WO2015028848A1 - Composés hétérocycliques bicycliques utilisés comme inhibiteurs de plusieurs kinases - Google Patents

Composés hétérocycliques bicycliques utilisés comme inhibiteurs de plusieurs kinases Download PDF

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WO2015028848A1
WO2015028848A1 PCT/IB2013/058215 IB2013058215W WO2015028848A1 WO 2015028848 A1 WO2015028848 A1 WO 2015028848A1 IB 2013058215 W IB2013058215 W IB 2013058215W WO 2015028848 A1 WO2015028848 A1 WO 2015028848A1
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alkyl
alkoxy
cancer
halo
cycloalkyl
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PCT/IB2013/058215
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Abhijit Roychowdhury
Rajiv Sharma
Valmik Aware
Sambhaji CHAVAN
Nitin GAIKWAD
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Piramal Enterprises Limited
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Publication of WO2015028848A1 publication Critical patent/WO2015028848A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to bicyclic heterocyclic compounds (referred to herein as the compounds of formula I), processes for their preparation, pharmaceutical compositions containing said compounds and their use in the prevention and treatment of diseases or disorders associated with abnormal protein kinase activity such as proliferative diseases.
  • Protein Kinases are enzymes that catalyze phosphorylation of phosphate groups from high- energy donor molecules, such as adenosine triphosphate (ATP) to specific substrates.
  • Protein Kinases (PK) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of proteins. This phosphorylation creates a phosphoprotein with altered protein activity, often acting as an on/off switch for protein functions. Protein kinases regulate cell functions like signal transduction, cell cycle, metabolism, differentiation, proliferation, and apoptosis.
  • abnormal protein kinase activity has been related to a host of diseases and disorders, ranging from relatively non life-threatening diseases such as psoriasis to extremely fatal diseases such as glioblastoma (brain cancer).
  • Protein kinases are mainly divided into nine groups and each of the groups is then split into families and subfamilies (Science, 2002, 298, 1912-1934).
  • Tyrosine kinases constitute an important group of protein kinases, which are specific for phosphorylation of tyrosine residues.
  • Other groups of protein kinases include serine/threonine kinases (STKs), which are specific for phosphorylation of serine and threonine residues.
  • STKs serine/threonine kinases
  • Some kinases referred to as "dual specificity" kinases, are able to phosphorylate tyrosine and serine/threonine residues.
  • Protein Tyrosine Kinases primarily act as growth factor receptors.
  • RTKs Receptor Tyrosine Kinases
  • RTKs Receptor Tyrosine Kinases
  • They comprise a large family of transmembrane receptors with diverse biological activity. In the human genome, at least ninety tyrosine kinases have been identified. Fifty-six receptor tyrosine kinases are expressed, which can be subdivided in nineteen families (Science, 2002, 298, 1912- 1934 and World Journal of Clinical Oncology, 2, 2, 80-93).
  • Insulin Receptors IR
  • PDGFR Platelet-Derived Growth Factor Receptors
  • VEGFR Vascular Endothelial Growth Factor Receptor
  • EGFR Epidermal Growth Factor Receptor
  • Insulin Receptor is a transmembrane receptor that is activated by insulin, insulinlike growth factor- 1 receptor (IGF-1R) and insulin receptor related receptor (IRR).
  • IGF-1R insulinlike growth factor- 1 receptor
  • IRR insulin receptor related receptor
  • IR and IGF- IR interact with insulin to activate a hetero-tetramer composed of two entirely extracellular glycosylated a subunits and two ⁇ subunits, which cross the cell membrane and which contain the tyrosine kinase domain.
  • the IGF-1R and its ligands, IGF-1 and IGF-2 are abnormally expressed in numerous tumors, including, but not limited to tumors of breast, prostate, thyroid, lung, hepatoma, colon, brain and neuroendocrine.
  • the Platelet-Derived Growth Factor Receptor (PDGFR) group includes PDGFRa,
  • PDGFRp colony stimulating factor- 1 receptor
  • CSF-1R colony stimulating factor- 1 receptor
  • c-kit stem cell factor receptor
  • c- fms human CSF-1 receptor
  • These receptors consist of glycosylated extracellular domains composed of variable numbers of immunoglobin-like loops and an intracellular domain wherein the tyrosine kinase domain is interrupted by unrelated amino acid sequences.
  • PDGF signaling is an interesting target for cancer treatment. In addition to its role in autocrine growth stimulation of tumor cells, PDGF is believed to regulate tumor stroma fibroblasts and tumor angiogenesis (Cancer Cell, 2003, 3, 439-443).
  • VEGF Vascular Endothelial Growth Factor
  • EGFR Epidermal Growth Factor Receptor family belongs to the ErbB (gene symbol derived from the name of a viral oncogene, Erythroblastic Leukemia Viral Oncogene) family of RTKs. These trans-membrane proteins are activated following binding with peptide growth factors of the EGF-family of proteins. Evidence suggests that the EGFR is involved in the pathogenesis and progression of different types of carcinoma. In particular, the growth and the survival of carcinoma cells appear to be sustained by a network of receptors/ligands of the ErbB family.
  • Vandetanib (ZD6474, AstraZenca) is an oral, multi-targeted tyrosine kinase that prevents both the blood supply to the tumor through inhibition of VEGFR-2 (antiangiogenesis), and the growth and survival of the tumor itself through inhibition of EGFR (Cancer Res., 2002, 62, 4645-4655; Cancer Res., 2002, 62, 7284-7290). Inhibition of EGFR signalling has been shown to inhibit the secretion of VEGF as well as other proangiogenic factors such as fibroblast growth factor (FGF) and transforming growth factor (TGF). Preclinical studies have shown vandetanib to be active in a wide range of models, including lung tumors (Clin.
  • Multi-target approach provides distinct advantages in anticancer therapies considering that progression of many cancers, particularly solid tumors is considered as a multifactorial process.
  • NSCLC non small cell lung carcinoma
  • a single-targeted agent may not be the optimal choice for this patient population.
  • NSCLC non small cell lung carcinoma
  • sunitinib (SU 11248, Pfizer), which is an oral, multi-targeted receptor tyrosine kinase inhibitor with direct antiproliferative effects and antiangio genie properties.
  • Sunitinib targets VEGFR-1, VEGFR -2 and VEGFR -3, PDGFR-a and PDGFR- ⁇ , KIT (stem-cell factor receptor), RET (a gene whose DNA sequence is 'Rearranged During Transfection'), colony- stimulating factor receptor (CSF-1R) and FMS-like receptor tyrosine kinase (FLT3) (Blood, 2003, 101, 3597-3605; Mol. Cancer Ther., 2003, 2, 471-478; Clin. Cancer Res., 2003, 9, 327-337).
  • KIT stem-cell factor receptor
  • RET a gene whose DNA sequence is 'Rearranged During Transfection'
  • CSF-1R colony- stimulating factor receptor
  • FLT3 FMS-like receptor tyrosine kinase
  • sorafenib was initially developed as a RAF (Rapidly Accelerated Fibrosarcoma)-specific inhibitor, also inhibits VEGFR-2 and VEGFR-3 and PDGFGR- ⁇ ⁇ Cancer Res., 2004, 64, 7099-7109).
  • sorafenib significantly inhibited tumor angiogenesis as measured by anti-CD31 (anti-cluster of differentiation 31) immunostaining (Curr. Pharm. Des., 2002, 8, 2255-2257).
  • Another example of a multi-kinase inhibitor is Motesanib (AMG 706, Amgen) which has antiangio genie and anti-tumor activity that is achieved by selectively targeting the VEGF, PDGF, KIT and RET receptors.
  • a bicyclic heterocyclic compound referred to herein as a compound of formula I (as described herein), or an isotopic form, a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug or N-oxide thereof.
  • compositions comprising the compounds of formula I, or an isotopic form, a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug or N-oxide thereof and at least one pharmaceutically acceptable carrier or excipient.
  • compounds of formula I which are multi-kinase inhibitors.
  • a method for the treatment of a disease or disorder associated with abnormal protein kinase activity comprising administering to a subject in need thereof a therapeutically effective amount of the compounds of formula I or an isotopic form, a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug or N-oxide thereof.
  • the present invention provides a compound of formula I,
  • Ri is selected from halogen, (Ci-C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (Ci-C 6 )-alkoxy, (C 3 -C 12 )- cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl or heteroaryl;
  • R 2 is selected from hydrogen, (C 1 -C6)-alkyl or (C 6 -C 14 )-aryl;
  • R 3 is selected from hydrogen, hydroxy, halogen, cyano, nitro, (Ci-C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (Ci-C 6 )-alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl, heteroaryl or NR a R t ,;
  • R a and R are independently selected from hydrogen, (C 1 -C 6 )-alkyl, amino(C 1 -C 6 )-alkyl, (Q- C 6 )-alkoxy, (Ci-C 6 )-alkoxy(Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )-ar(Ci-C 6 )- alkyl, heterocyclyl, heteroaryl, C(0)(Ci-C6)-alkyl, C(0)0(Ci-C 6 )-alkyl and S(0) m R 2 ; or
  • R a and R together with the N to which they are attached can optionally form a 3-8 membered heterocyclyl ring, optionally containing 1-3 additional heteroatoms selected from N, O or S, and the said heterocyclyl ring is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, nitro, (C 1 -C 6 )-alkyl, (Q-C ⁇ -alkoxy, (C 1 -C 6 )-alkoxy(C 1 - C 6 )-alkyl, amino(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkylamino, (C 3 -C 12 )-cycloalkyl, (C 3 -C 12 )-cycloalkyloxy, halo(C 1 -C 6 )-alkyl, halo(C 1 -C 6 )-alkoxy, (C 6 -C 14 )-aryl, (
  • R4, R 5 , R 6 and R 7 are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, (Q- C 6 )-alkyl, halo(Ci-C6)alkyl, (Ci-C 6 )-alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl, heteroaryl and S(0) m R 2 ; or
  • R4 and R5 or R 6 and R 7 can together form a 3-7 membered ring optionally containing 1-3 heteroatoms selected from N, O or S, wherein the said ring is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, nitro, (Ci-C 6 )-alkyl, (Ci-Q -alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )-alkyl, amino(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkylamino, (C 3 -C 12 )- cycloalkyl, (C 3 -C 12 )-cycloalkyloxy, halo(C 1 -C 6 )-alkyl, halo(C 1 -C 6 )-alkoxy, (C 6 -C 14 )-aryl, (C 6 - C 1 )-aryloxy
  • R4 and R 6 can together form a bridge containing 1-3 methylene groups
  • R5 and R 7 are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, (C 1 -C6)-alkyl, halo(Ci- C 6 )alkyl, (Ci-C 6 )-alkoxy, (C3-C 1 2)-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl, heteroaryl and S(0) m R 2 ;
  • R c is selected from halogen, hydroxy, cyano, nitro, (C 1 -C6)-alkyl-(R c )o-i, (C 1 -C 6 )-alkoxy-(R c )o -1 , (Ci-C 6 )-alkoxy(Ci-C 6 )-alkyl-(R c )o-i, (C 3 -Ci 2 )-cycloalkyl-(R c ) 0 -i, (C 3 -Ci 2 )-cycloalkyloxy-(R c ) 0 -i, (C 1 -C 6 )-hydroxyalkyl-(R c ) 0 -i, haloCQ- ⁇ -alkyl, halo(C 1 -C 6 )-alkoxy, (C 6 -C 14 )-aryl-(R c ) 0 -i, (C 6 - C 14 )-aryl
  • substitution means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
  • the terms “a”, “an” and “the” refers to “one or more” when used in the subject specification, including the claims.
  • reference to “a compound” may include a plurality of such compounds, or reference to “a disease” or “a disorder” includes a plurality of diseases or disorders.
  • the term “or” is generally employed in its sense including
  • substituents independently when used in the context of selection of substituents for a variable, it means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • (C 1 -C 6 )-alkyl” or “alkyl” whether used alone or as part of a substituent group refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups.
  • a straight-chain or branched chain alkyl has six or fewer carbon atoms in its backbone, for instance, CrC 6 for straight chain and C3-C 6 for branched chain.
  • Suitable alkyl groups containing from one to six carbon atoms include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl and 3-hexyl.
  • alkyl groups may be unsubstituted or substituted with one or more substituents.
  • a substituted alkyl refers to a (C 1 -C6)-alkyl substituted with one or more groups, preferably 1-3 groups, independently selected from halogen, hydroxy, nitro, cyano, (C 1 -C 6 )-alkoxy-(R c ) 0 -3, (C 3 -C 12 )-cycloalkyl-(R c )o-3, (C 3 -C 12 )-cycloalkyloxy-(R c ) 0 - 3 , halo(C 1 -C 6 )-alkoxy, (C 6 -C 14 )-aryl-(R c )o- 3 , (C 6 -C 14 )-aryloxy-(R c ) 0 - 3 , (C 6 -C 14 )-ar(C 1 -C 6 )-alky
  • substituted alkyls include, but are not limited to, chloromethyl, fluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, aminoethyl and the like.
  • halogen refers to a fluorine, chlorine, bromine, or iodine atom.
  • halo(C 1 -C 6 )-alkyl When the alkyl group is substituted with one or more halogens, it is specifically referred to as "halo(C 1 -C 6 )-alkyl" or "haloalkyl".
  • a monohalo(C 1 -C 6 )-alkyl radical for example, may have one chlorine, bromine, iodine or fluorine atom.
  • Dihalo and polyhalo(C 1 -C 6 )-alkyl radicals may have two or more of the same or different halogen atoms.
  • halo(C 1 -C 6 )-alkyl examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl and the like.
  • (C 1 -C 6 )-alkoxy refers to a (Ci-C 6 )-alkyl having an oxygen radical attached thereto.
  • Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like.
  • halo(C 1 -C 6 )-alkoxy refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens.
  • Representative examples of "haloalkoxy” or “halo(C 1 -C 6 )-alkoxy” groups include, but not limited to, difluoromethoxy (OCHF 2 ), trifluoromethoxy (OCF 3 ) or trifluoroethoxy (OCH 2 CF 3 ) and the like.
  • (C 3 -C 12 )-cycloalkyl or “cycloalkyl” whether used alone or as part of a substituent group, refers to a saturated or partially unsaturated cyclic hydrocarbon radical including 1, 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings.
  • the term cycloalkyl includes bridged, fused and spiro ring systems.
  • (C 3 -C 12 )- cycloalkyl refers to a cycloalkyl group having 3 to 8 (both inclusive) carbon atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1.0]pentane, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2-ene, spiro[3.3]heptane, l,2,3,3a-tetrahydropentalene and the like.
  • the "cycloalkyl” group may be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from halogen, hydroxy, nitro, cyano, (C 1 -C 6 )-alkyl-(R c ) 0 -3, (C 1 -C 6 )-alkoxy-(R c ) 0 -3, (C 1 -C 6 )-alkoxy(C 1 -C 6 )-alkyl-(R c )o-3, (C 3 -C 12 )-cycloalkyl-(R c ) 0 -3, (C 3 -C 12 )-cycloalkyloxy-(R c ) 0 -3, haloCQ- ⁇ -alkyl, halo(d-C 6 )- alkoxy, (C 6 -C 14 )-aryl-(R c )o-3, (C 6 -C 14 )-aryl
  • (CrC 12 )-cycloalkyloxy or cycloalkyloxy refers to a (C3-C 12 )-cycloalkyl having an oxygen radical attached thereto.
  • Representative cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the alkoxy and cycloalkyloxy may be unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, nitro, cyano, (C 1 -C 6 )-alkyl-(R c ) 0 -3, (C 1 -C 6 )-alkoxy-(R c )o- 3 , (C 1 -C 6 )-alkoxy(C 1 -C 6 )-alkyl-(R c ) 0 -3, (C 3 -C 12 )- cycloalkyl-(R c )o_3, (C 3 -C 12 )-cycloalkyloxy-(R c ) 0 -3, halo(C 1 -C 6 )-alkyl, halo(C 1 -C 6 )-alkoxy, (C 6 - C 14 )-aryl-(R c )o_3, (C 6 -C 14 )-ary
  • substituted (C 1 -C6)-alkoxy examples include, but are not limited to, chloromethoxy, 2-cyanoethoxy, trifluoromethoxy and benzyloxy group and the like.
  • a benzyloxy group refers to a benzyl having an oxygen radical attached thereto.
  • (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl refers to a (Ci-C 6 )-alkyl group, which is substituted with (Ci-C 6 )-alkoxy group.
  • (C 6 -C 14 )-aryl refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system.
  • Examples of (C 6 -C 14 )-aryl residues are phenyl, naphthyl, fluorenyl and anthracenyl and the like.
  • a preferred example of (C 6 -C 14 )-aryl residue is phenyl.
  • Aryl groups can be unsubstituted or substituted with one or more groups, for example 1, 2, 3, 4 or 5 groups independently selected from halogen, hydroxy, nitro, cyano, (C 1 -C 6 )-alkyl-(R c ) 0 -3, (C 1 -C 6 )-alkoxy-(R c ) 0 -3, (C 1 -C 6 )-alkoxy(C 1 -C 6 )-alkyl-(Rc)o-3, (C 3 -Ci 2 )-cycloalkyl-(R c )o-3, (C 3 -Ci 2 )-cycloalkyloxy-(R c ) 0 -3, halo(Ci-C 6 )-alkyl, halo(Ci-C 6 )- alkoxy, (C 6 -C 14 )-aryl-(R c )o-3, (C 6 -C 14 )-aryloxy-(
  • the substituent can be located in the 2-position, the 3-position or the 4- position. If the phenyl carries two substituents, they can be located in 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position.
  • mono substituted phenyl groups include, but are not limited to 3-trifluoromethylphenyl, 4-chlorophenyl and 4- cyanophenyl.
  • disubstituted phenyl groups include, but are not limited to, 3, 5- difluorophenyl, and 3, 4-dimethoxyphenyl.
  • (C 6 -C 14 )-aryloxy refers to an "(C 6 -C 14 )-aryl” group having an oxygen radical attached thereto.
  • the aryl of aryloxy group may be unsubstituted or substituted as explained in the definition of substituted (C 6 -C 14 )-aryl herein above.
  • Examples of aryloxy groups include, but are not limited to, phenoxy, 4-chlorophenoxy, and 3, 4- dimethoxyphenoxy.
  • (C 6 -C 14 )-ar(C 1 -C 6 )-alkyl” or “aralkyl” refers to (C 1 -C 6 )-alkyl group substituted with an (C 6 -C 14 )-aryl group, wherein the terms alkyl and aryl are as defined above.
  • exemplary aralkyl groups include (CH 2 ) p _phenyl, wherein p is an integer from 1 to 6, such as benzyl (CH 2 -phenyl).
  • the aryl of the (C 6 -C 14 )-aralkyl group may be unsubstituted or substituted as explained in the definition of substituted aryl herein above.
  • the term "(C 6 -C 14 )-ar(C 1 -C 6 )-alkyloxy" or “aralkyloxy” refers to an aralkyl group having an oxygen radical attached thereto.
  • the aryl of aralkyloxy group may be unsubstituted or substituted as explained in the definition of substituted aryl herein above.
  • the term “amino” refers to the group “NH 2 " which may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, (C 1 -C6)-alkyl, aryl or the like.
  • amino(C 1 -C 6 )-alkyl refers to an amino substituted alkyl radical. This term is meant to include (Ci-C 6 )-alkyl groups having an amino substituent at any position and wherein the aminoalkyl group attaches through alkyl radical.
  • the alkyl and/or amino portions of the amino(C 1 -C 6 )-alkyl group may be substituted or unsubstituted.
  • aminoalkyl groups include, but are not limited to -CH 2 -CH 2 -NH 2 , -CH 2 -CH 2 - NH(CH 3 ) and -CH 2 -CH 2 -N(CH 3 ) 2 and the like.
  • (C 1 -C 6 )-alkylamino refers to an alkyl substituted amino group. This term is meant to include an amino group having a (C 1 -C 6 )-alkyl substituent and wherein the alkylamino group attaches through amino radical.
  • the alkyl and/or amino portions of the (C 1 -C 6 )-alkylamino group may be substituted or unsubstituted.
  • alkylamino groups include, but are not limited to -NH-CH 2 -CH and -N(CH )-CH 2 -CH and the like.
  • heteroatom as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.
  • heterocyclyl or “heterocyclic” whether used alone or as part of a substituent group, refers to a 3- to 9-membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from a nitrogen (N), a sulphur (S) or an oxygen (O) atom.
  • Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bond. Partially unsaturated heterocyclic ring systems containing at least one double bond, but do not form an aromatic system containing hetero atom.
  • Suitable saturated and partially unsaturated heterocyclic groups include, but are not limited to, aziridine, oxirane, oxiridine, thiirane, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio-dihydropyran, thio- tetrahydropyran, piperidine, piperazine, morpholine, 1,3-oxazinane, 1,3-thiazinane, 4,5,6-tetra hydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydro pyridine, isoxazolidine, pyrazolidine, azepane, oxepane, thiepane and azocane.
  • heteroaryl refers to a 3 to 10-membered aromatic monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from N, S or an O atom.
  • heteroaryl examples include, but are not limited to pyrrole, pyrazole, imidazole, triazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrine), tetrazole, azepine, oxepine, thiepine and azocine.
  • the oxidized form of the ring nitrogen atom of the heteroaryl to provide N-oxide is also encompassed.
  • heterocyclyl or heteroaryl group may be unsubstituted or substituted.
  • a substituted heterocyclyl or heteroaryl refers to a heterocyclyl or heteroaryl substituted with 1-5 groups independently selected from halogen, hydroxy, nitro, cyano, (CrC 6 )- alkyl-(R c )o_3, (Ci-C 6 )-alkoxy-(R c ) 0 - 3 , (Ci-C 6 )-alkoxy(Ci-C 6 )-alkyl-(R c )o-3, (C 3 -Ci 2 )-cycloalkyl- (R c )o- 3 , (C 3 -C 12 )-cycloalkyloxy-(R c ) 0 - 3 , halo(Ci- ( 1 ⁇ 4)-alkyl, halo(C 1 -C 6 )-alkoxy, (C 6 -C 14 )-
  • bridge or “bridged” as used herein generally refers to a compound (bridged compound) containing at least two bridgehead carbon atoms or heteroatoms linked through a bridge containing at least one carbon atom.
  • a bridged compound includes bridge heads that connects at least two non-adjacent positions of the same ring.
  • bridged compounds include, but are not limited to, bicyclo[2.2.1]heptanes, bicyclo[2.2.2]octane, bicyclo[3.1.1]heptanes, bicyclo[3.3.2]decane, bicyclo[3.3.1]nonane, bicyclo[2.1.1]hexane, bicyclo[3.3.3]undecane, bicyclo[4.2.1]nonane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane and bicyclo[3.2.2]nonane.
  • solvate refers to an aggregate of a molecule (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof) with one or more solvent molecules.
  • solvents for the purpose of the invention may not interfere with the biological activity of the molecule.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water and the solvates obtained are referred to as hydrates.
  • suitable solvates are the mono- or di-hydrates or alcoholates of the compounds according to the invention.
  • stereoisomer or “stereoisomeric form” is a general term used for all isomers of individual compounds (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof) that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • tautomer or “tautomeric form” refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
  • the term "pharmaceutically acceptable” means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation (composition), and not deleterious to the recipient thereof.
  • salts or “salt(s)” as used herein includes salts of the active compound i.e. the compound of formula I, which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared with suitable acids or bases, depending on the particular substituents found on the compounds described herein.
  • polymorph or “pharmaceutically acceptable polymorph(s)” or “polymorphic form” refers to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof) in the crystal lattice.
  • N-oxide refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in the presence of an oxidizing agent such as m-chloro-perbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N- ⁇ O bond.
  • a prodrug or “pharmaceutically acceptable prodrug(s)” refers to any compound (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof), which are derivatives of the said compound, which following administration, release(s) the parent compound in vivo via a chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
  • the term "compound(s) of formula I" or “compounds of the present invention” are used interchangeably and includes all the stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, N- oxides and pharmaceutically acceptable polymorphs thereof.
  • the compound(s) of formula I can also be referred to herein as "the active compound” or "the active ingredient”.
  • therapeutically effective amount means an amount of a compound of formula I or a pharmaceutically acceptable salt thereof; or a composition comprising the compound of formula I or a salt thereof, effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder associated with abnormal protein kinase activity.
  • therapeutically effective amount includes the amount of the compound, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject.
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment.
  • the therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the disease or disorder being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other factors.
  • the term "pharmaceutically acceptable carrier” refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof), to the target site without terminating the activity of the agent.
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to warm-blooded vertebrate animals of the class 'mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
  • treatment is intended to mean to alleviate, slow the progression, attenuation or cure of existing disease or condition (e.g. disease or disorder associated with abnormal protein kinase activity). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.
  • multi-kinase inhibitor refers to a compound that exhibits a therapeutic effect by inhibiting more than one protein kinases.
  • multi-kinase inhibitor is a compound which does not specifically inhibit only one kinase as a molecular target, but primarily inhibits multiple protein kinases, at least two kinases.
  • PK protein kinase
  • PK-related disorder refers to a condition characterized by abnormal (i.e., diminished or, more commonly, excessive) PK catalytic activity, where the particular PK can be RTK (receptor tyrosine kinases) or STK (serine/threonine kinases).
  • Abnormal PK catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs; (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth; or (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth.
  • Excessive-activity of a PK refers to either amplification of the gene encoding a particular PK or its ligand, or production of a level of PK activity, which can correlate with a cell proliferation, differentiation and/or growth disorder such as cancer, inflammatory disorders, CNS disorders and autoimmune disorders.
  • the present invention relates to a compound of formula I, or an isotopic form, stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug or N-oxide thereof; wherein,
  • Ri is selected from halogen, (C 1 -C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (Ci-C 6 )-alkoxy, (C 3 -C 12 )- cycloalkyl or (C 6 -C 14 )-aryl; and
  • the present invention relates to a compound of formula I or an isotopic form, stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug or N-oxide thereof; wherein,
  • Ri is selected from (Ci-C 6 )-alkyl, (C 3 -C 12 )-cycloalkyl or (C 6 -C 14 )-aryl;
  • R 2 is hydrogen or (C 1 -C 6 )-alkyl;
  • R 3 is selected from hydrogen, hydroxy, halogen, cyano, nitro, (C 1 -C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (Ci-C 6 )-alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl, heteroaryl or NR a R t ,; where,
  • R a and R are independently selected from hydrogen, (C 1 -C 6 )-alkyl, amino(C 1 -C 6 )-alkyl, (Q- C 6 )-alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )-alkyl, (C 3 -C 12 )-cycloalkyl, (C 6 -C 14 )-aryl, (C 6 -C 14 )-ar(C 1 -C 6 )- alkyl, heterocyclyl and heteroaryl; or
  • R a and R b together with the N to which they are attached can optionally form a 3-8 membered heterocyclyl ring, optionally containing 1-3 additional heteroatoms selected from N, O or S and the said heterocyclyl ring is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )- alkyl, (C 3 -Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(d-C 6 )-alkyl, halo(d-C 6 )-alkoxy, (C 6 - C 14 )-aryl, (C 6 -C 14 )-aryloxy, (C 6 -C 14 )-ar(Ci-C 6
  • R4, R 5 , R 6 and R 7 are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, (Q- C 6 )-alkyl, halo(Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy and (C 3 -Ci 2 )-cycloalkyl or;
  • R4 and R 5 or R 6 and R 7 can together form a 3-7 membered ring optionally containing 1-3 heteroatoms selected from N, O or S, wherein the said ring is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, nitro, (Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy, (Ci-C 6 )-alkoxy(Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkoxy, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )-aryloxy, (C 6 -Ci 4 )-ar(Ci-C 6 )-alkyl, (C 6
  • R c is selected from halogen, hydroxy, cyano, nitro, (C 1 -C6)-alkyl-(R c )o-i, (C 1 -C6)-alkoxy-(R c )o-i, (Ci-C 6 )-alkoxy(Ci-C 6 )-alkyl-(R c )o-i, (C 3 -Ci 2 )-cycloalkyl-(R c ) 0 -i, (C 3 -Ci 2 )-cycloalkyloxy-(R c ) 0 -i, (C 1 -C 6 )-hydroxyalkyl-(R c ) 0 -i, haloCQ- ⁇ -alkyl, halo(C 1 -C 6 )-alkoxy, (C 6 -C 14 )-aryl-(R c ) 0 -i, (C 6 - C 14 )-aryloxy-(
  • the present invention relates to a compound of formula I;
  • Ri is selected from (Ci-C 6 )-alkyl, (C 3 -C 12 )-cycloalkyl or (C 6 -C 14 )-aryl;
  • R is selected from hydroxy, halogen, cyano, nitro, (C 1 -C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (C -C )- alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl or NR a R b ; and R 2 , R4, R5, R6, R7, R a , Rb, and n are as defined in the second embodiment.
  • the present invention relates to a compound of formula I;
  • Ri is selected from (C 1 -C 6 )-alkyl, (CrC 12 )-cycloalkyl or (C 6 -C 14 )-aryl;
  • R 3 is selected from hydroxy, halogen, cyano, nitro, (Ci-C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (C 1 -C 6 )- alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl or NR a Rt,;
  • Ri and R 6 can together form a bridge containing 1-3 methylene groups
  • R 2 , R 5 , R 7 , R a , R b and n are as defined in the second embodiment.
  • the present invention relates to a compound of formula I;
  • Ri is selected from (Ci-C 6 )-alkyl, (CrC 12 )-cycloalkyl or (C 6 -C 14 )-aryl;
  • R 3 is selected from hydroxy, halogen, cyano, nitro, (Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkyl, (Ci-Ce)- alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl or NR a Rt,;
  • Ri and R5 are independently selected from hydrogen, hydroxy, halogen, cyano, (Ci-C 6 )-alkyl and halo(Ci-C 6 )alkyl;
  • R 2 , R 6 , R7, R a , R b and n are as defined in the second embodiment.
  • the present invention relates to a compound of formula I;
  • Ri is selected from (Ci-C 6 )-alkyl, (C 3 -C 12 )-cycloalkyl or (C 6 -C 14 )-aryl;
  • R3 is selected from hydroxy, halogen, cyano, nitro, (Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkyl, (Ci-Ce)- alkoxy, (C 3 -C 12 )-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl or NR a R b ;
  • R4 and R5 can together form a 3-7 membered ring optionally containing 1-3 heteroatoms selected from N, O or S, wherein the said ring is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, (Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy, (CrC 12 )- cycloalkyl, halo(d-C 6 )-alkyl, halo(d-C 6 )-alkoxy, C(0)R a, C(0)OR a , NR a R b and C(0)NR a R b ; and
  • R 2 , R 6 , R 7 , R a , R b and n are as defined in the second embodiment.
  • the present invention relates to a compound of formula I; wherein,
  • Ri is selected from (C 1 -C6)-alkyl, (CrC ⁇ -cycloalkyl or (C 6 -C 14 )-aryl;
  • R 3 is selected from hydroxy, halogen, cyano, nitro, (Ci-C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (CrC 6 )- alkoxy, (C3-C 1 2)-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl or NR a R b ;
  • R 6 and R 7 are independently selected from hydrogen, hydroxy, halogen, cyano, (Ci-C 6 )-alkyl and halo(C 1 -C 6 )alkyl;
  • R 2 , R4, R5, R a , R b and n are as defined in the second embodiment.
  • the present invention relates to a compound of formula I;
  • Ri is selected from (Ci-C6)-alkyl, (CrC 12 )-cycloalkyl or (C 6 -C 14 )-aryl;
  • R 3 is selected from hydroxy, halogen, cyano, nitro, (C 1 -C 6 )-alkyl, halo(Ci-C6)-alkyl, (C -C )- alkoxy, (C3-C 12 )-cycloalkyl, (C 6 -C 14 )-aryl, heterocyclyl or NR a R b ;
  • R 6 and R 7 can together form a 3-7 membered ring optionally containing 1-3 heteroatoms selected from N, O or S, wherein the said ring is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, (Q-C ⁇ -alkyl, (Q-C ⁇ -alkoxy, (C 3 -C 12 )- cycloalkyl, halo(d-C 6 )-alkyl, halo(Ci-C 6 )-alkoxy, C(0)R a, C(0)OR a , NR a R b and C(0)NR a R b ; and
  • R 2 , R4, R5, R a , R b and n are as defined in the second embodiment.
  • the present invention relates to a compound of formula I;
  • Ri is (Ci-C 6 )-alkyl
  • R 3 is selected from halogen, (Ci-C 6 )-alkyl, halo(Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, heterocyclyl or NR a R b ;
  • R4, R5, R 6 and R 7 are independently selected from hydrogen, hydroxy, halogen, (Ci-C 6 )-alkyl and halo(Ci-C 6 )alkyl; or
  • R4 and R5 or R 6 and R 7 can together form a 3-7 membered ring optionally containing 1-3 heteroatoms selected from N, O or S, wherein the said ring is unsubstituted or substituted with one or more groups independently selected from halogen, (Ci-C 6 )-alkyl, (C3-C 1 2)-cycloalkyl, halo(Ci-Q -alkyl, C(0)R a , C(0)OR a , NR a R b and C(0)NR a R b ; and
  • R 2 , R a , Rb and n are as defined in the second embodiment.
  • the present invention relates to a compound of formula I;
  • Ri is (C 3 -C 12 )-cycloalkyl
  • R 3 is selected from halogen, (Ci-C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (C 3 -C 12 )-cycloalkyl, heterocyclyl or NR a R b ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, hydroxy, halogen, (Ci-C 6 )-alkyl and halo(C 1 -C 6 )alkyl; or
  • R 4 and R 5 or R 6 and R 7 can together form a 3-7 membered ring optionally containing 1-3 heteroatoms selected from N, O or S, wherein the said ring is unsubstituted or substituted with one or more groups independently selected from halogen, (C 1 -C 6 )-alkyl, (C 3 -C 12 )-cycloalkyl, halo(C 1 -C 6 )-alkyl, C(0)R a , C(0)OR a , NR a R b and C(0)NR a R b ; and
  • R 2 , R a , Rb and n are as defined in the second embodiment.
  • the present invention relates to a compound of formula I;
  • Ri is (C 6 -C 14 )-aryl
  • R 3 is selected from halogen, (Ci-C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (C 3 -C 12 )-cycloalkyl, heterocyclyl or NR a R b ;
  • R4, R 5 , R 6 and R 7 are independently selected from hydrogen, hydroxy, halogen, (Ci-C 6 )-alkyl and halo(C 1 -C 6 )alkyl; or
  • R ⁇ and R 5 or R 6 and R 7 can together form a 3-7 membered ring optionally containing 1-3 heteroatoms selected from N, O or S, wherein the said ring is unsubstituted or substituted with one or more groups independently selected from halogen, (C 1 -C 6 )-alkyl, (C 3 -C 12 )-cycloalkyl, halo(Ci-C 6 )-alkyl, C(0)R a, C(0)OR a , NR a R b and C(0)NR a R b ; and
  • R 2 , R a , R b and n are as defined in the second embodiment.
  • Representative compounds of formula I in accordance with the present invention include:
  • the compound of formula I can be prepared by various methods including using one or more methods well known to the person skilled in the art. Representative processes for the preparation of the compounds of formula I are described herein below and illustrated in the following schemes, but are not limited thereto. It will be appreciated by the person skilled in the art that within certain of the processes described herein, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent such as bases, solvents, coupling agents to be used in the reaction steps.
  • the process step (v) involves contacting the compounds of formula I obtained in step (iv) with a sufficient amount of an appropriate base or an appropriate acid, either neat or in a suitable inert solvent.
  • a hydrochloride salt can be prepared by contacting the compound of formula I with hydrochloric acid either neat or in a suitable solvent, such as alcohol.
  • a sodium salt of a compound of formula I containing an acidic group can be prepared by contacting the compound of formula I with sodium hydroxide in a suitable solvent, such as tetrahydrofuran.
  • step (i) of scheme 1 is preferably carried out using hydrochloric acid as a catalyst in the presence of alcohol as the solvent.
  • step (ii) of scheme 1 is preferably carried out using phosphorus oxychloride.
  • step (iii) of scheme 1 is preferably carried out using triethylamine as the base in the presence of an alcohol (e.g. ethanol) as the solvent.
  • an alcohol e.g. ethanol
  • step (iv) of scheme 1 is preferably carried out using triethylamine as the base in the presence of a solvent such as alcohol or N-methylpyrrolidone.
  • Scheme 2 depicts a process for the preparation of the compounds of formula I, wherein R 1; R 2 , R 3 , R4, R5, R 6 , R7 and n are as defined in the first aspect of the present invention.
  • step (f) can be carried out in a manner similar to that of step (v) of scheme 1 as described above.
  • step (a) of scheme 2 is preferably carried out using water as the solvent in the presence of sodium carbonate as the base.
  • step (b) of scheme 2 is preferably carried out using phosphorus oxychloride.
  • step (c) of scheme 2 is preferably carried out using m-CPBA as the oxidising agent.
  • step (d) of scheme 2 is preferably carried out using alcohol as the solvent in the presence of triethylamine as the base.
  • step (e) of scheme 2 is preferably carried out using triethylamine as the base in the presence of a solvent such as alcohol or N-methylpyrrolidone.
  • the present invention also includes within its scope pharmaceutically acceptable salts or solvates thereof of compound of formula I.
  • pharmaceutically acceptable salts refers to organic and inorganic salts of a compound of formula I of the present invention, depending on the particular group (acidic or basic group) present in the said compounds.
  • base addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts of the compounds of the present invention include their alkali metal salts such as sodium, potassium, calcium, magnesium, ammonium or organic base addition salt.
  • pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like or other organic bases known to the person skilled in the art.
  • acid addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate acid, either neat or in a suitable inert solvent.
  • an appropriate acid either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts particularly those derived from inorganic acids include hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, mono-hydrogensulfuric or hydriodic acids or other inorganic acids known to the person skilled in the art.
  • examples of pharmaceutically acceptable acid addition salts include the salts derived from organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic or galacturonic acids or other organic acids known to the person skilled in the art.
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of formula I may be regenerated from their corresponding salts by contacting the salt with an appropriate base or acid depending on the type of salt and isolating the parent compound in the conventional manner.
  • the compound may differ from the various salt forms in certain physical properties.
  • An example of physical properties that may differ is solubility in polar solvents.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • polymorphs of compounds of formula I can be prepared by crystallization of the compounds under different conditions.
  • the different conditions are, for example, using different solvents or their mixtures for crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymorphs can also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs can be determined by IR (Infra-Red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention includes all possible stereoisomers and geometric isomers of formula I and includes not only racemic compounds but also the optically active isomers as well.
  • a compound of formula I When a compound of formula I is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or an appropriate intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example, Chiral reagents for asymmetric synthesis by Leo A. Paquette; John Wiley & Sons Ltd (2003).
  • the present invention is intended to include all tautomeric forms of the compounds.
  • prodrugs of the compound of formula I are those compounds that are converted intracellularly, more preferably, where the cellular converting location is the site of therapeutic action.
  • preferred prodrugs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid.
  • pharmaceutically acceptable esters include lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters such as the pivaloyloxymethyl ester and the like conventionally used in the art (An introduction to Medicinal Chemistry, Graham. L.
  • the present invention relates to pharmaceutical composition(s) containing a therapeutically effective amount of at least one compound of formula I or its pharmaceutically acceptable salt or solvate thereof and a conventional pharmaceutically acceptable carrier.
  • the present invention also relates to a process for the production of a pharmaceutical composition, which includes bringing at least one compound of formula I, into a suitable administration form using a pharmaceutically acceptable and physiologically tolerable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries can be added.
  • composition(s) of the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
  • composition(s) according to the invention is/are prepared in a manner known and/or familiar to a person skilled in the art.
  • Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compound(s) of formula I, and/or its (their) pharmaceutically acceptable salt(s).
  • Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc.
  • Suitable carriers for the production of solutions for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.
  • the pharmaceutical composition(s) normally contain about 1 % to 99 , for example, about 5 % to 70 , or from about 10 % to about 30 % by weight of the compound of formula I or its pharmaceutically acceptable salt.
  • the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower that the specified range.
  • the dosage range which is suitable in a specific case depends on the type of disease or disorder to be treated and on the state of the respective condition or disorder.
  • the selected dosage level can be readily determined by a skilled medical practitioner in the light of the relevant circumstances, including the disease or disorder to be treated, the chosen route of administration including other factors such as age, weight and physical health and response of the individual patient (subject), pharmacokinetics, severity of the disease and other like factors known in the medical art.
  • Actual dosage levels of the active ingredients i.e. the compounds of formula I in the pharmaceutical composition of this present invention can be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient (subject in need of the treatment), composition, and mode of administration without being toxic to the patient.
  • the dose of the compounds of formula I or pharmaceutically acceptable salts thereof, which is to be administered can cover a wide range.
  • the dose to be administered daily is to be selected to suit the desired effect.
  • a suitable dosage is about 0.01 mg/kg/day to about 200 mg/kg/day of the compound of formula I or its pharmaceutically acceptable salt, for example, about 0.1 mg/kg/day to 100 mg/kg/day of a compound of formula I or its pharmaceutically acceptable salt. If required, higher or lower daily doses can also be administered.
  • the pharmaceutical compositions can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants.
  • Pharmaceutical compositions can also contain two or more compounds of formula I or their pharmaceutically acceptable salts.
  • the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.
  • the compounds of formula I or pharmaceutically acceptable salts thereof are multi-kinase inhibitors.
  • the compounds of formula I or pharmaceutically acceptable salts thereof are inhibitors of the protein kinases selected from the group consisting of Insulin-like Growth Factor- 1 Receptor (IGF-1R), Insulin Receptors (IR), Vascular Endothelial Growth Factor Receptor (VEGF) and Platelet-Derived Growth Factor Receptors (PDGFR).
  • IGF-1R Insulin-like Growth Factor- 1 Receptor
  • IR Insulin Receptors
  • VEGF Vascular Endothelial Growth Factor Receptor
  • PDGFR Platelet-Derived Growth Factor Receptors
  • the present invention relates to a method for the treatment of a disease or a disorder associated with abnormal protein kinase activity, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention relates to use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease
  • the present invention provides use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or a disorder associated with abnormal protein kinase activity.
  • the disease or disorder associated with abnormal protein kinase activity is selected from an inflammatory disease, an allergic disorder, a pulmonary disease, diabetes, diabetes related disorder, acromegaly, angiogenesis, a proliferative disease, a CNS (central nervous system) disorder, a cardiovascular disease or an autoimmune disease.
  • an inflammatory disease examples include, but are not limited to, acute or chronic pain, arthritis, rheumatoid arthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, spondyloarthropathy, pulmonary disorder such as asthma, chronic obstructive pulmonary disease (COPD) or lung inflammation, inflammatory bowel disease, Crohn's disease, multiple sclerosis, ulcerative colitis, irritable bowel syndrome, idiopathic thrombocytopenic purpura (ITP) and pelvic inflammatory disease.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • ITP idiopathic thrombocytopenic purpura
  • an allergic disorder examples include, but are not limited to, allergic rhinitis, allergic bronchitis, allergic sinusitis, dermatitis, atopic dermatitis, urticaria and asthma.
  • pulmonary disease examples include, but are not limited to, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), lung inflammation, bronchitis obliteraus and primary pulmonary hypertension.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • lung inflammation bronchitis obliteraus
  • primary pulmonary hypertension examples include, but are not limited to, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), lung inflammation, bronchitis obliteraus and primary pulmonary hypertension.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • Examples of a proliferative disease include, but are not limited to, cancer, tumors, mastocytosis, associated myeloproliferative syndrome, urticaria pigmentosa, an epidermal hyperproliferation, psoriasis and prostate hyperplasia.
  • Examples of a cardiovascular disease include, but are not limited to, artherosclerosis, myocardial infarction, congestive heart failure and cardiac reperfusion injury.
  • Examples of a central nervous system disorder include, but are not limited to, brain injury, cerebrovascular disease, corticobasal degeneration, dementia, Parkinson's disease, Alzheimer's disease, vascular dementia, dementia with Lewy bodies and frontotemporal dementia.
  • Examples of an autoimmune disease include, but are not limited to, lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, urticarial, scleroderma, psoriasis and renal disease
  • Examples of diabetes related diseases include, but are not limited to, diabetic retinopathy, retinal ischemia, and retinal neovascularization.
  • the disease or disorder associated with abnormal protein kinase activity is cancer.
  • the present invention relates to a method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention relates to use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of cancer.
  • the present invention provides use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.
  • cancer is selected from leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), diffuse large B-cell lymphoma and follicular lymphoma, astrocytoma, basal or squamous cell carcinoma, brain cancer, gliobastoma, bladder cancer, breast cancer, colorectal cancer, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, sarcoma
  • ALL acute lympho
  • cancer is selected from brain cancer, breast cancer, prostate cancer, epithelial cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, renal cell carcinoma or endometrial carcinoma.
  • the compounds of the present invention can be administered alone or in combination with other therapies suitable for the disease or disorder being treated. Where separate dosage formulations are used, the compound and the other therapeutic agent can be administered at essentially the same time (concurrently) or at separately staggered times (sequentially).
  • the pharmaceutical combination is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial therapeutic effect of the compound of formula I or a pharmaceutically acceptable salt thereof and the other therapeutic agent are realized by the patient at substantially the same time. Such beneficial effect is achieved when the target blood level concentrations of each active drug are maintained at substantially the same time.
  • the present invention encompasses use of the compound of formula I or a pharmaceutically acceptable salt thereof in combination with one further therapeutically active agent for the treatment of diseases or disorders associated with abnormal activity of protein kinases.
  • the compounds of the present invention are useful in combination with known anti-cancer agents.
  • Combinations of the compounds of the present invention with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of therapeutic agents would be useful based on the particular characteristics of the therapeutic agents and the cancer involved.
  • anti-cancer agents that can be used in combination with the compounds of formula I include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, agents that interfere with receptor tyrosine kinases and cancer vaccines.
  • the compounds of the present invention can be co-administered with radiation therapy. It is understood that modifications that do not substantially affect the activity of the various aspects of this invention are included. Accordingly, the following examples are intended to illustrate but not to limit the present invention. The following abbreviations or terms are used herein:
  • PDGFRa Platelet-derived growth factor receptor a
  • the compound of example 5 was prepared analogous to the compound of example 3 by reaction of the compound of example 2 with 5-cyclopropyl-lH-pyrazol-3-amine. Yield: 51.4 ; 1H NMR (DMSO- , 300 MHz): ⁇ 12.14 (s, 1H), 9.58 (s, 1H ), 6.27 (s, 1H ), 2.73 (m, 4H), 2.02 (m, 2H), 1.91 (m, 1H), 0.92 (d, 2H), 0.68 (d, 2H); MS (ES-): m/z 274.1 (M-l).
  • Example 6 Example 6:
  • the compound of example 6 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with N 1 ,N1 ,N2 -trimethylethane-l,2-diamine. Yield: 35.35 ; 1 H NMR (CDC1 3 , 300 MHz): ⁇ 6.70 (s, 1H), 5.99 (s, 1H), 3.80 (t, 2H), 3.19 (s, 3H), 2.80 (t, 2H), 2.64 (m, 4H), 2.37 (s, 6H), 2.08 (m, 2H), 1.90 (m,lH), 0.92 (m, 2H), 0.76 (m, 2H).
  • the compound of example 7 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with bis(2-methoxyethyl)amine. Yield: 37.03 ; 1H NMR (DMSO- , 300 MHz): ⁇ 11.97 (s, 1H), 8.71 (s, 1H), 6.30 (s, 1H), 3.69 (t, 4H), 3.47 (t, 4H), 3.25 (s, 6H), 2.63 (s, 4H), 1.89 (m, 3H), 0.91 (d, 2H), 0.67 (s, 2H); MS (ES+): 370.8 (M+l).
  • the compound of example 9 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with 4-propylpiperidine. Yield: 26.3 ; 1H NMR (CDC1 3 ,300 MHz): ⁇ 6.62 (s,lH ), 6.01 (bs, 1H), 4.63 (d, 2H), 2.92 (m, 2H), 2.81 (m, 2H), 2.66 (t, 2H), 2.09 (m, 2H), 1.89 (m, 1H), 1.99 (d, 2H), 1.51 (m,lH), 1.38 (m, 2H), 1.23 (m, 4H), 0.97 (m, 5H), 0.74 (m, 2H); MS (ES+): m/z 367.2593 (M+l).
  • the compound of example 10 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with piperidine-4-carboxylic acid. Yield: 42.15 ; 1H NMR (DMSO- , 300 MHz): ⁇ 12.04 (bs, 2H ), 6.19 (s, 1H), 6.19 (s,lH), 4.43 (d, 2H), 2.95 (t, 2H), 2.62 (m, 4H), 1.87 (m, 5H ), 1.47 (m, 2H), 1.23 (s, 1H), 0.92 (m, 2H), 0.62 (m, 2H); MS (ES+): m/z 369.2 (M+l).
  • the compound of example 11 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with ethyl piperidine-4-carboxylate. Yield: 23.14 ; 1H NMR (MeOD, 300 MHz): ⁇ 6.31 (s, 1H ), 4.62 (s, 1H), 4.51 (d, 2H), 4.15 (q, 2H), 3.06 (m, 2H), 2.73 (m, 5H), 2.08 (m, 2H), 1.93 (m, 3H ), 1.65 (m, 2H), 1.27 (t, 3H), 0.98 (bs, 2H), 0.70 (m, 2H); MS (ES+): m/z 397 (M+l).
  • Example 12 Example 12:
  • the compound of example 12 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with 4-(trifluoromethyl)piperidine. Yield: 18.77 ; 1H NMR (CDC1 3 , 300 MHz): ⁇ 6.68 (s,lH ), 6.14 (s, 1H), 4.83 (d, 2H), 2.84 (m, 4H), 2.67 (t, 2H), 2.30 (m,lH), 2.10 (m, 2H), 1.93 (m, 3H), 1.63 (m, 2H), 1.09 (m, 2H), 0.74 (m, 2H); MS (ES+): m/z 393.2 (M+l).
  • the compound of example 13 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with 4-(3-(trifluoromethyl)phenyl)piperidine. Yield: 17.66 ; 1H NMR (CDC1 3 , 300 MHz): ⁇ 7.45 (m, 4H ), 6.67 (s, 1H), 6.11 (bs,lH), 4.87 (d,2H), 3.00 (t, 2H), 2.86 (m, 3H), 2.68 (t, 2H), 2.11 (m, 2H), 1.96 (m, 2H), 1.88 (m, 1H),1.78 (m, 3H), 0.95 (m, 2H), 0.75 (m, 2H); MS (ES+): m/z 469.2 (M+l).
  • the compound of example 14 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with 4-phenylpiperidine. Yield: 36.69 ; 1H NMR (CDCI3, 300 MHz): ⁇ 7.28 (m, 2H ), 6.65 (s, 1H), 6.09 (s,lH), 4.85 (d, 2H), 3.0 (m, 2H), 2.81 (m, 2H), 2.68 (t, 2H), 2.68 (t, 2H), 2.11 (m, 2H), 1.94-1.73 (m,8H), 0.95 (m, 2H), 0.74 (m, 2H); MS (ES+): m/z 401.3 (M+l).
  • the compound of example 15 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with azepane. Yield: 17.57 ; 1H NMR (DMSO-Je, 300 MHz): ⁇ 11.90 (s ,1H ), 8.68 (s, IH), 6.27 (s, IH), 3.65 (s, 4H), 2.61 (m ,4H), 1.88 (m, 3H), 1.64 (s,4H ), 1.46 (s, 4H), 0.91 (d, 2H), 0.60 (s, 2H); MS (ES+): m/z 339.2 (M+l)
  • the compound of example 16 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with azocane. Yield: 23.14 ; 1H NMR (MeOD, 300 MHz): ⁇ 6.44 (s, IH ), 5.67 (s, IH), 4.62 (s, IH), 3.71 (t, 4H), 2.75 (m, 4H), 2.10 (m, 2H), 1.84 (m, 5H), 1.60 (m, 6H), 0.97 (bs, 2H), 0.69 (m, 2H); MS (ES+): m/z 353.2 (M+l).
  • the compound of example 17 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with 4-methylpiperazine. Yield: 54.32 ; 1H NMR (DMSO- , 300 MHz): ⁇ 11.94 (s,lH), 8.79 (s, IH), 6.19 (s,lH), 3.64 (bs, 4H), 2.64 (m, 4H), 2.37 (bs, 4H), 2.23 (s, 3H ), 1.91 (m, 3H), 0.90 (m, 2H), 0.64 (m, 2H); MS (ES+): m/z 339.9 (M+l).
  • the compound of example 18 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with 1-isopropylpiperazine. Yield: 35.15 ; 1H NMR (DMSO- , 300 MHz): ⁇ 11.92 (s, IH ), 8.79 (s, IH), 6.20 (s, IH), 3.62 (bs, 4H), 2.64 (m, 8H), 1.94 (m, 4H), 1.33 (s, 6H), 0.95 (d,2H), 0.75 (d, 2H); MS (ES+): m/z 393.2 (M+l).
  • the compound of example 19 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with 2-(piperazin-l-yl)ethanol. Yield: 65.42 ; 1H NMR (DMSO- , 300 MHz): ⁇ 11.95 (s,lH), 8.76 (s, 1H), 6.24 (s,lH), 4.43 (t, 1H), 3.62 (bs, 4H), 3.52 (q, 2H), 2.62 (q, 4H), 2.42 (m, 6H), 1.90 (m, 3H), 0.90 (d, 2H), 0.64 (m, 2H); MS (ES+): m/z 367.8 (M+l).
  • the compound of example 20 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with l-(piperazin-l-yl)ethanone. Yield: 42.05 ; 1H NMR (DMSO- , 300 MHz): ⁇ 11.96 (s, 1H), 8.81 (s, 1H), 6.24 (s,lH), 3.62 (m, 4H), 3.48 (bs, 4H), 2.64 (q, 4H), 2.04 (s, 3H), 1.92 (m, 3H), 0.93 (d, 2H), 0.66 (d, 2H); MS (ES+): m/z 367.9 (M+l).
  • the compound of example 22 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with l-(l-methylpiperidin-4-yl)piperazine. Yield: 28.45 ; 1H NMR (CDCI 3 , 300 MHz): ⁇ 6.75 (s,lH ), 6.11 (s, 1H), 3.83 (s, 4H), 3.60 (q, 1H), 3.26 (m, 2H), 2.81 (t, 2H), 2.70-2.64 (m,l lH), 2.10 (m, 6H), 1.90 (m, 2H), 0.97 (m, 2H), 0.75 (m, 2H); MS (ES+): m/z 423.3 (M+l).
  • Example 23 Example 23:
  • the compound of example 24 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with 1-benzylpiperazine. Yield: 37.19 ; 1H NMR (CDC1 3 , 300 MHz): ⁇ 7.39 (m, 3H), 7.30 (m, 2H), 6.71 (s, 1H), 6.09 (s, 1H), 3.86 (s, 4H), 3.70 (s, 2H), 2.79 (t, 2H), 2.60 (m, 6H), 1.89 (m, 2H), 1.83 (m,lH), 0.94 (m, 2H), 0.71 (m, 2H); MS (ES+): m/z 416.0 (M+l).
  • the compound of example 25 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with l-([l,l'-biphenyl]-4-yl)piperazine. Yield: 28.90 ; 1H NMR (CDCI 3 , 300 MHz): ⁇ 7.57 (dd, 4H), 7.43 (dd, 2H), 7.31 (d, 1H), 7.06 (d, 2H), 6.64 (s, 1H), 6.13 (bs, 1H), 3.98 (t, 4H), 3.34 (t, 3H), 2.85 (t, 2H), 2.69 (t, 2H), 2.12 (m, 2H), 1.92 (m, 2H), 1.01 (m, 2H), 0.80 (m, 2H); MS (ES+): m/z 478.3 (M+l).
  • the compound of example 26 was prepared analogous to the compound of example 4 by reaction of the compound of example 5 with morpholine. Yield: 42.10 ; 1H NMR (DMSO-J6, 300 MHz): ⁇ 11.94 (s, IH ), 8.80 (s, IH), 6.22 (s, IH), 3.61 (d, 8H), 2.63 (m, 4H), 1.89 (m, 3H), 0.91 (m, 2H ), 0.65 (m, 2H); MS (ES+): m/z 326.9 (M+l).
  • Example 29 Example 29:
  • Example 31 Example 31:
  • the compound of example 31 was prepared analogous to the compound of example 4 by reaction of the compound of example 27 with azocane. Yield: 48.1 ; 1H NMR DMSO-d 6 , 300 MHz): ⁇ 12.69 (s, 1H ), 8.85 (s, 1H), 7.64 (m, 2H), 7.42 (m, 2H), 7.30 (m, 1H), 7.10 (bs, 1H), 3.67 (bs, 4H), 2.67 (m, 4H), 1.92 (m, 2H), 1.74 (bs, 4H), 1.48 (m, 6H); MS (ES+): m/z 387.2 (M+l).
  • the compound of example 32 was prepared analogous to the compounds of examples 1 and 2. Ethyl 2-oxocyclohexanecarboxylate was refluxed with urea analogous to example 1 to yield 5,6,7, 8-tetrahydroquinazoline-2,4-diol. The resulting compound was then treated with phosphorus oxychloride analogous to example 2 to obtain the title compound. Yield: 24.55 ; MS (ES+): m/z 204.1 (M+l).
  • the compound of example 34 was prepared analogous to the compound of example 4 by reaction of the compound of example 33 with 4-methylpiperidine in the presence of N- methylpyrrolidone as a solvent. Yield: 41.16 ; 1H NMR (DMSO-J 6 , 300 MHz): 11.95 (s, 1H), 8.18 (s, 1H), 6.18 (s,lH), 4.53 (d, 2H), 2.72 (d, 2H), 2.45 (m, 2H), 2.36 (bs, 2H), 1.69 (bs, 4H), 1.58 (d, 3H), 1.02 (m, 2H), 0.90 (bs, 6H), 0.60 (d, 2H); MS(ES+): m/z 353.3 (M+l).
  • the compound of example 35 was prepared analogous to the compound of example 4 by reaction of the compound of example 33 with azocane in the presence of N-methylpyrrolidone as a solvent. Yield: 71.2 ; 1H NMR (CDC1 3 , 300 MHz): ⁇ 6.60 (s, 1H), 3.72 (s, 4H), 2.86 (bs, 2H), 2.62 (bs, 2H), 2.36 (bs, 2H), 1.58 (bs,HH), 1.32 (s, 2H), 0.97 (d, 2H), 0.60 (d, 2H); MS(ES+): m/z 367.7 (M+l).
  • the compound of example 39 was prepared analogous to the compound of example 3 by reaction of the compound of example 38 with 5-cyclopropyl-lH-pyrazol-3-amine. Yield: 44.9 ; 1H NMR (DMSO- , 300 MHz): ⁇ 12.1 (s, 1H), 8.98 (s, 1H), 6.2 (s, 1H), 2.05 (bs, 2H), 2.00 (m, 2H),1.78 (m, 2H), 1.70 (m, 5H), 1.63 (m, 2H), 1.53 (m, 2H), 0.93 (m, 2H), 0.68 (m, 2H); MS(ES+): m/z 344.2(M+1).
  • the compound of example 40 was prepared analogous to the compound of example 4 by reaction of compound of example 39 with 4-cyanopiperdine in the presence of N- methylpyrrolidone as solvent. Yield: 61.8 ; 1HNMR (DMSO-d 6 , 300 MHz): ⁇ 11.97 (s, 1H), 8.20 (s, 1H), 6.18 (s, 1H), 3.97 (m, 2H), 3.45 (m, 2H), 3.30 (m, 1H), 3.08 (m, 1H), 2.38 (bs, 2H), 2.02 (m, 2H), 1.85 (m, 5H), 1.67 (m, 5H), 1.61 (m, 2H), 1.47 (m, 2H), 0.91 (m, 2H), 0.64 (m, 2H); MS(ES+): m/z 418.3 (M+l).
  • the compound of example 47 was prepared analogous to the compound of example 4 by reaction of compound of example 46 with 4-methylpiperdine in the presence of N- methylpyrrolidone as solvent. Yield: 74 ; 1H NMR (DMSO-J 6 , 300 MHz): 12.10 (s, 1H), 9.43 (s, 1H), 6.27 (s, 1H), 4.58 (d, 2H), 2.89 (m, 2H) 2.73 (d, 3H), 1.88 (t, 1H), 1.66 (d, 3H), 1.23 (s, 1H), 1.1 (d, 2H), 0.90 (bs, 5H), 0.60 (bs, 2H); MS(ES+): m/z 375.3 (M+l).
  • the compound of example 49 was prepared from methyl 3-oxobicyclo[2.2.1]heptane-2- carboxylate by steps analogous to the corresponding steps involved in the preparation of the compounds of examples 43-47. Yield: 31.5 ; 1H NMR (CDC1 3 , 300 MHz): ⁇ 6.62 (s, 1H), 5.94 (br.
  • test compounds Representative compounds of formula I of the present invention (referred to as test compounds) are tested for their protein kinase or tyrosine kinase inhibitory activity using the assays and the methods described below:
  • IGF-IR kinase activity was assayed using a time resolved fluorescence energy transfer
  • TR-FRET in vitro kinase assay.
  • IGFR kinase enzyme used for the assay was human IGF-IR purified from a baculovirus expression system using glutathione-sepharose column chromatography. The kinase reaction was conducted in a 384-well plate.
  • the reaction buffer (TrisHCl (50 mM; pH: 7.4), EGTA (1 mM), MgCl 2 (10 mM, DTT (2 mM), Tween-20 (0.01%)) for peptide phosphorylation contained, in final concentrations, human IGF-IR kinase enzyme (0.25 nM), poly GT peptide substrate (50 nM) and adenosine triphosphate (ATP) (20 ⁇ ).
  • the test compounds in DMSO were evaluated at various concentrations with their final concentrations in the assay ranging from 40 ⁇ to 40 pM. The final concentration of DMSO in the assay was less than 1%.
  • IGFR kinase enzyme 2.5 ⁇
  • various concentrations of the test compounds 2.5 ⁇ > were incubated in the 384- well plate for 10 min at 23 °C followed by the addition of poly GT peptide substrate (2.5 ⁇ ).
  • the kinase reaction was initiated by the addition of ATP (2.5 ⁇ ) followed by incubation for 1 h at 23 °C.
  • the kinase reaction was stopped by the addition of EDTA (5 ⁇ > (final concentration in the assay: 10 mM).
  • Europium cryptate-labelled antiphosphotyrosine antibody PY20 5 ⁇
  • the intensity of light emission which was indicative of the quantum of substrate phosphorylation by the kinase enzyme was measured at 665 nm using Envision plate reader.
  • the ability of the test compounds to inhibit substrate phosphorylation which is indicative of the IGF-IR kinase inhibitory activity of the test compounds expressed as IC 50 values was determined by a four-parameter sigmoidal curve.
  • IGF-IR % inhibition @ 0.1 ⁇ is the percentage of IGF-IR inhibition observed for 0.1 ⁇ concentration of test compound. + denotes percentage inhibition ⁇ 50 %
  • Cells are grown and maintained in a medium containing 10 % FBS. Cells grown as subconfluent monolayer, are subjected to serum starvation by replacing the respective culture medium with plain medium (containing no serum) and incubated for about 16 h at 37 °C in 5 % C0 2 incubator. Serum starved cells are treated with test compounds at different concentrations for 1 h at 37 °C in 5 % C0 2 incubator and stimulated with IGF-1 (50 ng/mL) for the last 5 minutes of treatment with test compounds.
  • IGF-1 50 ng/mL
  • cell lysates are prepared using CelLyticTM M cell lysis reagent (Sigma) containing protease and phosphatase inhibitors. Estimation of the total protein content in each cell lysate is carried out using Bradford reagent. Equal amount of protein from each lysate is subjected to Sodium Dodecyl Sulphate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) followed by Western blotting protocol using specific antibody to pIGF-lR, IGF- ⁇ , pAkt, Akt, Pp70S6, p70S6, Pp44/42, p44/42 and loading control, ⁇ -actin. Imaging is done with BIO-RAD Image-Lab Software. The band density is then estimated using the software Image J. From the band densities of the various proteins at different concentrations of test compounds, the IC 50 concentrations for various proteins are calculated.
  • the cancer cell lines are seeded in triplicate (at density, from 3000-5000 cells/well depending on cell type) with 10 % FCS in 180 ⁇ ⁇ of culture medium in tissue culture grade 96 well plates and allowed to recover for 24 h in humidified 5 % C0 2 incubator at 37 + 1 °C. After 24 h, media is replaced from the plate completely and 180 ⁇ ⁇ of fresh media containing 100 ng/mL IGF-1 without FCS (fetal calf serum) is added followed by addition of 20 ⁇ ⁇ of 10X test compound (dissolved first in DMSO and then in cell medium, final DMSO concentration did not exceed 0.5 %) in wells.
  • 10X test compound dissolved first in DMSO and then in cell medium, final DMSO concentration did not exceed 0.5 %) in wells.
  • test compound is used at the concentrations of 0.1, 1, 3 and 10 ⁇ and the plates are incubated for 72 h in humidified 5 % C0 2 incubator at 37 + 1 °C. Control wells are treated with vehicle (DMSO). At the end of the incubation periods, the plates are assayed by the CellTiter-Glo® Luminescent Cell Viabilityassay protocol as provided herein. Percent cytoxicity is calculated at the various drug concentrations. Graph for cytotoxicity vs. test compound is plotted, and the IC 50 values are determined.
  • the CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells. The amount of ATP is directly proportional to the number of cells present in culture
  • the plate is equilibrated and its contents are maintained at room temperature for approximately 30 minutes.
  • a volume of CellTiter-Glo® Reagent is added in a volume equal to the volume of cell culture medium present in each well (e.g., 100 ⁇ ⁇ of reagent to 100 ⁇ ⁇ of medium containing cells for a 96- well plate).
  • the contents are mixed for 2 minutes on an orbital shaker to induce cell lysis.
  • the plate is allowed to incubate at room temperature for 10 minutes to stabilize the luminescent signal.
  • the luminescence is recorded using the POLARstar optima plate reader at excitation 536 nm and emission 590 nm.
  • Inhibitory activity of test compounds against the kinase activity of the insulin receptor (IR) is quantified employing the Insulin receptor (Ins-R) HTRF assay as described in the following paragraphs.
  • kinase domain of the human Ins-R expressed in SF-9 cells (Spodoptera frugiperda, American Type Culture Collection (ATCC), USA) is used as kinase.
  • SF-9 cells Spodoptera frugiperda, American Type Culture Collection (ATCC), USA
  • ATC American Type Culture Collection
  • biotinylated poly-(Glu,Tyr) is used as substrate for the kinase reaction.
  • Ins-R is incubated for 20 min at 22 °C in the presence of different concentrations of test compounds in 5 assay buffer [50 mM HEPES/NaOH pH 7, 15 mM MnCl 2 , 1 mM dithiothreitol, 0.1 ⁇ sodium ortho-vanadate, 0.015% (v/v) PEG20000, 10 ⁇ adenosine-triphosphate (ATP), 0.3 ⁇ g/ml substrate, 1% (v/v) dimethylsulfoxide].
  • concentration of Ins-R is adjusted depending on the activity of the enzyme lot and is chosen appropriate to have the assay in the linear range, typical concentrations are in the range of 10 pg/ ⁇ .
  • the reaction is stopped by the addition of 5 ⁇ ⁇ of a solution of HTRF detection reagents (0.1 ⁇ streptavidine- XLent and 1 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho-tyrosine antibody) in an aqueous EDTA-solution (80 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.0). The resulting mixture is incubated for 1 h at 22 °C to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu- Chelate.
  • HTRF detection reagents 0.1 ⁇ streptavidine- XLent and 1 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho-tyrosine antibody
  • aqueous EDTA-solution 80 m
  • the amount of phosphorylated substrate is evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm is measured in a HTRF reader. The ratio of the emissions at 665 nm and at 622 nm is taken as the measure for the amount of phosphorylated substrate. The data is normalized and IC 50 values are calculated for the test compounds.
  • VEGFR2 inhibitory activity of test compounds of the present invention is quantified employing the VEGFR2 HTRF assay as described in the following paragraphs.
  • kinase domain of the human VEGFR2 expressed in SF-9 cells is used as kinase.
  • substrate for the kinase reaction the biotinylated peptide biotin-Ahx- DFGLARDMYDKEYYSVG (C-terminus in acid form) is used.
  • VEGFR2 is incubated for 45 min at 22 °C in the presence of different concentrations of test compounds in 5 ⁇ ⁇ assay buffer [50 mM HEPES/NaOH pH 7.0, 25 mM MgCl 2 , 5 mM MnCl 2 , 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 10 ⁇ adenosine-tri-phosphate (ATP), 0.5 ⁇ substrate, 0.001% (v/v) Nonidet-P40, 1% (v/v) dimethylsulfoxide].
  • the concentration of VEGFR2 is adjusted depending of the activity of the enzyme lot and is chosen appropriate to have the assay in the linear range.
  • the reaction is stopped by the addition of 5 ⁇ ⁇ of a solution of HTRF detection reagents (0.1 ⁇ streptavidine-XLent and 2 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho- tyrosine antibody) in an aqueous EDTA-solution (125 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.0). The resulting mixture is incubated for 1 h at 22 °C to allow the binding of the biotinylated phosphorylated peptide to the strep tavidine-XLent and the PT66-Eu-Chelate.
  • HTRF detection reagents 0.1 ⁇ streptavidine-XLent and 2 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho- tyrosine antibody
  • the amount of phosphorylated substrate is evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine- XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm is measured in a HTRF reader. The ratio of the emissions at 665 nm and at 622 nm is taken as the measure for the amount of phosphorylated substrate. The data is normalized and IC 50 values are calculated for the test compounds.
  • PDGFRP inhibitory activity of test compounds of the present invention is quantified employing the PDGFRP HTRF assay as described in the following paragraphs.
  • kinase a GST-His fusion protein containing a C-terminal fragment of human
  • PDGFRP amino acids 561-1106, expressed in insect cells [SF9] and purified by affinity chromatography is used.
  • substrate for the kinase reaction the biotinylated poly-Glu, Tyr (4: 1) copolymer (#61GT0BLA) is used.
  • nL of a 100 fold concentrated solution of the test compound in DMSO is pipetted into a black low volume 384 well microtiter plate, 2 of a solution of PDGFRP in aqueous assay buffer [50 mM HEPES/NaOH pH 7.5, 10 mM MgCl 2 , 2.5 mM dithiothreitol, 0.01% (v/v) Triton-XlOO] are added and the mixture is incubated for 15 min at 22 °C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction.
  • aqueous assay buffer 50 mM HEPES/NaOH pH 7.5, 10 mM MgCl 2 , 2.5 mM dithiothreitol, 0.01% (v/v) Triton-XlOO
  • the kinase reaction is started by the addition of 3 ⁇ ⁇ of a solution of adenosine-tri-phosphate (ATP, 16.7 ⁇ : final cone, in the 5 ⁇ assay volume is 10 ⁇ ) and substrate (2.27 ⁇ g/ml: final cone, in the 5 ⁇ ⁇ assay volume is 1.36 ⁇ g/ml [-30 nM]) in assay buffer and the resulting mixture is incubated for a reaction time of 25 min at 22 °C.
  • adenosine-tri-phosphate adenosine-tri-phosphate
  • concentration of PDGFRP in the assay is adjusted depending on the activity of the enzyme lot and is chosen appropriate to have the assay in the linear range, typical enzyme concentrations are in the range of about 125 pg/ ⁇ (final cone, in the 5 ⁇ ⁇ assay volume).
  • the reaction is stopped by the addition of 5 ⁇ ⁇ of a solution of HTRF detection reagents (200 nM streptavidine-XLent [Cis Biointernational] and 1.4 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho-tyrosine antibody) in an aqueous EDTA-solution (100 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5).
  • HTRF detection reagents 200 nM streptavidine-XLent [Cis Biointernational] and 1.4 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho-tyrosine antibody
  • the resulting mixture is incubated for 1 h at 22 °C to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate.
  • the amount of phosphorylated substrate is evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm is measured in a HTRF reader. The ratio of the emissions at 665 nm and at 622 nm is taken as the measure for the amount of phosphorylated substrate.
  • the data is normalized and IC 50 values are calculated for the test compounds.

Abstract

La présente invention porte sur des composés hétérocycliques bicycliques (les composés de formule I) ou une forme isotope, un stéréoisomère ou un tautomère ou un sel pharmaceutiquement acceptable, un solvate, un polymorphe, un promédicament ou un N-oxyde de ceux-ci et sur des procédés pour leur préparation. L'invention porte en outre sur des compositions pharmaceutiques contenant lesdits composés et sur leur utilisation dans le traitement de maladies ou de troubles associés à une activité anormale de protéines kinases .
PCT/IB2013/058215 2013-09-02 2013-09-02 Composés hétérocycliques bicycliques utilisés comme inhibiteurs de plusieurs kinases WO2015028848A1 (fr)

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CN105732590A (zh) * 2016-03-28 2016-07-06 华东理工大学 嘧啶并饱和脂肪环二胺类化合物及其用途

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WO2002022604A1 (fr) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Composes de pyrazole utiles comme inhibiteurs de proteine kinase
WO2002059111A2 (fr) * 2000-12-21 2002-08-01 Vertex Pharmaceuticals Incorporated Composes de pyrazole utiles en tant qu'inhibiteurs de proteine kinase

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WO2002022604A1 (fr) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Composes de pyrazole utiles comme inhibiteurs de proteine kinase
WO2002059111A2 (fr) * 2000-12-21 2002-08-01 Vertex Pharmaceuticals Incorporated Composes de pyrazole utiles en tant qu'inhibiteurs de proteine kinase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105732590A (zh) * 2016-03-28 2016-07-06 华东理工大学 嘧啶并饱和脂肪环二胺类化合物及其用途

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