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WO2015025172A1 - Composés 5-aryl-thiazol -2-yl-amine et leur utilisation thérapeutique - Google Patents

Composés 5-aryl-thiazol -2-yl-amine et leur utilisation thérapeutique Download PDF

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WO2015025172A1
WO2015025172A1 PCT/GB2014/052574 GB2014052574W WO2015025172A1 WO 2015025172 A1 WO2015025172 A1 WO 2015025172A1 GB 2014052574 W GB2014052574 W GB 2014052574W WO 2015025172 A1 WO2015025172 A1 WO 2015025172A1
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independently
jjj
compound according
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Mark David Charles
Joanna Lola BROOKFIELD
Chukuemeka Tennyson Ekwuru
Martin Lee Stockley
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain 5-aryl-thiazol-2-yl-amine compounds (for convenience, collectively referred to herein as "5AT2A compounds"), which, inter alia, inhibit LIM kinase (LIMK) activity.
  • 5-aryl-thiazol-2-yl-amine compounds for convenience, collectively referred to herein as "5AT2A compounds”
  • LIMK LIM kinase
  • 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 LIMK activity, and in the treatment of diseases and conditions that are mediated by LIMK, that are ameliorated by the inhibition of LIMK activity, etc., including proliferative conditions such as cancer (e.g., breast cancer, prostate cancer, melanoma, glioma, etc.), as well as vasodilation (including, e.g., hypertension, angina, cerebral vasospasm, and ischemia following subarachnoid hemorrhage), neurodegenerative disorders, atherosclerosis, fibrosis, and inflammatory diseases (including, e.g., Crohn's disease and chronic obstructive pulmonary disease (COPD)), and glaucoma (also known as ocular hypertension).
  • cancer e.g., breast cancer, prostate cancer, melanoma, glioma, etc.
  • 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.
  • LIMK LIM kinase
  • Rho family of GTPases There are two members of the family, LIMK1 and LIMK2, both of which are directly involved in regulating multiple cellular processes via their ability to reorganise the actin-cytoskeleton network (see, e.g., Scott et al., 2007).
  • LIMKs share 50% homology (see, e.g., Mizuno et al., 1994; Nunoue et al., 1995). They are composed of two N-terminal LIM domains, each of which contains a double zinc-finger motif.
  • the LIM domains play an important role in regulating kinase activity (see, e.g., Nagata et al., 1999; Tomiyoshi et al., 2004) and may also contribute to LIMK function by mediating protein-to-protein and protein-to- DNA interactions (see, e.g., Hiraoka et al., 1996; Nishiya et al., 1998).
  • a proline/serine rich region then follows with the kinase domain of the protein being located at the extreme C-terminus.
  • the kinase domains of LIMK1 and LIMK2 are 70% identical and phosphorylation within the activation loop enhances their activity.
  • LIMK is activated via a number of signalling networks downstream of growth factors, integrins and cytokines (for a comprehensive review see, e.g., Scott et al., 2007).
  • Rho effector Rho kinase
  • ROCK Rho kinase
  • Thr-508 on LIMK1 or Thr-505 LIMK2 modifications that are essential for kinase activation
  • Pak1 see, e.g., Edwards et al., 1999
  • Pak4 see, e.g., Dan et al., 2001
  • MRCKa myotonic dystrophy kinase- related Cdc42-binding kinase
  • MRCKa myotonic dystrophy kinase- related Cdc42-binding kinase
  • MRCKa myotonic dystrophy kinase- related Cdc42-binding kinase
  • MRCKa myotonic dystrophy kinase- related Cdc42-binding kinase
  • MRCKa myotonic dystrophy kinase- related Cdc42-binding
  • LIMK1 Transphosphorylation of LIMK1 , following association with HSP90, has been shown to increase the half life of the protein and increases its specific activity (see, e.g., Li et al., 2006). Autophosphorylation of LIMK also occurs, although the site of phosphorylation and functional consequence remains uncertain (see, e.g., Kobayashi et al., 2006; Proschel et al., 1995). Conversely, LIMK is subject to deactivation by the direct action of phosphatases.
  • Slingshotl (SSH1) binds directly to the kinase domain and dephosphorylates LIMK1 on Thr-508 and additional autophosphorylated serine residues resulting in decreased activity (see, e.g., Soosairajah et al., 2005).
  • cofilin family of proteins cofilinl (non-muscle cofilin), cofilin2 (muscle cofilin) and destrin (also known as actin depolymerizing factor, ADF).
  • cofilinl non-muscle cofilin
  • cofilin2 muscle cofilin
  • destrin also known as actin depolymerizing factor, ADF.
  • Unphosphorylated active cofilin binds to actin filaments in vivo, depolymerises filamentous actin (F-actin), and produces free barbed ends that serve to nucleate new actin filaments (see, e.g., Ghosh et al., 2004; Lorenz et al., 2004). Ultimately it is a balance between phosphorylated and
  • LIMK dephosphorylated cofilin that determines a cell's ability to reorganise the cytoskeleton, controlling cell shape and influencing its ability to move, invade or metastasise.
  • LIMK reorganises actin-cytoskeleton dynamics through direct phosphorylation of cofilin on serine-3 resulting in its inactivation and subsequent inhibition of its actin-severing activity (see, e.g., Maekawa et al., 1999; Sumi et al., 1999). Through this modulation of the actin- cytoskeleton, LIMK is implicated to play pivotal a role in several human diseases with inhibition via small molecule kinase inhibitors having potential utility.
  • LIMK and Cancer Enhanced LIMK activity has been associated with tumour types.
  • LIMK1 has been found unregulated via chromosomal translocation in malignant melanoma cells (see, e.g., Okamoto et al., 2005), breast cancer tumours (see, e.g., Bagheri-Yarmand et al., 2006) and breast cancer cell lines (see, e.g., Yoshioka et al., 2003), in prostate tumours (see, e.g., Davila et al., 2003) and prostate cancer cell lines (see, e.g., Bagheri-Yarmand et al., 2006; Yoshioka et al., 2003).
  • LIMK expression levels have been linked to tumour cell growth. For example, reduction in LIMK1 caused a decrease in prostate cancer cell proliferation, arresting cells in G2/M (see, e.g., Davila et al., 2003). Similarly, lowering expression of LIMK2 in human fibrosarcoma cells limited their ability to form colonies in a long term growth assay (see, e.g., Suyama et al., 2004). LIMK has been reported to modify the p53 pathway (see, e.g., Freidman et al., 2002).
  • p53 is a potent tumour suppressor protein which is stabilised in response to cellular stress signals to induce cell-cycle arrest or apoptosis depending on signal strength and duration (see, e.g., Vousden et al., 2009).
  • LIMK regulates p53 signalling however remains unclear.
  • LIMK1 has been shown to increase the motility and invasive capacity of tumour cells in several different systems.
  • Overexpression of LIMK1 increased motility, invasiveness and metastatic ability of human breast cancer cells (see, e.g., Bagheri- Yarmand et al., 2006; Yoshioka et al., 2003) as well as increasing the invasive phenotype of benign prostate cells (see, e.g., Davila et al., 2003).
  • LIMK and Glaucoma Glaucoma is one of the leading causes of irreversible blindness in the world. It is characterized by degeneration of the optic nerve and progressive visual field loss and is often associated with elevated intraocular pressure (IOP) (see, e.g., Ferrer, 2006).
  • IOP intraocular pressure
  • the actin cytoskeleton network is thought to be an important modulator of IOP and
  • LIMK has been proposed to play a role in regulating IOP.
  • Downregulation of LIMK1 with short-interfering RNA in cultured corneal fibroblasts was shown to reduce actin polymerization, focal adhesion formation and delay cell migration.
  • deletion or downregulation of LIMK1 significantly reduced ocular inflammation (see, e.g., Gorovoy et al., 2008).
  • LIMK inhibitors have been proposed for the treatment of glaucoma (see, e.g., Hizaki et al., 2004; Harrison et al., 2009; Burgoon et al., 2009).
  • 5-aryl-thiazol-2-yl-amine compounds for convenience, collectively referred to herein as “5AT2A compounds"
  • 5AT2A compounds certain 5-aryl-thiazol-2-yl-amine compounds
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a 5AT2A compound, as described herein, and a
  • Another aspect of the invention pertains to method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of admixing a 5AT2A compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • a composition e.g., a pharmaceutical composition
  • Another aspect of the present invention pertains to a method of inhibiting LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a 5AT2A compound, as described herein.
  • LIMK LIM kinase
  • 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 5AT2A compound, as described herein.
  • 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 5AT2A compound, as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to a 5AT2A compound as described herein for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of a 5AT2A compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the treatment is treatment of a disease or condition that is mediated by LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2).
  • LIMK LIM kinase
  • the treatment is treatment of a disease or condition that is
  • the treatment is treatment of a proliferative condition. In one embodiment, the treatment is treatment of cancer.
  • the treatment is treatment of cancer characterised by, or further characterised by, cancer cells which overexpress LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2).
  • LIMK LIM kinase
  • the treatment is treatment of solid tumour cancer.
  • the treatment is treatment of breast cancer, prostate cancer, melanoma, or glioma. In one embodiment, the treatment is treatment of vasodilation.
  • the treatment is treatment of hypertension, angina, cerebral vasospasm, or ischemia following subarachnoid hemorrhage. In one embodiment, the treatment is treatment of a neurodegenerative disorder.
  • the treatment is treatment of atherosclerosis.
  • the treatment is treatment of fibrosis.
  • the treatment is treatment of an inflammatory disease.
  • the treatment is treatment of Crohn's disease or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the treatment is treatment of glaucoma (also known as ocular hypertension).
  • kits comprising (a) a
  • 5AT2A compound as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging;
  • instructions for use for example, written instructions on how to administer the compound.
  • Another aspect of the present invention pertains to a 5AT2A 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 5AT2A 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.
  • features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.
  • the compounds are also characterized by (a) the lack of a substituent at the 4-position of the thiazol-2-yl group, (b) the presence of an aromatic substituent positioned ortho to the thiazol-2-yl group, and (c) the presence of a nitrogen group (i.e., an amine, an amide, a carbamate, a urea, or a sulphonamide) at the 2-position of the thiazol-2-yl, for example, as shown below:
  • one aspect of the present invention pertains to compounds selected from compounds of the following formula, and salts, hydrates, and solvates thereof
  • a compound is selected from compounds having the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • each -R V2 s independently -H or -R T
  • each -R V3 s independently -H or -R T and
  • each -R TT is independently saturated aliphatic or saturated C3-ecycloalkyl; and wherein:
  • -Q is independently -Q CA or -Q HA ;
  • -Q CA is independently phenyl
  • -Q HA is independently Cs-6heteroaryl
  • each -R pp is independently:
  • two adjacent groups -R pp may form -0-CH 2 -0-, -0-CH 2 CH 2 -0-, -CH 2 -0-CH 2 -, or -0-CH 2 CH 2 -; wherein: each -R R is independently saturated aliphatic Ci-ealkyl, saturated C3-6cycloalkyl, phenyl, or -CH 2 -phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR RR , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R RR , -CF3, -OH, -OR RR , or -OCF3, wherein each -R RR is independently saturated aliphatic Ci-4alkyl;
  • each -R is independently aliphatic C 2 -6alkenyl
  • each -M R is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, or azepino, each optionally substituted, for example, with one or more groups selected from saturated aliphatic
  • each -L R - is independently saturated aliphatic C 2 -4alkylene
  • each -R K is independently saturated aliphatic and wherein:
  • each -R N is independently saturated aliphatic
  • each -M J is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, or azepino, each optionally substituted, for example, with one or more groups selected from saturated aliphatic Ci ⁇ alkyl
  • each -R J is independently:
  • each -R J is independently saturated aliphatic Ci-ealkyl
  • each -R J2 is independently saturated aliphatic Ci-ealkyl, and is substituted with one or more groups -R J2X ;
  • each -R J3 is independently saturated C3- 7 cycloalkyl, and is optionally substituted, for example, with one or more groups -R JJ ;
  • each -R J4 is independently non-aromatic C3-6heterocyclyl, and is optionally substituted, for example, with one or more groups -R JJ ;
  • each -R J5 is independently phenyl, and is optionally substituted, for example, with one or more groups -R JJ ;
  • each -R J6 is independently Cs-6heteroaryl, and is optionally substituted, for example, with one or more groups -R JJ ;
  • each -L J - is independently saturated aliphatic Ci-4alkylene; wherein: each -R J2X is independently -OH , -OR J2XX , -N H 2 , -N H R J2XX , -N R J2XX 2 , pyrrolidino, piperidino, piperizino, N-(Ci-4alkyl)piperizino, or morpholino;
  • each -R J2XX is independently saturated aliphatic
  • each -R JJ is independently:
  • each -R JJJ is independently saturated aliphatic Ci-4alkyl or saturated C3-6cycloalkyl
  • each -L JJJ - is independently saturated aliphatic C ⁇ alkylene.
  • N(0)- denotes an N-oxide, as in, for example:
  • each -R V if present, is independently -H or -R T ;
  • each -R V2 if present, is independently -H or -R T ;
  • each -R V3 if present, is independently -H or -R T ;
  • each -R V4 if present, is independently -H or -R T .
  • each -R V if present, is independently -H;
  • each -R V2 if present, is independently -H;
  • each -R V3 if present, is independently -H;
  • each -R V4 if present, is independently -H.
  • -R V2 is independently -H or -R T ;
  • each -R V3 is independently -H or -R T ;
  • each -R TT is independently saturated aliphatic or saturated C3-6cycloalkyl.
  • each -R TT is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R T is independently: -F, -CI, -Me, -Et, -OH, -OMe, -OEt, -NH 2 , -NHMe, or -NMe 2 .
  • the Group -Q is independently: -F, -CI, -Me, -Et, -OH, -OMe, -OEt, -NH 2 , -NHMe, or -NMe 2 .
  • two adjacent groups -R pp may form -0-CH 2 -0-, -0-CH 2 CH 2 -0-, -CH 2 -0-CH 2 -, or -0-CH 2 CH 2 -.
  • two adjacent groups -R pp may form -0-CH 2 -0-, -0-CH 2 CH 2 -0-, -CH 2 -0-CH 2 -, or -0-CH 2 CH 2 -.
  • two adjacent groups -R pp may form -0-CH 2 -0- or
  • each -R pp is independently: -F, -CI, -Br, -I, -R R , -R RA , -CF 3 , -OCF 3 , -OH, or -OR R .
  • each -R R is independently saturated aliphatic Ci-ealkyl, saturated C3-6cycloalkyl, phenyl, or -CH 2 -phenyl.
  • each -R R is independently saturated aliphatic Ci-ealkyl, phenyl, or -Ch -phenyl.
  • each -R R is independently saturated aliphatic
  • each -R R is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R R if present, is independently -Me, -Et, -nPr, or -iPr.
  • each of -R P2 , -R P3 , -R P4 , -R P5 , and -R P6 is independently -H or -R' PP- as in, for example:
  • -R P2 is independently -R pp ;
  • each of -R P3 , -R P4 , -R P5 , and -R P6 is independently -H or -R pp .
  • each of -R P2 and -R P4 is independently -R pp ;
  • each of -R P3 , -R P5 , and -R P6 is independently -H or -R pp .
  • each of -R P2 , -R P3 , -R P4 , -R P5 , and -R P6 is independently -R pp .
  • each of -R P2 and -R P4 is independently -R pp .
  • -R P2 is independently -R' as in, for example:
  • the Group -R P2 (69) A compound according to any one of (62) to (68), wherein -R P2 , if present, is independently -F, -CI, -Br, -I, -R P2R , -R P2RA , -CF 3 , -CHF 2 , -OH, -OR P2R , or -OCF 3 , wherein each -R P2R is independently saturated aliphatic saturated C3- 6 cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R AK , -CF 3 , -OH, -OR AK , or -OCF 3 , wherein each -R AK is independently saturated
  • -R P2 is independently -F, -CI, -Br, -I, -R P2R , -R P2RA , -CF 3 , -CHF 2 -OH, -OR P2R , or -OCF 3 , wherein each -R P2R is independently saturated aliphatic saturated C3-6cycloalkyl, phenyl, or -CH2-phenyl; and wherein -R P2RA is independently aliphatic C ⁇ alkenyl.
  • -R P2 is independently -F, -CI, -Br, -I, -R P2R , -CF 3 , -CHF 2 -OH, -OR P2R , or -OCF 3 , wherein each -R P2R is independently saturated aliphatic Ci-4alkyl.
  • a compound according to any one of (62) to (68), wherein -R P2 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -nPr, -iPr, -cPr, -CH CH 2 , -Ph, -CH 2 Ph, -CH 2 OH, -CF 3 , -OH, -OMe, -OEt, -O(nPr), -O(iPr), -OCF 3 , -OPh, or -OCH 2 Ph.
  • a compound according to any one of (62) to (68), wherein -R P2 , if present, is independently -F, -CI, -Br, -I, -Me, -Et, -nPr, -iPr, -CH CH 2 , -CH 2 OH, -CF 3 , -OH, -OMe, -OEt, -O(nPr), -O(iPr), or -OCF 3 .
  • the Group -R P3 (79) A compound according to any one of (62) to (78), wherein -R P3 , if present, is independently -F, -CI, -Br, -I, -R P3R , -R P3RA , -CF 3 , -CHF 2 , -OH, -OR P3R , or -OCF 3 , wherein each -R P3R is independently saturated aliphatic saturated C3- 6 cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I , -R AK , -CF 3 , -OH, -OR AK , or -OCF 3 , wherein each -R AK is independently
  • -R P3 is independently -F, -CI, -Br, -I, -R P3R , -CF 3 , -CHF 2 , -OH, -OR P3R , or -OCF 3 , wherein each -R P3R is independently saturated aliphatic Ci-4alkyl, saturated C 3 -6cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I , -R AK , -CF 3 , -OH, -OR AK , or -OCF 3 , wherein each -R AK is independently saturated aliphatic Ci-4alkyl, saturated C 3 -6cycloalkyl, phenyl, or -CH2-pheny
  • -R P3 is independently -F, -CI, -Br, -I, -R P3R , -CF 3 , -CHF 2 , -OH, -OR P3R , or -OCF 3 , wherein each -R P3R is independently saturated aliphatic Ci-4alkyl, saturated C 3 -6cycloalkyl, phenyl, or -CH 2 -phenyl.
  • -R P3 is independently -F, -CI, -Br, -I , -Me, -Et, -nPr, -iPr, -cPr, -CF 3 , -OH, -OMe, -OEt, -O(nPr), -O(iPr), or -OCF 3 .
  • -R P4 if present, is independently -F, -CI, -Br, -I, -R P4R , -R P4RA , -CF 3 , -OH, -OR P4R , or -OCF 3 , wherein each -R P4R is independently saturated aliphatic Ci-4alkyl, saturated C 3 - 6 cycloalkyl, phenyl, or -CH2-phenyl; and wherein -R P4RA is independently aliphatic C2- 4 alkenyl.
  • -R P5 is independently -F, -CI, -Br, -I, -R P5R , _ C F 3 , -OH, -OR P5R , or -OCF 3 , wherein each -R P5R is independently saturated aliphatic Ci-4alkyl, saturated C 3 -6cycloalkyl, phenyl, or -CH 2 -phenyl; and wherein -R P5RA is independently aliphatic C2-4alkenyl.
  • -R P5 if present, is independently -F, -CI, -Br, -I, -R P5R , -CF 3 , -OH, -OR P5R , or -OCF 3 , wherein each -R P5R is independently saturated aliphatic (106)
  • -R P5 if present, is independently -F, -CI, -Br, -I, -Me, -Et, -nPr, -iPr, -cPr, -CF 3 , -OH, -OMe, -OEt, -O(nPr), -O(iPr), or -OCFs.
  • the Group -R P6 (1 10) A compound according to any one of (62) to (109), wherein -R P6 , if present, is independently -F, -CI, -Br, -I, -R P6R , -R p 6RA, -CF 3 , -CHF 2 , -OH, -OR P6R , or -OCF 3 , wherein each -R P6R is independently saturated aliphatic saturated C 3 -6cycloalkyl, phenyl, or -CH2-phenyl, wherein said is optionally substituted with one or more groups selected from: -OH or -OR AK , and wherein each phenyl is optionally substituted with one or more groups selected from: -F, -CI, -Br, -I, -R AK , -CF 3 , -OH, -OR AK , or -OCF 3 , wherein each -R AK is independently saturated
  • -R P6R is independently saturated aliphatic Ci-4alkyl, saturated C 3 -6cycloalkyl, phenyl, or -CH 2 -phenyl; and wherein -R P6RA is independently aliphatic C 2 - 4 alkenyl.
  • -R P6R is independently saturated aliphatic Ci- 4 alkyl; and wherein -R P6RA is independently aliphatic C ⁇ alkenyl.
  • each -M J is independently pyrrolidino, piperidino, piperazino, or morpholino, each optionally substituted, for example, with one or more groups selected from saturated aliphatic Ci- 4 alkyl.
  • each -R N if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R N if present, is independently -Me or -Et.
  • each -L J - is independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(Me)-, -C(Me) 2 -, -CH(Me)CH 2 -, -C(Me) 2 CH 2 -, -CH 2 CH(Me)-, or -CH 2 CH(Me) 2 -.
  • each -L J -, if present, is independently -CH 2 - or -CH(Me)-.
  • each -R J is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R J if present, is independently -Me, -Et, -nPr, -iPr, or -iBu.
  • each -R J if present, is independently -nPr, -iPr, or -iBu.
  • each -R J2 if present, is independently -Me or -Et, and is substituted with one or more groups -R J2X .
  • each -R J2X if present, is independently -NH 2 , -NHR J2XX , -NR J2XX 2 , pyrrolidino, piperidino, piperizino,
  • each -R J2X if present, is independently -NH 2 , -NHR J2XX , or -NR J2XX 2 .
  • each -R J2XX is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • the Group -R J3 (171) A compound according to any one of (1) to (170), wherein each -R J3 , if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more groups -R JJ .
  • each -R J3 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each -R J4 is independently azetidinyl, oxitanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,
  • tetrahydropyranyl piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1 , 1 -dioxide, azepanyl, diazepanyl, or oxazepanyl, and is optionally substituted with one or more groups -R JJ .
  • each -R J4 if present, is independently, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl piperizinyl, or morpholinyl, and is optionally substituted with one or more groups -R JJ .
  • each -R J4 if present, is independently tetrahydropyranyl, and is optionally substituted with one or more groups -R JJ .
  • each -R J6 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, and is optionally substituted, for example, with one or more groups -R JJ .
  • each -R J6 is independently furanyl, thienyl, pyrrolyl, pyridyl, or pyrimidinyl, and is optionally
  • each -R J6 is independently pyridyl or pyrimidinyl, and is optionally substituted, for example, with one or more groups -R JJ .
  • each -R J6 if present, is independently pyridyl, and is optionally substituted, for example, with one or more groups -R JJ .
  • each -L JJJ - is independently -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • One aspect of the present invention pertains to 5AT2A 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.
  • substantially purified form refers to the compound in any
  • 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
  • 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. ln 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.
  • 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
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, 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; a- 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").
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g. , Ci- 7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • reference to a specifc group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space.
  • a reference to a methoxy group, -OCH3 is not to be construed as a reference to its structural isomer, a
  • ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,
  • keto enol enolate Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions.
  • H may be in any isotopic form, including H, 2 H (D), and 3 H (T);
  • C may be in any isotopic form, including 2 C, 3 C, and 4 C;
  • O may be in any isotopic form, including 6 0 and 8 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • 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 ⁇ 3 .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from:
  • ethylamine diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH.3) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, trifluoroacetic, 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.
  • Suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • 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. 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.
  • 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).
  • a hydroxy group may be protected as an ether (-OR) or an ester
  • the aldehyde or ketone group is readily regenerated, for example, by hydrolysis using 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-CH3); 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 ⁇ CeFUCeHs, -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 (> ⁇ -0 ⁇ ).
  • a carboxylic acid group may be protected as an ester for example, as: an Ci- 7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci- 7 haloalkyl ester (e.g., a
  • Ci- 7 trihaloalkyl ester a triCi- 7 alkylsilyl-Ci- 7 alkyl ester; or a C5-2oaryl-Ci- 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 yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), lipid directed enzyme prodrug therapy (LIDEPT), etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a 5AT2A compound, as described herein, and a
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing a 5AT2A compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • LIMK LIM kinase
  • LIMK LIM kinase
  • One aspect of the present invention pertains to a method of inhibiting LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity), in vitro or in vivo, comprising contacting LIMK (e.g., LIMK1 and/or LIMK2) with an effective amount of a LIMK (e.g., LIMK1 and/or LIMK2) with an effective amount of a
  • LIMK LIM kinase
  • Suitable assays for determining LIMK activity inhibition are described herein and/or are known in the art.
  • the 5AT2A 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 5AT2A 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 5AT2A compound, as described herein.
  • the method is performed in vitro.
  • the method is performed in vivo.
  • the 5AT2A 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.
  • 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 5AT2A compound, as described herein, for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of a 5AT2A compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the medicament comprises the 5AT2A compound.
  • 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 5AT2A compound, as described herein, preferably in the form of a pharmaceutical composition.
  • the treatment is treatment of a disease or condition that is mediated by LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2).
  • LIMK LIM kinase
  • the treatment is treatment of: a disease or condition that is ameliorated by the inhibition of LIM kinase (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity).
  • LIMK LIM kinase
  • 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 LIM kinase (LIMK) (e.g., LIMK1 and/or LIMK2).
  • LIMK LIM kinase
  • 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.
  • LIMK LIM kinase
  • 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;
  • hematopoietic tumor of myeloid lineage for example acute and chronic myelogenous leukemias, myelodysplasia syndrome, or promyelocytic leukemia;
  • 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 melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma
  • pigmentoum pigmentoum
  • keratoctanthoma thyroid follicular cancer
  • Kaposi's sarcoma Kaposi's sarcoma
  • the treatment is treatment of solid tumour cancer.
  • the treatment is treatment of breast cancer, prostate cancer, melanoma, or glioma.
  • the treatment is treatment of cancer metastasis.
  • 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 cell migration (the spread of cance cells to other parts of the body), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis
  • the compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein. Conditions Treated - Additional Conditions
  • the treatment is treatment of vasodilation. In one embodiment, the treatment is treatment of hypertension, angina, cerebral vasospasm, or ischemia following subarachnoid hemorrhage.
  • the treatment is treatment of a neurodegenerative disorder. In one embodiment, the treatment is treatment of atherosclerosis.
  • the treatment is treatment of fibrosis.
  • the treatment is treatment of an inflammatory disease.
  • the treatment is treatment of Crohn's disease or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the treatment is treatment of glaucoma (also known as ocular hypertension).
  • 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 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
  • 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 5AT2A compounds described herein may also be used as cell culture additives to inhibit (LIMK) activity (e.g., LIMK1 activity and/or LIMK2 activity), e.g., to inhibit cell proliferation, etc.
  • LIMK e.g., LIMK1 activity and/or LIMK2 activity
  • the 5AT2A 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 5AT2A compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other LIMK activity inhibitors, other anti-proliferative agents, other anti-cancer agents, etc.
  • kits comprising (a) a 5AT2A compound as described herein, or a composition comprising a 5AT2A 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 written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
  • the 5AT2A compound or pharmaceutical composition comprising the 5AT2A 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,
  • 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 5AT2A compound While it is possible for the 5AT2A compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one 5AT2A 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 5AT2A 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, non- aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • solutions e.g., aqueous, non- aqueous
  • suspensions e.g., aqueous, non-aqueous
  • Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
  • the compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients.
  • the compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
  • Formulations suitable for oral administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g. , aqueous, non-aqueous), emulsions (e.g. , oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • 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. , oil-in-water, water-in-oil
  • pessaries e.g. , oil-in-water, water-in-oil
  • 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 e.g. , methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid
  • flavours e.g. , methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid
  • flavours e.g. , methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid
  • flavours e
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
  • Creams are typically prepared from the compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier also known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
  • Formulations suitable for intranasal administration, where the carrier is a solid include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Formulations suitable for pulmonary administration include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other micro particulate).
  • Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • the concentration of the compound in the liquid is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Dosage
  • 5AT2A compounds, and compositions comprising the 5AT2A 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 5AT2A compound, the route of administration, the time of administration, the rate of excretion of the 5AT2A 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 5AT2A 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 5AT2A 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.
  • Analytical method employed Waters 2545 pumps, a Waters System fluidics organiser and a Waters 2998 diode array detector. The detection was performed between 210nm and 650nm.
  • the mass spectrometer used was a Waters 3100 and a Waters Sunfire, 5 ⁇ pore size, C18 column of dimensions 50 x 4.6mm was used. The injection volume was 5 ⁇ _.
  • the flow rate was 1.5 mL/min and the mobile phases of water and methanol contained 0.1 % formic acid.
  • the elution was started at 85% water: 15% methanol ramping up to 5% water:95% methanol over 4.5minutes. These conditions were held for 1 minute.
  • the eluent level was returned to the starting conditions of 85% water: 15% methanol over 0.1 minutes. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 minutes in total.
  • Analytical 2 Analytical 2
  • Analytical method employed Waters 2545 pumps, a Waters System fluidics organiser and a Waters 2998 diode array detector. The detection was performed between 210nm and 650nm.
  • the mass spectrometer used was a Waters 3100 and a Waters Sunfire, 5 ⁇ pore size, C18 column of dimensions 50 x 4.6mm was used. The injection volume was 5 ⁇ _.
  • the flow rate was 1.5 mL/min and the mobile phases of water and acetonitrile contained 0.1 % formic acid.
  • the elution was started at 95% water:5% acetonitrile ramping up to 5% water:95% acetonitrile over 5.5minutes.
  • the eluent level was returned to the starting conditions of 95% water:5% acetonitrile over 0.1 minutes. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 minutes in total.
  • Chromatography employed Waters 2545 and 515 pumps, a Waters System fluidics organiser and a Waters 2998 diode array detector. The detection was performed between 210nm and 650nm.
  • the mass spectrometer used was a Waters 3100 and Waters Sunfire, 5 ⁇ pore size, C18 column of dimensions 50 x 19mm was used.
  • the injection volume was up to 500 ⁇ _ of solution at a maximum concentration of 50mg/ml_.
  • the flow rate was 25 mL/min and the mobile phases of water and methanol contained 0.1 % formic acid. The elution was started at 85% water: 15% methanol ramping up to 5% water:95% methanol over 4.5 minutes. These conditions were held for 1 minute.
  • the eluent level was returned to the starting conditions of 85% water: 15% methanol over 30 seconds. There are 2 purification columns so the second one was equilibrated at 85% water: 15% methanol during the previous run so the next injection could be performed straight away.
  • Chromatography employed Waters 2545 and 515 pumps, a Waters System fluidics organiser and a Waters 2998 diode array detector. The detection was performed between 210nm and 650nm.
  • the mass spectrometer used was a Waters 3100 and Waters Sunfire, 5 ⁇ pore size, C18 column of dimensions 50 x 19mm was used.
  • the injection volume was up to 500 of solution at a maximum concentration of 50mg/mL.
  • the flow rate was 25 mL/min and the mobile phases of water and acetonitrile contained 0.1 % formic acid.
  • the elution was started at 95% water:5% acetonitrile ramping up to 5% water:95% acetonitrile over 5 minutes.
  • the eluent level was returned to the starting conditions of 95% water:5% acetonitrile over 30 seconds. There are 2 purification columns so the second one was equilibrated at 5% acetonitrile 95% water during the previous run so the next injection could be performed straight away.
  • NMR Proton NMR spectra were recorded using a Bruker AMX-300 NMR machine at 300 MHz or a Bruker AVANCE 500 at 500 MHz. Shifts were reported in ppm values relative to an internal standard of trimethylsilane (TMS) or residual protic solvent. The following abbreviations were used to describe the shifting patterns:s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double-doublet), dt (double-triplet), br (broad).
  • TMS trimethylsilane
  • the microwave reactor used was a Biotage 30-lnitiator 60.
  • N-Propylthiourea (45 mmol, 5.32 g) was dissolved in ethanol (200 mL) and treated with dimethylformamide dimethylacetal (49.5 mmol, 6.6 g) and heated at reflux for 90 minutes The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residual oil was stirred vigorously in cyclohexane (60 mL) for 2 hours. The resultant white suspension was stirred, with cooling for 30 minutes and then filtered. The white precipitate was washed with cyclohexane and dried to give a white solid.
  • the reaction mixture was evaporated under reduced pressure then diluted with DCM (10 mL) and washed with water (10 mL). The organics were evaporated under reduced pressure re-dissolved in DCM (1 mL) and treated with TFA (1 mL) and left to stir for 15 hours at room temperature. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL). The aqueous was extracted into DCM (5 mL), passed through a phase separating cartridge and evaporated under reduced pressure. The residue was taken up in DMSO and purified by mass directed HPLC using prep method 1. The fractions were evaporated to yield the title compound as a white solid.
  • the starting material 5-(3-bromo-pyridin-4-yl)-thiazol-2-ylamine was synthesised by an analogous method outlined in General Method 1 and 1 b starting from thiourea.
  • Acetyl chloride (0.2 mmol, 0.016 g) was added to a suspension of 5-[3-(4-methoxy-2- trifluoromethyl-phenyl)-pyridin-4-yl]-thiazol-2-ylamine (0.16 mmol 0.060 g) in THF (1 mL) and triethylamine (0.2 mmol, 0.02 mL). This was left to stir for 30 minutes at room temperature then the reaction was quenched with saturated sodium bicarbonate solution ( ⁇ 3 mL). The reaction mixture was washed with DCM (3 mL), passed through a phase separator then evaporated under reduced pressure. The residue was then taken up in DMSO (1 mL) and purified by mass directed HPLC using prep method 1. The fractions were evaporated under reduced pressure to yield the title compound.
  • amide and carbamate examples were synthesised in an analogous fashion to the method described in general method 3 from 5-[3-(2-chloro-phenyl)-pyridin-4-yl]-thiazol-2- ylamine and the appropriate acid chloride or chloroformate.
  • reaction mixture was then diluted with DCM (100 mL), washed with water (100 mL) and brine (100 mL). The organics were separated, dried with MgS0 4 , filtered and evaporated under reduced pressure. The residue was then purified by flash column chromatography eluting with 0-50% ethyl acetate:cyclohexane, both mono and diboc material were combined and evaporated. The residue was dissolved in DCM (15 mL), TFA (5 mL) was added and this was left to stir for 15 hours at room temperature.
  • N-(5-Bromo-4-chloromethyl-pyridin-2-yl)-acetamide (6.8 mmol, 1.79 g) was dissolved in acetonitrile (70 mL) and triethylamine (13.6 mmol, 1.9 mL) and treated with 1-[1- dimethylamino-meth-(E)-ylidene]-3-propyl-thiourea (6.8 mmol, 1.17 g).
  • the reaction mixture was heated at reflux for 3 hours and allowed to cool to room temperature.
  • the reaction mixture was allowed to cool to room temperature and then evaporated under reduced pressure to a pale brown solid.
  • N-[5-Bromo-4-(2-propylamino-thiazol-5-yl)-pyridin-2-yl]-acetamide (3 mmol, 1.07 g), ditert butyl dicarbonate (6.3 mmol, 1.37 g) and dimethylaminopyridine (0.01 g) were weighed into a round bottom flask and dissolved in triethylamine (6.3 mmol, 0.88 mL) and DCM (45 mL). The resultant solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (2x50 mL).
  • the organics were passed through a phase separation cartridge and evaporated under reduced pressure to a light brown oil which was purified by passing through a small column of silica 1 :4 ethyl acetate:cyclohexane to provide the title compound as a pale yellow gum.
  • palladium(ll)dichloride (0.005 mmol, 0.035 g) were weighed into a microwave vial and treated with dioxane (3 mL) and water (1 mL). The vial was sealed and heated in a microwave reactor at 150 °C for 15 minutes. The solvent was removed under reduced pressure, redissolved in DCM (50 mL) and washed with water (50 mL). The organics were washed with brine (10 mL) and separated using a phase separation cartridge. The organics were evaporated under reduced pressure to an orange solid. This solid was suspended in 3M hydrochloric acid (50 mL) and heated at reflux for 1 hour.
  • reaction mixture was carefully neutralised with 2M sodium hydroxide solution and extracted with DCM (2x50 mL). The organics were evaporated under reduced pressure, the residue was dissolved in DMSO and purified by mass directed LCMS using prep method 1. The fractions were evaporated to yield the title compound as a yellow solid.
  • Compound AA-013 was synthesised from ⁇ 5-[2-chloro-5-(2-chloro-phenyl)-pyridin-4-yl]- thiazol-2-yl ⁇ -propyl-amine using methylamine solution in THF in place of dimethylamine.
  • Compound AA-035 was synthesised from ⁇ 5-[2-chloro-5-(2-chloro-phenyl)-pyridin-4-yl]- thiazol-2-yl ⁇ -propyl-amine using sodium ethoxide and ethanol in place of sodium methoxide and methanol. Code MW TR/mins Ml+H Method
  • N-Methyl propylamine (1 mmol, 0.072 g) was added to a solution of 3-(2-chloro-phenyl)-4- (2-chloro-thiazol-5-yl)-pyridine (0.2 mmol, 0.060 g) in methanol (2 ml_) and heated to 150 °C in a microwave reactor for 15 minutes.
  • the reaction mixture was then diluted with DCM (5 ml_) and washed with water (5 ml_) and passed through a phase separator.
  • the solvent was then evaporated under reduced pressure, dissolved in DMSO and purified by mass directed HPLC using prep method 1. The fractions were evaporated under reduced pressure to yield the title compound.
  • reaction mixture was then diluted with DCM (5 ml_) and washed with saturated sodium bicarbonate solution (10 ml_), passed through a phase separator and evaporated under reduced pressure.
  • the residue was then taken up in DMSO and purified by mass directed HPLC using prep method 1.
  • the product was purified by SCX eluting first with methanol, then 1 M ammonia in methanol, this was evaporated to yield the title compound as a yellow solid.

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Abstract

La présente invention concerne de manière générale le domaine des composés thérapeutiques, et plus spécifiquement certains composés 5-aryl-thiazol-2-yl-amine représentés par la formule suivante (par souci de commodité, collectivement appelés « composés 5AT2A»), qui, entre autres, inhibent l'activité de la LIM kinase (LIMK). La présente invention concerne en outre des compositions pharmaceutiques comprenant de tels composés, et l'utilisation de tels composés et compositions, à la fois in vitro et in vivo, pour inhiber l'activité LIMK, et dans le traitement de maladies et affections qui sont médiées par LIMK, qui sont améliorées par l'inhibition de l'activité LIMK, etc., comprenant des affections prolifératives telles que le cancer (par exemple, le cancer du sein, le cancer de la prostate, le mélanome, le gliome, etc.), ainsi que la vasodilatation (comprenant, par exemple, l'hypertension, l'angor, un angiospasme cérébral, et une ischémie consécutive à une hémorragie sous-arachnoïdienne ), des troubles neurodégénératifs, l'athérosclérose, la fibrose, et des maladies inflammatoires (comprenant, par exemple, la maladie de Crohn et la bronchopneumopathie chronique obstructive (BPCO)), et le glaucome (également appelé hypertension oculaire). (Formule (I))
PCT/GB2014/052574 2013-08-22 2014-08-22 Composés 5-aryl-thiazol -2-yl-amine et leur utilisation thérapeutique Ceased WO2015025172A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018055097A1 (fr) 2016-09-23 2018-03-29 Cellipse Inhibiteurs de kinase lim, composition pharmaceutique et procédé d'utilisation dans des maladies induites par limk
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
CN114436991A (zh) * 2021-12-25 2022-05-06 上海泰坦科技股份有限公司 一种2-氨基噻唑类化合物的合成方法
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006084017A2 (fr) * 2005-02-04 2006-08-10 Bristol-Myers Squibb Company Composes pyrimidine a substitution phenyle utilises en tant qu'inhibiteurs de kinases
WO2009131940A1 (fr) * 2008-04-21 2009-10-29 Lexicon Pharmaceuticals, Inc. Inhibiteurs de limk2, compositions les comprenant et leurs procédés d'utilisation
WO2010024903A1 (fr) * 2008-08-29 2010-03-04 Yangbo Feng Benzo[d]oxazoles et benzo[d]thiazoles comme inhibiteurs de la kinase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006084017A2 (fr) * 2005-02-04 2006-08-10 Bristol-Myers Squibb Company Composes pyrimidine a substitution phenyle utilises en tant qu'inhibiteurs de kinases
WO2009131940A1 (fr) * 2008-04-21 2009-10-29 Lexicon Pharmaceuticals, Inc. Inhibiteurs de limk2, compositions les comprenant et leurs procédés d'utilisation
WO2010024903A1 (fr) * 2008-08-29 2010-03-04 Yangbo Feng Benzo[d]oxazoles et benzo[d]thiazoles comme inhibiteurs de la kinase

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018055097A1 (fr) 2016-09-23 2018-03-29 Cellipse Inhibiteurs de kinase lim, composition pharmaceutique et procédé d'utilisation dans des maladies induites par limk
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US12365668B2 (en) 2018-03-08 2025-07-22 Incyte Corporation Aminopyrazine diol compounds as PI3K-y inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US12421197B2 (en) 2018-07-02 2025-09-23 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
CN114436991A (zh) * 2021-12-25 2022-05-06 上海泰坦科技股份有限公司 一种2-氨基噻唑类化合物的合成方法

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