WO2014091265A1 - Dérivés de pyrimidine-2,4-diamine en tant qu'inhibiteurs de kinase - Google Patents

Dérivés de pyrimidine-2,4-diamine en tant qu'inhibiteurs de kinase Download PDF

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WO2014091265A1
WO2014091265A1 PCT/IB2012/002645 IB2012002645W WO2014091265A1 WO 2014091265 A1 WO2014091265 A1 WO 2014091265A1 IB 2012002645 W IB2012002645 W IB 2012002645W WO 2014091265 A1 WO2014091265 A1 WO 2014091265A1
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amino
bromo
pyrimidin
phenyl
oxo
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PCT/IB2012/002645
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Siva Sanjeeva Rao THUNUGUNTLA
Subramanya Hosahalli
Chitty Venkata SRIKANTH
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Aurigene Discovery Technologies Limited
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Priority to PCT/IB2012/002645 priority Critical patent/WO2014091265A1/fr
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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 application relates to novel Pyrimidine-2,4-diamine derivatives as inhibitors derivatives of formula (I), as protein kinase inhibitors.
  • the invention particularly relates to compounds of formula (I), preparation of compounds and pharmaceutical compositions thereof.
  • the invention further relates to prodrugs, derivatives, polymorphs, pharmaceutically acceptable salts and compositions comprising the said novel Pyrimidine-2,4-diamine derivatives as kinase inhibitors and their derivatives and their use in the treatment of various disorders.
  • Protein Kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families. Protein kinases participate in the signalling events that control 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.
  • Protein kinases play crucial role in regulating the different cell processes which include, but are not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation, signaling process and various regulatory mechanisms, by adding phosphate groups to the target protein residues.
  • This phosphorylation event acts as molecular on off switches that can modulate or regulate the target position biological function. Phosphorylation of targeted proteins occurs in response to a variety of extracellular signals.
  • the appropriate protein kinase functions in signaling pathways to activate or deactivate. Uncontrolled signaling due to defective control of protein phosphorylation is known to contribute to various diseases.
  • kinases are known to regulate many aspects of the cell growth, invasion that intrudes upon and destroys adjacent tissues and sometimes metastasis, or spreading to other locations in the body via lymph or blood.
  • the protein kinase family members include enzymes that control cell growth, migration, activation, proliferation, differentiation, signalling, survival and regulation of the cell cycle.
  • Many diseases and/or disorders are associated with aberrant, abnormal or deregulated activity of one or more kinases. These diseases and/or disorders include, but are not limited to cancers, allergic diseases and/or disorders, autoimmune diseases and/or disorders, inflammatory diseases and/or disorder and/or conditions associated with inflammation and pain, proliferative diseases, hematopoietic disorders, haematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative diseases/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases. Therefore, inhibition of one or more of kinases would have multiple therapeutic indications.
  • JAK kinases are a family of cytoplasmic protein tyrosine kinases including JAK1, JAK2, JAK3 and TYK2.
  • the protein tyrosine kinases JAK 1 , JAK2, JAK3 and TYK2 have essential roles in cytokine-dependent regulation of proliferation and function of cells involved in immune response. They are critical in signal transduction in response to their activation via tyrosine phosphorylation by stimulation of interleukin receptors.
  • Each of the JAK kinases is selective for the receptors of certain cytokines, though multiple JAK kinases can be affected by particular cytokine or signalling pathways.
  • JAK1 interacts with, among others, the receptors for cytokines IL-2, IL-4, IL-7, IL-9 and IL-21
  • JAK2 interacts with, among others, the receptors for IL-9 and TNF-a.
  • cytokines e.g., IL-2, IL-4, IL-7, IL-9, IL- 15 and IL-21
  • receptor oligomerization occurs, resulting in the cytoplasmic tails of associated JAK kinases being brought into proximity and facilitating the trans-phosphorylation of tyrosine residues on the JAK kinase. This trans-phosphorylation results in the activation of the JAK kinase.
  • STAT proteins which are DNA binding proteins activated by phosphorylation of tyrosine residues, function both as signaling molecules and transcription factors and ultimately bind to specific DNA sequences present in the promoters of cytokine-responsive genes. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant (allograft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematologic malignancies such as leukemia and lymphomas.
  • JAK kinases and JAK2 mutations are implicated in myeloproliferative disorders, cancers, including blood borne and solid tumors.
  • Exemplary disorders include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML) and systemic mastocytosis (SM).
  • CML chronic myeloid leukemia
  • PV polycythemia vera
  • ET essential thrombocythemia
  • PMF primary myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CMML chronic myelomonocytic leukemia
  • SM systemic mastocytosis
  • FAK Fluorescence Activated kinase
  • FAC farnesoic acid
  • EMC extracellular matrix
  • the activation of FAK can be further enhanced by co-stimulation of the growth factors by ECM associated growth factors, such as bFGF, EGF or PDGF.
  • FAK does't phosphorylate other proteins. However, activated FAK auto phosphorylates and binds Src kinase which in turn phosphorylate other sites of FAK and other FAK binding proteins such as Cas and paxillin. Phosphorylated FAK provides the docking site for mediators of multiple signalling events and consequently involves in the regulation of ceil growth and survival through activation of Pi3K/Akt/mTOR and Grb2/SOS/RAS/Raf/MEK ERK pathways. Overexpression of FAK has been associated with malignancy in a variety of cancers.
  • Inhibition of FAK has been shown the inhibition of tumour growth in different cancer cells (Oncogene 25: 4429-4440). However, inhibition of FAK in normal human fibroblasts or immortalized mammary ceils didn't cause loss of attacliment or apoptosis. FurtheiTnore, loss of FAK activity (reconstitution of FAK-/-cells with kinase-dead FAK) reduced growth of v-Src tumors in mice and decreased angiogenesis. Therefore, Inhibition of FAK is a potential therapy for the treatment of hyper-proliferative diseases such as cancers.
  • Axl is a receptor protein tyrosine kinase (RTK) that comprises a C-terminal extracellular ligand-binding domain and N-terminal cytoplasmic region containing the catalytic domain.
  • RTK receptor protein tyrosine kinase
  • the extracellular domain of Axl has a unique structure that juxtaposes immunoglobulin and fibronectin Type III repeats and is pronounced of the structure of neural cell adhesion molecules.
  • Gas6 growth arrest specific-6
  • Protein S Protein S.
  • the Axl extracellular domain has been shown to undergo hemophilic interactions that mediate cell aggregation, suggesting that one important function of Axl may be to mediate cell-cell adhesion.
  • Axl is predominantly expressed in the vasculature in both endothelial cells (EC's) and vascular smooth muscle cells (VSMC's) and in cells of the myeloid lineage and is also detected in breast epithelial cells, chondrocytes, Sertoli cells and neurons.
  • protein kinase inhibitors particularly receptor tyrosine kinase and non-receptor tyrosine kinase inhibitors, more particularly JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL.
  • JAK Janus Kinase
  • FAK Fincal Adhesion Kinase
  • the present invention relates to pyrimidine-2,4-diamine derivatives of formula (I)
  • L is direct bond or group selected from -(CH 2 , -CO- or -S0 2 -;
  • Ri is hydrogen or alkyl
  • R 2 is hydrogen, halogen, optionally substituted alkyl, haloalkyl. cyano, -CONHRi ;
  • R 3 is CR 9 or N
  • R4 is independently selected from optionally substituted alkyl, cyanoalkyl , -(CH 2 ) qCONRjoRi ! , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl; wherein optionally substituent, in each occurrence is independently selected from -ORi 2 , -SRi 2 , -
  • R5 is independently selected from hydrogen, halogen, optionally substituted alkyl or - NR n R, 4 ;
  • ii) taken together with the nitrogen to which they are attached may optionally form 3 to 7 membered saturated, partially saturated or unsaturated ring having 0-2 additional heteroatoms selected from N, O, S; wherein the said ring is optionally substituted with halo, alkyl, acyl, alkyloxy, hydroxyl, hydroxyalkyl, oxo, cycloalkyl, heterocycloalkyl or -NR13R14;
  • Re or R 7 together with the nitrogen to which it is attached and adjacent carbon atom of the phenyl group may optionally form 3 to 7 membered saturated, partially unsaturated or fully unsaturated ring having 0-2 additional heteroatoms selected from N, O, S; wherein the said ring is optionally substituted with oxo;
  • Rs is independently selected from hydrogen, halo or alkyloxy
  • R9 at each occurrence is independently selected from hydrogen, alkyl or -NR13R14;
  • Rio and n at each occurrence are independently selected from hydrogen, alkyl or alkyloxy;
  • Ri2 in each occurrence are independently selected from hydrogen or alkyl
  • R ⁇ and R J in each occurrence are independently selected from hydrogen, alkyl, acyl or - S(0) 2 R, 2 ;
  • n 0 or 1 ;
  • p is selected from 1 to 5;
  • q is selected from 0 to 5; or a pharmaceutically acceptable salts, stereoisomers, polymorphs or prodrugs thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I), and atleast one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the present invention relates to the preparation of the compounds of formula (I).
  • the present invention provides pyrimidine-2,4-diamine derivatives of formula (I), which are used for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting protein kinases enzymes, particularly receptor tyrosine kinase and non-receptor tyrosine kinase inhibitors, more particularly JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL.
  • protein kinases enzymes particularly receptor tyrosine kinase and non-receptor tyrosine kinase inhibitors, more particularly JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL.
  • JAK Japanese Kinase
  • FAK Fluor Adhesion Kinase
  • AXL Adhesion Kinase
  • the term 'compound(s)' comprises the compounds disclosed in the present invention.
  • substituted refers to a non-hydrogen radical is in the place of hydrogen radical on a carbon or nitrogen of the substituent.
  • a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different, unless otherwise stated.
  • the term "optionally substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio.
  • alkyl alone or in combination with other term(s) means saturated aliphatic groups, including Ci-Qo straight or C i-C io branched alkyl groups.
  • branched alkyl means secondary or tertiary alkyl groups.
  • acyl alone or in combination with other term(s) means RC(O)-, wherein R is alkyl as defined above. For example, acetyl, - and the like.
  • halo or halogen alone or in combination with other term(s) means fluorine, chlorine, bromine and Iodine.
  • haloalkyl means alkyl substituted with one or more halogen atoms, where alkyl groups are as defined above.
  • halo is used herein interchangeably with the term “halogen” means F, CI, Br or I.
  • haloalkyl include but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl and the like.
  • cyanoalkyl means alkyl substituted with cyano group, where alkyl groups are as defined above.
  • alkyl groups are as defined above.
  • examples of “cyanoalkyl” include but are not limited to cyanomethyl, cyanoethyl and the like.
  • cycloalkyi alone or in combination with other term(s) means -C3-C10 saturated cyclic hydrocarbyl ring.
  • a cycloalkyi may be a single ring, which typically contains from 3 to 7 carbon ring atoms and more typically from 3 to 6 ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyi may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls.
  • heterocycloalkyl alone or in combination with other term(s) means a saturated ⁇ i.e., “heterocycloalkyl”) or partially saturated ⁇ i.e., “he erocycloalkenyl" ring structure containing a total of 3 to 12 ring atoms. At least one of the ring atoms is a heteroatom ⁇ i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heterocycloalkyl may be a single-ring (monocyclic), bicyclic or polycyclic ring structure.
  • heteroaryl alone or in combination with other terni(s) means a 5- 15 membered mono-, bi-, or other multi-cyclic, aromatic ring system containing one or more heteroatoms; wherein heteroatoms are selected from nitrogen, oxygen, and sulfur. Heteroaryls can also be fused to nonromantic rings.
  • fused means that the second ring is attached or formed by having two adjacent atoms in common with the first ring. The term “fused” is equivalent to the term “condensed”.
  • aryl alone or in combination with other term(s) means a carbocyclic aromatic system containing one or two rings wherein such rings may be fused.
  • fused means that the second ring is attached or formed by having two adjacent atoms in common with the first ring.
  • fused is equivalent to the term “condensed”.
  • Examples of aryl groups include but are not limited to phenyl, naphthyl, 3,4-dihydroquinolin-2(l H)-one, benzo[d][l ,3]dioxole, 2,3-dihydrobenzo [b][ l ,4]dioxine and the like. Unless otherwise specified, all aryl groups described herein may be substituted or unsubstituted.
  • cycloalkylalkyr alone or in combination with other term(s) means alkyl substituted with cycloalkyl group, wherein the terms “alkyl” and “cycloalkyl” are as defined above.
  • arylalkyP alone or in combination with other term(s) means alkyl substituted with aryl group, wherein the terms “alkyl” and “aryl” are as defined above.
  • heteroarylalkyl alone or in combination with other term(s) means alkyl substituted with heteroaryl group, wherein the terms “alkyl” and “heteroaryl” are as defined above
  • alkyloxy refers to alkyl (groups as defined above) hydrocarbon radical bonded to an oxygen atom that is attached to a core structure.
  • alkyloxy groups include methoxy, ethoxy, propoxy and the like.
  • hydroxy means an -OH group.
  • hydroxyalkyl means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 2-methyl-2-hydroxyethyl ; 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4- hydroxyheptyl.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • prevent refers to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • terapéuticaally effective amount refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
  • modulate refers to the ability of a compound to increase or decrease the function, or activity, of a kinase.
  • Module as used herein in its various forms, is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of the activity associated with kinase.
  • Kinase inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction.
  • Kinase activators are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize or up regulate signal transduction.
  • the present invention provides novel pyrimidine-2,4-diamine derivatives of formula (I), which are used for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting protein kinases enzymes, particularly receptor tyrosine kinase and non-receptor tyrosine kinase inhibitors, more particularly JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL.
  • protein kinases enzymes particularly receptor tyrosine kinase and non-receptor tyrosine kinase inhibitors, more particularly JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL.
  • the present invention further provides to pharmaceutical compositions comprising the said novel pyrimidine-2,4-diamine compounds and their derivatives as therapeutic agents.
  • the first embodiment of the present invention provides the structure of compounds as set forth in formula (I).
  • L is direct bond or group selected from -(CH>) P -, -CO- or -SO2-;
  • Ri is hydrogen or alkyl
  • R2 is hydrogen, halogen, optionally substituted alky], haloalkyl, cyano, -CONHRi ;
  • R 3 is CR 9 or N
  • R4 is independently selected from optionally substituted alkyl, cyanoalkyl , -(CH 2 ) qCONRioRn, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl; wherein optionally substituent, in each occurrence is independently selected from -O 12 , -SR12, - S(0) 2 R i 2 or -NR, 3 Ri4;
  • R5 is independently selected from hydrogen, halogen, optionally substituted alkyl or -
  • ii) taken together with the nitrogen to which they are attached may optionally form 3 to 7 membered saturated, partially saturated or unsaturated ring having 0-2 additional heteroatonis selected from N, O, S; wherein the said ring is optionally substituted with halo, alkyl, acyl, alkyloxy, hydroxyl, hydroxyalkyl, oxo, cycloalkyl, heterocycloalkyl or -NR13R14 ;
  • 3 ⁇ 4 or R 7 together with the nitrogen to which it is attached and adjacent carbon atom of the phenyl group may optionally form 3 to 7 membered saturated, partially unsaturated or fully unsaturated ring having 0-2 additional heteroatonis selected from N, O, S; wherein the said ring is optionally substituted with oxo;
  • R 8 is independently selected from hydrogen, halo or alkyloxy
  • R 9 at each occurrence is independently selected from hydrogen, alkyl or -NR13R14;
  • Rio and R u at each occurrence are independently selected from hydrogen, alkyl or alkyloxy;
  • 2 in each occurrence are independently selected from hydrogen or alkyl
  • Ri 3 and Ru in each occurrence are independently selected from hydrogen, alkyl, acyl or - S(0) 2 R 12 ;
  • n 0 or 1 ;
  • p is selected from 1 to 5;
  • q is selected from 0 to 5;
  • R 2 is halogen (for example bromo, chloro or fluoro), alkyl (for example methyl) or haloalkyl (for example trifluoromethyl).
  • R 3 is -CR9 or N; wherein R9 is hydrogen, methyl or -N(CH 3 )SC>2CH 3 .
  • R4 is selected from optionally substituted alkyl, cyanoalkyl, -(CH 2 ) q CONRi Rn, optionally substituted cycloalkyl, optionally substituted aryi, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl.
  • R4 is optionally substituted alkyl; and optional substituent is selected from -OCH 3 , - SCHj , -S(0) 2 CH 3 or -N(CH 3 )S0 2 CH 3 .
  • R_i is cyanoalkyl, wherein cyanoalkyl is 2-propanenitrile or -CH 2 CN.
  • R4 is wherein q is 1 or 2 and, R 10 and R u are independently hydrogen, alkyl (for example methyl or isopropyl) or alkoxy (for example methoxy).
  • R is cycloalkyl; wherein cycloalkyl is cyclopentane.
  • R4 is arylalkyl; wherein arylalkyl is benzyl optionally substituted with methoxy.
  • R4 is heteroarylalkyl (for example 5-methyl-l H-tetrazole).
  • R6 and R7 are independently selected from hydrogen, alkyl or acyl; wherein alkyl is methyl and acyl is -C(0)CH 3 .
  • R0 and R 7 are taken together with the nitrogen to which they are attached may optionally fonn 3 to 7 membered saturated ring (for example piperazine, piperidine, morpholine or 1 ,4-diazepane) or unsaturated ring (for example pvridinone); wherein the said ring may be optionally substituted with halo (for example fluoro), alkyl (for example methyl, and ethyl), acyl (for example -COCH3), alkyloxy (for example methoxy), hydroxyl, hydroxyalkyl (for example - CH1OH, -CH2CH2OH), oxo, cycloalkyl (cyclopropyl) or - R13 14 (for example R13 and Ru are selected from hydrogen, methyl, -COCH 3 , or -S0 2 CH 3 ).
  • halo for example fluoro
  • alkyl for example methyl, and ethyl
  • acyl for example
  • R 7 when L is direct bond
  • R 7 together with the nitrogen to which it is attached and adjacent carbon atom of the phenyl group may form 3 to 7 membered ring having 0-2 additional heteroatoms selected from N, O, S; wherein the said ring is optionally substituted with oxo.
  • R 8 is selected from hydrogen, halogen (for example fluorine) or alkoxy (for example methoxy).
  • Another embodiment of the present invention provided a pharmaceutical composition
  • a pharmaceutical composition comprising the compound as disclosed, and a pharmaceutically acceptable carrier or diluent.
  • the compounds as disclosed in the present invention are formulated for pharmaceutical administration.
  • Yet another embodiment of the present invention provides use of the compounds as disclosed in the present invention for the preparation of a medicament for the treatment of cancer.
  • Yet another embodiment of the present invention provides a method of treatment of cancer, wherein the method comprises administration of an effective amount of the compound of the present invention to the subject in need thereof.
  • Yet another embodiment of the present invention provides a method for inhibiting growth of tumour cells and/or metastasis by administering an effective amount of the compound of the present invention to the subject in need thereof.
  • the compounds and pharmaceutically compositions of the present invention are used for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting protein kinases enzymes, particularly receptor tyrosine kinase and non-receptor tyrosine kinase inhibitors, more particularly JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL.
  • protein kinases enzymes particularly receptor tyrosine kinase and non-receptor tyrosine kinase inhibitors, more particularly JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL.
  • the compounds and pharmaceutically compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL kinase contribute to the pathology and/or symptomology of such diseases and/or disorders.
  • JAK Janus Kinase
  • FAK Fluor Adhesion Kinase
  • AXL kinase mediated by one or more of these kinases are provided herein.
  • the compounds of the invention are used in the treatment and/or prevention of diseases and/or disorders mediated by JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL kinase.
  • JAK to which the compounds of the present invention bind and/or modulate includes any member of the JAK family.
  • the JAK is JAKl , JAK2, JAK3 or TYK2.
  • the JAK is JAKl or JAK2.
  • the JAK is JAK2.
  • the compounds of the present invention are used as JAK (Janus Kinase), FAK (Focal Adhesion Kinase) or AXL kinase iniiibitors.
  • the compounds are used as multiple kinase inhibitors, particularly inhibiting JAK, FAK and AXL kinases.
  • the compounds are used as dual kinase inhibitors, particularly inhibiting JAK and FAK, JAK and AXL or FAK and AXL; more particularly JAK and FAK; still more particularly JAK2 and FAK.
  • tumour cells include cancer such as but not limited to melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia
  • the pharmaceutical composition is usually administered by a parenteral administration route, but can be administered by oral or inhalation routes.
  • parenteral administration include administration by injection, and percutaneous, transmucosal, transnasal and trans pulmonary administrations.
  • the injectable materials include a solution, a suspension, and a solid injection that is dissolved or suspended in a solvent before use.
  • the injection is used after one or more active ingredients are dissolved, suspended or emulsified in a solvent.
  • the solvent include water-soluble solvents (e.g., distilled water, physiological saline and Ringer's solution), oil solvents (e.g., vegetable oils such as olive oil, sesame oil, cotton oil and corn oil, and alcohols such as propylene glycol, polyethylene glycol and ethanol), and combinations thereof.
  • the dosage of the compounds of the present invention varies depending on age, weight, symptom, therapeutic efficacy, dosing regimen and/or treatment time. Generally, they may be administered by a parenteral route (preferably intravenous administration) in an amount of 1 mg to 100 mg per time, from once a couple of days, once 3 days, once 2 days, once a day to a couple of times a day, in the case of an adult, or continuously administered by intravenous administration from 1 to 24 hours a day. Since the dosage is affected by various conditions, ⁇ an amount less than the above dosage may sometimes work well enough, or higher dosage may be required in some cases.
  • Parenteral administration by injection includes all forms of injections, and also includes intravenous fluids.
  • intramuscular injections includes intramuscular injections, subcutaneous injections, intradermal injections, intra-arterial injections, intravenous injections, intraperitoneal injections, injections to spinal cavity, and intravenous drops.
  • the compounds of the present invention may be administered in combination with other drugs for (1 ) complementation and/or enhancement of prevention and/or therapeutic efficacy of the preventive and/or therapeutic drug of the present invention, (2) dynamics, absorption improvement, dosage reduction of the preventive and/or therapeutic drug of the present invention, and/or (3) reduction of the side effects of the preventive and/or therapeutic drug of the present invention.
  • a concomitant medicine comprising the compounds of the present invention and other drug may be administered as a combination preparation in which both components are contained in a single formulation, or administered as separate formulations.
  • the administration by separate formulations includes simultaneous administration and administration with some time intervals.
  • the compound of the present invention can be administered first, followed by another drug or another drug can be administered first, followed by the compound of the present invention.
  • the administration method of the respective drugs may be the same or different.
  • the dosage of the other drug can be properly selected, based on a dosage that has been clinically used.
  • the compounding ratio of the compound of the present invention and the other drug can be properly selected according to age and weight of a subject to be administered, administration method, administration time, disorder to be treated, symptom and combination thereof.
  • the other drug may be used in an amount of 0.01 to 100 parts by mass, based on 1 part by mass of the compound of the present invention.
  • the other drug may be a combination of two or more kind of arbitrary drugs in a proper proportion.
  • the other drug that complements and/or enhances the preventive and/or therapeutic efficacy of the compound of the present invention includes not only those that have already been discovered, but those that will be discovered in future, based on the above mechanism.
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • step a commercially available 3- nitropyridin-2-ol is reacted with alkyl halide using conditions such as those described in General procedure #A to afford compound 1 which is further reduced using conditions such as those described in General procedure #B to afford compound 2.
  • the combined organic layers is washed successively with water and brine, dried over sodium sulphate and evaporated to dryness.
  • the crude material is optionally purified by precipitation, crystallization or trituration from an appropriate solvent or solvents or by column chromatography to get the target compound.
  • a suitable boronic acid (2 to 5 equiv preferably 2.5 equiv), copper(II)acetate (1 to 3 equiv preferably 1 equiv) and pyridine( 5 to 12 equiv, preferably 8 equiv).
  • the reaction mixture is heated to reflux a for about 4 to 24 h (preferably 12h). Cooled the reaction mixture to room temperature and quenched with 2N HCl. The product is extracted with ethyl acetate.
  • the combined organic layers are washed with brine, dried over sodium sulphate and evaporated to dryness.
  • the crude material is optionally purified by precipitation, crystallization or trituration from an appropriate solvent or solvents or by column chromatography to get the target compound.
  • a solution of appropriate Nitro derivative (1 equiv) in an protic solvent such as EtOH, MeOH preferably EtOH
  • an protic solvent such as EtOH, MeOH preferably EtOH
  • the reaction is hydrogenated under balloon pressure for 3 to 7h (preferably 4hrs).
  • the reaction mixture is filtered through a Celite ® pad and washed with MeOH.
  • the filtrate is evaporated to dryness under reduced pressure.
  • the crude material is optionally purified by precipitation, crystallization or trituration from an appropriate solvent or solvents or by column chromatography to get the target compound.
  • a sealed tube is charged with an substituted pyrimidine derivative (1 equiv), DIPEA (2 to 5 equivalents preferably 2.5 equivalents), appropriate amine derivative (1 to 3 equivalents preferably 1 equivalents) and IPA.
  • the reaction mixture is heated to 100 °C to 1 10°C (preferably 100°C) for about 4-12h (preferably 6hrs).
  • the reaction mixture is cooled to 0°C, obtained solid is filtered, washed with cold IPA and dried under vacuum. Obtained crude material is optionally purified by precipitation, crystallization or trituration from an appropriate solvent or solvents or by column chromatography to get the target compound.
  • a 50 mL sealed tube was charged with 5-bromo-2,4-dichloropyrimidine ( l g,0.004mol, combi blocks), DIPEA ( 1.7g,0.013 mol, Spectrochem), 3-amino- l -(pentan-3-yl)pyridin-2(lH)-one (0.79g, 0.004mol, B.1.1 ) and IPA(10 mL).
  • the reaction mixture was heated to 100 °C about 12h.
  • the reaction mixture was cooled to 0°C, obtained solid was filtered washed with cold IPA and dried under vacuum.
  • the 5-bronio-2,4-dichloi'opyrimidine ( 1 to 5 equiv, preferably 1.1 equiv) is added and heated to 80 to 100 °C ( preferably 80 °C) for 10 tol 8h ( preferably 16h).
  • the reaction mixture is cooled to 0°C,
  • the reaction mixture is filtered through a Celite ® pad and washed with MeOH .
  • the filtrate is evaporated to dryness under reduced pressure.
  • the residue obtained is re- dissolved in EtOAc, washed successively with water and brine solution.
  • the organic solvent is dried over sodium sulphate and concentrated under reduced pressure.
  • the crude material is optionally purified by precipitation . , crystallization or trituration from an appropriate solvent or solvents or by column chromatography to get the target compound.
  • a sealed tube is charged with a substituted pyrimidine derivative (1 equiv), appropriate amine derivative ( 1 to 3 equiv preferably 1 equiv) , n-BuOH and Cone. HC1.
  • the reaction mixture is heated to 100 °C to 140°C (preferably 120°C) for about 8 to 12hrs (preferably l Ohrs).
  • the reaction mixture is cooled to RT diluted with Ice cold water and basified with saturated sodium bicarbonate solution.
  • the product is extracted with ethyl acetate. Combined organic layers washed successively with water, brine, dried over sodium sulphate and concentrated under reduced pressure.
  • the crude material obtained is optionally purified by precipitation, crystallization or trituration from an appropriate solvent or solvents or by column chromatography, preparative HPLC to get the target compound.
  • a sealed tube is charged with a substituted pyrimidine derivative (1 equiv), appropriate amine derivative (1 to 3 equiv preferably 1 equiv) , n-BuOH and TFA.
  • the reaction mixture is heated to 100 °C to 140°C (preferably 120°C) for about 8 to 12krs (preferably l Ohrs).
  • the reaction mixture is cooled to RT diluted with Ice cold water and basified with saturated sodium bicarbonate solution.
  • the product is extracted with ethyl acetate. Combined organic layers washed successively with water, brine, dried over sodium sulphate and concentrated under reduced pressure.
  • the crude material obtained is optionally purified by precipitation, crystallization or trituration from an appropriate solvent or solvents or by column chromatography, preparative HPLC to get the target compound
  • Step #.1 tert-butyl ((2-hydroxypyridin-3-yl)methyi)carbamate
  • Step#2 tert-butyl ((l-benzyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamate
  • Step #1 Preparation of l-(2-(methyIthio)ethyl)-2-oxo-l,2-dihydropyridine-3-carbonitrile
  • an appropriate sulphide derivative in an protic solvent such as EtOH, MeOH, water preferably mixture of MeOH, water
  • an appropriate oxidizing agent such as mCPBA, Oxone, H O2 preferably oxone 2 to 5 equiv preferably 2.5 equiv
  • the reaction mixture is allowed to stirred at room temperature for about 0.5 to lhr (preferably 0.5hrs).
  • Excess solvent is removed under reduced pressure and the crude material is basified with sat,NaHC0 3 solution.
  • the product extracted with ethyl acetate.
  • the combined organic layers dried over sodium sulphate and evaporate to dryness.
  • the crude material is optionally purified by precipitation, crystallization or trituration from an appropriate solvent or solvents or by column chromatography to get the target compound.
  • Step 2 l-(2-(methyIsalfonyl)ethyl)-2-oxo-l,2-dihydropyridine-3-carbonitrile
  • Step #3 Preparation of 3-(aminometh l)-l-(2-(methyIsulfonyl)ethyl)pyndin-2(lH)-one
  • N-(3 -(aminomethyl)- 1 -methyl-6-oxo- 1 ,6-dihydropyridin-2-y l)-N-methylmethanesulfonamide hydrochloride was synthesized using Scheme IV starting from 2-chloro-l -methyl-6-oxo- l ,6- dihydropyridine-3-carboxylic acid
  • Step #1 2-chloro-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxamide
  • Oxalyl chloride (5.7g, 0.045mol. Spectrochem) was added drop wise to a cold solution of 2- chloro- l -methyl-6-oxo-l ,6-dihydropyridine-3-carboxylic acid (2.8g, 0.015mol, US2008004551 1) in DCM (50ml) and DMF (0.1 ml). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for about 2h. The reaction mixture was concentrated under vacuum. The crude material was dissolved in DCM (50ml) and added to cold solution of ammonium solution (50ml). The reaction mixture was stirred for 10- I 5min. The biphasic layer was separated and aqueous was extracted with DCM (2x50ml).
  • Step #2 2-chloro-l-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile
  • Step#4 tert-butyl ((l-methyI-2-(N-methylmethylsulfonamido)-6-oxo-l,6-dihydropyridin-3- yl)methyl)carbamate:
  • Step#5 N-(3-(aminomethyl)-l-methyl-6-oxo-l,6-dihydropyridin-2-yl)-N-methyImethane sulfonamide:
  • Step #1 ethyl 2-chloro-4-((l-isopropyI-2-oxo-l,2-dihydropyridin-3-yl)amino)pynmidine- 5-carboxylate
  • Step #3 2-chloro-4-((l-isopropyl-2-oxo-l,2-dihydropyridin-3-yI)amino)pyrimidine-5- carboxamide
  • Oxalyl chloride (0.66g, 0.005mol proposition Spectrochem) was added drop wise to a cold solution of 2- chloro-4-((l -isopropyl-2-oxo- l ,2-dihydropyridin-3-yl)amino)pyrimidine-5-carboxylic acid (0.8g, 0.002rnol, preparation #4,Step-2) in DCM ( 10ml) and DMF (0.1 ml). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for about 2h. The reaction mixture was concentrated under vacuum. The crude material was dissolved in DCM (50ml) and added to cold solution of ammonium solution ( 15ml). The reaction mixture was stirred for 15- 30min.
  • Step #1 4-((5-bromo-4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)amino) pynmidin-2- y])amino)benzoic acid:
  • Step #2 3-((5-bromo-2-((4-(4-methylpiperazine-l-carbonyl)phenyI)amino) pyrimidin-4-yI) amino)-l-methylpyridin-2(lH)-one:
  • the reaction mixture was stirred at room temperature for 16h and was quenched with ice cold water (10 mL).
  • the product was extracted with DCM (3 x 20 mL).
  • the combined organic layers were dried over sodium sulphate and evaporated to dryness under vacuum.
  • the residue obtained was purified by silica gel column chromatography by eluting with 40-60% EtOAc in hexane.
  • N-(piperidin-4-yl)acetamide (I g, 7.04 mmol, Alfa-aesar) in DMF was added K2CO3 ( 1 .6 g, 14.18 mmol, Rankem) followed by l-fluoro-4-nitrobenzene (1 g, 7.04 mmol, AVRA) at 0 °C.
  • K2CO3 1 .6 g, 14.18 mmol, Rankem
  • l-fluoro-4-nitrobenzene (1 g, 7.04 mmol, AVRA
  • Example D.1.81 Individual enantiomers of Example D.1.81 are separated using Chiral preparative HPLC (Method Table-E)
  • TR-FRET assay The enzymatic assay was standardized using recombinant human JA 2 enzyme (Cat# 14-640) from Millipore using Ultra Light Poly GT (Cat# TRF OI OOD) from Perkin Elmer as a substrate. TR-FRET (Time resolved fluorescence resonance energy transfer) detection technology was used for the read out.
  • the final assay conditions were 2.5 ng JAK2 , 10 nM U- light pGT peptide substrate, 10 ⁇ ATP (Km cone), 1 nM Eu-Ab,W1024 (Cat# AD0203, Perkin Elmer) , 50mM Tris pH 7.5, 20 mM MgCl 2 , I mM EGTA, 2mM DTT, 0.01 % Tween, 1 % DMSO (20 ⁇ rxn volume: 30 min pre-incubation of enzyme with compound, 1 hr reaction time with substrate ) in 384 well format.
  • the TR-FRET signal (Excitation at 340 nm, Emission at 615 m and 665 run) was read with 50 xs delay time on Victor 3 V fluorimeter. The data is calculated using the ratio of reading at 665 nm to 615 nm. The final concentration of DMSO was 1 % in the assay. Each individual IC50 was determined using 10 point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using non-linear regression curve fit for sigmoidal dose response (variable slope).
  • FAK TR-FRET assay The enzymatic assay was standardized using recombinant human FAK enzyme (Cat# 14-720) from Millipore using Ultra Light Poly GT (Cat# TRF O I OOD) from Perkin Elmer as a substrate. TR-FRET (Time resolved fluorescence resonance energy transfer) detection technology was used for the read out.
  • the final assay conditions were 5 ng FAK , 40 nM U-Iight pGT peptide substrate, 15 ⁇ ATP (Km cone), 1 nM Eu-Ab,W1024 (Cat# AD0203, Perkin Elmer) , 50mM Tris pH 7.5, 20 mM MgCl 2 , I mM EGTA, 2mM DTT, 0.01 % Tween, 1 % DMSO (20 ⁇ rxn volume: 30 min pre-incubation of enzyme with compound, 1 hr reaction time with substrate ) in 384 well format.
  • the TR-FRET signal (Excitation at 340 nm.
  • Emission at 615 nm and 665 nm was read with 50 ⁇ & delay time on Victor 3 V fluorimeter. The data is calculated using the ratio of reading at 665 nm to 615 nm. The final concentration of DMSO was 1 % in the assay. Each individual IC50 was determined using 10 point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using non- linear regression curve fit for sigmoidal dose response (variable slope).
  • pStat3 ICW protocol in A549 cells was determined using 10 point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using non- linear regression curve fit for sigmoidal dose response (variable slope).
  • A549 cells are seeded at a density of 20,000 cells/well in a 96 well flat bottom plate. After 6 hours cells are serum starved and incubated overnight at 37°C/5% COi . The dilutions of the compound to be tested are done in DMSO. ⁇ ⁇ , of diluted compound is added to the cells. Final DMSO concentration less than 0.5%. The cells with compound are incubated for 3h at 37°C/5% COo. Cells are stimulated with 25ng/ml IL6 for 20 minutes. The cells are fixed with 100 ⁇ /well of methanol. Then, cells are washed with 3 ⁇ 100 ⁇ 1 of IX PBST.
  • Cells are incubated with blocking buffer, 5%BSA in I X PBST for l h at room temperature on plate shaker.
  • the primary antibody pStat3 is diluted ( 1 : 100) in the blocking buffer. 50 ⁇ 1 of the primary antibody is added to each wells and incubated at 4°C overnight on a rocking plate. The cells are washed with 3x 100 ⁇ I X wash buffer.
  • the Europium labeled rabbit secondary antibody is diluted ( 1 :2000) in the assay buffer (Delfia Assay Buffer). 50 ⁇ 1 of the secondary antibody is added to all wells of the plate. The plate is incubated at room temperature on plate shaker for 2h. The cells are washed with 3 100 ⁇ I X wash buffer.
  • 4T1 cells are seeded at a density of 10000 cells/well in in a 96 well flat bottom plate. Cells are incubated at 37°C/5% COi overnight. The dilutions of the compound to be tested and the standard compound are done in ⁇ 8 ⁇ 10 ⁇ of diluted compound is added to the cells. Final DMSO concentration less than 0.5%. The cells with compound are incubated for 3h at 37°C/5% C0 2 . The cells are fixed with 100 ⁇ /well of 4% paraformaldehyde in PBS and incubated for 60 min at room temperature. The cells are washed with 3 ⁇ 100 ⁇ 1 of I X PBST.
  • Cells are incubated with blocking buffer, 5%BSA in IX PBST for l h at room temperature on plate shaker.
  • the primary antibody pFAK is diluted (1 : 100) in the blocking of the primary antibody is added to each wells and incubated at 4°C overnight on a rocking plate.
  • the cells are washed with 3x100 ⁇ IX wash buffer (Delfia/Autodelfia wash concentrate).
  • the Europium labeled rabbit secondary antibody is diluted (1 :2000) in the assay buffer (Delfia Assay Buffer). 50 ⁇ 1 of the secondary antibody is added to all wells of the plate.
  • the plate is incubated at room temperature on plate shaker for 2h.
  • the cells are washed with 3x100 ⁇ I X wash buffer.
  • Table D cell free assay and cell based assay data for the examples described above

Abstract

La présente invention concerne de nouveaux dérivés de pyrimidine-2,4-diamine en tant que dérivés inhibiteurs de kinase de dérivés de formule (I), en tant qu'inhibiteurs de protéine kinase. Formule (I). L'invention concerne en particulier des composés de formule (I), la préparation des composés et des compositions pharmaceutiques de ceux-ci. L'invention concerne en outre des promédicaments, des dérivés, des polymorphes, des sels pharmaceutiquement et des compositions comprenant lesdits nouveaux dérivés de pyrimidine-2,4-diamine en tant qu'inhibiteurs de kinase et leurs dérivés et leur utilisation dans le traitement de différents troubles.
PCT/IB2012/002645 2012-12-11 2012-12-11 Dérivés de pyrimidine-2,4-diamine en tant qu'inhibiteurs de kinase WO2014091265A1 (fr)

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WO2017146236A1 (fr) 2016-02-26 2017-08-31 小野薬品工業株式会社 Médicament pour le traitement du cancer caractérisé par l'administration d'une association d'un inhibiteur de l'axl et d'un inhibiteur de point de contrôle immunitaire
WO2019039525A1 (fr) 2017-08-23 2019-02-28 小野薬品工業株式会社 Produit pharmaceutique destiné au traitement du cancer comprenant un inhibiteur d'axl en tant que principe actif
WO2019074116A1 (fr) 2017-10-13 2019-04-18 小野薬品工業株式会社 Agent thérapeutique pour cancers solides, qui contient un inhibiteur d'axl en tant que principe actif
CN111072571A (zh) * 2018-10-18 2020-04-28 北京西博医药研究有限公司 作为fak抑制剂的氨基二硫代甲酸酯类化合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017146236A1 (fr) 2016-02-26 2017-08-31 小野薬品工業株式会社 Médicament pour le traitement du cancer caractérisé par l'administration d'une association d'un inhibiteur de l'axl et d'un inhibiteur de point de contrôle immunitaire
WO2019039525A1 (fr) 2017-08-23 2019-02-28 小野薬品工業株式会社 Produit pharmaceutique destiné au traitement du cancer comprenant un inhibiteur d'axl en tant que principe actif
WO2019074116A1 (fr) 2017-10-13 2019-04-18 小野薬品工業株式会社 Agent thérapeutique pour cancers solides, qui contient un inhibiteur d'axl en tant que principe actif
CN111072571A (zh) * 2018-10-18 2020-04-28 北京西博医药研究有限公司 作为fak抑制剂的氨基二硫代甲酸酯类化合物
CN111072571B (zh) * 2018-10-18 2021-05-14 北京西博医药研究有限公司 作为fak抑制剂的氨基二硫代甲酸酯类化合物

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