afforded the title compound (0.62 mg, 0.00016 mmol, 2%). 1H NMR (d6-DMSO, 400MHz) δ 9.34 (s, 1 H), 8.40 (s, 1 H), 8.23 (s, 1 H), 7.69-7.65 (m, 1 H), 7.37 (d, 1 H, J = 8.3 Hz), 6.99 (d, 1 H, J = 7.6 Hz), 5.53-5.47 (m, 1H), 4.02 (s, 3H), 2.68-2.63 (m, 1H), 2.57-2.53 (m, 1H), 2.21 (s, 6H), 1.46 (d, 3H, J = 6.3 Hz). LC-MS (2) Rt = 3.18 min; m/z (ESI+) 379 (M+H).
Synthesis 21-1 -A
Ethyl 2-(3-cyano-6-(isoquinolin-3-ylamino)pyrazin-2-yloxy)acetate (AA-068)
Figure imgf000137_0001
A mixture of tris(dibenzylideneacetone)dipalladium (0) (39 mg, 0.043 mmol) and 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (50 mg, 0.086 mmol) in toluene (1.5 mL) and DMF (1.5 mL) was degassed under a stream of nitrogen gas with stirring for
15 minutes. 3-Chloroisoquinoline (70 mg, 0.428 mmol), caesium carbonate (279 mg, 0.856 mmol) and ethyl 2-(6-amino-3-cyanopyrazin-2-yloxy)acetate (105 mg, 0.471 mmol) were added and the mixture was degassed for a further 5 minutes. The mixture was then heated at 100°C for 20 minutes, then at 13O°C for 20 minutes in a microwave reactor. The reaction mixture was partitioned between aqueous Na2HCO3 solution (2.5%) and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4), passed sequentially through two PS-Thiol cartridges and concentrated to dryness. The residue was triturated with methanol and then ether affording ethyl 2-(3-cyano-6-(isoquinolin-3-ylamino)pyrazin-2- yloxy)acetate (37 mg, 0.107 mmol, 25%). LC-MS (2) Rt 2.89 min; m/z (ESI+) 350 (M+H).
Synthesis 21-1 -B
2-(3-Cyano-6-(isoquinolin-3~ylamino)pyrazin-2-yloxy)acetic acid (AA-069)
Figure imgf000137_0002
Ethyl 2-(3-cyano-6-(isoquinolin-3-ylamino)pyrazin-2-yloxy)acetate (35 mg, 0.099 mmol) was dissolved in THF (1 ml_) and lithium hydroxide (2.4 mg, 0.099 mmol) added. The reaction was stirred at room temperature for 15 hours. Methanol (1 mL) was added and the reaction mixture was stirred for a further 24 hours and then concentrated to dryness. Purification by preparative HPLC afforded the title compound (10.8 mg, 0.0336 mmol, 34%). 1H NMR (MeOD, 400MHz) δ 9.04 (s, 1 H), 8.53 (s, 1 H), 8.14-8.10 (m, 2H), 7.97 (d, 1 H, J = 8.0 Hz), 7.72-7.67 (m, 1 H), 7.53-7.48 (m, 1H), 4.96 (br s, 2H), 2.67 (s, 1 H). LC- MS (2) Rt = 1.46 min; No ionization.
Synthesis 22-1
(R)-2-(6-(8-Chloroisoquinolin-3-ylamino)-3-cyanopyrazin-2-yloxy)-N,N-dimethylpropan-1- amine oxide (AA-071)
Figure imgf000138_0001
(R)-5-(8-Chloroisoquinolin-3-ylamino)-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2- carbonitrile (30 mg, 0.078 mmol) was dissolved in DCM (1 mL) and cooled to -10°C.
3-Chloroperoxybenzoic acid (77% wt.,12 mg, 0.086 mmol) dissolved in DCM (1 mL) was added dropwise to the solution. The reaction mixture was stirred at -1O°C for 15 minutes, and was then warmed to room temperature. The reaction mixture was diluted with water, the layers partitioned and the aqueous phase extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated to dryness. The residue was dissolved in methanol and absorbed on to an SPE (TsOH) cartridge. The cartridge was washed with methanol and the compound eluted with 2 M and 7 M ammonia in methanol. Preparative HPLC afforded the title compound (23 mg, 0.057 mmol, 73%). 1H NMR (d6-DMSO, 400MHz) δ 9.25 (s, 1 H), 8.39 (s, 1 H), 8.30 (s, 1 H), 8.12 (s, 1 H), 7.73-7.71 (m, 1 H), 7.57-7.56 (m, 1 H), 6.10-6.07 (m, 1 H), 4.16-4.10 (m, 1 H), 3.77 (br d, 1 H, J = 14 Hz), 3.43 (s, 3H), 3.28 (s, 3H), 1.44 (d, 3H, J = 6.6 Hz). LC-MS (2) Rt = 2.20 min; m/z (ESI+) 399 & 401 (M+H).
Synthesis 23-1 -A tert-Butyl 5-chloro-1 H-pyrrolo[2,3-c]pyridine-1 -carboxylate
Figure imgf000138_0002
Triethylamine (0.147 mL, 1.05 mmol) was added to a solution of 5-chloro-1 H-pyrrolo[2,3- φyridine (0.100 g, 0.655 mmol) and di-tert-butyl dicarbonate (0.215 g, 0.983 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 16 hours. The solution was washed with aqueous 0.2 M HCI and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. Purification by column chromatography gave tert-butyl 5-chloro-1 H- pyrro!o[2,3-c]pyridine-1-carboxylate (0.164 g, 0.649 mmol, 99%). LC-MS (3) Rt = 2.70 min; m/z (ESI+) 197 & 199 ((M+H-*Bu)+H).
Synthesis 23-1 -B 5-(1 H-Pyrrolo[2,3-c]pyridin-5-ylamino)pyrazine-2-carbonitrile (CC-001 )
Figure imgf000139_0001
A mixture of tert-butyl 5-chloro-1 H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.030 g, 0.119 mmol), 5-aminopyrazine-2-carbonitrile (0.017 g, 0.142 mmol), cesium carbonate (0.077 g, 0.237 mmol), Xantphos (0.011 g, 0.019 mmol) and tris(benzylideneacetone)dipalladium (0) (0.009 g, 0.010 mmol) in dioxane (0.8 mL) was degassed by bubbling argon through the mixture for 10 minutes. The sealed reaction vessel was heated to 150°C for 1 hour in a microwave reactor. The crude mixture was filtered through an SCX-2 acidic resin cartridge, eluting with 2 M ammonia in methanol. The basic filtrate was concentrated and purified by column chromatography to give the title compound (0.018 g, 0.054 mmol, 45%). LC-MS (3) Rt = 1.30 min; m/z (ESI+) 237 (M+H).
Biological Methods
Measurement of Inhibition of CHK1 Kinase Function
CHK1 kinase function was measured in a DELFIA® assay in order to monitor phosphorylation of a CDC25C peptide using a specific phospho antibody.
The enzyme reaction was carried out in polypropylene plates (Greiner) using a reaction mix (25 μL) containing enzyme and peptide mix (CHK1 , 1nM; Biotin- KKKVSRSGLYRSPSMPENLNRPR, 1 μM or 15 μL), ATP (30 μM or 5 μL) and either DMSO (2.5%) or test compound (5 μL) diluted to a give a range of concentrations (from 0 to 100 μM in 2.5% DMSO, final concentrations) in assay buffer (40 mM Tris, 40 mM NaCI, 2 mM MgCI2, 1 mM DTT and 0.1% Tween 20). The reaction mixture was incubated for 30 minutes at room temperature and then stopped by the addition of buffer (125 μL) containing 40 mM EDTA, 0.05% Tween 20, 0.1% BSA in TBS (10x concentrate, Sigma). An aliquot (100 μL) of the stopped reaction mixture was transferred to a black neutravidin- coated plate (Perbio) and incubated for 1 hour on a shaker (Titertek, Flow Laboratories) at room temperature. The plates were washed four times with wash buffer (25 mM Tris (pH 8), 150 mM NaCI, and 0.1% Tween 20) (WellWash4, Thermo Life Sciences) and incubated for 1 hour as before with an antibody mixture (100 μL) consisting of anti- phospho CDC25C (1.25 nM, #9528, Cell Signalling Technology) and europium-labelled anti-rabbit IgG (0.3 μg/mL, AD0105, PerkinElmer Life Sciences) diluted in DELFIA assay buffer (PerkinElmer Life Sciences). The plates were washed a further four times with wash buffer before the addition of enhancement solution (100 μL/well, PerkinElmer Life Sciences). The plate was read on a Victor2 1420 multilabel counter (Perkin Elmer Life Sciences) using a time-resolved measurement mode reading fluorescence at 615 nm.
Cytotoxicity Assay
HT29 colon carcinoma cells were obtained from ATCC (Rockville, MD, USA). Cells were grown in DMEM supplemented with 10% foetal calf serum and containing L-glutamine 5 mM, glucose, penicillin, and streptomycin. Cells were grown at 37°C in a dry 5% CO2 atmosphere. Cytotoxicity assays were carried out in 96-well plates using quadruplicate wells for each dose. Cells were seeded at 1.6 x 103 per well in 160 μL medium and were allowed to attach for 36 hours prior to treatment. Test compounds were dissolved in DMSO at 10 mM and serially diluted in culture medium to 5 x final concentration prior to addition in a volume of 40 μl per well. Cells were left for 4 doublings (96 hours) in the presence of the test compounds and then fixed in 10% TCA for 30 minutes, washed in water, and dried. The fixed cells were stained with Sulfurhodamine B (SRB, 0.4% in 1% acetic acid, Sigma, Dorset, UK) for 30 minutes, washed in 1% acetic acid, and dried. SRB was resolubilised in 10 mM Tris base and the OD was measured at 490 nm. Results were expressed relative to untreated controls and the concentration of compound required to inhibit growth by 50% (SRB IC50) was calculated.
Mitosis Inhibition Assay (MIA)
Checkpoint abrogation by CHK1 kinase function inhibitors in combination with genotoxic agents was assessed using a europium based ELISA assay designed to quantify the number of cells trapped in mitosis after treatment with a genotoxic agent (to induce G2 arrest) followed by a test compound in combination with nocodazole to abrogate this arrest.
HT29 cells were seeded at 104 cells per well into 96 well plates in a volume of 160 μL and left to attach for 36 hours. Etoposide (10 mM stock in DMSO) was diluted in medium to 250 μM and then 40 μL was added to appropriate wells to give a final concentration of 50 μM and incubated for 1 hour. This treatment had previously been optimised to induce a G2 arrest in 80% of cells 16 hours following treatment. After genotoxic drug exposure, the medium was removed and replaced with fresh medium (160 μL). Cells were either untreated (untreated control or etoposide pre-treatment alone), exposed to nocodazole following etoposide pre-treatment or nocodazole alone (100 ng/mL final concentration), or exposed to increasing concentrations of test compound (200 μM - 0.01 nM final concentration) in combination with nocodazole (100 ng/mL final concentration). Test compounds were added in 40 μL using quadruplicate wells for each dose. After 21 hours exposure, the medium was removed and cells were fixed in 4% formaldehyde in phosphate buffered saline (PBS, pH 7.4, pre-cooled to 4°C) for 30 minutes at 4°C, followed by 100% methanol (pre-cooled to -20°C) for 10 minutes at ambient temperature. Wells were washed with PBS and blocked with 5% dried milk (Marvel) in Tris-buffered saline (TBS, pH 7.4) at 37°C for 30 minutes. Each well was washed three times with water containing 0.1% tween 20. Primary antibody (MPM-2, Upstate cat# 05-368, 1 μg/mL in 5% milk in TBS) was added to each well and incubated overnight with shaking at 4°C. Primary antibody was removed and wells were washed with water containing 0.1% Tween 20. The secondary antibody (europium labelled anti-mouse, Perkin-Elmer cat# AD0124, 333 ng/mL in assay buffer Perkin-Elmer cat# 1244-111 ) was added to each well and incubated at 37°C for 1 hour. Each well was washed with water 0.1% containing tween 20 and treated with enhancement solution (Perkin-Elmer cat# 1244- 105). Europium emissions were counted on a Wallac, Victor2 counter (Perkin-Elmer, Bucks UK). Appropriate controls were included and results were expressed as the concentration of test compound required to allow 50% of cells to enter mitosis (MIA IC50).
Biological Data
Biological data were obtained using the CHK1 kinase function inhibition assay described above for the following compounds: AA-001 through AA-072, BB-001 through BB-028, and CC-001.
For the CHK1 kinase function inhibition assay, the following compounds had IC50 values of 1 μM or less: AA-001 , AA-003, AA-004, AA-006, AA-007, AA-008, AA-009, AA-010, AA-013, AA-014, AA-015, AA-016, AA-020, AA-022, AA-023, AA-025, AA-026, BB-011 , BB-014, BB-021 , BB-024, BB-025, BB-026, BB-027, BB-028.
For the CHK1 kinase function inhibition assay, the following compounds had IC50 values of 1 μM or less: AA-001, AA-003, AA-004, AA-006, AA-007, AA-008, AA-009, AA-010, AA-013, AA-014, AA-015, AA-016, AA-020, AA-022, AA-023, AA-025, AA-026, AA-027, AA-028, AA-029, AA-030, AA-031 , AA-032, AA-033, AA-034, AA-035, AA-036, AA-037, AA-038, AA-039, AA-040, AA-041, AA-042, AA-043, AA-044, AA-045, AA-048, AA-049, AA-050, AA-051 , AA-052, AA-054, AA-055, AA-056, AA-057, AA-058, AA-059, AA-060, AA-061 , AA-062, AA-064, AA-067, AA-071, AA-072, BB-011, BB-014, BB-021, BB-024, BB-025, BB-026, BB-027, BB-028.
For the CHK1 kinase function inhibition assay, the following compounds had IC50 values of more than 1 μM and less than 10 μM: AA-002, AA-005, AA-011, AA-017, AA-018, AA-021 , AA-024, BB-001 , BB-006, BB-012, BB-013, BB-018, BB-019, BB-020, BB-022, BB-023.
For the CHK1 kinase function inhibition assay, the following compounds had IC50 values of more than 1 μM and less than 10 μM: AA-002, AA-005, AA-011 , AA-017, AA-018, AA-019, AA-021 , AA-024, AA-046, AA-047, AA-053, AA-063, AA-066, AA-068, AA-069, AA-070, BB-001, BB-006, BB-012, BB-013, BB-018, BB-019, BB-020, BB-022, BB-023, CC-001.
For the CHK1 kinase function inhibition assay, all of the compounds had IC50 values of less than 100 μM. One compound, compound AA-002, had an IC50 value of 1.8 μM. One compound, compound BB-012, had an IC50 value of 1.9 μM. One compound, compound CC-012, had 34% inhibition at 1 μM.
Biological data were obtained using the mitosis inhibition assay (MIA) described above.
For the mitosis inhibition assay (MIA), the following compounds had IC50 values of 10 μM or less: AA-001, AA-003, AA-004, AA-006, AA-007, AA-008, AA-010, AA-014, AA-020, AA-022, AA-023, AA-025, AA-026, AA-027, AA-029, AA-030, AA-031, AA-032, AA-033, AA-034, AA-035, AA-036, AA-037, AA-038, AA-039, AA-040, AA-041 , AA-043, AA-044, AA-049, AA-050, AA-051, AA-052, AA-054, AA-055, AA-057, AA-058, AA-059, AA-060, AA-061 , AA-066, AA-067, AA-071 , AA-072.
One compound, compound AA-001 , had an IC50 value of 0.16 μM. One compound, compound BB-012, had an IC50 value of 33 μM. * * *
Biological data were obtained using the cytotoxicity assay described above.
For the cytotoxicity assay, the following compounds had IC50 values of 10 μM or less: AA-001 , AA-003, AA-006, AA-007, AA-008, AA-010, AA-014, AA-015, AA-020, AA-022, AA-023, AA-025, AA-026, AA-027, AA-031 , AA-032, AA-033, AA-034, AA-037, AA-038, AA-039, AA-040, AA-041, AA-043, AA-044, AA-049, AA-050, AA-051 , AA-052, AA-054, AA-055, AA-057, AA-058, AA-059, AA-060, AA-061, AA-067,
One compound, compound AA-001 , had an IC50 value of 1.4 μM. One compound, compound BB-012, had an IC50 value of 61 μM.
The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention. REFERENCES
A number of patents and publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Balaint and Vousden, 2001 , "Activation and activities of the p53 tumour suppressor protein," Br. J. Cancer, Vol. 85, pp. 1813-1823. Bartek and Lukas, 2003, "Chk1 and Chk2 kinases in checkpoint control and cancer,"
Cancer Cell, Vol. 3, pp. 421-429.
Carson and Lois, 1995, "Cancer progression and p53," Lancet, Vol. 346, pp. 1009-1011. Dixon and Norbury, 2002, "Therapeutic exploitation of checkpoint defects in cancer cells lacking p53 function," Cell Cycle, Vol. 1 , pp. 362-368. Durola et al., 2007, "A New Family of Biisoquinoline Chelates", Eur. J. Org. Chem.,
Issue 1 , pp. 125-135.
Greenblatt et al., 1994, "Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis," Cancer Res., Vol. 54, pp. 4855-4878.
Liu et al., 2000, "Chk1 is an essential kinase that is regulated by Atr and required for the
G(2)/M DNA damage checkpoint," Genes Dev.. Vol. 14, pp. 1448-1459. Plettenburg et al., 2007, "Isoquinoline Derivatives as Inhibitors of Rho-Kinase", international patent application publication number WO 2007/000240 A1 , published 04 January 2007.
Sanchez et al., 1997, "Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25," Science, Vol. 277, pp. 1497-1501.
Sorensen et al., 2005, "Cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair," Nat. Cell Biol., VoI 7, pp. 195-201.
Tao and Lin, 2006, "Chk1 inhibitors for novel cancer treatment," Anti-Cancer Agents in
Medicinal Chemistry, Vol. 6, pp. 377-388. Wang et al., 1996, "UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53," J. Natl. Cancer Inst., Vol. 8, pp. 956-965. Weinert and Hartwell, 1989, "Control of G2 delay by the rad9 gene of Saccharomyces cerevisiae," J. Cell Sci. SUPPL Vol. 12, pp. 145-148. White et al., 1967, "Gattermann reaction of 3,5-dimethoxyphenylacetonitrile. Synthesis of
6,8-dioxyisoquinolines" J. Org. Chem., Vol. 32, pp. 2689-2692. Xiao et al., 2006, "Differential roles of checkpoint kinase 1 , checkpoint kinase 2, and mitogen-activated protein kinase-activated protein kinase 2 in mediating DNA damage-induced cell cycle arrest: implications for cancer therapy," MoI. Cancer
Then, Vol. 5. pp. 1935-1943. Zachos et al., 2003, "Chk1 -deficient tumour cells are viable but exhibit multiple checkpoint and survival defects," EMBO J., Vol. 22, pp. 713-723. Zhao et al., 2002, "Disruption of the checkpoint kinase 1/ceII division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints," Proc. Natl. Acad. Sci. USA. Vol. 99, pp. 14795-14800.

Claims

1. A compound selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
B6
R'
,A3 ,B5
R'
^r^r N
R ,A; 6. N
W
B3
Figure imgf000145_0001
R1 wherein the ring denoted A is independently selected from:
,C3
E2
R
Figure imgf000145_0002
and wherein: each of -RC1, -RC2, -RC3, and -RC4 is independently -H or -Qc;
-RD1 is independently -H or -QD; each of -RE1 and -RE2 is independently -H or -QE;
and wherein:
-RA3 is independently -H or -QA3; -RA6 is independently -H or -QA6; -RB3 is independently -H or -QB3; -RB5 is independently -H or -QB5; -RB6 is independently -H or -QB6;
and wherein:
-Q , if present, is independently: -F, -Cl, -Br, -I, -CF3, -OCF3,
_pQA3
-OH, -OR^3,
-SH, -SRQA3,
-NH2, -NHR^3, -NRQA3 2, or -NR^R0*38; wherein: each -R0^3 is independently saturated aliphatic C1-6alkyl; and
_|VJR QA3A R QA3B js independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from saturated aliphatic Chalky!, -F, and -CF3; -QA6, if present, is independently:
-CF3, -OCF3,
-R^6, -OH, -OR^6,
-SH, -SR^6,
-NH2, -NHR^6, -NRQA6 2, or -NR^R^66; wherein: each -R^6 is independently saturated aliphatic C^alkyl; and _NR QA6A R QA6B js jncjepenc|ent|y azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from saturated aliphatic C1-3alkyl, -F, and -CF3;
-QB3, if present, is independently:
-CF3, -OCF3,
_pQB3
-OH, -0RQB3, -SH, -SRQB3, -NH2, -NHRQB3, -NRQB3 2, or _NRQB3ARQB3B; wherein: each -RQB3 is independently saturated aliphatic C1-6alkyl; and -NRQB3ARQB3B is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from saturated aliphatic
C1-3alkyl, -F, and -CF3;
-QB5, if present, is independently:
-R1A1, -F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH, -L1A-OH, -O-L1A-OH,
-0R1A1, -L1A-OR1A1, -O-L1A-OR1A1,
-SH, -SR1A1, -CN,
-NO2,
-NH2, -NHR1A1, -NR1A1 2, -NR1A2R1A3,
-L1A-NH2, -L1A-NHR1A1, -L1A-NR1A1 2, -L1A-NR1A2R1A3,
-O-L1A-NH2, -O-L1A-NHR1A1, -O-L1A-NR1A1 2, -O-L1A-NR1A2R1A3, -OC(=O)R1A1,
-C(=O)OH, -C(=O)OR1A1,
-C(=O)R1A1,
-C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3,
-NHC(=O)R1A1, -NR1A1C(=O)R1A1, -NHC(=O)OR1A1, -NR1A1C(=O)OR1A1,
-OC(=O)NH2, -OC(=O)NHR1A1, -OC(=O)NR1A1 2, -OC(=O)NR1A2R1A3,
-NHC(=O)NH2, -NHC(=O)NHR1A1,
-NHC(=O)NR1A1 2, -NHC(=O)NR1A2R1A3, -NR1A1C(=O)NH2, -NR1A1C(=O)NHR1A1,
-NR1A1C(=O)NR1A1 2, -NR1AlC(=O)NR1A2R1A3,
-NHS(=O)2R1A1, -NR1A1S(=O)2R1A1,
-S(=O)2NH2> -S(=O)2NHR1A1, -S(=O)2NR1A1 2, -S(=O)2NR1A2R1A3,
-S(=O)R1A1, -S(=O)2R1A1, -OS(=O)2R1A1, or -S(=O)2OR1A1; wherein: each -L1A- is independently saturated aliphatic C1-5alkylene; in each group -NR1A2R1A3, R1A2 and R1A3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R1A1 is independently:
R1B1 o1B2 D1B3 p1B4 _1B5 p1B6 p1B7 p1B8
-L1B-R1B4, -L1B-R1B5, -L1B-R1B6, -L1B-R1B7, or -L1B-R1B8; each -R1B1 is independently saturated aliphatic C1-6alkyl; each -R1B2 is independently aliphatic C2-6alkenyl; each -R1B3 is independently aliphatic C2-6alkynyl; each -R1B4 is independently saturated C3-6cycloalkyl; each -R1B5 is independently C3-6cycloalkenyl; each -R1B6 is independently non-aromatic C^sheterocyclyl; each -R1B7 is independently C6-1ocarboaryl; each -R1BS is independently C5-10heteroaryl; each -L1B- is independently saturated aliphatic C1-3alkylene; wherein: each -R184, -R1B5, -R1Bδ, -R1B7, and -R1B8 is optionally substituted with one or more substituents -R1C1 and/or one or more substituents -R1C2, each -R1B1, -R1B2, -R1B3, and -L1B- is optionally substituted with one or more substituents -R1C2, and wherein: each -R1C1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -R1C2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3,
-OH, -L1D-OH, -O-L1D-OH, -OR1D1, -L1D-OR1D1, -O-L1D-OR1D1,
-SH, -SR1D1, -CN, -NO2, -NH2, -NHR1D1, -NR1D1 2l -NR102R103, -L1D-NH2, -L10-NHR1D1, -L1D-NR1D1 2, -L1D-NR1D2R1D3, -C(=O)OH, -C(=O)OR1D1,
-C(=O)NH2, -C(=O)NHR1D1, -C(=O)NR1D1 2, or -C(=O)NR1D2R1D3; wherein: each -R1D1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -L1D- is independently saturated aliphatic C1-5alkylene; and in each group -NR102R103, R102 and R103, taken together with the nitrogen atom to which they are attached, form a A-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O;
-QB6 is independently -O-RQB6, -S-RQB6, or -NRBN-RQB6; -RBN is independently -H or saturated aliphatic C1-4alkyl;
-RQB6, if present, is independently:
-R4A1,
-L4A-OH, -L4A-OR4A1,
-L4A-NH2, -L4A-NHR4A1, -L4A-NR4A1 2, or -L4A-NR4A2R4A3, wherein: each -L4A- is independently saturated aliphatic C2-6alkylene; in each group -NR4A2R4A3, R4A2 and R4A3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R4A1 is independently:
Figure imgf000148_0001
each -R4B1 is independently saturated aliphatic C1-6alkyl; each -R4B2 is independently aliphatic C2-6alkenyl; each -R4B3 is independently aliphatic C2-6alkynyl; each -R4B4 is independently saturated C3-6cycloalkyl; each -R4B5 is independently C3-6cycloalkenyl; each -R4B6 is independently non-aromatic C3-8heterocyclyl; each -R4B7 is independently C6-10carboaryl; each -R4B8 is independently C5-10heteroaryl; each -L4B- is independently saturated aliphatic C1-3alkylene; wherein: each -R4B4, -R4B5, -R4B6, -R4B7, and -R4B8 is optionally substituted with one or more substituents -R4C1 and/or one or more substituents -R4C2, each -R4B1, -R4B2, -R4B3, and -L4B- is optionally substituted with one or more substituents -R4C2, and wherein: each -R4C1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -R4C2 is independently: -F, -Cl1 -Br, -I, -CF3, -OCF3, -OH, -L4D-OH, -O-L4D-OH,
-0R4D1, -L4D-OR4D1, -O-L4D-OR4D1, -SH, -SR4D1, . -CN, -NO2, -NH2, -NHR4D1 , -NR4D1 2, -NR402R403,
-L40-NH2, -L4O-NHR401, -L4O-NR4O1 2, -L40-N R402R403, -C(=O)OH, -C(=O)OR4D1,
-C(=O)NH2, -C(=O)NHR401, -C(=O)NR401 2, or -C(=O)NR4D2R403; wherein: each -R401 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -L40- is independently saturated aliphatic C1-5alkylene; and in each group -NR402R403, R402 and R403, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O;
and wherein:
each -Qc and each -QE is independently selected from:
-F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH, -L2A-OH, -O-L2A-OH, -NH-L2^OH, -N R2*1 -L2^OH, -OR2*1, -L2^OR2*1, -0-L2^OR2*1, -NH-L2^OR2A1, -NR^-L2A-OR2*1,
-SH, -SR2*1,
-CN,
-NO2,
-NH2, -NHR2A1, -NR2A1 2, -NR2A2R2*3, -L2A-NH2, -L2^-NHR2*1, -L2^NR2A1,, -L2A-NR2*^2*3,
-0-L2A-NH2, -O-L2A-NHR2*1, -O-L2A-NR2*1,, -O-L2A-NR^R2*3,
-NH-L2A-NH2, -NR^-L2A-NH,, -NH-L2A-NHR2*1, -NR^-L2A-NHR2*1,
-NH-L2A-NR2*^, -NR^-L2A-NR^z,
-NH-L2A-NR^R2*3, -NR^-L2A-NR^R2*3, -OC(=O)R2*1,
-C(=O)OH, -C(=O)OR2*1,
-C(=O)R2A1,
-C(=O)NH2, -C(=O)NHR2*1, -C(=O)NR2A1;,, -C(=O)NR2A2R2*3,
-C(=O)NH-L2A-OH, -C(=O)NH-L2A-OR2A1, -C(=O)NH-L2A-NH2, -C(=O)NH-L2A-NHR2A1,
-C(=O)NH-L2A-NR2A1 2, -C(=O)NH-L2A-NR2A2R2A3,
-NHC(=O)R2A1, -NR2A1C(=O)R2A1,
-NHC(=O)-L2A-OH, -NHC(=O)-L2A-OR2A1, -NHC(=O)-L2A-NH2, -NHC(=O)-L2A-NHR2Λ1,
-NHC(=O)-L2A-NR2A1 2, -NHC(=O)-L2A-NR2A2R2A3,
-NHC(=O)OR2A1, -NR2A1C(=O)OR2A1,
-0C(=0)NH2, -OC(=O)NHR2A1, -OC(=O)NR2A1 2| -OC(=O)NR2A2R2A3,
-NHC(=O)NH2, -NHC(=O)NHR2A1, -NHC(=O)NR^2, -NHC(=O)NR2A2R2A3,
-NR2A1C(=O)NH2, -NR2A1C(=O)NHR2A1,
-NR2A1C(=O)NR2A1 2, -NR2A1C(=O)NR2A2R2A3,
-NHS(=O)2R2A1, -NR2A1S(=O)2R2A1,
-S(=O)2NH2, -S(=O)2NHR2A1, -S(=O)2NR2A1,, -S(=O)2NR2A2R2A3, -S(=O)R2A1 , -S(=O)2R2A1 , -OS(=O)2R2A1 , and -S(=O)2OR2A1 ; wherein: each -L2A- is independently saturated aliphatic C1-5alkylene; in each group -NR2A2R2A3, R2A2 and R2A3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R2A1 is independently:
Figure imgf000150_0001
each -R2B1 is independently saturated aliphatic C1-6alkyl; each -R2B2 is independently aliphatic C2-6alkenyl; each -R2B3 is independently aliphatic C2-6alkynyl; each -R2B4 is independently saturated C3-6cycloalkyl; each -R2B5 is independently C3-6cycloalkenyl; each -R2B6 is independently non-aromatic C3-8heterocyclyl; each -R2B7 is independently C6-10carboaryl; each -R2B8 is independently C5-10heteroaryl; each -L2B- is independently saturated aliphatic C1-3alkylene; wherein: each -R2B4, -R2B5, -R2B6, -R2B7, and -R2B8 is optionally substituted with one or more substituents -R2C1 and/or one or more substituents -R2C2, each -R2B1, -R2B2, -R2B3, and -L2B- is optionally substituted with one or more substituents -R2C2, and wherein: each -R2C1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -R2C2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L2D-OH, -O-L2D-OH, -OR2D1, -L2D-OR2D1, -O-L2D-OR2D1, -SH, -SR2D1, -CN, -NO2,
-NH2, -NHR2D1, -NR2D1 2, -NR2D2R2D3, -L2D-NH2, -L2D-NHR2D1, -L2D-NR2D1 2, -L2D-NR2D2R2D3, -C(=O)OH, -C(=O)OR2D1,
-CO=O)NH2, -C(=O)NHR2D1, -C(=O)NR2D1 2, or -C(=O)NR2D2R2D3; wherein: each -R2D1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -L2D- is independently saturated aliphatic C1-5alkylene; and in each group -NR2D2R2D3, R2D2 and R2D3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O;
-QD is independently selected from: -R3A1,
-L3A-OH, -L3A-OR3A1,
-L3A-NH2, -L3A-NHR3A1, -L3A-NR3A1 2, and -L3A-NR3A2R3A3; wherein: each -L3A- is independently saturated aliphatic C2-5alkylene; in each group -NR3A2R3A3, R3A2 and R3A3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; each -R3A1 is independently:
Figure imgf000151_0001
each -R3B1 is independently saturated aliphatic C1-6alkyl; each -R3B2 is independently aliphatic C2-6alkenyl; each -R3B3 is independently aliphatic C2-6alkynyl; each -R3B4 is independently saturated C3-6cycloalkyl; each -R3B5 is independently C3-6cycloalkenyl; each -R3B6 is independently non-aromatic C3-sheterocyclyl; each -R3B7 is independently C6-1ocarboaryl; each -R3B8 is independently C5-10heteroaryl; each -L3B- is independently saturated aliphatic C1-3alkylene; wherein: each -R3B4, -R3B5, -R3B6, -R3B7, and -R3B8 is optionally substituted with one or more substituents -R3C1 and/or one or more substitiients -R3C2, each -R3B1, -R3B2, -R3B3, and -L3B- is optionally substituted with one or more substituents -R3C2, and wherein: each -R3C1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -R3C2 is independently:
-F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L3D-OH, -O-L3D-OH,
_0R3D1 , _L3D_OR 3D1, -O-L3D-OR3D1, -SH, -SR3D1,
-CN, -NO2,
-NH2, -NHR3D1, -NR3D1 2, -NR302R303, -L3O-NH2, -L30-NHR301, -L30-NR301 2, -L3D-NR302R303, -C(=O)OH, -C(=O)OR3D1,
-C(=O)NH2, -C(=O)NHR3D1, -C(=O)NR3D1 2, or -C(=O)NR3D2R303; wherein: each -R301 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -L3D- is independently saturated aliphatic C1-5alkylene; and in each group -NR302R303, R302 and R3D3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O;
with the proviso is that the compound is not [6-(piperidin-4-yloxy)-isoquinolin-3-yl]- pyrazin-2-yl-amine, or a salt, hydrate, or solvate thereof.
2. A compound according to claim 1, wherein the ring denoted A is independently:
Figure imgf000152_0001
3. A compound according to claim 1, wherein the ring denoted A is independently selected from:
Figure imgf000152_0002
4. A compound according to claim 1 , wherein the ring denoted A is independently:
Figure imgf000153_0001
5. A compound according to claim 1, wherein the ring denoted A is independently:
Figure imgf000153_0002
A compound according to claim 1 , wherein the ring denoted A is independently selected from:
Figure imgf000153_0003
A compound according to claim 1 , wherein the ring denoted A is independently:
Figure imgf000153_0004
8. A compound according to claim 1 , wherein the ring denoted A is independently:
Figure imgf000153_0005
9. A compound according to any one of claims 1 to 8, wherein -RA3 is independently -H.
10. A compound according to any one of claims 1 to 8, wherein -RA3 is independently -QA3.
11. A compound according to any one of claims 1 to 10, wherein -RA6 is independently -H.
12. A compound according to any one of claims 1 to 10, wherein -RA6 is independently -QA6. * * *
13. A compound according to any one of claims 1 to 12, wherein -RB3 is independently -H.
14. A compound according to any one of claims 1 to 12, wherein -RB3 is independently -QB3.
15. A compound according to any one of claims 1 to 14, wherein -RB5 is independently -H.
16. A compound according to any one of claims 1 to 14, wherein -RB5 is independently -QB5.
* * *
17. A compound according to any one of claims 1 to 16, wherein -RB6 is independently -H.
18. A compound according to any one of claims 1 to 16, wherein -RB6 is independently -QB6.
19. A compound according to any one of claims 1 to 18, wherein: -RC1, if present, is independently -Qc; and each of -RC2, -RC3, and -RC4, if present, is independently -H or -Qc.
20. A compound according to any one of claims 1 to 18, wherein: -RC1, if present, is independently -Qc; and each of -RC2, -RC3, and -RC4, if present, is independently -H.
21. A compound according to any one of claims 1 to 18, wherein: -RC3, if present, is independently -H; and each of -Rc1, -RC2, and ~RC4, if present, is independently -H or -Qc.
22. A compound according to any one of claims 1 to 18, wherein: -RC3, if present, is independently -H; and each of -Rc1, -RC2, and -RC4, if present, is independently -H.
23. A compound according to any one of claims 1 to 18, wherein: each of -Rc1 and -RC3, if present, is independently -Qc; and each of -RC2 and -RC4, if present, is independently -H or -Qc.
24. A compound according to any one of claims 1 to 18, wherein: each of -RC1 and -RC3, if present, is independently -Qc; and each of -RC2 and -RC4, if present, is independently -H.
25. A compound according to any one of claims 1 to 24, wherein -RD1, if present, is independently -H.
26. A compound according to any one of claims 1 to 24, wherein -RD1, if present, is independently -QD.
27. A compound according to any one of claims 1 to 26, wherein -RE1, if present, is independently -H.
28. A compound according to any one of claims 1 to 26, wherein -RE1, if present, is independently -QE.
29. A compound according to any one of claims 1 to 28, wherein -RE2, if present, is independently -H.
30. A compound according to any one of claims 1 to 28, wherein -RE2, if present, is independently -QE.
31. A compound according to any one of claims 1 to 30, wherein -QA3, if present, is independently: -F, -Cl1 -Br, -I1 -Me, -Et, -nPr, -iPr, -CF3, -OCF3, -OH1 -OMe, -OEt, -SH, -SMe, -NH2, -NHMe, or -NMe2.
32. A compound according to any one of claims 1 to 31 , wherein -QA6, if present, is independently:
-Me, -Et, -nPr, -iPr,
-CF3, -OCF3,
-OH, -OMe1 -OEt1
-SH1 -SMe, -NH21 -NHMe1 Or -NMe2.
33. A compound according to any one of claims 1 to 32, wherein -QB3, if present, is independently:
-OCF3,
-Me, -Et,
-OH, -OMe, -OEt,
-SH1 -SMe, -NH2, -NHMe, or -NMe2.
34. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently:
-R1A1,
-CF3, -OCF3,
-OH, -L1A-OH, -O-L1A-OH,
-0R1A1, -L1A-OR1A1, -O-L1A-OR1A1, -CN,
-NO2,
-NH2, -NHR1A1, -NR1A1 2l -NR1A2R1A3,
-L1A-NH2, -L1A-NHR1A1, -L1A-NR1A1 2, -L1A-NR1A2R1A3,
-O-L1A-NH2, -O-L1A-NHR1A1, -O-L1A-NR1A1 2l -O-L1A-NR1A2R1A3, -0C(=0)R1A1,
-C(=0)0H, -C(=0)0R1A1,
-C(=0)NH2l -C(=O)NHR1A1, -C(=0)NR1A1 2l -C(=O)NR1A2R1A3,
-NHC(=O)R1A1, or -NR1A1C(=O)R1A1.
35. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently:
-R1B1, p1B8 -CF3,
-OH, -L1A-OH, -O-L1A-OH, -OR1A1, -L1A-OR1A1, -O-L1A-OR1A1, -CN,
-OC(=O)R1A1, -C(=O)OH, -C(=O)OR1A1,
-C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3, -NHC(=O)R1A1, or -NR1A1C(=O)R1A1.
36. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently:
-R1B1, -OR1A1, -CN, .
-C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, or -C(=O)NR1A2R1A3.
37. A compound according to any one of claims 1 to 33, wherein -QBS, if present, is independently -CN.
38. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently -C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, or -C(=O)NR1A2R1A3.
39. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently -C(=O)NH2.
40. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently -R1B1.
41. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently -Me.
42. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently -R1B8.
43. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently -OR1A1.
44. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently -OMe.
45. A compound according to any one of claims 1 to 44, wherein each -L1A-, if present, is independently -(CH2)n1-, wherein n1 is independently 1 to 4.
46. A compound according to any one of claims 1 to 44, wherein each -L1A-, if present, is independently -CH2- or -CH2CH2-.
47. A compound according to any one of claims 1 to 46, wherein each -NR1A2R1A3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morphόlino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
48. A compound according to any one of claims 1 to 46, wherein each -NR1A2R1A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
49. A compound according to any one of claims 1 to 48, wherein each -R1A1, if present, is independently:
_R1 B1 -R1 B4 -R1 B6 _R1 B7 -p1B8 -L1B-R1B4, -L1B-R1B6, -L1B'-R1B7, or -L1B-R1B8.
50. A compound according to any one of claims 1 to 48, wherein each -R1A1, if present, is independently:
_p1B1 _p1B7 _p1B8 -L1B-R1 B7, or -L1B-R1B8.
51. A compound according to any one of claims 1 to 48, wherein each -R1A1, if present, is independently:
-R1B1, -R1B7, or -L1B-R1B7.
52. A compound according to any one of claims 1 to 48, wherein each -R1A1, if present, is independently: -R1B7, -R1B8, -L1B-R1B7, or -L1B-R1B8.
53. A compound according to any one of claims 1 to 52, wherein each -R1B6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
54. A compound according to any one of claims 1 to 52, wherein each -R1B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
55. A compound according to any one of claims 1 to 54, wherein each -R1B7, if present, is independently phenyl, and is optionally substituted.
56. A compound according to any one of claims 1 to 55, wherein each -R1B8, if present, is independently C5-6heteroaryl, and is optionally substituted.
57. A compound according to any one of claims 1 to 55, wherein each -R1B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
58. A compound according to any one of claims 1 to 55, wherein each -R1B8, if present, is independently C9.10heteroaryl, and is optionally substituted.
59. A compound according to any one of claims 1 to 55, wherein each -R1B8, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
60. A compound according to any one of claims 1 to 59, wherein each -L1B-, if present, is independently -CH2- or -CH2CH2-.
61. A compound according to any one of claims 1 to 59, wherein each -L1B-, if present, is independently -CH2-.
62. A compound according to any one of claims 1 to 61 , wherein each -R1C1, if present, is independently saturated aliphatic C-i-4alkyl.
63. A compound according to any one of claims 1 to 62, wherein each -R1C2 is independently:
-F, -Cl, -Br, -I,
-OH,
-OR1D1, -CN,
-NO2,
-NH2, -NHR1D1, -NR1D1 2, or -NR1D2R1D3.
64. A compound according to any one of claims 1 to 63, wherein each -R1D1, if present, is independently saturated aliphatic C^alkyl.
65. A compound according to any one of claims 1 to 64, wherein each -L1D-, if present, is independently -(CH2)mr, wherein ml is independently 1 to 4.
66. A compound according to any one of claims 1 to 64, wherein each -L1D-, if present, is independently -CH2- or -CH2CH2-.
67. A compound according to any one of claims 1 to 66, wherein each -NR102R103, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
68. A compound according to any one of claims 1 to 66, wherein each -NR102R103, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
69. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently:
-CN, -ORX4, -RX4, -C(=O)NH2, -C(=O)NHRX4, or -C(=O)NRX4 2; wherein each RX4 is independently saturated aliphatic C1-4alkyl.
70. A compound according to any one of claims 1 to 33, wherein -QB5, if present, is independently -CN, -OMe, -Me, or -C(=O)NH2.
71. A compound according to any one of claims 1 to 70, wherein -QB6 is independently -O-RQB6.
72. A compound according to any one of claims 1 to 70, wherein -QB6 is independently -S-RQB6.
73. A compound according to any one of claims 1 to 70, wherein -QBδ is independently -NRBN-RQB6.
74. A compound according to any one of claims 1 to 73, wherein -RBN, if present, is independently -H or -Me.
75. A compound according to any one of claims 1 to 73, wherein -RBN, if present, is independently -H.
76. A compound according to any one of claims 1 to 75, wherein -RQB6, if present, is independently: -L4A-OH, -L4A-OR4A1, -L4A-NH2, -L4A-NHR4A1, -L4A-NR4A1 2, or -L4A-NR4A2R4A3.
77. A compound according to any one of claims 1 to 75, wherein -RQB6, if present, is independently -L4A-OH or -L4A-OR4A1.
78. A compound according to any one of claims 1 to 75, wherein -RQB6, if present, is independently -L4A-NH2, -L4A-NHR4A1, -L4A-NR4A1 2, or -L4A-NR4A2R4A3.
79. A compound according to any one of claims 1 to 75, wherein -RQB6, if present, is independently -R4A1.
80. A compound according to any one of claims 1 to 79, wherein each -L4A-, if present, is independently -(CH2)n4-, wherein n4 is independently 2 to 6.
81. A compound according to any one of claims 1 to 79, wherein each -L4A-, if present, is independently -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.
82. A compound according to any one of claims 1 to 81 , wherein each -NR4A2R4A3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, diazepino, or oxazepino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and
-F.
83. A compound according to any one of claims 1 to 81 , wherein each -NR4A2R4A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and
-F.
84. A compound according to any one of claims 1 to 83, wherein each -R4A1, if present, is independently: -R4B1, -R4B4, -R4B6, -R4B7, -R4B8,
-L4B-R4B4, -L4B-R4B6, -L4B-R4B7, or -L4B-R4B8.
85. A compound according to any one of claims 1 to 83, wherein each -R4A1, if present, is independently: -R4B1, -R4B7, -R4B8,
-L4B-R4B7, or -L4B-R4B8.
86. A compound according to any one of claims 1 to 83, wherein each -R4A1, if present, is independently: -R4B1, -R4B7, or -L4B-R4B7.
87. A compound according to any one of claims 1 to 83, wherein each -R4A1, if present, is independently: -R4B7, -R4B8, -L4B-R4B7, or -L4B-R4B8.
88. A compound according to any one of claims 1 to 83, wherein each -R4A1, if present, is independently -R4B6 or -L4B-R4B6.
89. A compound according to any one of claims 1 to 88, wherein each -R4B6, if present, is independently a C3-8heterocyclyl group that is a 4-, 5-, 6-, or 7- membered non-aromatic monocyclic ring or a 7-, 8-, or 9-membered non-aromatic bicyclic ring, said ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ring heteroatoms is independently N, O, or S; and is optionally substituted.
90. A compound according to any one of claims 1 to 88, wherein each -R4B6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, oxazepanyl, 3-aza-bicyclo[3.2.1]octanyl, 8-aza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3-aza-bicyclo[3.1.1]heptanyl,
6-aza-bicyclo[3.1.1]heptanyl, 3,6-diaza-bicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.2]octanyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl, or 9-azabicyclo[3.3.1]nonanyl; and is optionally substituted.
91. A compound according to any one of claims 1 to 88, wherein each -R4B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, 8-aza-bicyclo[3.2.1]octanyl, or quinuclidinyl, and is optionally substituted.
92. A compound according to any one of claims 1 to 88, wherein each -R4B6, if present, is independently pyrrolidinyl, piperidinyl, or morpholinyl; and is optionally substituted.
93. A compound according to any one of claims 1 to 92, wherein each -R4B7, if present, is independently phenyl, and is optionally substituted.
94. A compound according to any one of claims 1 to 93, wherein each -R4BB, if present, is independently C5-6heteroaryl, and is optionally substituted.
95. A compound according to any one of claims 1 to 93, wherein each -R4B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
96. A compound according to any one of claims 1 to 93, wherein each -R4B8, if present, is independently C9.10heteroaryl, and is optionally substituted.
97. A compound according to any one of claims 1 to 93, wherein each -R4B8, if present, is independently benzofuranyl, benzothienyj, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
98. A compound according to any one of claims 1 to 97, wherein each -L4B-, if present, is independently -CH2- or -CH2CH2-.
99. A compound according to any one of claims 1 to 97, wherein each -L4B-, if present, is independently -CH2-.
100. A compound according to any one of claims 1 to 99, wherein each -R4C1, if present, is independently saturated aliphatic C1-4alkyl.
101. A compound according to any one of claims 1 to 100, wherein each -R4C2 is independently:
-F, -Cl, -Br, -I, -OH, -OR4D1, -CN, -NO2,
-NH2, -NHR4D1 , -NR4D1 2, or -NR402R403.
102. A compound according to any one of claims 1 to 101 , wherein each -R4D1, if present, is independently saturated aliphatic C1-4alkyl.
103. A compound according to any one of claims 1 to 102, wherein each -L40-, if present, is independently -(CH2)mr, wherein ml is independently 1 to 4.
104. A compound according to any one of claims 1 to 102, wherein each -L40-, if present, is independently -CH2- or -CH2CH2-.
105. A compound according to any one of claims 1 to 104, wherein each -NR402R403, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
106. A compound according to any one of claims 1 to 104, wherein each -NR402R403, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
107. A compound according to any one of claims 1 to 75, wherein -RQB6, if present, is independently selected from groups of the following formulae, wherein p1 is independently 1 , 2, 3, or 4; p2 is independently 1 , 2, 3, or 4; p3 is independently 0, 1, or 2; and p4 is independently 1, 2, 3, or 4:
Figure imgf000164_0001
wherein: each -RNN1, if present, is independently -H, saturated aliphatic C1-4alkyl, phenyl, or benzyl; or, the group -NRNN1RNN1, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1-3alkyl, -CF3, and -F; each -RNN2, if present, is independently -H or saturated aliphatic C1-4alkyl; each -RNN3, if present, is independently -H, saturated aliphatic C1-4alkyl, phenyl, or benzyl;
-RNN4, if present, is independently -saturated aliphatic C1-6alkyl.
108. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-1).
109. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-1B).
110. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-2).
111. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-3).
112. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-4).
113. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-5).
114. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-6).
115. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-7).
116. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-8).
117. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-9).
118. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-10).
119. A compound according to claim 107, wherein -RQB6, if present, is independently a group of formula (B6-11).
120. A compound according to claim 107, wherein -RQBδ, if present, is independently a group of formula (B6-12).
121. A compound according to any one of claims 107 to 120, wherein p1 , if present, is independently 1.
122. A compound according to any one of claims 107 to 120, wherein p3, if present, is independently 0.
123. A compound according to any one of claims 107 to 120, wherein p3, if present, is independently 1 or 2.
124. A compound according to any one of claims 107 to 120, wherein p4, if present, is independently 1.
125. A compound according to any one of claims 107 to 124, wherein each -RNN1, if present, is independently -H, saturated aliphatic C1-4alkyi, phenyl, or benzyl; or, the group -NRNN1RNN1, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1-3a!kyl, -CF3, and -F.
126. A compound according to any one of claims 107 to 124, wherein each -RNN1, if present, is independently -H, saturated aliphatic C^alkyl, phenyl, or benzyl; or, the group -NRNN1RNN1, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
127. A compound according to any one of claims 107 to 124, wherein each -RNN1, if present, is independently -H, saturated aliphatic C1-4alkyl, phenyl, or benzyl.
128. A compound according to any one of claims 107 to 124, wherein each -RNN1, if present, is independently -H or saturated aliphatic C1-4alkyl.
129. A compound according to any one of claims 107 to 124, wherein each -RNN1, if present, is independently -H or -Me.
130. A compound according to any one of claims 107 to 124, wherein each -RNN1, if present, is independently -H.
131. A compound according to any one of claims 107 to 130, wherein -RNN2, if present, is independently -H or saturated aliphatic C1-4alkyl.
132. A compound according to any one of claims 107 to 130, wherein -RNN2, if present, is independently -H or -Me.
133. A compound according to any one of claims 107 to 130, wherein -RNN2, if present, is independently -H.
134. A compound according to any one of claims 107 to 133, wherein -RNN3, if present, is independently -H, saturated aliphatic C1-4alkyl, phenyl, or benzyl.
135. A compound according to any one of claims 107 to 133, wherein -RNN3, if present, is independently -H or saturated aliphatic C^alkyl.
136. A compound according to any one of claims 107 to 133, wherein -RNN3, if present, is independently -H or -Me.
137. A compound according to any one of claims 107 to 133, wherein -RNN3, if present, is independently -H.
138. A compound according to any one of claims 107 to 133, wherein -RNN3, if present, is independently -Me.
139. A compound according to any one of claims 107 to 133, wherein -RNN4, if present, is independently saturated aliphatic C^alkyl.
140. A compound according to any one of claims 1 to 139, wherein each -Qc, if present, and each -QE, if present, is independently selected from:
-R2A1,
-F, -Cl, -Br, -I,
-CF3, -OCF3, -OH, -L2A-OH, -O-L2A-OH, -NH-L2A-OH, -NR2A1-L2A-OH,
_OR 2A1,-L2A- OR2 A1, -O-L2A-OR2A1, -NH-L2A-OR2A1, -NR2A1-L2A-OR2A1,
-CN,
-NH2, -NHR2A1, -NR2A1 2, -NR2A2R2A3,
-L2A-NH2, -L2A-NHR2A1, -L2A-NR2A1,, -L2A-NR^R2A3, -0-L2A-NH2, -0-L2A-NHR2A1, -0-L2A-N R2A1 2, -O-L2A-NR^R2*3,
-NH-L2A-NH2, -NR^-L2A-NH,, -NH-L2A-NHR2*1, -NR^-L2A-NHR2*1,
-NH-L2A-NR2A1 2, -NR^-L2A-NR2^,
-NH-L2A-NR2A2R2A3, _NR2A1_L2A_NR2A2R2A3,
-OC(=O)R2A1, -C(=O)OH, -C(=O)OR2A1,
-C(=O)NH2, -C(=O)NHR2A1, -C(=O)NR^2, -C(=O)NR2A2R2A3,
-C(=O)NH-L2A-OH, -C(=O)NH-L2A-OR2A1 ,
-C(=O)NH-L2A-NH2, -C(=O)NH-L2A-NHR2A1,
-C(=O)NH-L2A-NR2A1 Z, -C(=O)NH-L2A-NR2A2R2A3, -NHC(=O)R2A1, -NR2A1C(=O)R2A1,
-NHC(=O)-L2A-OH, -NHC(=O)-L2A-OR2A1 ,
-NHC(=O)-L2A-NH2, -NHC(=O)-L2A-NHR2A1,
-NHC(=O)-L2A-NR2A1 2, -NHC(=O)-L2A-NR2A2R2A3,
-NHC(=O)NH2, -NHC(=O)NHR2A1, -NHC(=O)NR2A1,, -NHC(=O)NR2A2R2A3,
-NR2A1C(=O)NH2, -NR2A1C(=O)NHR2A1,
-NR2A1C(=O)NR2A1 , -NR2A1C(=O)NR2A2R2A3, .
-NHS(=O)2R2A1 1 -NR2A1S(=O)2R2A1,
-S(=O)2NH2, -S(=O)2NHR2A1, -S(=O)2NR2A1 2, -S(=O)2NR2A2R2A3, -S(=O)R2A1, -S(=O)2R2A1, -OS(=O)2R2A1, and -S(=O)2OR2A1.
141. A compound according to any one of claims 1 to 139, wherein each -Qc, if present, and each -QE, if present, is independently selected from: -R2A1,
-F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH, -L2A-OH, -O-L2A-OH, -NH-L2A-OH,
_OR 2A1, -L2A-OR2A1, -0-L2A-OR2A1, -NH-L2A-OR2A1, . -CN,
-NH2, -NHR2A1, -NR2A1 2, -NR^R2A3,
-L2A-NH2, -L2A-NHR2A1, -L2A-NR2^, -L2A-NR2A2R2A3,
-0-L2A-NH2, -0-L2A-NHR2A1, -O-L2A-NR2A1,, -O-L2A-NR^R2A3,
-NH-L2A-NH2, -NH-L2A-NHR2A1, -NH-L2A-NR2A1,, -NH-L2A-NR2A2R2A3, -OC(=O)R2A1,
-C(=O)OH, -C(=O)OR2A1,
-C(=O)NH2, -C(=O)NHR2A1, -C(=O)NR2A1,, -C(=O)NR2A2R2A3,
-C(=O)NH-L2A-OH1 -C(=O)NH-L2A-OR2A1,
-C(=O)NH-L2A-NH2, -C(=O)NH-L2A-NHR2A1, -C(=O)NH-L2A-NR2A1 2, -C(=O)NH-L2A-NR2A2R2A3,
-NHC(=O)R2A1, -NR2A1C(=O)R2A1.
-NHC(=O)-L2A-OH1 -NHC(=O)-L2A-OR2A1,
-NHC(=O)-L2A-NH21 -NHC(=O)-L2A-NHR2A1,
-NHC(=O)-L2A-NR2A1 2, -NHC(=O)-L2A-NR2A2R2A3.
142. A compound according to any one of claims 1 to 141. wherein each -Qc, if present, is independently selected from:
-R2A1,
-F, -Cl, -Br, -I, -CF3, -OCF3,
-OH, -L2A-OH, -0-L2A-OH, -NH-L2A-OH,
-OR2 A1, -L22A-OR2 A1, -O-L2A-OR2A1, -NH-L2A-OR2A1,
-CN,
-NO2, -NH2, -NHR2A1, -NR2A1 2, -NR2A2R2A3,
-L2A-NH2, -L2A-NHR2A1, -L2A-NR2A1 2, -L2A-NR2A2R2A3,
-0-L2A-NH2, -0-L2A-NHR2A1, -O-L2A-NR2A1 2, -0-L2A-NR2A2R2A3,
-NH-L2A-NH2, -NH-L2A-NHR2A1, -NH-L2A-NR2A1 2, -NH-L2A-NR2A2R2A3,
-OC(=O)R2A1, -C(=O)OH1 -C(=O)OR2A1,
-C(=O)NH2, -C(=O)NHR2A1, -C(=O)NR2A1 2, -C(=O)NR2A2R2A3,
-C(=O)NH-L2A-OH1 -C(=O)NH-L2A-OR2A1,
-C(=O)NH-L2A-NH21 -C(=O)NH-L2A-NHR2A1,
-C(=O)NH-L2A-NR2A1 2, -C(=O)NH-L2A-NR2A2R2A3, -NHC(=O)R2A1, -NR2A1C(=O)R2A1, -NHC(=O)-L2A-OH, -NHC(=O)-L2A-OR2A1, -NHC(=O)-L2^NH2, -NHC(=O)-L2^NHR2A1, -NHC(=O)-L2A-NR2A1 2, -NHC(=O)-L2A-NR2A2R2A3, -NHC(=O)NH2, -NHC(=O)NHR2*1,
-NHC(=O)NR^2, -NHC(=O)NR2^R2*3, -NR2A1C(=O)NH2, -NR2A1C(=O)NHR2*1, -NR2A1C(=O)NR2A1 2, -NR2A1C(=O)NR2A2R2*3, -NHS(=O)2R2A1 , -NR2A1S(=O)2R2A1, -S(=O)2NH2, -S(=O)2NHR2A1, -S(=O)2NR2A1 Z, -S(=O)2NR2A2R2A3,
-S(=O)R2*1, -S(=O)2R2A1, -OS(=O)2R2A1, and -S(=O)2OR2A1.
143. A compound according to any one of claims 1 to 141 , wherein each -Qc, if present, is independently selected from: -R2A1, -F, -Cl, -Br, -I, -CF3, -OCF3,
-OH, -L2A-OH, -0-L2A-OH, -NH-L2A-OH,
-OR2A1 , -L2A-OR2*1, -0-L2A-OR2A1, -NH-L2A-OR2A1,
-NH2, -NHR2A1, _NR2A12, _NR2A2R2A3,
-L2A-NH2, -L2A-NHR2A1, -L2A-NR2^, -L2A-NR^R2*3, -0-L2A-NH2, -0-L2A-NHR2A1, -O-L2A-NR2A1,, -0-L2A-NR2A2R2A3,
-NH-L2A-NH2, -NH-L2A-NHR2A1, -NH-L2A-NR2*1^ -NH-L2A-NR2A2R2A3,
-C(=O)NH2, -C(=O)NHR2*1, -C(=O)NR2*1,, -C(=O)NR2A2R2*3,
-C(=O)NH-L2A-OH, -C(=O)NH-L2A-OR2*1 ,
-C(=O)NH-L2A-NH2, -C(=O)NH-L2A-NHR2*1 , -C(=O)NH-L2A-NR2A1,, -C(=O)NH-L2*-NR2A2R2*3,
-NHC(=O)R2A1, -NR2A1C(=O)R2*1,
-NHC(=O)-L2A-OH, -NHC(=O)-L2A-OR2A1 ,
-NHC(=O)-L2A-NH2, -NHC(=O)-L2A-NHR2*1,
-NHC(=O)-L2*-NR2A1 2, and -NHC(=O)-L2A-NR2A2R2*3.
144. A compound according to any one of claims 1 to 141 , wherein each -Qc, if present, is independently selected from:
-R2A1, -F1 -CI1 -Br1 -I1 -CF31 -OCF3, -OH, -L2A-OH, -0-L2A-OH, -NH-L2A-OH, -OR2A1 , -L2A-OR2A1 , -0-L2A-OR2A1 , -NH-L2A-OR2A1 ,
-NH2, -NHR2A1, -NR2A1 2, -NR2A2R2A3, -L2A-NH2, -L2A-NHR2*1, -L2A-NR2*1,, -L2^N R2*^3, -0-L2A-NH2, -0-L2A-NHR2*1, -O-L2A-N R2A1,, -O-L2A-NR2*^3, -NH-L2A-NH2, -NH-L2A-NHR2A1, -NH-L2A-NR2^ and -NH-L2A-NR2A2R2A3.
145. A compound according to any one of claims 1 to 141 , wherein each -Qc, if present, is independently selected from:
-R2A1, -F, -Cl, -Br, -I, -CF3, -OCF3, -NH-L2A-OH, -NH-L2A-OR2A1, -NH-L2A-NH2, -NH-L2^NHR2A1, -NH-L2A-NR2A1,, and -NH-L2A-NR2A^2A3.
146. A compound according to any one of claims 1 to 145, wherein each -QE, if present, is independently selected from: -R2A1 ,
-CF3, -OH, -L2A-OH, -O-L2A-OH,
.QR2AI1 _L2A_OR2A1; _O.L2A_OR2A^!
-CN, -NH2, -NHR2A1, -NR2A1,, -NR2A2R2A3,
-L2A-NH2, -L2A-NHR2A1, -L2A-NR2A1,, -L2A-N R2A2R2A3,
-C(=O)OH, -C(=O)OR2A1,
-C(=O)R2A1,
-C(=O)NH2, -C(=O)NHR2A1, -C(=O)NR2A1 2, -C(=O)NR2A2R2A3 I -NHC(=O)R2A1, -NR2A1C(=O)R2A1,
-NHC(=O)NH2, -NHC(=O)NHR2A1,
-NHC(=O)NR2A1 2, -NHC(=O)NR2A2R2A3,
-NR2A1C(=O)NH2, -NR2A1C(=O)NHR2A1,
-NR2A1C(=O)NR2A1 2, -NR2A1C(=O)NR2A2R2A3, -NHS(=O)2R2A1, -NR2A1S(=O)2R2A1,
-S(=O)2NH2, -S(=O)2NHR2A1, -S(=O)2NR2A1 2, -S(=O)2NR2A2R2A3,
-S(=O)R2A1, -S(=O)2R2A1, -OS(=O)2R2A1, and -S(=O)2OR2A1.
147. A compound according to any one of claims 1 to 145, wherein each -QE, if present, is independently selected from:
-R2A1,
-CF3,
-OH, -L2A-OH, -O-L2A-OH,
-OR2A1, -L2A-OR2A1, -O-L2A-OR2A1, -CN,
-NH2, -NHR2A1, -NR2A1 2, -NR2^R2A3,
-L2A-NH2, -L2A-NHR2A1, -L2A-NR2A1,, -L2A-N R2A2R2A3,
-C(=O)OH, -C(=O)OR2A1,
-C(=O)NH2, -C(=O)NHR2A1, -C(=O)NR2A1,, and -C(=O)NR2A2R2A3.
148. A compound according to any one of claims 1 to 147, wherein each -L2A-, if present, is independently -(CH2)n2-, wherein n2 is independently 1 to 4.
149. A compound according to any one of claims 1 to 147, wherein each -L2A-, if present, is independently -CH2- or -CH2CH2-.
150. A compound according to any one of claims 1 to 149, wherein each -NR2A2R2A3, if present, is independently azetidino, pyrrolidine, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
151. A compound according to any one of claims 1 to 149, wherein each -NR2A2R2A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and
152. A compound according to any one of claims 1 to 151 , wherein each -R2*1, if present, is independently:
_p2B1 _D2B4 _O2B6 _p2B7 _p2B8
-L2B-R2B4, -L2B-R2B6, -L2B'-R2B7, or -L2B-R2B8.
153. A compound according to any one of claims 1 to 151 , wherein each -R2A1 1 if present, is independently:
_p2B1 _p2B7 D2B8
-L2B-R2B7, or -L2B-R2B8.
154. A compound according to any one of claims 1 to 151 , wherein each -R2A1 1 if present, is independently:
-R2B1, -R2B7, or -L2B-R2B7.
155. A compound according to any one of claims 1 to 151 , wherein each -R2A1, if present, is independently: -R2B7, -R2B8, -L2B-R2B7, or -L2B-R2B8.
156. A compound according to any one of claims 1 to 155, wherein each -R2BΘ, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
157. A compound according to any one of claims 1 to 155, wherein each -R2B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
158. A compound according to any one of claims 1 to 157, wherein each -R2B7, if present, is independently phenyl, and is optionally substituted.
159. A compound according to any one of claims 1 to 158, wherein each -R2B8, if present, is independently C5-6heteroaryl, and is optionally substituted.
160. A compound according to any one of claims 1 to 158, wherein each -R2B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
161. A compound according to any one of claims 1 to 158, wherein each -R2B8, if present, is independently C9-10heteroaryl, and is optionally substituted.
162. A compound according to any one of claims 1 to 158, wherein each -R2B8, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
163. A compound according to any one of claims 1 to 162, wherein each -L2B-, if present, is independently -CH2- or -CH2CH2-.
164. A compound according to any one of claims 1 to 162, wherein each -L2B~, if present, is independently -CH2-.
165. A compound according to any one of claims 1 to 164, wherein each -R2C1, if present, is independently saturated aliphatic C1-4alkyl.
166. A compound according to any one of claims 1 to 165, wherein each -R2C2 is independently:
-F, -Cl, -Br, -I, -OH,
-OR2D1,
-CN,
-NO2,
-NH2, -NHR2D1, -NR2D1 2, or -NR202R203.
167. A compound according to any one of claims 1 to 166, wherein each -R201, if present, is independently saturated aliphatic C1-4alkyl.
168. A compound according to any one of claims 1 to 167, wherein each -L20-, if present, is independently -(CH2)m2-, wherein m2 is independently 1 to 4.
169. A compound according to any one of claims 1 to 167, wherein each -L20-, if present, is independently -CH2- or -CH2CH2-.
170. A compound according to any one of claims 1 to 168, wherein each -NR202R203, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
171. A compound according to any one of claims 1 to 168, wherein each -NR202R203, if present, is independently pyrrolidine, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
172. A compound according to any one of claims 1 to 139, wherein each -Qc, if present, is independently selected from:
-RX1,
-F, -Cl, -Br, -I, -CF31 -OCF3,
-OH, -ORX1,
-NH2, -NHRX1, -NRX1 2, -RM1,
-O-(CH2)z-OH, -O-(CH2)Z-ORX1,
-O-(CH2)Z-NH2, -O-(CH2)z-NHRx1, -O-(CH2)Z-NRX1 2, -O-(CH2)Z-RM1, -NH-(CH2)Z-OH, -NH-(CH2)Z-ORX1,
-NH-(CH2)Z-NH2, -NH-(CH2)Z-NHRX1, -NH-(CH2)Z-NRX1 2, -NH-(CH2)Z-RM1,
-C(=O)NH-(CH2)Z-OH, -C(=O)NH-(CH2)Z-ORX1,
-C(=O)NH-(CH2)Z-NH2, -C(=O)NH-(CH2)Z-NHRX1,
-C(=O)NH-(CH2)Z-NRX1 2, -C(=O)NH-(CH2)Z-RM1, -NHC(=O)-(CH2)Z-OH, -NHC(=O)-(CH2)Z-ORX1,
-NHC(=O)-(CH2)Z-NH2, -NHC(=O)-(CH2)Z-NHRX1,
-NHC(=O)-(CH2)Z-NRX1 2, and -NHC(=O)-(CH2)Z-RM1, wherein: each z is independently 2 or 3; each -RX1 is independently saturated aliphatic C^alkyl; and each -RM1 is independently piperidino, piperizino, or morpholino, and is optionally substituted with one or more saturated aliphatic C1-4alkyl groups.
173. A compound according to any one of claims 1 to 139, wherein each -Qc, if present, is independently selected from:
-RX1, -F, -Cl, -Br1 -I, -CF3, -OCF3, -NH-(CH2)Z-OH, -NH-(CH2)Z-ORX1,
-NH-(CH2)Z-NH2, -NH-(CH2)Z-NHRX1, -NH-(CH2)Z-NRX1 2, and -NH-(CH2)2-RM1; wherein: each z is independently 2 or 3; each -RX1 is independently saturated aliphatic C1-4alkyl; and each -RM1 is independently piperidino, piperizino, or morpholino, and is optionally substituted with one or more saturated aliphatic C1-4alkyl groups.
174. A compound according to any one of claims 1 to 139, wherein each -Qc, if present, is independently selected from: -Me, -F, -Cl, -Br, -I, and -CF3.
175. A compound according to any one of claims 1 to 139 and 174, wherein each -QE, if present, is independently selected from:
-RX2,
-RX2A, -CH2-RX2A, -CH2CH2-RX2A, -OH, -ORX2,
-NH2, -NHRX2, -NRX2 2, -RM2,
-0-(CHa)2-OH1 -O-(CH2)Z-ORX2,
-(CH2)Z-OH1 -(CH2)2-ORX2,
-(CH2)Z-NH2, -(CH2)Z-NHRX2, -(CH2)Z-NRX2 2, and -(CH2)Z-RM2; wherein: each z is independently 2 or 3; each -RX2A is independently phenyl, pyridyl, thienyl, piperidinyl, or C3-6cycloalkyl, and is optionally substituted with one or more groups selected from -RX2, -OH,
-0RX2, -NH2, -NHRX2, -NRX2 2, or -RM2; each -RX2 is independently saturated aliphatic C1-4alkyl; and each -RM2 is independently piperidino, piperizino, or morpholino, and is optionally substituted with one or more saturated aliphatic C1-4alkyl groups.
176. A compound according to any one of claims 1 to 175, wherein -QD, if present, is independently selected from: -R3A1, -L3A-NH2, -L3A-NHR3A1, -L3A-NR3A1 2, and -L3A-NR3A2R3A3.
177. A compound according to any one of claims 1 to 175, wherein -QD, if present, is independently selected from: -L3A-NH2, -L3A-NHR3A1, -L3A-NR3A1 2, and -L3A-NR3A2R3A3.
178. A compound according to any one of claims 1 to 175, wherein -QD, if present, is independently selected from: -R3A1, -L3A-OH, and -L3A-OR3A1.
179. A compound according to any one of claims 1 to 175, wherein -QD, if present, is independently selected from: -L3A-OH and -L3A-OR3A1,
180. A compound according to any one of claims 1 to 179, wherein each -L3A-, if present, is independently -(CH2)n3-, wherein n3 is independently 1 to 4.
181. A compound according to any one of claims 1 to 179, wherein each -L3A-, if present, is independently -CH2CH2- or -CH2CH2CH2-.
182. A compound according to any one of claims 1 to 181 , wherein each -NR3A2R3A3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
183. A compound according to any one of claims 1 to 181, wherein each -NR3A2R3A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
184. A compound according to any one of claims 1 to 183, wherein each -R3A1, if present, is independently:
R3B1 o3B4 r>3B6 D3B7 r>3B8 , -r\ , -K , -K , -K , -L3B-R3B4, -L3B-R3B6, -L3B-R3B7, or -L3B-R3B8.
185. A compound according to any one of claims 1 to 183, wherein each -R3A1, if present, is independently: -R3B1, -R3B6, or -L3B-R3B6.
186. A compound according to any one of claims 1 to 183, wherein each -R3A1, if present, is independently: -R3B1, -R3B7, -R3B8, -L3B-R3B7, or -L3B-R3B8.
187. A compound according to any one of claims 1 to 183, wherein each -R3A1, if present, is independently: -R3B1, -R3B7, or -L3B-R3B7.
188. A compound according to any one of claims 1 to 183, wherein each -R3A1, if present, is independently: -R3B7, -R3B8, -L3B-R3B7, or -L3B-R3B8.
189. A compound according to any one of claims 1 to 188, wherein each -R3Be, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
190. A compound according to any one of claims 1 to 188, wherein each -R3B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
191. A compound according to any one of claims 1 to 190, wherein each -R3B7, if present, is independently phenyl, and is optionally substituted.
192. A compound according to any one of claims 1 to 191 , wherein each -R3B8, if present, is independently C5-6heteroaryl, and is optionally substituted.
193. A compound according to any one of claims 1 to 191 , wherein each -R3B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
194. A compound according to any one of claims 1 to 191..wherein each -R3B8, if present, is independently C9-10heteroaryl, and is optionally substituted.
195. A compound according to any one of claims 1 to 191, wherein each -R3B8, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.
196. A compound according to any one of claims 1 to 195, wherein each -L3B-, if present, is independently -CH2- or -CH3CH2-.
197. A compound according to any one of claims 1 to 195, wherein each -L3B-, if present, is independently -CH2-.
198. A compound according to any one of claims 1 to 197, wherein each -R3C1, if present, is independently saturated aliphatic d^alkyl.
199. A compound according to any one of claims 1 to 198, wherein each -R302 is independently:
-F, -Cl, -Br, -I, -OH, -OR3D1, -CN, -NO2,
-NH2, -NHR3D1, -NR3D1 2, or -NR302R303.
200. A compound according to any one of claims 1 to 199, wherein each -R301, if present, is independently saturated aliphatic C1-4alkyl.
201. A compound according to any one of claims 1 to 200, wherein each -L3D-, if present, is independently -(CH2)m3-, wherein m3 is independently 1 to 4.
202. A compound according to any one of claims 1 to 200, wherein each -L30-, if present, is independently -CH2- or -CH3CH2-.
203. A compound according to any one of claims 1 to 202, wherein each -NR302R303, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
204. A compound according to any one of claims 1 to 202, wherein each -NR302R303, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1-3alkyl, -CF3, and -F.
205. A compound according to any one of claims 1 to 175, wherein each -QD, if present, is independently selected from: -RX3, -CH2CH2-OH, -CH2CH2-ORX3,
-CH2CH2CH2-OH, -CH2CH2CH2-ORX3, -CH2CH2-NH2, -CH2CH2-NHRX3, -CH2CH2-NRX3 2, -CH2CH2CH2-NH2, -CH2CH2CH2-NHR^, and -CH2CH2CH2-NRX3 2; wherein each -RX3 is independently saturated aliphatic C1-4alkyl.
206. A compound according to claim 1 , selected from the following compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof: Compound Nos. AA-001 through AA-072.
207. A compound according to claim 1 , selected from the following compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof: Compound Nos. BB-001 through BB-028.
208. A compound according to claim 1, selected from the following compound, and pharmaceutically acceptable salts, hydrates, and solvates thereof: Compound No. CC-001. * * *
209. A pharmaceutical composition comprising a compound according to any one of claims 1 to 208, and a pharmaceutically acceptable carrier or diluent.
210. A method of preparing a pharmaceutical composition comprising the step of admixing a compound according to any one of claims 1 to 208, and a pharmaceutically acceptable carrier or diluent.
211. A compound according to any one of claims 1 to 208, for use in a method of treatment of the human or animal body by therapy.
212. A compound according to any one of claims 1 to 208, without the recited proviso, for use in a method of treatment of a disease or condition that is mediated by
CHK1.
213. A compound according to any one of claims 1 to 208, without the recited proviso, for use in a method of treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function.
214. A compound according to any one of claims 1 to 208, without the recited proviso, for use in a method of treatment of a proliferative condition.
215. A compound according to any one of claims 1 to 208, without the recited proviso, for use in a method of treatment of cancer.
216. A compound according to any one of claims 1 to 208, without the recited proviso, for use in a method of treatment of p53 cancer.
217. A compound according to any one of claims 1 to 208, without the recited proviso, for use in a method of treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
218. A compound according to any one of claims 211 to 217, wherein the treatment further comprises treatment with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
219. Use of a compound according to any one of claims 1 to 208, without the recited proviso, in the manufacture of a medicament for the treatment of a disease or condition that is mediated by CHK1.
220. Use of a compound according to any one of claims 1 to 208, without the recited proviso, in the manufacture of a medicament for the treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function.
221. Use of a compound according to any one of claims 1 to 208, without the recited proviso, in the manufacture of a medicament for the treatment of a proliferative condition.
222. Use of a compound according to any one of claims 1 to 208, without the recited proviso, in the manufacture of a medicament for the treatment of cancer.
223. Use of a compound according to any one of claims 1 to 208, without the recited proviso, in the manufacture of a medicament for the treatment of p53 cancer.
224. Use of a compound according to any one of claims 1 to 208, without the recited proviso, in the manufacture of a medicament for the treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
225. Use according to any one of claims 219 to 224, wherein the treatment further comprises treatment with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
226. A method of treatment of a disease or condition that is mediated by CHK1 comprising administering to a subject in need of treatment a therapeutically- effective amount of a compound according to any one of claims 1 to 208, without the recited proviso.
227. A method of treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 208, without the recited proviso.
228. A method of treatment of a proliferative condition comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 208, without the recited proviso.
229. A method of treatment of cancer comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 208, without the recited proviso.
230. A method of treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 208, without the recited proviso.
231. A method according to any one of claims 226 to 230, wherein the treatment further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
232. A method of inhibiting CHK1 kinase function, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 208, without the recited proviso.
233. A method of inhibiting CHK1 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 208, without the recited proviso.
234. A method of inhibiting cell proliferation, inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 208, without the recited proviso.
PCT/GB2009/000438 2008-02-19 2009-02-19 Bicyclylaryl-aryl-amine compounds and their use Ceased WO2009103966A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP09712330.1A EP2288601B1 (en) 2008-02-19 2009-02-19 Bicyclylaryl-aryl-amine compounds and their use
US12/918,266 US8530468B2 (en) 2008-02-19 2009-02-19 Bicyclylaryl-aryl-amine compounds and their use
ES09712330.1T ES2527519T3 (en) 2008-02-19 2009-02-19 Bicyclyl-aryl-amine compounds and their use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US2962108P 2008-02-19 2008-02-19
US61/029,621 2008-02-19
GB0803018.1 2008-02-19
GBGB0803018.1A GB0803018D0 (en) 2008-02-19 2008-02-19 Therapeutic compounds and their use

Publications (1)

Publication Number Publication Date
WO2009103966A1 true WO2009103966A1 (en) 2009-08-27

Family

ID=39271933

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2009/000438 Ceased WO2009103966A1 (en) 2008-02-19 2009-02-19 Bicyclylaryl-aryl-amine compounds and their use

Country Status (5)

Country Link
US (1) US8530468B2 (en)
EP (1) EP2288601B1 (en)
ES (1) ES2527519T3 (en)
GB (1) GB0803018D0 (en)
WO (1) WO2009103966A1 (en)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011121555A1 (en) 2010-03-31 2011-10-06 Actelion Pharmaceuticals Ltd Antibacterial isoquinolin-3-ylurea derivatives
WO2012123745A1 (en) 2011-03-14 2012-09-20 Cancer Research Technology Limited Pyrrolopyridineamino derivatives as mps1 inhibitors
WO2013068755A1 (en) 2011-11-09 2013-05-16 Cancer Research Technology Limited 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
WO2013117646A1 (en) * 2012-02-10 2013-08-15 Galapagos Nv Novel compound useful for the treatment of degenerative and inflammatory diseases
WO2013117649A1 (en) * 2012-02-10 2013-08-15 Galapagos Nv Imidazo [4, 5 -c] pyridine derivatives useful for the treatment of degenerative and inflammatory diseases
US8530468B2 (en) 2008-02-19 2013-09-10 Cancer Research Technology Limited Bicyclylaryl-aryl-amine compounds and their use
WO2013171470A1 (en) 2012-05-15 2013-11-21 Cancer Research Technology Limited 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile and therapeutic uses thereof
WO2014111380A1 (en) * 2013-01-17 2014-07-24 Galapagos Nv Novel compound useful for the treatment of degenerative and inflammatory diseases
EP2818472A1 (en) * 2013-06-27 2014-12-31 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Imidazo[4,5-c]pyridine and pyrrolo[3,2-c]pyridine compounds as G-protein-coupled receptor kinase 5 (GRK5) modulators
US9334286B2 (en) 2012-09-07 2016-05-10 Cancer Research Technology Limited Pharmacologically active compounds
US9409907B2 (en) 2012-09-07 2016-08-09 Cancer Research Technology Limited Inhibitor compounds
JP2017504628A (en) * 2014-01-31 2017-02-09 小野薬品工業株式会社 Condensed imidazole compounds
WO2017114351A1 (en) * 2015-12-27 2017-07-06 Chongqing Fochon Pharmaceutical Co., Ltd. Certain protein kinase inhibitors
US9902721B2 (en) 2014-02-28 2018-02-27 Cancer Research Technology Limited N2-phenyl-pyrido[3,4-d]pyrimidine-2, 8-diamine derivatives and their use as Mps1 inhibitors
CN107857737A (en) * 2017-11-16 2018-03-30 贵州大学 A kind of preparation technology of the chloropyrazine of 2 bromine 3,5,6 3
CN110437062A (en) * 2019-08-23 2019-11-12 成都美域高制药有限公司 It is a kind of how the synthetic method of his your intermediate of ground
JP2021532109A (en) * 2018-07-24 2021-11-25 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト Isoquinoline compounds and their use
US11207321B2 (en) 2017-06-20 2021-12-28 The Institute Of Cancer Research: Royal Cancer Hospital Methods and medical uses
WO2022146920A1 (en) * 2020-12-28 2022-07-07 Celgene Corporation Heterocyclic compounds and their use for parasitic diseases
US11534441B2 (en) 2020-01-15 2022-12-27 Blueprint Medicines Corporation MAP4K1 inhibitors
US11566003B2 (en) 2017-03-30 2023-01-31 Genentech, Inc. Isoquinolines as inhibitors of HPK1
US11612606B2 (en) 2018-10-03 2023-03-28 Genentech, Inc. 8-aminoisoquinoline compounds and uses thereof
US12202844B2 (en) 2021-07-14 2025-01-21 Blueprint Medicines Corporation MAP4K1 inhibitors
US12331063B2 (en) 2021-04-29 2025-06-17 Incyte Corporation Hetero-bicyclic inhibitors of KRAS
US12473301B2 (en) 2018-10-02 2025-11-18 Genentech, Inc. Isoquinoline compounds for the treatment of cancer

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0719644D0 (en) 2007-10-05 2007-11-14 Cancer Rec Tech Ltd Therapeutic compounds and their use
WO2013169793A2 (en) * 2012-05-09 2013-11-14 Ipierian, Inc. Methods and compositions for tdp-43 proteinopathies
CN112839648B (en) 2018-06-07 2025-04-04 达萨玛治疗公司 SARM1 inhibitors
EP3860980A1 (en) * 2018-10-03 2021-08-11 F. Hoffmann-La Roche AG 8-aminoisoquinoline compounds and uses thereof
JP7212781B2 (en) 2018-12-19 2023-01-25 ディスアーム セラピューティクス， インコーポレイテッド Inhibitors of SARM1 in combination with neuroprotective agents

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035065A1 (en) * 2001-10-26 2003-05-01 Aventis Pharmaceuticals Inc Benzimidazoles and analogues and their use as protein kinases inhibitors
WO2003093297A2 (en) * 2002-05-03 2003-11-13 Exelixis, Inc. Protein kinase modulators and methods of use
WO2005011597A2 (en) * 2003-07-29 2005-02-10 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2005034869A2 (en) * 2003-10-08 2005-04-21 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2007000240A1 (en) * 2005-06-28 2007-01-04 Sanofi-Aventis Isoquinoline derivatives as inhibitors of rho-kinase
WO2008077554A1 (en) * 2006-12-27 2008-07-03 Sanofi-Aventis Cycloalkylamine substituted isoquinoline derivatives

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2292812T3 (en) 2001-10-19 2008-03-16 Ortho-Mcneil Pharmaceutical, Inc. 2-FENIL BENZIMIDAZOL AND IMIDAZO- (4,5) -PIRIDINAS AS INHIBITORS OF CDS1 / CHK2 AND COADYUVANTS FOR CHEMOTHERAPY OR RADIOTHERAPY IN THE TREATMENT OF CANCER.
AU2003243318A1 (en) 2002-05-29 2003-12-19 Millennium Pharmaceuticals, Inc. Diarylurea compounds and derivatives as chk-1 inhibitors for the treatment of cancer
AU2004281154A1 (en) 2003-10-16 2005-04-28 Novartis Vaccines And Diagnostics, Inc. 2,6-disubstituted quinazolines, quinoxalines, quinolines and isoquinolines as inhibitors of Raf kinase for treatment of cancer
AU2005252160A1 (en) 2004-04-13 2005-12-22 Astellas Pharma Inc. Polycyclic pyrazines as potassium ion channel modulators
US20070054916A1 (en) 2004-10-01 2007-03-08 Amgen Inc. Aryl nitrogen-containing bicyclic compounds and methods of use
DK2134689T3 (en) 2007-03-16 2014-06-30 Scripps Research Inst Focal adhesion kinase inhibitors
GB0719644D0 (en) 2007-10-05 2007-11-14 Cancer Rec Tech Ltd Therapeutic compounds and their use
GB0803018D0 (en) 2008-02-19 2008-03-26 Cancer Rec Tech Ltd Therapeutic compounds and their use

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035065A1 (en) * 2001-10-26 2003-05-01 Aventis Pharmaceuticals Inc Benzimidazoles and analogues and their use as protein kinases inhibitors
WO2003093297A2 (en) * 2002-05-03 2003-11-13 Exelixis, Inc. Protein kinase modulators and methods of use
WO2005011597A2 (en) * 2003-07-29 2005-02-10 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2005034869A2 (en) * 2003-10-08 2005-04-21 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2007000240A1 (en) * 2005-06-28 2007-01-04 Sanofi-Aventis Isoquinoline derivatives as inhibitors of rho-kinase
WO2008077554A1 (en) * 2006-12-27 2008-07-03 Sanofi-Aventis Cycloalkylamine substituted isoquinoline derivatives

Cited By (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8530468B2 (en) 2008-02-19 2013-09-10 Cancer Research Technology Limited Bicyclylaryl-aryl-amine compounds and their use
WO2011121555A1 (en) 2010-03-31 2011-10-06 Actelion Pharmaceuticals Ltd Antibacterial isoquinolin-3-ylurea derivatives
CN103517903A (en) * 2011-03-14 2014-01-15 癌症研究科技有限公司 Pyrrolopyridineamino derivatives as MPS1 inhibitors
WO2012123745A1 (en) 2011-03-14 2012-09-20 Cancer Research Technology Limited Pyrrolopyridineamino derivatives as mps1 inhibitors
AU2012228090B2 (en) * 2011-03-14 2017-03-30 Cancer Research Technology Limited Pyrrolopyridineamino derivatives as Mps1 inhibitors
CN103517903B (en) * 2011-03-14 2017-03-01 癌症研究科技有限公司 Pyrrolopyridine aminoderivative as MPS1 inhibitor
US9371319B2 (en) 2011-03-14 2016-06-21 Cancer Research Technology Limited Pyrrolopyridineamino derivatives as MPS1 inhibitors
JP2014508185A (en) * 2011-03-14 2014-04-03 キャンサー・リサーチ・テクノロジー・リミテッド Pyrrolopyridine amino derivatives as Mps1 inhibitors
JP2014532751A (en) * 2011-11-09 2014-12-08 キャンサー・リサーチ・テクノロジー・リミテッド 5- (Pyridin-2-yl-amino) -pyrazine-2-carbonitrile compound and therapeutic use thereof
CN104105696B (en) * 2011-11-09 2017-11-14 癌症研究技术有限公司 The nitrile compound of 5 (the base amino of pyridine 2) pyrazine 2 and its therapeutical uses
AU2012335409B2 (en) * 2011-11-09 2017-07-13 Cancer Research Technology Limited 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
CN104105696A (en) * 2011-11-09 2014-10-15 癌症研究技术有限公司 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
US9765059B2 (en) 2011-11-09 2017-09-19 Cancer Research Technology Limited 5-(Pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
WO2013068755A1 (en) 2011-11-09 2013-05-16 Cancer Research Technology Limited 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
US9040540B2 (en) 2011-11-09 2015-05-26 Cancer Research Technology Limited 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
RU2641693C2 (en) * 2011-11-09 2018-01-22 Кансер Ресёрч Текнолоджи Лимитед 5-(pyridine-2-ylamino)-pyrasin-2-carbonitrile compounds and their therapeutic application
US9403797B2 (en) 2011-11-09 2016-08-02 Cancer Research Technology Limited 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
WO2013117646A1 (en) * 2012-02-10 2013-08-15 Galapagos Nv Novel compound useful for the treatment of degenerative and inflammatory diseases
WO2013117649A1 (en) * 2012-02-10 2013-08-15 Galapagos Nv Imidazo [4, 5 -c] pyridine derivatives useful for the treatment of degenerative and inflammatory diseases
WO2013117645A1 (en) * 2012-02-10 2013-08-15 Galapagos Nv Imidazo [4, 5 -c] pyridine derivatives useful for the treatment of degenerative and inflammatory diseases
US10259806B2 (en) 2012-05-15 2019-04-16 Cancer Research Technology Limited 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2 pyridyl]amino]pyrazine-2-carbonitrile and therapeutic uses thereof
JP2017036314A (en) * 2012-05-15 2017-02-16 キャンサー・リサーチ・テクノロジー・リミテッド 5-[[4-[[morpholine-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile and therapeutic use thereof
JP2015520753A (en) * 2012-05-15 2015-07-23 キャンサー・リサーチ・テクノロジー・リミテッド 5-[[4-[[morpholin-2-yl] methylamino] -5- (trifluoromethyl) -2-pyridyl] amino] pyrazine-2-carbonitrile and its therapeutic use
WO2013171470A1 (en) 2012-05-15 2013-11-21 Cancer Research Technology Limited 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile and therapeutic uses thereof
US9663503B2 (en) 2012-05-15 2017-05-30 Cancer Research Technology Limited 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile and therapeutic uses thereof
EP3210980A1 (en) 2012-05-15 2017-08-30 Cancer Research Technology Limited Process for manufacturing 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)- 2-pyridyl]amino]pyrazine-2-carbonitrile
US11787792B2 (en) 2012-05-15 2023-10-17 Cancer Research Technology Limited 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2 Pyridyl]Amino]Pyrazine-2-carbonitrile and therapeutic uses thereof
US9834552B2 (en) 2012-09-07 2017-12-05 Cancer Research Technology Limited Inhibitor compounds
US10479788B2 (en) 2012-09-07 2019-11-19 Cancer Research Technology Limited Compounds that inhibit MPS1 kinase
US11046688B2 (en) 2012-09-07 2021-06-29 Cancer Research Technology Limited Inhibitor compounds
US11897877B2 (en) 2012-09-07 2024-02-13 Cancer Research Technology Limited Inhibitor compounds
US9409907B2 (en) 2012-09-07 2016-08-09 Cancer Research Technology Limited Inhibitor compounds
US9334286B2 (en) 2012-09-07 2016-05-10 Cancer Research Technology Limited Pharmacologically active compounds
US9890157B2 (en) 2012-09-07 2018-02-13 Cancer Research Technology Limited Inhibitor compounds
US9895364B2 (en) 2012-09-07 2018-02-20 Cancer Research Technology Limited Pharmacologically active compounds
US10188642B2 (en) 2012-09-07 2019-01-29 Cancer Research Technology Limited Pharmacologically active compounds
WO2014111380A1 (en) * 2013-01-17 2014-07-24 Galapagos Nv Novel compound useful for the treatment of degenerative and inflammatory diseases
EP2818472A1 (en) * 2013-06-27 2014-12-31 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Imidazo[4,5-c]pyridine and pyrrolo[3,2-c]pyridine compounds as G-protein-coupled receptor kinase 5 (GRK5) modulators
US10016439B2 (en) 2014-01-31 2018-07-10 Ono Pharmaceutical Co., Ltd. Fused imidazole compounds
JP2017504628A (en) * 2014-01-31 2017-02-09 小野薬品工業株式会社 Condensed imidazole compounds
EP3099672A4 (en) * 2014-01-31 2017-09-20 ONO Pharmaceutical Co., Ltd. Fused imidazole compounds
US9902721B2 (en) 2014-02-28 2018-02-27 Cancer Research Technology Limited N2-phenyl-pyrido[3,4-d]pyrimidine-2, 8-diamine derivatives and their use as Mps1 inhibitors
US10399974B2 (en) 2014-02-28 2019-09-03 Cancer Research Technology Limited N2-phenyl-pyrido[3,4-D]pyrimidine-2, 8-diamine derivatives and their use as Mps1 inhibitors
EP3575299A1 (en) 2014-02-28 2019-12-04 Cancer Research Technology Limited N2-phenyl-pyrido[3,4-d]pyrimidine-2,8-diamine derivatives and their use as mps1 inhibitors
WO2017114351A1 (en) * 2015-12-27 2017-07-06 Chongqing Fochon Pharmaceutical Co., Ltd. Certain protein kinase inhibitors
CN108779117A (en) * 2015-12-27 2018-11-09 重庆复创医药研究有限公司 Kinase inhibitor
US11566003B2 (en) 2017-03-30 2023-01-31 Genentech, Inc. Isoquinolines as inhibitors of HPK1
US11207321B2 (en) 2017-06-20 2021-12-28 The Institute Of Cancer Research: Royal Cancer Hospital Methods and medical uses
CN107857737A (en) * 2017-11-16 2018-03-30 贵州大学 A kind of preparation technology of the chloropyrazine of 2 bromine 3,5,6 3
JP2021532109A (en) * 2018-07-24 2021-11-25 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト Isoquinoline compounds and their use
JP7386841B2 (en) 2018-07-24 2023-11-27 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Isoquinoline compounds and their uses
US12378249B2 (en) 2018-07-24 2025-08-05 Genentech, Inc. Isoquinoline compounds and uses thereof
US12473301B2 (en) 2018-10-02 2025-11-18 Genentech, Inc. Isoquinoline compounds for the treatment of cancer
US11612606B2 (en) 2018-10-03 2023-03-28 Genentech, Inc. 8-aminoisoquinoline compounds and uses thereof
CN110437062B (en) * 2019-08-23 2022-07-05 成都美域高制药有限公司 Synthetic method of neratide intermediate
CN110437062A (en) * 2019-08-23 2019-11-12 成都美域高制药有限公司 It is a kind of how the synthetic method of his your intermediate of ground
US11534441B2 (en) 2020-01-15 2022-12-27 Blueprint Medicines Corporation MAP4K1 inhibitors
US12042495B2 (en) 2020-01-15 2024-07-23 Blueprint Medicines Corporation MAP4K1 inhibitors
WO2022146920A1 (en) * 2020-12-28 2022-07-07 Celgene Corporation Heterocyclic compounds and their use for parasitic diseases
US12331063B2 (en) 2021-04-29 2025-06-17 Incyte Corporation Hetero-bicyclic inhibitors of KRAS
US12202844B2 (en) 2021-07-14 2025-01-21 Blueprint Medicines Corporation MAP4K1 inhibitors

Also Published As

Publication number Publication date
GB0803018D0 (en) 2008-03-26
EP2288601A1 (en) 2011-03-02
US20100331328A1 (en) 2010-12-30
ES2527519T3 (en) 2015-01-26
US8530468B2 (en) 2013-09-10
EP2288601B1 (en) 2014-10-15

Similar Documents

Publication Publication Date Title
EP2288601B1 (en) Bicyclylaryl-aryl-amine compounds and their use
EP2170886A1 (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
EP2197874B1 (en) Pyrazin-2-yl-pyridin-2-yl-amine and pyrazin-2-yl-pyrimidin-4-yl-amine compounds and their use
EP2822656B1 (en) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
AU2017268508C1 (en) 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile and therapeutic uses thereof
EP2227460B1 (en) Therapeutic oxy-phenyl-aryl compounds and their use
WO2008075007A1 (en) Morpholino-substituted bicycloheteroaryl compounds and their use as anti cancer agents
DK3044221T3 (en) 3-ARYL-5-SUBSTITUTED-ISOQUINOLIN-1-ON COMPOUNDS AND THERAPEUTIC APPLICATION THEREOF
NZ584760A (en) Polo-like kinase inhibitors
AU2016254385A1 (en) JAK inhibitors
CN105073751A (en) Novel substituted imidazoles as casein kinase 1 [delta]/[epsilon] inhibitors
CA2849566C (en) 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
WO2010007389A1 (en) 5 -amidothiazole derivatives and their use as checkpoint kinase inhibitors

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: 09712330

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 12918266

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2009712330

Country of ref document: EP