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WO2014155300A2 - Dérivés pyrimidine aminée substitués en tant qu'inhibiteurs de tak-1 - Google Patents

Dérivés pyrimidine aminée substitués en tant qu'inhibiteurs de tak-1 Download PDF

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Publication number
WO2014155300A2
WO2014155300A2 PCT/IB2014/060155 IB2014060155W WO2014155300A2 WO 2014155300 A2 WO2014155300 A2 WO 2014155300A2 IB 2014060155 W IB2014060155 W IB 2014060155W WO 2014155300 A2 WO2014155300 A2 WO 2014155300A2
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compound
fluoro
pyrimidin
ethyl
amine
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PCT/IB2014/060155
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WO2014155300A3 (fr
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Vamsee Krishna Chintakunta
Vidyadhar Paradkar
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Aurigene Discovery Technologies Limited
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Publication of WO2014155300A3 publication Critical patent/WO2014155300A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to substituted pyrimidine amine derivatives of formula (I), useful as TAKl inhibitors.
  • the invention also relates to the process for preparation thereof, pharmaceutical compositions comprising them, and their use for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder associated as TAKl inhibitors.
  • Protein kinases are well known to regulate the majority of cellular pathways and constitute one of the largest and most functionally diverse gene families. Their participation in the signaling events controls the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these protein kinases fall into several groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues.
  • TGF-f3-activated kinase 1 TGF-f3-activated kinase 1
  • TGF Transforming growth factor
  • MAK mitogen-activated protein kinase family
  • BMP bone morphogenetic protein
  • TAKl has role in the control of morphogenesis and tissue homeostasis.
  • TAKl is expressed in most tissues and cell types and has key role in proinflammatory cytokine signaling, including tumor necrosis factor-a (TNF-a), inter leukin- 1 (IL- 1), and Toll-like receptor (TLR) ligands [Shirakabe, K.
  • TNF-a tumor necrosis factor-a
  • IL- 1 inter leukin- 1
  • TLR Toll-like receptor
  • TAKl has a critical role in innate and adaptive immune response. Recently it has been shown that the Smad-independent non-canonical TAKl pathway is involved in TGF-b signaling pathways [Landstro ' m, M. (2010) Int. J. Biochem. Cell Biol. 42, 585-589].
  • TAKl interacts with TAKl-binding protein 1 and 2 (TAB 1/2) to activate MAPK kinase 3/6 (MKK3/6) and p38, MKK4 and c-Jun N-terminal kinase (JNK), as well as the nuclear factor-kB NF- ⁇ pathways.
  • MAPK kinase 3/6 MKK3/6
  • MKK4 MAPK kinase 3/6
  • JNK c-Jun N-terminal kinase
  • NF-kB and AP-1 are critical regulators of stress responses, immunity, inflammation and cancer in a variety of cell types.
  • TAK1 is a key molecule in the pro-inflammatory NF-kB signaling pathway a TAK1 inhibitor would be effective in diseases associated with inflammation and tissue destruction such as rheumatoid arthritis and inflammatory bowel disease (Crohn's), as well as in cellular processes such as stress responses, apoptosis, proliferation and differentiation.
  • Various pro-inflammatory cytokines and endotoxins trigger the kinase activity of endogenous TAK1 (Ninomiya-Tsuji J et al., Nature 398 252-256 (999); Irie T et al., FEBS Lett. 467 60-164 (2000); Sakurai H. et al., J. Biol. Chem.
  • TAK1 Blockade of TAK1 is potentially an attractive strategy to target the three main proinflammatory pathways (p38, JNK, and NF-kB) and the major profibrotic growth factor, TGF- 1 , in the development of kidney disease.
  • Knock out data has shown that TAK1 deletion caused profound suppression of renal inflammation and fibrosis (Frank Y. Ma et al., Am J Physiol Renal Physiol 300: F1410-F1421, 2011). Cardiomyocyte hypertrophy and neuronal death in cerebral ischemia are also prevented by suppression of TAK1 [Neubert, M. et al., Cell Death Differ. 18, 1521-1530 (2011)].
  • TAK1 deletion in dendritic cells leads to a reduction in the hapten-elicited contact hypersensitivity response in the ear [Zhao, Y.G. et al., Cell. Mol. Immunol. 8, 315-324 (2011)].
  • a naturally occurring inhibitor of TAK1, 5Z-7-oxozeaenol has been identified with an IC50 value of 8 nM.
  • 5Z-7-oxozeaenol has been shown to be selective for TAK1 within the MAPKKK family and relieves inflammation in a picryl chloride- induced ear swelling mouse model (Ninomiya-Tsuji J. et al., J. Biol. Chem. 278 18485 (2003)).
  • TAK1 siRNA particles potently protects mice from arthritis progression, decreasing both systemic and local inflammatory features (i.e., proinflammatory key cytokines and joint destruction [Gabriel Courties et al., blood 116: 3505-3516 (2010)].
  • TAK1 TAK1: IKK3: NF-kB signaling axis forms aberrantly in breast cancer cells, and consequently, enables oncogenic signaling by TGF-[beta] (Neil J et al., Cancer Res. 68 1462 (2008)).
  • TGF- ⁇ signaling contributes to tumor angiogenesis and invasion via a mechanism involving matrix metalloproteinase 9 (MMP9) (Safina A et al., Oncogene 26 p2407 (2007)), and that TAK1 is required for TGF i-mediated regulation of matrix metalloproteinase-9 and metastasis (Safma A et al., Oncogene 2008; 27(9): 1 198- 12072008).
  • MMP9 matrix metalloproteinase 9
  • TGF-[beta] signaling can induce an epithelial-to- mesenchymal transition (EMT) and contributes to tumor invasion and progression (Ikushima H et al., Nature Reviews Cancer 10 p415 (2010)) and that TAK1 is required for this process (Neil J et al., Cancer Res. 68 1462 (2008)).
  • EMT epithelial-to- mesenchymal transition
  • TAK1 is required for this process.
  • TAK1 has been suggested as providing an opportunity for selective inhibition of pro-oncogenic function of TGF- ⁇ .
  • TAK1 signaling pathways to EGFR via MAPKs in a tyrosine kinase- independent manner suggesting a new paradigm for inflammation-related cancer progression.
  • TAK1 inhibition reduced chemoresistance LYTAK1, an orally active TAK1 inhibitor, significantly reduced NF-kB activity and sensitized cancer cells to gemcitabine, SN38 and oxaliplatin in vitro [72 and LYTAK1 in combination with gemcitabine reduced tumor volume and prolonged survival in a nude mouse model in vivo [Melisi, D. et al., J. Natl. Cancer Inst. 103, 1190-1204 (2011)].
  • TAK1 has also drives cell survival in KRAS-dependent cells, in which KRAS regulates TAK1 and Wnt signaling through BMP-7 receptor activation and 5Z-7- oxozeaenol can suppress tumor growth of KRAS-dependent cell lines in vivo [Anurag Singh et al., Cell 148, 639-650 (2012)]. Recently it has been shown that in a panel lymphoma cell lines, including mantle cell, anaplastic large cell, and Hodgkin lymphoma cell lines there is increase active TAK1 expression. Silencing TAK1 expression using small interfering RNA inhibited the activation of NF- ⁇ and p38, and induced apoptosis in lymphoma cell lines (Daniela Buglio et al., Blood 2012).
  • TAK1 has been characterized as key regulator in inflammatory and immune signaling pathways, and in addition microbial proteins and components of host cell signaling scramble for the TAK1 complex in innate immunity. Hence the finding indicates that TAK1 inhibitors have therapeutic value for cancer and inflammatory diseases. Accordingly, there has been an interest in finding selective inhibitors of TAK1 that are effective as therapeutic agents. A challenge has been to find protein kinase inhibitors that act in a selective manner, targeting only TAK1. Since there are numerous protein kinases that are involved in a variety of cellular responses, nonselective inhibitors may lead to unwanted side effects. In this regard, the three-dimensional structure of the kinase would assist in the rational design of inhibitors.
  • the determination of the amino acid residues in TAK1 binding pockets and the determination of the shape of those binding pockets would allow one to design selective inhibitors that bind favorably to this class of enzymes.
  • the determination of the amino acid residues in TAK1 binding pockets and the determination of the shape of those binding pockets would also allow one to determine the binding of compounds to the binding pockets and to, e.g., design inhibitors that can bind to
  • the search targeting protein kinases raises the potential for new therapeutic options for cancer (such as proliferative disease, primary cancers and metastatic disease), and inflammatory disorders (rheumatoid arthritis, airway inflammation and fibrosis in particular kidney) and targeted therapies, including tyrosine kinase inhibitors, such as TAK1 inhibitors, including selective inhibitors, and for potent, orally bioavailable, and efficacious inhibitors continues with great intensity.
  • cancer such as proliferative disease, primary cancers and metastatic disease
  • inflammatory disorders rheumatoid arthritis, airway inflammation and fibrosis in particular kidney
  • targeted therapies including tyrosine kinase inhibitors, such as TAK1 inhibitors, including selective inhibitors, and for potent, orally bioavailable, and efficacious inhibitors continues with great intensity.
  • the substituted pyrimidine amine derivatives according to the present invention may possess inhibitory activity of one or more protein kinases including TAK1 and are, therefore, expected to be useful in the treatment of kinase-associated diseases or disorders.
  • the present invention provides substituted pyrimidine amine derivatives of the following formula (I), useful as TAK1 inhibitors.
  • Ring 'A' is an optionally substituted C4-C10 monocyclic or bicyclic ring containing 1-4 heteroatoms/groups independently selected from N, NH and CO; wherein the optional substituent at each occurrence is independently selected from one or more R 2 ;
  • Ri is selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxy, amino and alkoxy;
  • R 2 is selected from halogen, alkoxy, alkyl, cyano, aryl, -S(0) 2 aryl and arylalkyl;
  • Z represents:
  • R 3 is selected from hydrogen, alkyl, amino, hydroxy and alkoxy
  • Ring 'B' is an optionally substituted N-linked C 4 -Cs monocyclic ring; wherein the optional substituent at each occurrence is independently selected from hydroxy and alkoxy;
  • L represents direct bond or aryl
  • Ring 'C is an optionally substituted C11-C14 tricyclic heterocyclyl ring; wherein the optional substituent at each occurrence is independently selected from alkyl, halogen, hydroxyalkyl, -C(0)cycloalkyl and -S(0)2alkyl;
  • R3 is selected from hydrogen, alkyl, amino, hydroxy, alkoxy and heterocyclyl
  • R4 is selected from hydrogen, alkyl and hydroxyalkyl
  • 'm' is selected from an integer 1 to 2, both inclusive;
  • 'n' is selected from an integer 0 to 2, both inclusive.
  • the present invention provides pharmaceutical composition comprising compounds of present invention and their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, for use in the treatment and prevention of diseases and disorders for which TAK1 inhibitor is indicated.
  • Embodiment of the present invention provides the substituted pyrimidine amine derivatives of formula (I), useful as TAK1 inhibitors.
  • Ring 'A' is an optionally substituted C4-C10 monocyclic or bicyclic ring containing 1-4 heteroatoms/groups independently selected from N, NH and CO; wherein the optional substituent at each occurrence is independently selected from one or more R 2 ;
  • Ri is selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxy, amino and alkoxy;
  • R2 is selected from halogen, alkoxy, alkyl, cyano, aryl, -S(0) 2 aryl and arylalkyl;
  • Ring 'B' is an optionally substituted N-linked C 4 -Cs monocyclic ring; wherein the optional substituent at each occurrence is independently selected from hydroxy and alkoxy;
  • L represents direct bond or aryl
  • Ring 'C is an optionally substituted Cn-C 14 tricyclic heterocyclyl ring; wherein the optional substituent at each occurrence is independently selected from alkyl, halogen, hydroxyalkyl, -C(0)cycloalkyl and -S(0) 2 alkyl;
  • R 3 is selected from hydrogen, alkyl, amino, hydroxy, alkoxy and heterocyclyl
  • R 4 is selected from hydrogen, alkyl and hydroxyalkyl
  • 'm' is selected from an integer 1 to 2, both inclusive;
  • 'n' is selected from an integer 0 to 2, both inclusive.
  • the compounds of formula (I) may involve one or more embodiments.
  • the embodiments below are illustrative of the compound of formula (I) of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
  • the compound of formula (I) is a compound of (la)
  • Ring 'A' is an optionally substituted N-linked C4-C10 monocyclic or bicyclic ring containing 1-4 heteroatoms and/or heterogroups selected from N, NH and C(O); wherein the optional substituent at each occurrence is independently selected from one or more R2;
  • Ri is selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxy, amino and alkoxy;
  • R2 is selected from halogen, alkoxy, alkyl, cyano and aryl
  • R3 is selected from hydrogen, alkyl, amino, hydroxy and alkoxy.
  • the compound of formula (I) is a compound of formula (lb)
  • Ring 'A' is an optionally substituted C4-C10 monocyclic or bicyclic ring containing 1-3 heteroatoms; wherein the heteroatom is 'N' and the optional substituent at each occurrence is independently selected from one or more R2;
  • Ring 'C is an optionally substituted C11-C14 tricyclic heterocyclyl ring containing 1-4 heteroatoms independently selected from N, O and NH; wherein the optional substituent at each occurrence is independently selected from alkyl, halogen, hydroxyalkyl, -C(0)cycloalkyl and - S(0) 2 alkyl;
  • L represents direct bond or aryl
  • Ri is selected from hydrogen, alkyl, halogen, haloalkyl, cyano, hydroxy, amino and alkoxy;
  • R 2 is selected from alkyl, halogen and -S(0) 2 aryl.
  • the compound of formula (I) is a compound of formula (Ic)
  • Ring 'A' is an optionally substituted C4-C10 monocyclic or bicyclic ring containing 1-4 heteroatoms/groups independently selected from N, NH and CO; wherein the optional substituent is arylalkyl; with a proviso that ring A is not selected from oxazole and isoxazole;
  • Ri is selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxy, amino and alkoxy;
  • R3 is selected from hydrogen, alkyl, amino, hydroxy, alkoxy and heterocyclyl
  • R4 is selected from hydrogen, alkyl and hydroxyalkyl
  • 'm' is selected from an integer 1 to 2, both inclusive;
  • 'n' is selected from an integer 0 to 2, both inclusive.
  • R3 is heterocyclyl; in particular heterocyclyl is 2-thiophene and 1H- pyrazole.
  • R4 is hydrogen or hydroxyalkyl; in particular hydroxyalkyl is - CH2CH2OH.
  • the compound of formula (I) is selected from the group consisting of
  • the definition "compound of formula (I)” inherently includes all the all stereoisomers of the compound of formula (I) either as pure stereoisomer or as a mixture of two or more stereoisomers.
  • stereoisomers include enantiomers, diasteroisomers, racemates, cis-isomers, trans-isomers and mixture thereof.
  • the absolute configuration at an asymmetric atom is specified by either R or S.
  • Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1% of the other isomers.
  • the present invention provides processes for preparing novel substituted pyrimidine amine derivatives of formula (I).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • Alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Ci-Cio alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-C 6 alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is Ci- C 4 alkyl group which may have 1 to 4 (inclusive) carbon atoms in it.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert -butyl, isopentyl, neopentyl, and isohexyl.
  • An alkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Alkoxy refers to the group alkyl-0- or -O-alkyl, where alkyl group is as defined above.
  • exemplary alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy and i-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
  • Halogen or "halo” includes fluorine, chlorine, bromine or iodine.
  • Haloalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with - F,- CI,- Br or -I.
  • Representative examples of an haloalkyl group include, but are not limited to -CH 2 F, -CCI3, -CF 3 , -CH2CI, -CH 2 CH 2 Br, - CH 2 CH 2 I, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 C1, -CH 2 CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 I, - CH2CH2CH2CH2B1-, -CH2CH2CH2CH2I, -CH 2 CH(Br)CH 3 , -CH 2 CH(C1)CH 2 CH 3 , and - CH(F)CH 2 CH 3 .
  • Cyano refers to -CN group.
  • Hydroxy or “Hydroxyl” refers to -OH group.
  • Hydroxyalkyl refers to the an alkyl group substituted with one or more hydroxy groups; the alkyl group and hydroxy group are same as defined above.
  • Representative examples of an hydroxyalkyl group includes but are not limited to -CH2OH, -CH2CH2OH, -CH 2 CH(OH)CH 3 , - CH 2 CH(OH)CH 2 CH 3 and the like.
  • Amino refers to an -N- group, the nitrogen atom of said group being attached to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or any suitable groups.
  • Representative examples of an amino group include, but are not limited to -NH2, -NHCH 3 and -NH-cyclopropyl.
  • An amino group can be unsubstituted or substituted with one or more of the suitable groups.
  • Aryl refers to an optionally substituted monocylic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms.
  • Examples of a C 6 -Ci4 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl.
  • Aryl group can be unsubstituted or substituted with one or more suitable groups;
  • Cycloalkyl refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system.
  • Representative examples of a cycloalkyl include, but are not limited to cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-l-yl, octahydro-lH- inden-2-yl and decahydro-lH-benzo[7] annulen-2-yl.
  • a cycloalkyl can be unsubstituted or substituted with one or more suitable groups.
  • Heterocyclyl includes the definitions of "heterocyclo alkyl” and “heteroaryl”.
  • the term “Heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0)2, NH and C(O).
  • Exemplary heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4- dioxanyl and the like.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups;
  • Heteroaryl refers to an unsaturated, monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatoms selected from oxygen, sulfur and nitrogen.
  • C5-C10 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4- triazole, l-methyl-l,2,4-triazole, IH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimi
  • Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom.
  • a heteroaryl group can be unsubstituted or substituted with one or more suitable groups.
  • Hetero atom refers to a sulfur, nitrogen or oxygen atom.
  • Hetero group refers to -C(O)-, -S(O), -NH and S(0) 2 .
  • monocyclic refers to a saturated, partially saturated or unsaturated 4-16 membered ring, in which 1 to 4 of the ring carbon atoms have been independently replaced with a heteroatom/heterogroups such as N, O, S, -C(O)-, -S(O), -NH and S(0) 2 .
  • a 4 to 16 membered ring include, but are not limited to 1H- imidazole, lH-pyrrole, lH-l,2,3-triazole, lH-benzo[d] imidazole, 3H-imidazo[4,5-b]pyridine, lH-indole, 3H-imidazo[4,5-c]pyridine, lH-benzo[d][l,2,3]triazole, lH-benzo[d]imidazol-2(3H)- one, 4,5,6,7-tetrahydro-lH-benzo[d]imidazole, 3H-[l,2,3]triazolo[4,5-b]pyridine, imidazo[l,2- b]pyridazine, imidazo[l,2-a]pyridine, imidazo[l,2-a]pyrimidine, pyrazolo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine
  • the terms “treat”, “treating” or “treatment” encompass either or both responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms.
  • responsive and prophylaxis measures e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms.
  • the terms “treat,” “treating” or “treatment” include, but are not limited to, prophylactic and/or therapeutic treatments.
  • the terms "subject” or “patient” are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human.
  • the subject is a subject in need of treatment or a subject with a disease or disorder.
  • the subject can be a normal subject.
  • the term does not denote a particular age or sex. Thus, adult and new-born subjects, whether male or female, are intended to be covered.
  • terapéuticaally effective amount refers to a sufficient amount of a compound or a composition being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • therapeutically effective amount includes, for example, a prophylactically effective amount.
  • “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and "Pharmaceutically acceptable salt” or “pharmaceutically acceptable derivatives” is taken to mean an active ingredient, which comprises a compound of the present invention of formula (I) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier.
  • the pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
  • the compounds of the present invention and their pharmaceutically compositions are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of TAK-1, AAK-1, BIKE, CDK (CDK- 1,2,3,4,5,9), Syk, ALK , BTK, FLT (FLT-3,4), JAK (J AK- 1,2,3), KDR, VEGR-2, ZAP- 70, INSR, Aurora, p38, AXL, MUSK, Trk A, GSK-3, c-SRC, PDGFR, IRAK-4, GLK, Erk, FLT, GAK, KIT, MAP2K, MNK, NIK, NLK, PBK, PKD, PRP4, RSK, SPEG, TGFR or ZAK kinase contribute to the pathology and/or symptomology of such diseases and/or disorders.
  • diseases and/or disorders mediated by one or more of these kinases are provided herein.
  • TAK-1, AAK-1, BIKE, CDK (CDK- 1,2,3,4,5,9), Syk, ALK , BTK, FLT (FLT-3,4), JAK (JAK- 1,2,3), KDR, VEGR-2, ZAP-70, INSR, Aurora, p38, AXL, MUSK, Trk A, GSK-3, c-SRC, PDGFR, IRAK-4, GLK, Erk, FLT, GAK, KIT, MAP2K, MNK, NIK, NLK, PBK, PKD, PRP4, RSK, SPEG, TGFR or ZAK kinases include, but are not limited to allergic disorders and/or autoimmune and/or inflammatory diseases and/or conditions associated with inflammation and pain, cancers, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases
  • the compounds according to the present invention possess potential of providing cancer cell growth inhibiting effects and are effective in treating cancers, autoimmune and inflammatory diseases; in particular cancer includes all types of solid cancers and malignant lymphomas but not limited to leukaemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumour & etc; and particularly the compounds according to the present invention are used in the treatment of autoimmune and/or inflammatory diseases and/or conditions associated with inflammation and pain include, but are not limited to acid reflux, heart burn, acne, allergies and allergen sensitivities, bronchitis, carditis, celiac disease, chronic pain, cirrhosis, colitis, dementia, dermatitis, diabetes, dry eyes, edema, emphysema, eczema, fibromyalgia, gastroenteritis, gingivitis, heart disease, hepatitis, high blood pressure,
  • the subject treated in the present methods is a mammal, preferably mice, rat, rabbit, dog, horse, monkey or a human being, male or female, in whom modulation of TAK-1, AAK-1, BIKE, CDK (CDK- 1,2,3,4,5,9), Syk, ALK , BTK, FLT (FLT-3,4), JAK (JAK- 1,2,3), KDR, VEGR-2, ZAP-70, INSR, Aurora, p38, AXL, MUSK, Trk A, GSK-3, c-SRC, PDGFR, IRAK-4, GLK, Erk, FLT, GAK, KIT, MAP2K, MNK, NIK, NLK, PBK, PKD, PRP4, RSK, SPEG, TGFR or ZAK receptor activity may be desired.
  • Modulation as used herein is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism.
  • therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds and pharmaceutically compositions of the present invention may be used in combination with other drugs that are used in the treatment/pre vention/suppression or amelioration of the diseases or conditions for which compounds of the present invention may be useful. Such other drugs may be administered, by a route and in an amount commonly used there for, contemporaneously or sequentially with a compound of the present invention.
  • compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • a pharmaceutical composition of the invention may be formulated as being compatible with its intended route of administration, which may preferably be an oral administration.
  • the pharmaceutical compositions of the invention may be formulated for administration by inhalation, such as aerosols or dry powders; for oral administration, such in the form of tablets, capsules, gels, syrups, suspensions, emulsions, elixirs, solutions, powders or granules; for rectal or vaginal administration, such as suppositories; or for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) such as a sterile solution, suspension or emulsion.
  • the compounds of the present invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethyl cellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • the substituted pyrimidine amine derivatives of formula (I) according to the present invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The specifics of the processes according to the present invention are detailed in the example section mentioned below.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H ("D"), 3 ⁇ 4, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • DMSO Dimethyl sulfoxide
  • nM nanomolar
  • ppm- ⁇ parts per million
  • Hz Hertz
  • MeOH methanol
  • ⁇ micro molar
  • LC/MS Liquid chromatography-mass spectrometry
  • m/z molecular weight
  • Substituted 2-chloro pyrimidine derivatives (9) and appropriate amines (10) were reacted in presence of organic solvents (such as dioxane, acetonitrile, DME, DMF, THF), base (such as cesium carbonate, potassium carbonate, sodium carbonate), palladium(0) catalysts and xantphos at about 60°C for about 30 min to 1 h under microwave condition to get the compound of general formula 11.
  • organic solvents such as dioxane, acetonitrile, DME, DMF, THF
  • base such as cesium carbonate, potassium carbonate, sodium carbonate
  • palladium(0) catalysts and xantphos at about 60°C for about 30 min to 1 h under microwave condition to get the compound of general formula 11.
  • Compound of general formula 11 are treated with NaBH 4 , LiAlH 4 and the like, solvents used such as (MeOH, EtOH, z ' PrOH, in combination of THF) at RT for about 30 min to
  • Substituted 2-chloro pyrimidine derivatives (9) are treated with appropriate amines (12) in presence of organic solvents (such as dioxane, acetonitrile, DME, DMF, THF), base (such as cesium carbonate, potassium carbonate, sodium carbonate), palladium(0) catalyst and xantphos at about 80°C to 100°C for about 30 min to 1 h to get the compound of general formula lb.
  • organic solvents such as dioxane, acetonitrile, DME, DMF, THF
  • base such as cesium carbonate, potassium carbonate, sodium carbonate
  • palladium(0) catalyst and xantphos at about 80°C to 100°C for about 30 min to 1 h to get the compound of general formula lb.
  • the general formula lb can be prepared from substituted 2-chloro pyrimidine derivatives (9) and appropriate amines (12) in presence of organic solvents (such as z ' PrOH, iBuOH), base (such as triethylamine, diisopropylethylamine, DBU) at about 90°C to 110°C for about 12 h to 16 h.
  • organic solvents such as z ' PrOH, iBuOH
  • base such as triethylamine, diisopropylethylamine, DBU
  • Substituted 2-chloro pyrimidine derivatives (9) are treated with appropriate amines (13) in presence of organic solvents (such as dioxane, acetonitrile, DME, DMF, THF), base (such as CS2CO3, K2CO3, Na 2 C03 and the like), palladium(O) catalysts and xantphos at about 80°C to 100°C for about 30 min to 1 h to get the compound of general formula 14.
  • organic solvents such as dioxane, acetonitrile, DME, DMF, THF
  • base such as CS2CO3, K2CO3, Na 2 C03 and the like
  • palladium(O) catalysts and xantphos at about 80°C to 100°C for about 30 min to 1 h to get the compound of general formula 14.
  • Compound of general formula 14 is treated with trifluoro acetic acid, HCl in dioxane/diethyl ether, acetic acid and the like in suitable organic solvents such as DCM, dioxane, acetonitrile, DME, DMF, THF at about 25°C to 35°C for about 1 h to 4 h to get the compound of general formula Ic (wherein R4 is H).
  • suitable organic solvents such as DCM, dioxane, acetonitrile, DME, DMF, THF at about 25°C to 35°C for about 1 h to 4 h to get the compound of general formula Ic (wherein R4 is H).
  • Compound of general formula Ic (wherein R4 is H) is treated with 2-bromoethanol, solvents used such as (such as dioxane, acetonitrile, DME, DMF, THF), base (such as TEA, DIPEA and the like) at 30°C to 40°C for about 1 h to 2 h to get the compound of general formula Ic (wherein R 4 is hydroxy alkyl).
  • solvents used such as (such as dioxane, acetonitrile, DME, DMF, THF), base (such as TEA, DIPEA and the like) at 30°C to 40°C for about 1 h to 2 h to get the compound of general formula Ic (wherein R 4 is hydroxy alkyl).
  • the microwave chemistry was performed on a CEM Explorer.
  • Step-iii Synthesis of l-bromo-3-(2-bromoethoxy)-5-nitrobenzene:
  • Step-v Synthesis of l-(2-(3-nitro-5-vinylphenoxy) ethyl) piperidin-4-one:
  • Step-i Synthesis of N 1 -(2-chloro-5-fluoropyrimidin-4-yl)-4,5-difluorobenzene-L2-diamine:
  • Step-ii Synthesis of l-(2-chloro-5-fluoropyrimidin-4-yl)-5,6-difluoro-lH-benzordl imidazole:
  • N 1 -(2-chloro-5-fluoropyrimidin-4-yl)-4,5-difluorobenzene-l,2-diamine (0.42 g, 1.53 mmol)
  • j?-toluenesulfonic acid 0.026 g, 0.153 mmol
  • reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na 2 S0 4 , and concentrated. The crude was then purified by triturating with n- pentane to obtain the titled compound as a brown solid (0.32 g, 73%).
  • 2,4-dichloro-5-fluoropyrimidine (1 g, 7.19 mmol) was added in single portion, to a stirred solution of butyl vinyl ether (0.76 g, 7.6 mmol), Pd(II) acetate (0.16 g, 0.72 mmol) and triethyl amine (0.76 g, 7.6 mmol) in polyethylene glycol (15 mL). Reaction mixture was stirred at 80°C for 2 h. After completion of reaction, reaction mixture was cooled to room temperature and diluted with diethyl ether. Organic layer was washed with water followed by brine and dried over anhydrous Na 2 S04.
  • Desired compound was obtained by concentrating the dried organic layer under reduced pressure as a gummy brown solid (0.85 g, 51%).
  • Step-ii Synthesis of 3-(2-chloro-5-fluoropyrimidin-4-yl)imidazorL2-blpyridazine:
  • Step-i Synthesis of 3-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyrazolorL5-alpyrimidine:
  • reaction mixture was cooled to room temperature and diluted with pentane passed through celite and washed with 2:3 (EtOAc : Ether) and concentrated under reduced pressure to obtain crude product.
  • Step-ii Synthesis of 3-(2-chloro-5-fluoropyrimidin-4-yl)pyrazolori.5-alpyrimidine:
  • Step-iii Synthesis of tert-butyl 8-amino-3,4-dihydro-lH-pyridor4,3-blindole-2(5H)-carboxylate:
  • Step-iv Synthesis of tert-butyl 5-(2-ethoxy-2-oxoethyl)-8-nitro-3,4-dihydro-lH-pyrido[4,3- blindole-2(5H)-carboxylate:
  • Step-i Synthesis of tert-butyl 5-(methylsulfonyl)-8-nitro-3,4-dihydro-lH-pyridor4,3-blindole- 2(5H)-carboxylate:
  • Step-ii The process of this step was adopted from step-iii of Intermediate-32.
  • the desired product obtained as a pink solid (400 mg, 86%); MS (ES) m/e 366 (M+H) + .
  • Step-(i, ii and iii) The process of these steps were adapted from step-i to step-iii of Intermediate- 32.
  • Intermediate- Synthesis of 2,3A9-tetrahydro-lH-carbazol-7-amine
  • Step-i and ii The process of these steps was adopted from step-i and step-iii of Intermediate-32.
  • the desired product obtained as dark brown semi-solid (0.2 g, 23%).
  • Step-i Synthesis of fe/ -butyl 5-ethyl-7-nitro-3,4-dihydro-lH-pyridor4,3-blindole-2(5H)- carboxylate:
  • Step-ii Synthesis of fe/t-butyl 7-amino-5-ethyl-3,4-dihydro-lH-pyrido[4,3-blindole-2(5H)- carboxylate:
  • step-iii of Intermediate-32 The process of this step was adopted from step-iii of Intermediate-32.
  • the desired product obtained as an off-white solid (0.18 g, 98%).
  • reaction mixture was quenched with ice water and resulted reaction mixture was extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the obtained crude material was purified by column chromatography, eluting with 0- 5% ethyl acetate in n-hexane to afford the titled product (0.5 g, 42%).
  • Step-iii Synthesis of 7-nitro-l,2,3,4-tetrahvdrobenzofuro[3,2-clpyridine hydrochloride:
  • Step-iv and v The process of these steps was adopted from step-ii and step-iii of Intermediate- 32.
  • the desired product obtained as a brown color semi-solid (0.15 g, 66%).
  • Step-i Synthesis of ethyl 6-bromo-3-(2-ethoxy-2-oxoethyl)imidazorL2-alpyridine-2- carboxylate:
  • Step-ii Synthesis of 2-(6-bromo-2-(hvdroxymethyl)imidazo[ l,2-alpyridin-3-yl)ethanol:
  • Step-iii Synthesis of 2-(2-(azidomethyl)-6-bromoimidazor L2-alpyridin-3-yl)ethyl diphenyl phosphate:
  • Step-iv Synthesis of tert-butyl 7-bromo-3,4-dihydroimidazo[l,2-a:4,5-c'ldipyridine-2(lH)- carboxylate:
  • Step-v Synthesis of tert-butyl 7-amino-3,4-dihydroimidazor L2-a:4,5-c'ldipyridine-2( lH)- carboxylate:
  • reaction mixture was cooled to room temperature and diluted with EtOAc, washed with brine, dried over MgS0 4 and the residue was purified by flash chromatography (DCM/MeOH 9: 1 ) to afford the desired product (0.2 g, 50%).
  • Step-i The process of this step was adopted from Intermediate-40.
  • the desired product obtained as a yellow solid (0.5 g, 89%).
  • MS (ES) m/e 395 (M+H) + and 339 (M-i-buytl).
  • Step-ii The process of this step was adopted from step-iii of Intermediate-32.
  • the desired product obtained as a brown solid (0.14 g, 60%).
  • Step-ii Synthesis of (E)-ethyl 2-(2-(3-bromophenyl)hvdrazono)propanoate:
  • Step-iii Synthesis of ethyl 6-bromo-lH-indole-2-carboxylate:
  • Step-iv Synthesis of ethyl 6-bromo-l-(cyanomethyl)-lH-indole-2-carboxylate:
  • Step-v Synthesis of 7-bromo-l,2,3,4-tetrahydropyrazino[l,2-alindole:
  • Step-vi and vii Synthesis of tert-butyl 7-amino-3,4-dihydropyrazinorL2-alindole-2(lH)- carboxylate:
  • step-ii and step-iii of Intermediate-32 The process of these steps was adopted from step-ii and step-iii of Intermediate-32.
  • the desired product obtained as a brown semi-solid (160 mg, 49%); MS (ES) m/e 288 (M+H) + .
  • Step-ii Synthesis of /er/-butyl 3-(3-bromo-5-nitrophenoxy)azetidine-l-carboxylate:
  • Step-iii Synthesis of fe/t-butyl 3-(3-nitro-5-vinylphenoxy)azetidine-l-carboxylate:
  • Step-iv Synthesis of fe/t-butyl 3-(3-amino-5-ethylphenoxy)azetidine-l-carboxylate:
  • Step-i Synthesis of l-(2-(3-((4-(lH-benzordlimidazol-l-yl)-5-fluoropyrimidin-2-yl)amino)-5- ethylphenoxy)ethyl)piperidin-4-one:
  • Step-ii Synthesis of l-(2-(3-((4-(lH-benzordlimidazol-l-yl)-5-fluoropyrimidin-2-yl)amino)-5- ethylphenoxy)ethyl)piperidin-4-ol:
  • Example-I with appropriate variations in reactants, quantities of reagents and reaction conditions.
  • the physiochemical characteristics of the compounds are summarized herein below table.
  • Boc deprotection-conditions Boc-protected compound dissolved in DCM (5 mL) and cooled at 0°C. To the above solution trifluoro acetic acid (0.5 mL) was added dropwise over a period of 10 min and stirred at RT for 3 h. Excess of TFA and DCM was removed under vacuo and the crude compound was triturated with diethyl ether to afford the compound- 14 as an off-white solid (20 mg, 25%).
  • Example-II Synthesis of N-(4-( lH-benzordlimidazol- l-yl)-5-fluoropyrimidin-2-yl)-2,3,4,5- tetrah dro-lH-pyridor4 -blindol-8-amine.trifluoroacetic acid (Compound- 20).
  • Step-i Synthesis of tert-butyl 8-((4-( lH-benzo[(ilimidazol-l-yl)-5-fluoropyrimidin-2-yl)amino)- 3 , 4-dihydro- 1 H-pyr ido ⁇ 4 , 3 -b indo le-2( 5H) -carboxylate :
  • Step-ii Synthesis of N-(4-( lH-benzordlimidazol- l-yl)-5-fluoropyrimidin-2-yl)-2,3,4,5- tetrahydro-lH-pyridor4,3-blindol-8-amine trifluoro acetic acid:
  • Example-IV Synthesis of 2-(8-((5-fluoro-4-(imidazorL2-blpyridazin-3-yl)pyrimidin-2- yl)amino)-3,4-dihydro-lH-pyridor4,3-blindol-5(2H)-yl)ethanol 2,2,2-trifluoroacetate
  • Step-i Synthesis of tert -butyl 5-(2-ethoxy-2-oxoethyl)-8-((5-fluoro-4-(iim
  • reaction mixture was concentrated under reduced pressure, crude material was diluted with EtOAc washed with water. Organic layer was washed with brine and dried over anhydrous Na 2 S0 4 , concentrated under reduced pressure, crude compound was purified by column over 230-400 mesh silica gel by eluting with EtOAc/n-hexane (3:7) to give title compound as a pale yellow solid (160 mg, 34%); MS (ES) m/e 587 (M+H) + .
  • Step-ii Synthesis of tert-butyl 8-((5-fluoro-4-(imidazorL2-blpyridazin-3-yl)pyrimidin-2- yl)amino)-5-(2-hvdroxyethyl)-3,4-dihvdro-lH-pyrido[4,3-blindole-2(5H)-carboxylate:
  • Step-iii Synthesis of 2-(8-((5-fluoro-4-(imidazorL2-blpyridazin-3-yl)pyrimidin-2-yl)amino)- 3,4-dihydro- lH-pyrido[4,3-blindol-5(2H)-yl)ethanol 2,2,2-trifluoroacetate (Compound-48):
  • step-ii of compound-20 The process of this step was adopted from step-ii of compound-20.
  • Step-i Synthesis of fe/ -butyl 3-(3-ethyl-5-((5-fluoro-4-(lH-imidazol-l-yl)pyrimidin-2- yl)amino)phenoxy)azetidine- 1 -carboxylate:
  • reaction mixture tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol) and xantphos (35 mg, 0.06 mmol) were added and again degassed with argon for 30 min. Reaction mixture was stirred at 90°C for 30 min. After completion of reaction, reaction mixture was cooled to room temperature, diluted with EtOAc and passed through celite. Filtrate was washed with water followed by brine. Organic layer was dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to obtain crude compound.
  • Step-ii Synthesis of N-(3-(azetidin-3-yloxy)-5-ethylphenyl)-5-fluoro-4-(lH-imidazol-l- yl)pyrimidin-2-amine 2,2,2-trifluoroacetate: tert-butyl 3-(3-ethyl-5-((5-fluoro-4-(lH-imidazol-l-yl)pyrimidin-2-yl)amino)phenoxy) azetidine- 1 -carboxylate (0.13 g, 0.26 rnmol) was dissolved in DCM (10 mL) and cooled at 0°C.
  • Example- VI Synthesis of 2-(3-(3-((4-(lH-benzo[dlimidazol-l-yl)-5-fluoropyrimidin-2- yl)amino)- -ethylphenoxy)pyrrolidin- l-yl)ethanol 2,2,2-trifluoroacetate (Compound-63):
  • TAK1 radiometric kinase assay was performed by incubating 250ng of TAK1-TAB1 fusion protein with the compound in the assay buffer (50mM Tris-HCl, pH: 7.5, lOmM Magnesium chloride, lOmM dithiotreitol, O. lmM EGTA) for 30 min at room temperature. 3 ⁇ g of Mylein basic protein (MBP), 10 ⁇ unlabelled ATP and ⁇ ⁇ 32 ⁇ labeled ATP diluted in assay buffer were added and incubated for additional 15mins at room temperature.
  • MBP Mylein basic protein
  • the reaction was quenched with l3 ⁇ L ⁇ of lOOmM ATP in 8N HC1. 30 ⁇ 1 of the sample was spotted onto a P81 Whatman Chromatography paper. The strips were washed several times with 0.5% Ortho Phosphoric acid and acetone. The p81 filter strips were then dried and placed in a 96well plate. ⁇ of Microscint-0 scintillation fluid was added and incubated for lOmins at room temperature and read in Perkin Elmer NXL-Top Count. The percent inhibition of activity of the enzyme is calculated by comparing counts in the presence and absence of compounds. Dose response curves were generated for compound with 12 concentrations using GraphPad Prism software Version 5 (San Diego, California, USA) using non linear regression curve fit for sigmoidal dose response ( variable slope).
  • the selected compounds were screened at 1 ⁇ concentration and the results are summarized in below table.
  • the IC50 values of the compounds are set forth in below Table, wherein Group “A” refers to an IC50 value in less than 0.2 ⁇ , Group “B” refers to IC50 value in range of 0.2 to 0.5 ⁇ and Group “C” refers to IC50 value in greater than 0.5.

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Abstract

La présente invention concerne des dérivés pyrimidine aminée substitués de la formule (I) et leurs sels pharmaceutiquement acceptables, ou des stéréoisomères pharmaceutiquement acceptables de ceux-ci, qui sont utiles en tant qu'inhibiteurs de TAK1. (I) En particulier, l'invention concerne également leur procédé de préparation, des compositions pharmaceutiques les comprenant, et leur utilisation pour le traitement et la prévention de maladies ou de troubles, en particulier leur utilisation dans des maladies ou troubles associés en tant qu'inhibiteurs de TAK1.
PCT/IB2014/060155 2013-03-28 2014-03-26 Dérivés pyrimidine aminée substitués en tant qu'inhibiteurs de tak-1 WO2014155300A2 (fr)

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