Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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

Definitions

• the present invention relates to substituted furo[3,2-6]pyridines as inhibitors of various protein kinases, regulators or modulators, pharmaceutical compositions containing the compounds, and pharmaceutical use of the compounds and compositions in the treatment of the diseases such as, for example, cancer, inflammation, pain, neurodegenerative diseases or viral infections.
• Protein kinases are involved in regulation of practically all processes that are central to the growth, development, and homeostasis of eukaryotic cells. In addition, some protein kinases have an important role in oncogenesis and tumor progression and several kinase inhibitors are now approved for the treatment of cancer (D. J. Matthews and M. E. Gerritsen: Targeting protein kinases for cancer therapy, Wiley, 2010).
• kinase inhibitors that are used in modern oncology include: imatinib (treatment of CML); dasatinib (CML with resistance to prior treatment, including imatinib); nilotinib (CML); bosutinib (CML); gefitinib (non-small cell lung cancer); erlotinib (non-small cell lung cancer and pancreatic cancer); lapatinib (breast cancer); sorafenib (metastatic renal cell carcinoma, hepatocellular cancer); vandetanib (metastatic medullary thyroid cancer); vemurafenib (inoperable or metastatic melanoma); crizotinib (non- small cell lung cancer); sunitinib (metastatic renal cell carcinoma, gastrointestinal stromal tumor that is not responding to imatinib, or pancreatic neuroendocrine tumors); pazopanib (renal cell carcinoma and advanced soft tissue sarcoma);
• kinases are regarded as good targets for pharmacological inhibition in order to treat proliferative and/or neurodegenerative diseases.
• Biological and potential therapeutic significance of some selected kinases is briefly summarized below.
• the regulation of splice site usage provides a versatile mechanism for controlling gene expression and for the generation of proteome diversity, playing an essential role in many biological processes.
• the importance of alternative splicing is further illustrated by the increasing number of human diseases that have been attributed to mis-splicing events. Appropriate spatial and temporal generation of splicing variants demands that alternative splicing be subjected to extensive regulation, similar to transcriptional control.
• CLK Cdc2-like kinase
• Pharmacological inhibition of CLKl/Sty results in blockage of SF2/ASF-dependent splicing of beta-globin pre-mRNA in vitro by suppression of CLK- mediated phosphorylation. It also suppresses dissociation of nuclear speckles as well as CLK1 /Sty-dependent alternative splicing in mammalian cells and was shown to rescue the embryonic defects induced by excessive CLK activity in Xenopus ⁇ Journal of Biological Chemistry 2004, 279, 24246.).
• Alternative mRNA splicing is a mechanism to regulate protein isoform expression and is regulated by alternative splicing factors.
• the alternative splicing factor 45 (SPF45) is overexpressed in cancer and its overexpression enhances two processes that are important for metastasis, i.e. cell migration and invasion, dependent on biochemical regulation by CLK1 ⁇ Nucleic Acids Research 2013, 41, 4949.).
• CLK1 phosphorylates SPF45 on eight serine residues.
• CLK1 expression enhances, whereas CLK1 inhibition reduces, SPF45- induced exon 6 exclusion from Fas mRNA. Inhibition of CLK1 increases SPF45 degradation through a proteasome-dependent pathway.
• small-molecule inhibitors of specific CLKs can suppress HIV-1 gene expression and replication ⁇ Retrovirology 2011, 8, 47.), which could be used in concert with current drug combinations to achieve more efficient treatment of the infection. Inhibition of CLK1 can be applicable in the treatment of Alzmeimer's disease ⁇ Current Drug Targets 2014, 15, 539.).
• DYRK dual specifity tyrosine phosphorylation-regulated kinase family enzymes are essential components of important signaling cascades in the pathophysiology of cancer and Alzheimer's disease and their biological expression levels regulate key signaling processes in these diseases.
• DYR 2 is over-expressed in adenocarcinomas of the esophagus and lung ⁇ Cancer Research 2003, 63, 4136.) and DYRK1A in glioblastoma where its inhibition compromised tumors' survival and produced a profound decrease in tumor burden ⁇ Journal of Clinical Investigation 2013, 123, 2475.).
• DYRKIB activation that is induced by microtubule damage triggers microtubule stabilization and promotes the mitochondrial translocation of p21Ci l/wafl to suppress apoptosis. Its inhibition caused reduced viability of cancer cells (ACS Chemical Biology 2014, 9, 731.).
• inhibition of DYRK kinases alone or in combination with other chemotherapeutic drugs may have tumor suppression effect and the enzymes are therefore appropriate targets for pharmacological inhibition (Bioorganic & Medicinal Chemistry Letters 2013, 23, 6610.; Medicinal Chemistry Research 2014, 23, 1925.).
• DYRK kinases are also over-expressed in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Pick disease (Neurobiology of Disease 2005, 20, 392.; Cellular and Molecular Life Sciences 2009, 66, 3235.).
• HIPK2 homeodomain-interacting protein kinase
• This kinase regulates a vast array of biological processes that range from the DNA damage response and apoptosis to hypoxia signaling and cell proliferation.
• Recent studies showed the tight control of HIPK2 by hierarchically occurring posttranslational modifications such as phosphorylation, small ubiquitin-like modifier modification, acetylation, and ubiquitination.
• Dysregulation of HIPK2 can result in increased proliferation of cell populations as it occurs in cancer or fibrosis. Inappropriate expression, modification, or localization of HIPK2 can be a driver for these proliferative diseases (Journal of Molecular Medicine 2013, 91, 1051.).
• FMS-like tyrosine kinase 3 FLT3
• RTK receptor tyrosine kinase
• FLT3 The majority of B-cell acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) blasts (> 90%) express FLT3 at various levels (Clinical Cancer Research 2009, 15, 4263.). Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment (Oncologist 2011, 16, 1162.; PLoS One 2014, 9, e83160/1.; Leukemia Lymphoma 2014, 55, 243.).
• TRK Tropomyosin-related kinase
• TRK-A regulates proliferation and is important for development and maturation of the nervous system, promotes survival of cells from death. Point mutations, deletions and chromosomal rearrangements cause ligand-independent receptor dimerization and activation of TRK-A.
• TRK-A In mutated version of TRK, abnormal function will render cells unable to undergo differentiation in response to ligand in their microenvironment, so they would continue to grow when they should differentiate, and survive when they should die.
• TRK-A oncogenes have been associated with several human malignancies, e.g., breast, colon, prostate, thyroid carcinomas and AML ⁇ Cell Cycle 2005, 4, 8.; Cancer letters 2006, 232, 90.).
• inhibition of TRK can be relevant for the treatment of inflammation (PLoS One 2013, 8, e83380.) and pain (Expert Opinion on Therapeutic Patents 2009, 19, 305.).
• the present invention provides substituted furo[3 ,2 -b] pyridine compounds, methods of preparing such compounds, pharmaceutical compositions comprising one or more of such compounds, and their use in the treatment, prevention, inhibition or amelioration of one or more diseases associated with protein kinases using such compounds or pharmaceutical compositions.
• the present invention provides compounds represented by the structural formula (I):
• L 5 is selected from the group consisting of a bond, -N(R U )-;
• L 2 is selected from the group consisting of a bond, -0-;
• L 3 is selected from the group consisting of a bond, -N(R ] ')-, -0-;
• L 6 is selected from the group consisting of a bond, -0-;
• L 7 is selected from the group consisting of a bond, -N(R n )-;
• R 5 is selected from the group consisting of Ci-C 6 alkyl; aryl; heteroaryl; biaryl; bi(heteroaryl); cycloalkylaryl; heterocyclylaryl; heteroarylaryl; arylheteroaryl; cycloalkylheteroaryl; heterocyclylheteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted;
• R 2 is selected from the group consisting of H; -CF 3 ; N3 ⁇ 4; -CI; -Br; -F; C]-C 6 alkyl;
• R 3 is selected from the group consisting of H; C C 6 alkyl; aryl; cycloalkyl; heteroaryl; biaryl; heteroarylaryl; arylheteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted;
• R 6 is selected from the group consisting of H; -CF3; NH 2 ; -CI; -Br; -F; Ci-Ce alkyl; aryl; heteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted;
• R 7 is selected from the group consisting of H; Q-C6 alkyl; aryl; cycloalkyl; heteroaryl; biaryl; heteroarylaryl; arylheteroaryi; wherein each of the substituent moieties can be unsubstituted or optionally substituted;
• R 11 is selected from the group consisting of H, Ci-C 6 alkyl; provided that the substituent in position 5 (L5-R5) is not oxadiazolyl or methyl- oxadiazolyl.
• alkyl means an aliphatic hydrocarbon group which may be straight or branched and contains 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms in the chain. Examples of suitable alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl.
• the alkyl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF 3 , OCF 3 , OR 9 , SR 9 , SOH, S0 2 H, S0 2 N(H, C1-C4 alkyl) 2 ⁇ CHO, COO(H, C r C 4 alkyl), COH, C(0)N(H 5 C1-C4 alkyl), 0(CH 2 ) p N(CH 3 ) 2 and NR 9 R 10 ;
• aryl means an aromatic monocyclic or polycyclic ring system containing 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Examples of suitable aryls are phenyl, naphthyl.
• the aryl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF 3 , OCF 3 , OR 9 , SR 9 , SOH, S0 2 H, S0 2 N(H, C,-C 4 alkyl) 2 , CHO, COO(H, d-C 4 alkyl), COH, C(0)N(H, C C 4 alkyl), NR 9 R 10 , -(CR 9 R 10 ) P R 3 ⁇ 4 , 0(CH 2 ) p N(CH 3 ) 2 and -(CR 9 R 10 ) p OR 9a ;
• cycloalkyl means an aliphatic monocyclic or bicyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 7 carbon atoms. Suitable examples include cyclopentyl, cyclohexyl, cycloheptyl, 1-decalinyl, norbornyl, adamantyl.
• the cycloalkyl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF 3 , OCF 3 , OR 9 , SR 9 , SOH, S0 2 H, S0 2 N(H, C 1 -C4 alkyl) 2 , CHO, COO(H, C 1-C4 alkyl), COH, C(0)N(H 5 d-C 4 alkyl), NR 9 R 10 , -(CR 9 R 10 ) p R 9a 5 0(CH 2 ) p N(CH 3 ) 2 and - (CR 9 R 10 ) p OR 9a ;
• heterocyclyl means an aliphatic monocyclic or bicyclic ring system containing 3 to 10 carbon atoms, preferably 4 to 8 carbon atoms, and at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. Suitable examples include piperazinyl and morpholinyl. Preferably, heterocyclyl is not a bicyclic ring system containing only N heteroatoms.
• the heterocyclyl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF 3 , OCF 3 , OR 9 , SR 9 , SOH, S0 2 H, S0 2 N(H, C1 -C4 alkyl) 2 , CHO, COO(H, C r C 4 alkyl), COH, C(0)N(H, Ci-C 4 alkyl), NR 9 R 10 , -(CR 9 R 10 ) p R 9a , 0(CH 2 ) p N(CH 3 ) 2 and -(CR 9 R 10 ) p OR 9a ;
• heteroaryl means an aromatic monocyclic or bicyclic ring system containing 1 to 14 carbon atoms, preferably 3 to 7 carbon atoms, most preferably 3 to 5 carbon atoms, and at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
• suitable heteroaryls are pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrrolyl, imidazolyl.
• heteroaryl is not indolyl, indolinolyl or imidazopyridazinyl.
• the heteroaryl can be unsubstituted or optionally substituted by one or more substituents which can be the same or different, each substituent being independently selected from the group consisting of F, CI, Br, CF 3 , OCF 3 , OR 9 , SR 9 , SOH, S0 2 H, S0 2 N(H, C r C 4 alkyl) 2 , CHO, COO(H, C1-C4 alkyl), COH, C(0)N(H, C C alkyl), NR 9 R 10 , -(CR 9 R 10 ) p R 9a , 0(CH 2 ) p N(CH 3 ) 2 and - (CR 9 R I0 ) p OR 9a ;
• bias means an aryl-aryl- group in which each of the aryls is independently as previously described.
• An example is biphenyl
• bi(heteroaryl) means an heteroaryl-heteroaryl- group in which each of the heteroaryls is independently as previously described;
• cycloalkylaryl means a cycloalkyl-aryl- group in which the cyclo alkyl and aryl are as previously described;
• heterocyclylaryl means a heterocyclyl-aryl- group in which the heterocyclyl and aryl are as previously described;
• heteroarylaryl means a heteroaryl-aryl- group in which the heteroaryl and aryl are as previously described;
• arylheteroaryl means a aryl-heteroaryl- group in which the aryl and heteroaryl are as previously described;
• cycloalkylheteroaryl means a cycloalkyl-heteroaryl- group in which the heteroaryl and cycloalkyl are as previously described;
• heterocyclylheteroaryl means a heterocyclyl-heteroaryl- group in which the heterocyclyl and heteroaryl are as previously described;
• each of aryl, cycloalkyl, heterocyclyl, heteroaryl, biaryl, bi(heteroaryl), cycloalkylaryl, heterocyclylaryl, heteroarylaryl, arylheteroaryl, cycloalkylheteroaryl, and heterocyclylheteroaryl can be bound directly or via a methylene or ethylene spacer;
• p is an integer in the range of from 1 to 7, more preferably from 1 to 5, even more preferably 1 to 3;
• R 9 is H or C 1 -C6 alkyl, unsubstituted or optionally substituted by -OH, -NH 2 , -N(CH 3 ) 2 ;
• R 9a is H or C1-C6 alkyl, unsubstituted or optionally substituted by -OH, -NH 2 , -N(CH 3 ) 2 ;
• R 10 is H or C1-C6 alkyl, unsubstituted or optionally substituted by -OH, -NH 2 , -N(C3 ⁇ 4) 2 .
• R is selected from the group consisting of aryl; heteroaryl; heterocyclylaryl; heteroarylaryl; arylheteroaryl; heterocyclylheteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted, preferably by at least one substituent selected from the group consisting of F, CI, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, OH, NH 2 , N(CH 3 ) 2 , 0(CH2) P N(CH 3 ) 2 .
• R 5 is selected from the group consisting of aryl; heteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted, preferably by at least one substituent selected from the group consisting of F, CI, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, OH, NH 2 , N(CH 3 ) 2 , 0(CH 2 ) p N(CH 3 ) 2 .
• the heteroaryl in R 5 is pyrazolyl.
• any of L 5, L 7 is independently selected from the group consisting of a bond, -NH-.
• any of L 2 , L 6 is a bond.
• L 3 is a bond or -0-.
• R is selected from the group consisting of aryl; heteroaryl; biaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted, preferably by at least one substituent selected from the group consisting of F, CI, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, OH, NH 2 , N(C3 ⁇ 4) 2 , 0(CH2) P N(CH 3 )2.
• the aryl in R 3 is phenyl, naphthyl (e.g., 2-naphthyl) and the biaryl in R 3 is biphenyl (e.g., 3- biphenyl).
• R 6 is selected from the group consisting of H; -CI; -Br; -F; - OH; -NH 2 ; or methyl.
• R 2 is selected from the group consisting of H; -CI; -Br; -F; - OH; -N3 ⁇ 4; or methyl.
• R 7 is selected from the group consisting of H; Cj-Ce alkyl; aryl; heteroaryl; wherein each of the substituent moieties can be unsubstituted or optionally substituted, preferably by at least one substituent selected from the group consisting of F ⁇ CI, Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, OH, N3 ⁇ 4, N(CH 3 ) 2 , 0(CH 2 ) P N(CH 3 )2.
• At least one of R and R is not H when the corresponding L (i.e., L or L , respectively) is a bond.
• -L 2 -R 2 , -L 6 -R 6 , -L 7 -R 7 are hydrogens and -L 3, -R 3 is not hydrogen.
• -L 2 -R 2 , -L 6 -R 6 , -L 7 -R 7 are hydrogens, -L 3 -R 3 is aryl or biaryl (optionally substituted) and -L s -R 5 is heteroaryl (optionally substituted).
• any of aryl; cycloalkyl; heterocyclyl; heteroaryl; biaryl; bi(heteroaryl); cycloalkylaryl; heterocyclylaryl; heteroarylaryl; arylheteroaryl; cycloalkylheteroaryl; heterocyclylheteroaryl is unsubstituted or substituted with at least one substituent selected from the group consisting of NH 2 , N(CH 3 )2, OH, methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert -butyl.
• any of -L 2 -R 2 , -L 3 -R 3 , -L 6 -R 6 , -L 7 -R 7 , -L 5 -R 5 can be hydroxy(C C6)alkylamino, amino (C 1 -C 6 )alkylamino or dimethylamino(Ci-C 6 )alkylamino.
• Pharmaceutically acceptable salts are salts with acids or bases, or acid addition salts.
• the acids and bases can be inorganic or organic acids and bases commonly used in the art of formulation, such as hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartarate, gluconate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, primary, secondary and tertiary amides, ammonia.
• the compounds described in this invention can be prepared through the general routes described below in Schemes 1-6.
• intermediate 2 can be subjected to amination to yield amine-containing compounds 4 depicted in Scheme 2.
• TMS group in 10 can be removed by KF in methanol to yield intermediate 11, which can be subjected to Pd-catalyzed C-C bond formation or animation (indicated in Scheme 5) to yield compounds 12 and 13, respectively.
• 6-chloro-2-iodopyridin-3-oI can be allylated to give intermediate 14, which can be cyclized to furopyridine intermediate 15, which upon Pd-catalyzed C-C bond formation or animation yields compounds 16 and 17, respectively.
• the compounds of formula (I) can be useful as protein kinase inhibitors and can be useful in the treatment and prevention of proliferative diseases, e.g. cancer, inflammation and arthritis, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral diseases, and fungal diseases.
• proliferative diseases e.g. cancer, inflammation and arthritis
• neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral diseases, and fungal diseases.
• the protein kinase is not GSK3.
• the protein kinase is selected from CLK2, CLK4, HIPK1, HIPK2, HIPK3, FLT3, TRKA and DYRK2.
• the present invention thus provides the compounds of formula (I) for use as medicaments. More specifically, it provides the compounds of formula (I) for use in the treatment and prevention of conditions selected from proliferative diseases, neurodegenerative diseases, cardiovascular diseases, pain, viral diseases, and fungal diseases.
• the present invention also provides a method for treatment, inhibition, amelioration or prevention of a condition selected from proliferative diseases, neurodegenerative diseases, cardiovascular diseases, pain, viral diseases, and fungal diseases, in a patient suffering from such condition, comprising the step of administering at least one compound of formula (I) to said patient.
• the present invention further includes pharmaceutical compositions comprising at least one compound of formula (I) and at least one pharmaceutically acceptable auxiliary compound.
• auxiliary compounds may include, e.g., carriers, diluents, fillers, preservatives, stabilisers, binders, wetting agents, emulsifiers, buffers, etc. Suitable auxiliary compounds are well known to those skilled in the art of formulation.
• the pharmaceutical compositions are prepared by known methods, e.g., mixing, dissolving etc.
• Preparative Example 46 The product from Preparative Example 45 (285 mg, 0.746 mmol), KF (130 mg, 2.24 mmol) and MeOH (16 mL) were placed into a 50 mL round bottom flask and the mixture was stirred under N 2 at 62 °C for 43 h.. The solvent was evaporated and the residue was purified by column chromatography on silica gel (EtOAc/hexane; 1 :1). The product was obtained as a white solid (213 mg, 92 %).
• Preparative Example 48 The product from Preparative Example 47 (1.67 g, 5,81 mmol), chloroform (12 mL) and POCl 3 (9.75 mL, 105 mmol) were placed into a 100 mL round bottom flask and the mixture was refluxed under N 2 for 45 min. The solvent and POCI 3 were evaporated and the residue was mixed with saturated aqueous solution of NaHC0 3 (40 mL) and extracted with CH2CI2 (50+30+30 mL). The organic phase was dried over MgS0 4 and filtered. The solvent was evaporated and the residue was purified by column chromatography on silica gel (CH 2 Ci2/MeOH; 14:1). The product was obtained as a white solid (1.15 g, 65 %).
• 6-chloro-5-methylpyridin-3-ol (2.51 g, 17.5 mmol), iodine (4.44 g, 17.5 mmol), H 2 0 (35 mL), THF (30 mL) and Na 2 C0 3 (3.90 g, 36.8 mmol) were placed into a 100 mL round bottom flask. The mixture was stirred under N 2 at 25 °C for 18 h. The solvent was evaporated and the solution was neutralized with 1 M aqueous solution of HC1 (38 mL).
• the stock solution was added to the individual assay wells in such amounts that the concentrations of the compound were either in the row A (0.001 ⁇ , 0.003 ⁇ , 0.01 ⁇ , 0.03 ⁇ , 0.1 ⁇ , 0.3 ⁇ , 1.0 ⁇ , 3.0 ⁇ , and 10.0 ⁇ ) or in the row B (0.0001 ⁇ , 0.0003 ⁇ , 0.001 ⁇ , 0.003 ⁇ , 0.01 ⁇ , 0.03 ⁇ , 0.1 ⁇ , 0.3 ⁇ , and 1.0 ⁇ ). There was no pre-incubation step between the compound and the kinase prior to initiation of the reaction.
• the positive control wells contained all components of the reaction, except the compound of interest; however, DMSO (at a final concentration of 2%) was included in these wells to control for solvent effects.
• the blank wells contained all components of the reaction, with staurosporine as a reference inhibitor replacing the compound of interest. This abolished kinase activity and established the base-line (0% kinase activity remaining).
• CLK2 (h) was diluted in the buffer (20 mM MOPS (3 ⁇ (N-morpholino)propanesulfonic acid), 1 mM EDTA (ethylendiaminotetraacetic acid), 0.01% Brij-35 (detergent), 5% Glycerol, 0.1% ⁇ -mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.
• the above stock solution of CLK2(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 20 ⁇ YRRAAVPPSPSLSRHSSPHQS(p) EDEEE in such amount that the resulting concentration of CLK2(h) was 2.1 nM.
• This mixture was added to the stock solution of the tested compound.
• the reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [ ⁇ - 33 ⁇ - ⁇ ] (specific activity approx. 500 cpm/pmol) was 15 ⁇ . After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 ⁇ of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
• CLK4 (h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% ⁇ -mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.
• the above stock solution of CLK4(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 200 ⁇ YRRAAVPPSPSLSRHSSPHQS(p) EDEEE in such amount that the resulting concentration of CLK4(h) was 140.8 nM.
• This mixture was added to the stock solution of the tested compound.
• the reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [ ⁇ - P-ATP] (specific activity approx. 500 cpm/pmol) was 15 ⁇ . After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 ⁇ , of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
• HIP l(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% ⁇ -mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.
• HIPKl(h) The above stock solution of HIPKl(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0,2 mM EDTA, and 0.33 mg/mL myelin basic protein in such amount that the resulting concentration of HIP l(h) was 4.7 nM. This mixture was added to the stock solution of the tested compound. The reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [ ⁇ - 33 ⁇ - ⁇ ] (specific activity approx. 500 cpm/pmol) was 45 ⁇ . After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 ⁇ ⁇ of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
• HIPK2(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% ⁇ -mercaptoethanol, 1 mg/niL BSAs) to the concentration of 1.01 mg/niL prior to addition to the reaction mix.
• the above stock solution of HIPK2(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 0.33 mg/mL myelin basic protein in such amount that the resulting concentration of HIPK2(h) was 1.4 nM.
• This mixture was added to the stock solution of the tested compound.
• the reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [ ⁇ - 33 ⁇ - ⁇ ] (specific activity approx. 500 cpm/pmol) was 10 ⁇ . After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 ⁇ , of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
• HIP 3(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% ⁇ -mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.
• the above stock solution of HIPK3(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 1.0 mg/mL myelin basic protein in such amount that the resulting concentration of HIPK3(h) was 6.4 nM.
• This mixture was added to the stock solution of the tested compound.
• the reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [ ⁇ - 33 ⁇ - ⁇ ] (specific activity approx. 500 cpm/pmol) was 15 ⁇ . After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 ⁇ of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
• FLT3 assay FLT3(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% ⁇ -mercaptoethanol, 1 mg/niL BSAs) to the concentration of 1.01 mg/n L prior to addition to the reaction mix.
• TRKA(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% ⁇ -mercaptoethanol, 1 mg/mL BSAs) to the concentration of 1.01 mg/mL prior to addition to the reaction mix.
• the above stock solution of TRKA(h) was added to a mixture containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, and 250 ⁇ KSPGEYVNIEFG, in such amount that the resulting concentration of TRKA(h) was 28.2 nM.
• This mixture was added to the stock solution of the tested compound.
• the reaction was initiated by the addition of the MgATP mix in such amount that the resulting concentration of Mg acetate in the reaction mixture was 10 mM and [ ⁇ - 33 ⁇ - ⁇ ] (specific activity approx. 500 cpm/pmol) was 120 ⁇ . After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 ⁇ , of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. Results

Landscapes

• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Heart & Thoracic Surgery (AREA)
• Virology (AREA)
• Cardiology (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=50679866

Family Applications (1)

Country Status (4)

Cited By (5)

Families Citing this family (1)

Citations (3)

Family Cites Families (9)

• 2014
  • 2014-04-30 EP EP14166547.1A patent/EP2940022B1/en active Active
• 2015
  • 2015-04-29 US US15/304,043 patent/US9902733B2/en active Active
  • 2015-04-29 WO PCT/CZ2015/000038 patent/WO2015165428A1/en not_active Ceased
  • 2015-04-29 JP JP2016565050A patent/JP6386585B2/ja active Active

Patent Citations (3)

Non-Patent Citations (27)

Also Published As

Similar Documents

Legal Events