WO2019006548A1 - Composés de 2,4-diaminopyrimidine fluorés utilisés en tant qu'inhibiteurs de la tyrosine kinase mer (mertk) et leurs utilisations - Google Patents

Composés de 2,4-diaminopyrimidine fluorés utilisés en tant qu'inhibiteurs de la tyrosine kinase mer (mertk) et leurs utilisations Download PDF

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WO2019006548A1
WO2019006548A1 PCT/CA2018/050815 CA2018050815W WO2019006548A1 WO 2019006548 A1 WO2019006548 A1 WO 2019006548A1 CA 2018050815 W CA2018050815 W CA 2018050815W WO 2019006548 A1 WO2019006548 A1 WO 2019006548A1
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compound
6alkyl
cancer
compounds
mertk
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Abdelmalik Slassi
Peter Dove
David Alexander ROSA
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Trillium Therapeutics Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present application relates to fluorinated 2,4- diaminopyrimidine compounds, to processes for their preparation, to compositions comprising them, and to their use in therapy. More particularly, it relates to compounds useful in the treatment of diseases, disorders or conditions treatable by inhibition of the C-MER proto-oncogene tyrosine kinase (MERTK) receptor, such as in the treatment or prevention of a number of different cancers.
  • MERTK C-MER proto-oncogene tyrosine kinase
  • RTKs Receptor tyrosine kinases
  • TYR03, AXL and MER comprise the TAM family of RTKs.
  • the TAM family share many structural features, including two extracellular immunoglobulin (Ig)-like domains as well as two fibronectin type
  • phosphatidylserine PtdSer
  • GAS6 growth arrest-specific protein 6
  • PROS1 vitamin K-dependent protein S
  • Phosphatidylserine bound GAS6 and PROS1 exhibit differential affinity for members of the TAM family, with GAS6 binding to all three members while
  • PROS1 interacts with TYR03 and MER.
  • members of the TAM family of RTKs share a highly conserved kinase domain typified by the presence of a unique KWIAIES sequence.
  • the kinase domain located on the intracellular leaf of the plasma membrane, is responsible for transducing extracellular signals within the cell through the activation and recruitment of various intracellular effector proteins, such as RAF, PI3K, and N FKB.
  • TAM RTKs A diverse array of cellular functions are mediated by TAM RTKs.
  • MER is implicated in the efferocytosis of apoptotic cells by macrophages and dendritic cells.
  • MER and AXL also play key roles in the innate immune system and the dampening of autoimmune reactions.
  • murine AXL and MER knockouts exhibit difficulties in clearing apoptotic cells and a propensity towards the production of autoantibodies.
  • MER, AXL, and TYR03 triple knockout mice suffer severe autoimmune reactions.
  • the TAM family of RTKs have also been associated with angiogenesis, controlling both blood vessel integrity as well as permeability and platelet aggregation.
  • the TAMs employ a variety of signal transduction pathways, such as RAF, PI3K, and N FKB, which are often implicated in oncogenesis and tumor progression.
  • TAM receptor signaling can be associated with three hallmark characteristics of cancerous cells: tissue invasion, sustained angiogenesis and evasion of apoptosis.
  • TAM gene mutation or amplification has not been observed in cancerous cells, rather, increased transcription stimulated by the tumor microenvironment is responsible for TAM overexpression.
  • Multiple malignancies of epithelial and hematological origin exhibit increased expression of AXL, and to a lesser extent MER, which portends a poor prognosis.
  • AXL and MER coincide with the development of drug resistance to conventional chemotherapies. This is unsurprising since AXL is associated with epithelial to mesenchymal transition (EMT), a common characteristic of metastatic tumors and mechanism of drug resistance.
  • EMT epithelial to mesenchymal transition
  • the kinase domain of the TAM family has a variety of conformations that affect its function. Activation of the kinase domain is dictated by the phosphorylation status of the DFG-containing activation loop. When the activation loop is not phosphorylated, otherwise known as "DFG-out", the kinase is in an inactive state. Once phosphorylated, "DFG-in”, the kinase domain is opened up to allow the phosphorylation of various effector proteins. As a corollary, a small molecule inhibitor's ability to bind the kinase domain is dependent on the kinase's activations status.
  • Type I inhibitors compete with adenosine triphosphate (ATP) for occupancy of the kinase domain in the active (DFG-in) conformation.
  • ATP adenosine triphosphate
  • Type II inhibitors benefit from accessing an allosteric pocket in the DFG-out conformation, allowing for further increases in specificity as the allosteric pocket is less conserved among kinases. Although crucial for target selectivity, accessibility to the allosteric pocket is complicated by the presence of bulky "gatekeeper" residues in certain kinases.
  • TAM RTKs have garnered a significant amount of attention as a therapeutic target.
  • Many therapeutic modalities have been described, such as soluble decoy receptors (i.e. AXL decoy receptor MYD1 -72), MER and AXL specific antibodies and small molecule inhibitors of the TAM tyrosine kinase domain (e.g. R428, MRX- 6313 and MRX-2843). While soluble decoy receptors and neutralizing antibodies primarily exert their effects on the extracellular leaf of the plasma membrane, small molecule inhibitors, such as those described above, rely on intracellular kinase domain blockade to obstruct receptor function.
  • TAM receptors In normal adult tissues, TAM receptors have widespread expression patterns, being expressed in the brain (hippocampus, cerebellum), heart, and liver as well as in monocytes, platelets, and endothelial cells. Their physiological function resides mostly in the regulation of inflammation and elimination of debris via phagocytosis. Overall, MER is more specifically expressed by cells from the hematopoietic lineage (monocytes, macrophages, dendritic cells, natural killer cells, platelets) while AXL expression pattern is more constrained to epithelial tissues [Nat Rev Cancer. 2014, 14(12):769-85].
  • TAM RTK function is the role of MERTK in efferocytosis, the process by which apoptotic material is cleared by both monocyte-derived and epithelial cells.
  • the key role of MERTK in macrophage efferocytosis was discovered using Mertk-/- mice [Nature 41 1 , 207-21 1 (2001 )].
  • An epithelial role for MERTK was uncovered in genetic studies of retinitis pigmentosa in rats, which identified the MERTK mutation as causative. Without MERTK, the pigmented epithelial cells lining the retina cannot efficiently ingest the apoptotic material that is shed nightly by rods and cones, which leads to inflammation and scarring.
  • MERTK-/- mice also show retinal degeneration, and these rodent models are being used to test intraocular MERTK gene therapy, as rare human families carrying MERTK-inactivating mutations have variable age penetrance for retinitis.
  • Other specialized epithelial cells also rely on MERTK-dependent efferocytosis to clear damaged material, including mammary epithelial cells during weaning-induced involution, podocytes in the renal glomerulus (which induce MERTK following nephrotoxic injury) and Sertoli cells in the testes.
  • neurite endings that do not form productive synapses are cleared by MERTK-dependent microglial pruning [Nat Rev Cancer. 2014, 14(12):769-85; Blood. 1994, 84(6): 1931 -41 ].
  • MER/AXL mediated resistance to standard forms of cancer therapy have been documented in neuroblastoma, melanoma, NSCLC, HNSCC, renal cell carcinoma, CML, GIST, glioblastoma (GBM), B-ALL, T-ALL and cancers of the breast, colon, ovaries and esophagus [Curr Oncol Rep 2017 19: 19].
  • GBM glioblastoma
  • B-ALL glioblastoma
  • T-ALL cancers of the breast, colon, ovaries and esophagus
  • MER/AXL inhibition has also been shown to overcome acquired resistance to immune checkpoint therapies [Abstract LB-218: development of Axl/Mer inhibitor, ONO-9330547: preclinical evidence supporting the combination with immunotherapeutics. Cancer Res. 2016]. These findings suggest that MERTK is a novel therapeutic target for the re- sensitization of treatment refractory cancers.
  • MRX-6313 also known as UNC2025
  • MERTK inhibitor Zahang, W., et al. J. Med. Chem. 2014, 57, 7031 - 7041 ).
  • the compound MRX-2843 has been reported as a type 1 small- molecule tyrosine kinase inhibitor that abrogates activation of both MERTK and FMS-like tyrosine kinase 3 (FLT3) and their downstream effectors (Minson K.A., et al. JCI Insight, 2016; 1 (3):e85630).
  • Fluorine substitution has been investigated in drug research as a means of enhancing biological activity and/or increasing chemical and/or metabolic stability.
  • Factors to be considered when synthesising fluorine- containing compounds include (a) the relatively small size of the fluorine atom (van der Waals radius of 1 .47 A), comparable to hydrogen (van der Waals radius of 1 .20 A), (b) the highly electron-withdrawing nature of fluorine, (c) the greater stability of the C-F bond compared to the C-H bond and (d) the greater lipophilicity of fluorine compared to hydrogen.
  • fluorine is slightly larger than hydrogen
  • several studies have demonstrated that it is a reasonable hydrogen mimic and is expected to cause minimal steric perturbations with respect to the compound's mode of binding to a receptor or enzyme [Annu. Rev. Pharmacol. Toxicol. 2001 , 41, 443-470].
  • the introduction of a fluorine atom can significantly alter the physicochemical properties of the compound due to its high electronegativity. Therefore this type of modification can induce altered and unpredictable biological responses of the molecule.
  • the present application includes a compound of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • R 1 is selected from Ci-6alkyl, Ci-6alkylene-0-Ci-6alkyl, C3-iocycloalkyl, C3- loheterocycloalkyl, C6-ioaryl and Cs-ioheteroaryl;
  • Z is selected from a direct bond, NH-NH and NH;
  • Z' is selected from a direct bond, O, S, SO2, C(O), C(S), NR 7 , C(0)0, C(0)N(R 7 ), C(S)0, C(S)N(R 7 ), OC(O), N(R 7 )C(0), OC(S) and N(R 7 )C(S); R 3 is selectred from H and CH3,
  • Q is selected from C(O) and C(S), or
  • Q and R 3 are joined to form an alkylene or alkenylene bridge that together with the atoms therebetween, result in 5 or 6 membered saturated or unsaturated ring;
  • R 4 is selected from Ci-6alkyl, C3-iocycloalkyl, and C3-ioheterocycloalkyl each of which is optionally substituted with one or two OH;
  • R 5 and R 6 are independently selected from H and Ci-6alkyl, or R 5 and R 6 are joined to form, together with the atoms therebetween, a 5 or 6 membered saturuted or unsaturated ring, optionally containing one additional heteroatom selected from NR 8 , O and S;
  • R 7 is selected from H and Ci-6alkyl
  • R 8 is selected from H, Ci-6alkyl and Ci-6alkylene-0-Ci-6alkyl;
  • R 1 and R 2 comprises a CFH2, CF2H or CF3 group.
  • the compound of Formula I is selected from a compound of Formula l-A and l-B, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  • R 1 , R 2 , R 3 and R 4 are as defined in Formula I above.
  • the present application also includes a composition comprising one or more compounds of the application and a carrier.
  • the composition is a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.
  • the compounds of the application have been shown to be capable of inhibiting MERTK protein function. Therefore the compounds of the application are useful for treating diseases, disorders or conditions treatable by inhibition of MERTK. Accordingly, the present application also includes a method of treating a disease, disorder or condition treatable by inhibition of MERTK, comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the compounds of the application are used as medicaments. Accordingly, the application also includes a compound of the application for use as a medicament.
  • the present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition treatable by inhibition of MERTK as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition treatable by inhibition of MERTK.
  • the application further includes one or more compounds of the application for use in treating a disease, disorder or condition treatable by inhibition of MERTK.
  • the compounds of the application are useful for treating diseases, disorders or conditions mediated by MERTK inhibition. Accordingly, the present application also includes a method of treating a disease, disorder or condition mediated by MERTK protein inhibition, comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition mediated by MERTK protein inhibition as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition mediated by MERTK protein inhibition.
  • the application further includes one or more compounds of the application for use in treating a disease, disorder or condition mediated by MERTK protein inhibition.
  • the disease, disorder or condition mediated by MERTK protein inhibition, or treatable by inhibition of MERTK is a neoplastic disorder.
  • the treatment comprises administration or use of an amount of one or compounds of the application that is effective to ameliorate at least one symptom of the neoplastic disorder, for example, reduced cell proliferation or reduced tumor mass in a subject in need of such treatment.
  • the disease, disorder or condition mediated by MER protein inhibition, or treatable by inhibition of MERTK is cancer.
  • the disease, disorder or condition mediated by MERTK protein inhibition, or treatable by inhibition of MERTK is a disease, disorder or condition associated with an uncontrolled and/or abnormal cellular activity affected directly or indirectly by MERTK.
  • the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by MERTK is proliferative activity in a cell.
  • the application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds of the application to the cell.
  • the disease, disorder or condition mediated by MERTK protein inhibition, or treatable by inhibition of MERTK is cancer and the one or more compounds of the application are administered in combination with one or more additional cancer treatments.
  • the additional cancer treatment is selected from radiotherapy, chemotherapy, targeted therapies such as antibody therapies and small molecule therapies such as other tyrosine-kinase inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies.
  • the compound(s) of the application may also exhibit advantageous physical properties (for example higher permeability, enhanced CNS penetration and/or lower plasma protein binding) and/or favourable toxicity profiles (for example a decreased affinity for other TK proteins) and/or favourable metabolic profiles in comparison with other known MERTK inhibitors. Therefore, such compound(s) may be especially useful in the treatment of disease states in which MERTK and/or resistance mutations of MERTK are implicated, for example in the treatment of cancer.
  • Figure 1 shows the results from the maximum tolerated dose study in mice (Example 19) which compares MRX-2843 and exemplary compound I-87.
  • compound of the application or “compound of the present application” and the like as used herein refers to a compound of Formula I, and pharmaceutically acceptable salts, solvates and/or prodrugs thereof.
  • composition of the application or “composition of the present application” and the like as used herein refers to a composition comprising one or more compounds the application and at least one additional ingredient.
  • the second component as used herein is chemically different from the other components or first component.
  • a “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.
  • suitable means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the species to be transformed, but the selection would be well within the skill of a person trained in the art. All method steps described herein are to be conducted under conditions sufficient to provide the desired product. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.
  • the compounds described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.
  • the compounds of the present application may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form are included within the scope of the present application.
  • the compounds of the present application may further exist in varying polymorphic forms and it is contemplated that any polymorphs which form are included within the scope of the present application.
  • alkyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix "Cn-iV.
  • Ci-6alkyl means an alkyl group having 1 , 2, 3, 4, 5 or 6 carbon atoms. All alkyl groups are optionally fluorosubstituted unless otherwise stated.
  • alkenyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond.
  • the number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix "Cni-n2".
  • C2-6alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkynyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkynyl groups containing at least one triple bond.
  • the number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix "Cni-n2".
  • C2-6alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkylene as used herein, whether it is used alone or as part of another group, means a straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends.
  • the number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix "Cn-iV.
  • Ci-6alkylene means an alkylene group having 1 , 2, 3, 4, 5 or 6 carbon atoms. All alkylene groups are optionally fluorosubstituted unless otherwise stated.
  • cycloalkyl as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing one or more rings.
  • the number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix "C ni-n2".
  • C3-iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • aryl refers to carbocyclic groups containing at least one aromatic ring.
  • the aryl group contains from 6, 9 or 10 carbon atoms, such as phenyl, indanyl or naphthyl.
  • heterocycloalkyl refers to cyclic groups containing at least one non-aromatic ring in which one or more of the atoms are a heteroatom selected from O, S and N. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds). When a heterocycloalkyl group contains the prefix Cni-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above.
  • heteroaryl refers to cyclic groups containing at least one heteroaromatic ring in which one or more of the atoms are a heteroatom selected from O, S and N.
  • a heteroaryl group contains the prefix Cni-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above.
  • All cyclic groups including aryl and cyclo a groups, contain one or more than one ring (i.e. are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused or linked by a bond.
  • a first ring being "fused" with a second ring means the first ring and the second ring share two adjacent atoms there between.
  • a first ring being "bridged" with a second ring means the first ring and the second ring share two non-adjacent atoms there between.
  • a first ring being "spirofused" with a second ring means the first ring and the second ring share one atom there between.
  • halo refers to a halogen atom and includes fluoro, chloro, bromo and iodo.
  • fluorosubstituted refers to the substitution of one or more, including all, hydrogens in a referenced group with fluorine.
  • protecting group refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule.
  • PG protecting group
  • the selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in "Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W.
  • cell refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.
  • subject as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus the methods and uses of the present application are applicable to both human therapy and veterinary applications.
  • pharmaceutically acceptable means compatible with the treatment of subjects, for example humans.
  • pharmaceutically acceptable carrier means a nontoxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.
  • pharmaceutically acceptable salt means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.
  • An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.
  • Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids.
  • organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2- hydroxyethanesulfonic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.
  • acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, orfor subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • a base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.
  • Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, EGFRaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, polyamine resins, and the like.
  • organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • the selection of the appropriate salt may be useful so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.
  • solvate means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate”.
  • inert organic solvent refers to a solvent that is generally considered as non-reactive with the functional groups that are present in the compounds to be combined together in any given reaction so that it does not interfere with or inhibit the desired synthetic transformation.
  • Organic solvents are typically non-polar and dissolve compounds that are non soluble in aqueous solutions.
  • treating means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable.
  • Treating and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Treating” and “treatment” as used herein also include prophylactic treatment.
  • a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence.
  • Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations.
  • the compounds of the application may be administered at least once a week.
  • the compounds may be administered to the subject from about one time per three weeks, or about one time per week to about once daily for a given treatment.
  • the compounds are administered 2, 3, 4, 5 or 6 times daily.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and/or the activity of the compounds of the application, and/or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the patient.
  • “Palliating" a disease or disorder means that the extent and/or undesirable clinical manifestations of a disorder or a disease state are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.
  • prevention or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder or condition mediated by MERTK protein inhibition or treatable by inhibition of MERTK, or manifesting a symptom associated with a disease, disorder or condition mediated by MERTK protein inhibition or treatable by inhibition of MERTK.
  • the "disease, disorder or condition mediated by MERTK” as used herein refers to a disease, disorder or condition treatable by inhibition of MERTK activity and particularly using an MERTK inhibitor, such as a compound of the application herein described.
  • MERTK mediated by MERTK
  • the disease, disorder or condition to be treated is affected by, modulated by and/or has some biological basis, either direct or indirect, that includes aberrant MERTK activity, in particular, increased MERTK activity or, also, decreased MERTK activity such as results from mutation or splice variation and the like.
  • aberrant MERTK activity in particular, increased MERTK activity or, also, decreased MERTK activity such as results from mutation or splice variation and the like.
  • an effective amount means an amount of a compound, or one or more compounds, of the application that is effective, at dosages and for periods of time necessary to achieve the desired result.
  • an effective amount is an amount that, for example, increases MERTK protein inhibition, or inhibits MERTK activity, compared to the inhibition without administration of the one or more compounds. Effective amounts may vary according to factors such as the disease state, age, sex and/or weight of the subject.
  • the amount of a given compound that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • the effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom.
  • amounts that are effective can cause a reduction in the number, growth rate, size and/or distribution of tumours.
  • the term “administered” as used herein means administration of a therapeutically effective amount of a compound, or one or more compounds, or a composition of the application to a cell either in cell culture or in a subject.
  • neoplastic disorder refers to a disease, disorder or condition characterized by cells that have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth.
  • neoplasm refers to a mass of tissue resulting from the abnormal growth and/or division of cells in a subject having a neoplastic disorder.
  • Neoplasms can be benign (such as uterine fibroids and melanocytic nevi), potentially malignant (such as carcinoma in situ) or malignant (i.e. cancer).
  • exemplary neoplastic disorders include but are not limited to carcinoma, sarcoma, metastatic disorders (e.g., tumors arising from the prostate), hematopoietic neoplastic disorders, (e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders), metastatic tumors and other cancers.
  • Prevalent cancers include breast, prostate, colon, lung, liver, brain, ovarian and pancreatic cancers.
  • cancer refers to cellular-proliferative disease states, including but not limited to: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS- Related Lymphoma; AI DS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant
  • Compounds of the present application were prepared and were found to inhibit uncontrolled and/or abnormal cellular activities affected directly or indirectly by inhibition of the MERTK protein.
  • compounds of the present application exhibited activity as MERTK inhibitors, and are therefore useful in therapy, for example for the treatment of neoplastic disorders such as cancer.
  • the present application includes a compound of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • R 1 is selected from Ci-6alkyl, Ci-6alkylene-0-Ci-6alkyl, C3-iocycloalkyl, C3- -loheterocycloalkyl, C6-ioaryl and Cs-ioheteroaryl;
  • Z is selected from a direct bond, NH-NH and NH;
  • Z' is selected from a direct bond, O, S, SO2, C(O), C(S), NR 7 , C(0)0, C(0)N(R 7 ), C(S)0, C(S)N(R 7 ), OC(O), N(R 7 )C(0), OC(S) and N(R 7 )C(S);
  • R 3 is selectred from H and CH3,
  • Q is selected from C(O) and C(S), or
  • Q and R 3 are joined to form an alkylene or alkenylene bridge that together with the atoms therebetween, result in 5 or 6 membered saturated or unsaturated ring;
  • R 4 is selected from Ci-6alkyl, C3-iocycloalkyl and C3-ioheterocycloalkyl, each of which is optionally substituted with one or two OH;
  • R 5 and R 6 are independently selected from H and Ci-6alkyl, or R 5 and R 6 are joined to form, together with the atoms therebetween, a 5 or 6 membered saturuted or unsaturated ring, optionally containing one additional heteroatom selected from NR 8 , O and S;
  • R 7 is selected from H and Ci-6alkyl
  • R 8 is selected from H, Ci-6alkyl and Ci-6alkylene-0-Ci-6alkyl;
  • R 1 and R 2 comprises a CFH2, CF2H or CF3 group.
  • R 1 is selected from Ci-6alkyl, Ci-6alkylene- 0-Ci-6alkyl, Ci-6alkyleneC3-6cycloalkyl and C6-ioaryl, each of which is optionally
  • R 1 is selected from :
  • Ci -4 alkyl, Ci- 4 alkyleneC3-6cycloalkyl and fluoro-substituted phenyl wherein R a , R b , R c and R d are independently selected from H and CH3 and R e , R f and R g are independently selected from H and F.
  • R 1 is wherein one of R a , R b , R c and R d is CH3 and the others are all H and at least one of R e , R f and R g is F.
  • R 1 is
  • R 1 is or In some embodiments R 1 in some
  • R 1 is
  • Z is selected from a direct bond and NH.
  • Z' is selected from a direct bond, O, S, SO2, C(O), NR 7 , C(0)0, C(0)N(R 7 ), OC(O) and N(R 7 )C(0).
  • R 2 is _ wherein Cy 1 is selected from Cs-
  • X 1 is selected from O, S, NH, NCH3 and
  • Cy 1 is selected from thiophenyl, furanyl, pyridinyl and phenyl. i (CH 2 )o-i
  • Z is selected from NH and a direct bond and R 2 is selected from Ci-6alkyleneOCi-6alkyl, Ci-6alkyleneOCi-6fluoroalkyl, Ci-6alkyl and Ci-6fluoroalkyl.
  • Z is a direct bond and R 2 is selected from C2-6alkenyl and C2-6alkynyl both of which are optionally substituted by 1 -3 F or 1 substituent selected from NH2 and N(Ci-6alkyl)2.
  • Z is NH or a direct bond and R 2 is or
  • Z is NH or a direct bond and R 2 is or comprises a group that is substituted with e embodiments, R 2 is or comprises
  • Q is C(O).
  • Q and R 3 are joined to form an alkenylene bridge that together with the atoms therebetween, result in 5 membered unsaturated ring.
  • R 4 is selected from C3-6cycloalkyl, C3- 6heterocycloalkyl and Ci- 4 alkyl each of which is optionally substituted with one OH. In some embodiments, R 4 is C5-6cycloalkyl substituted with one OH. In some embodiments R 4 is 3 ⁇ 4 ⁇ — / -OH . In some embodiments R 4 is
  • R 4 is - ⁇ -( ⁇ — ' ) " OH
  • R 4 is unsubstituted C5-6heterocycloalkyl.
  • 4 is tetrahydrofuranyl or tetrahydropyranyl.
  • R 4 is
  • R 5 and R 6 are independently selected from H and Ci-4alkyl. In some embodiments, R 5 and R 6 are joined to form, together with the atoms therebetween, a 5 or 6 membered saturuted or unsaturated ring, optionally containing one additional heteroatom selected from NR 8 , O and S, wherein R 8 is selected from H, Ci-6alkyl and Ci-6alkylene-0-Ci- 6alkyl, wherein each alkyl and alkylene group is optionally fluorosubstituted. In
  • R 8 is R R N R RJ , wherein one of R h , R', R j and R k is CH3 and the others are all H and at least one of R', R m and R n is F.
  • R k are both H and at least two of R 1 , R m and R n is F.
  • R 8 is or .
  • R 8 is . in
  • R 8 is
  • R 7 is selected from H and Ci- 4 alkyl
  • At least one of R 1 and R 2 comprises a CF2H or CF3 group. In some embodiments, at least one of R 1 and R 2 comprises a CH2CH2CFH2, CH2CH2CF2H, CH2CH2CF3, CH(CH 3 )CH 2 CFH2, CH(CH3)CH 2 CF 2 H, or CH(CH 3 )CH 2 CF3 group.
  • the compound of Formula I is selected from a compound of Formula 1-1 A and l-B, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • the compound of the present application is selected from the compounds listed below, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • the compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.
  • the compounds of the application may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • a compound of the application may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. Administration can be by means of a pump for periodic or continuous delivery.
  • Parenteral administration includes intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration.
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • a compound of the application may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like.
  • carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid.
  • Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. , lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. , lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g
  • Oral dosage forms also include modified release, for example immediate release and timed- release, formulations.
  • modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time- release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet.
  • Timed-release compositions can be formulated, e.g.
  • Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • useful carriers or diluents include lactose and dried corn starch.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use.
  • aqueous suspensions and/or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and/or suspending agents.
  • certain sweetening and/or flavoring and/or coloring agents may be added.
  • Such liquid preparations for oral administration may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxybenzoates or sorbic acid.
  • Useful diluents include lactose and high
  • a compound of the application may also be administered parenterally.
  • Solutions of a compound of the application can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • suitable formulations For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic.
  • ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers.
  • Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers.
  • diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.
  • the compounds of the application may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas.
  • the dosage unit is suitably determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges made, for example, from gelatin
  • an inhaler or insufflator may be formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations.
  • Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature.
  • the substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.
  • Compounds of the application may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide- phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • compounds of the application may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • the compounds of the application including pharmaceutically acceptable salts, solvates and prodrugs thereof are suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient (one or more compounds of the application), and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.
  • Compounds of the application may be used alone or in combination with other known agents useful for treating diseases, disorders or conditions mediated by MERTK protein inhibition, or that are treatable by inhibition of MERTK.
  • compounds of the application are administered contemporaneously with those agents.
  • "contemporaneous administration" of two substances to a subject means providing each of the two substances so that they are both biologically active in the individual at the same time.
  • the exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art.
  • two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances.
  • a combination of agents is administered to a subject in a non-contemporaneous fashion.
  • a compound of the present application is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present application provides a single unit dosage form comprising one or more compounds of the application (e.g. a compound of Formula I), an additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the dosage of compounds of the application can vary depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • Compounds of the application may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of compounds of the application from about 0.01 ⁇ g/cc to about 1000 g/cc, or about 0.1 ⁇ g/cc to about 100 ⁇ g/cc.
  • oral dosages of one or more compounds of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day.
  • a representative amount is from about 0.001 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 1 mg/kg or about 0.1 mg/kg to about 1 mg/kg will be administered.
  • a representative amount is from about 0.001 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 1 mg/kg or about 0.1 mg/kg to about 1 mg/kg.
  • a representative amount is from about 0.1 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 1 mg/kg.
  • compositions are formulated for oral administration and the compounds are suitably in the form of tablets containing 0.25, 0.5, 0.75, 1 .0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient per tablet.
  • Compounds of the application may be administered in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three or four daily doses.
  • the compounds of the application have been shown to be capable of inhibiting MERTK activity, such as MERTK protein activity.
  • the present application includes a method for inhibiting MERTK in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the application to the cell.
  • the application also includes a use of one or more compounds of the application for inhibiting MERTK in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibiting MERTK in a cell.
  • the application further includes one or more compounds of the application for use in inhibiting MERTK in a cell.
  • the compounds of the application have been shown to be capable of inhibiting MERTK protein activity, the compounds of the application are useful for treating diseases, disorders or conditions by inhibiting MERTK. Therefore the compounds of the present application are useful as medicaments. Accordingly, the present application includes a compound of the application for use as a medicament.
  • the present application also includes a method of treating a disease, disorder or condition by inhibition of MERTK comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition by inhibition of MERTK as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition by inhibition of MERTK.
  • the application further includes one or more compounds of the application for use in treating a disease, disorder or condition by inhibition of MERTK.
  • the disease, disorder or condition is a neoplastic disorder.
  • the present application also includes a method of treating a neoplastic disorder comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of a neoplastic disorder as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a neoplastic disorder.
  • the application further includes one or more compounds of the application for use in treating a neoplastic disorder.
  • the treatment is in an amount effective to ameliorate at least one symptom of the neoplastic disorder, for example, reduced cell proliferation or reduced tumor mass, among others, in a subject in need of such treatment.
  • the disease, disorder or condition that is treated by inhibition MERTK is cancer.
  • the present application also includes a method of treating cancer comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of cancer as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of cancer.
  • the application further includes one or more compounds of the application for use in treating cancer.
  • the compound is administered for the prevention of cancer in a subject such as a mammal having a predisposition for cancer.
  • the cancer is selected from a cancer of the skin, blood, prostate, colorectum, pancreas, kidney, ovary, breast, for example mammary, liver, tongue and lung.
  • the cancer is selected from leukaemia, lymphoma, non-Hodgkin's lymphoma and multiple myeloma.
  • the cancer is selected from leukemia, melanoma, lung cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer and kidney cancer.
  • the disease, disorder or condition that is treated by inhibition of MERTK is a disease, disorder or condition associated with an uncontrolled and/or abnormal cellular activity affected directly or indirectly by inhibition of MERTK.
  • the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by inhibition of MERTK is proliferative activity in a cell.
  • the application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds of the application to the cell.
  • the present application also includes a use of one or more compounds of the application for inhibition of proliferative activity in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of proliferative activity in a cell.
  • the application further includes one or more compounds of the application for use in inhibiting proliferative activity in a cell.
  • the present application also includes a method of inhibiting uncontrolled and/or abnormal cellular activities affected directly or indirectly by MERTK protein in a cell, either in a biological sample or in a subject, comprising administering an effective amount of one or more compounds of the application to the cell.
  • the application also includes a use of one or more compounds of the application for inhibition of uncontrolled and/or abnormal cellular activities affected directly or indirectly by MERTK protein in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of uncontrolled and/or abnormal cellular activities affected directly or indirectly by MERTK protein in a cell.
  • the application further includes one or more compounds of the application for use in inhibiting uncontrolled and/or abnormal cellular activities affected directly or indirectly by MERTK protein in a cell.
  • the present application also includes a method of treating a disease, disorder or condition that is treatable by inhibition of MERTK comprising administering a therapeutically effective amount of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibition of MERTK to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibition of MERTK for treatment of a disease, disorder or condition treatable by inhibition of MERTK, as well as a use of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibition of MERTK for the preparation of a medicament for treatment of a disease, disorder or condition treatable by inhibition of MERTK.
  • the application further includes one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibition of MERTKfor use in treating a disease, disorder or condition treatable by inhibition of MERTK.
  • the disease, disorder or condition treatable by inhibition of MERTK is cancer such as acute myloid leukemia (AML), acute lyphocytic leukemia (ALL), melanoma, prostate cancer, endometrial cancer, schwannoma, mantel cell lymphoma, rhabdomyosarcoma, glioma, glioblastoma, B-ALL, T-ALL, lung cancer, gastric cancer, pancreatic cancer and breast cancer.
  • the disease, disorder or condition treatable by inhibition of MERTK is cancer and the one or more compounds of the application are administered in combination with one or more additional cancer treatments.
  • the additional cancer treatment is selected from radiotherapy, chemotherapy, targeted therapies such as antibody therapies and small molecule therapies such as tyrosine-kinase inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies.
  • the subject is a mammal. In some embodiments, the subject is human.
  • compounds of Formula I are prepared as shown in Scheme 1 . Therefore compounds of Formula A are reacted with various amines B, for example in the presence of a base, such as diethylpropyl ethylamine (DIPEA) or CS2CO2 in an inert solvent to provide compounds of Formula I.
  • a base such as diethylpropyl ethylamine (DIPEA) or CS2CO2
  • DIPEA diethylpropyl ethylamine
  • CS2CO2 CS2CO2
  • the amines B are used in the form of an acid addition salt, such as a hydrochloride salt.
  • Scheme 1 [00135] In some embodiments compounds of Formula 1-1 are prepared as shown in Scheme 2. Therefore compounds of Formula C are reacted with various amines B, for example in the presence of a base, such as diethylpropyl ethylamine (DIPEA) or CS2CO3 in an inert solvent to provide compounds of Formula D. Hydrolysis of the methyl ester of compounds of Formula D provides compounds of Formula E which can be reacted with various amines F to provide compounds of Formula 1-1 .
  • DIPEA diethylpropyl ethylamine
  • CS2CO3 CS2CO3
  • compounds of Formula I-2 are prepared as shown in Scheme 3. Therefore compounds of Formula G are coupled to various amines B either by displacement using various bases (CS2CO3, DI PEA etc.) or by cross coupling using palladium cataslysis.
  • the resulting compounds H can be brominated using reagents such as NBS to give compounds J which are coupled with various boronic acids using palladium catalysis to provide compounds of Formula I-2.
  • the compounds of Formula A, B, C, D, E, F, G, H and J may be prepared using methods known in the art or are commercially available.
  • Salts of the compounds of the application are generally formed by dissolving the neutral compound in an inert organic solvent and adding either the desired acid or base and isolating the resulting salt by either filtration or other known means.
  • solvates of the compounds of the application will vary depending on the compound and the solvate.
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent.
  • the solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.
  • Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups.
  • available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine).
  • a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation.
  • Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified.
  • CS2CO3, DMA LiOH, MeOH, THF, H2O
  • c HBTU, DIPEA, DMF.
  • Example 8 4-[2-[[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]amino]-5-[4-
  • Tetrakis(triphenylphosphine)palladium(0) (516 mg, 0.447 mmol) was added, the flask was flushed with nitrogen. Dry dioxane (15 ml_) was added and the mixture was stirred at 90 °C overnight. The mixture was diluted with ethyl acetate and washed with brine (2x). The organic phase was dried, fitered and concentrated in vacuo then chromatographed in 0-60% ethyl acetate in hexanes. Product containing fractions were concentrated in vacuo giving the desired product as a pale solid (1 .15 g, 83%).
  • [00171 ] Mer (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 mM NaCI, 250 ⁇ GGMEDIYFEFMGGKKK (SEQ ID NO: 1 ), 10 mM 40 magnesium acetate and [9-33P]-ATP (specific activity and concentration as required). The reaction was initiated by the addition of the Mg/ATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of phosphoric acid to a concentration of 0.5%. 10 ⁇ _ of the reaction was then spotted onto a P30 filter mat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting. Axl (h)
  • Axl (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 ⁇ KKSRGDYMTMQIG (SEQ ID NO:2), 10 mM magnesium acetate and [9-33P]-ATP (specific activity and concentration as required). The reaction is initiated by the addition of the Mg/ATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of phosphoric acid to a concentration of 0.5%. 10 ⁇ _ of the reaction was then spotted onto a P30 filter mat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting.
  • the compounds of the invention were found to be inhibitors of one or more of MER, AXL and TYR03. The results are presented as ICso or percent inhibition at 300 nM in Table 1 .
  • the letter “A” indicates an ICso ⁇ 10 nM; “B” indicates and ICso > 10 nM but ⁇ 100 nM; and “C” indicates and ICso > 100 nM.
  • the kinase of interest was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 mM NaCI, 10 mM 40 magnesium acetate and [9-33P]-ATP (specific activity and concentration as required). The reaction was initiated by the addition of the Mg/ATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of phosphoric acid to a concentration of 0.5%. 10 ⁇ _ of the reaction was then spotted onto a P30 filter mat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting.
  • P-glycoprotein is a member of the ABC-transporter family that transports substances across cellular membranes acting as an energy- dependent efflux pump extruding drugs out of the cells. Increased expression of Pgp in cancer cells is one of the major mechanisms of cancer resitances and chemotherapy and thus Pgp plays a key role on the pharmacokinetics of drug absorption and distribution.
  • the permeability assay buffer was Hanks Balanced Salt Solution containing 10 mM HEPES and 15 mM glucose at a pH of 7.4.
  • the dosing buffer contained 5 ⁇ metoprolol (positive control), 5 ⁇ atenolol (negative control) and 100 ⁇ lucifer yellow.
  • the buffer in the receiver chamber also contained 1 % bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • the dosing solution concentration was 5 ⁇ in the assay buffer.
  • Digoxin (20 ⁇ ) was used as Pgp substrate control.
  • the assays were performed with and without a known Pgp inhibitor (e.g. Verapamil or Ketoconazole). The known Pgp inhibitor was co-dosed at 50 ⁇ with compound at 5 ⁇ .
  • Narrow-window mass extraction LC/MS analysis was performed for all samples from this study using a Waters Xevo quadrupole time-of-flight (QTof) mass spectrometer, to determine relative peak areas of parent compound. The percent of transported drug was calculated based on these peak areas, relative to the initial, dosing concentration.
  • QTof Waters Xevo quadrupole time-of-flight
  • the final volume for each reaction was 100 ⁇ _, which includes the addition of an NADPH-Regeneration solution (NRS) mix.
  • NRS NADPH-Regeneration solution
  • This NRS mix was comprised of glucose 6-phosphate dehydrogenase (0.4 U/mL), NADP+ (1 .3 mM), MgCI2 (3.3 mM), and glucose 6-phosphate (3.3 mM) in assay mixtures.
  • reactions were terminated by the addition of 1 .5-volumes (150 ⁇ _) of ice-cold, acetonitrile with 0.5% formic acid and internal standard. Samples were then centrifuged at 4,000 rpm for 10 minutes to remove debris and precipitated protein. Approximately 150 ⁇ _ of supernatant was subsequently transferred to a new 96 well microplate for LC/MS analysis.
  • Narrow-window mass extraction LC/MS analysis was performed for all samples using a Waters Xevo quadrupole time-of-flight (QTof) mass spectrometer and an ACQUITY UPLC system, to determine relative peak areas of parent compound.
  • QTof Waters Xevo quadrupole time-of-flight
  • Human and mouse liver microsomes contain a wide variety of drug metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism and excretion) studies. These microsomes are used to examine the potential first-pass metabolism byproducts of orally administered drugs. Representative compounds of the application were evaluated for their stability in human and mouse liver microsomes. Results for representative compounds of Formula I are presented in Table 3. Table 4: Metabolic stability of MERTK inhibitors in human and mouse liver microsomes incubated with NADPH
  • test compound and positive control compounds prepared stock solutions of the test compound and positive control compounds descibed in Table 4 in DMSO at 0, 0.2, 1 , 2, 10, 50, 200, 2000 and 10000 ⁇ . Transfer 1 ⁇ _ of the stock solutions to the Incubation Plate.
  • the final concentrations of test compound or positive control compound are 0, 0.001 , 0.005, 0.01 , 0.05, 0.25, 1 , 10 and 50 ⁇ . All experiments are performed in duplicate.
  • Procedures were designed to avoid or minimize discomfort, distress and pain to the animals in accordance with the principles of the Animal for Research Act of Ontario and the guidelines of Canadian Council on Animal Care (CCAC). The CCAC Guide forthe Care and Use of Experimental Animals and related policies will be followed. In orderto ensure compliance, the protocol will be reviewed and approved by the Study Facility's Institutional Animal Care and Use Committee (IACUC) before the start of the study as per IACUC standard operating procedures.
  • IACUC Institutional Animal Care and Use Committee
  • Samples (plasma and dosing solutions) were analyzed using a AB Sciex API 4000 Q-TRAP or 6500 Q-TRAP MS/MS system equipped with an Agilent or Exion LC system with a binary pump, a solvent degasser, a thermostatted column compartment and a multiplate autosampler. All samples were analyzed using a qualified LC-MS/MS method in the presence of internal stadards.
  • CHO-K1 Choinese Hamster Ovary cells stably transfected with human hERG cDNA was used. The cells are harvested by trypsinization and maintained in Serum Free Medium at room temperature before recording. The cells are washed and re-suspended in Extracellular Solution before being applied to the automated patch-clamp sites. Five concentrations (0.01 , 0.1 , 1 , 10 and 100 ⁇ ) are used for IC50 determination.
  • the cell is depolarized to +20 mV for 2 s, followed by a 1 s pulse to -40 mV to reveal the hERG tail current.
  • This paradigm is delivered once every 5 s to monitor the current amplitude.
  • the assay is conducted at room temperature.
  • the Extracellular Solution (control) is applied first and the cell is stabilized in the solution for 5 min.
  • the test compound is applied from low to high concentrations sequentially on the same cell.
  • the reference compound E-4031 is tested concurrently at multiple concentrations to obtain an IC50 value.
  • the percent inhibition of hERG channel is calculated by comparing the tail current amplitude before and after application of the compound (the current difference is normalized to control).
  • Example 17 Inhibition of efferocytosis by MERTK inhibitors
  • MDM cells were suspended in a polarizing cocktail containing 100 nM of dexamethasone in cell media. Approximately 4.8x10 6 cells and accompanying media (approx.1 ml_) were added to wells containing a combination of X-VIVO-15 cell media with M-CSF. The cells were incubated at 37 °C in an atmosphere of 5% CO2 overnight.
  • the primed MDM cells were detached from the plate, spun down at 300g for 10 min. at ambient temperature and the supernatant removed. The pelleted cells were subsequently resuspended in 3 mL X-VIVO 15 + 20ng/ml_ rhM-CSF. The cells were seeded at a density of 4.5 x 10 4 cells per well in a 96 well plate and incubated overnight 37 °C in an atmosphere of 5% CO2.
  • each well was washed with 200 ⁇ _ of ice cold FACS buffer.
  • the cell suspensions were spun down at 400xg for 4 min. at 4 °C and the supernatant discarded. The above procedure was done once more prior to cell staining.
  • the washed MDM cell pellet was resuspended in 25 ⁇ _ of Fc block and left at ambient temperature for 10 min.
  • a mixture of staining antibodies comprised of anti-MerTK-PE, anti-CD14-APC and LIVE/DEAD dye was added to each well of resuspended cells.
  • the plate was incubated on ice for 30 min. and protected from light.
  • 100 ⁇ _ of FACS buffer was added per well and the plate spun down at 400xg for 4 min. at 4 °C and the supernatant discarded.
  • the pellet was resuspended in 100 ⁇ _ of BD Stabalizing Fixative and the plate wraped with foil and refrigerated overnight. Percent efferocytosis was determined on a FACSVerse instrument the following day.

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Abstract

Une classe de composés de 2,4-diaminopyrimidine fluorés de formule (I) a été préparée pour être utilisée dans le traitement de cancers et d'autres troubles liés à MERTK. (Formule (I))
PCT/CA2018/050815 2017-07-04 2018-07-04 Composés de 2,4-diaminopyrimidine fluorés utilisés en tant qu'inhibiteurs de la tyrosine kinase mer (mertk) et leurs utilisations WO2019006548A1 (fr)

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EP3541391A4 (fr) * 2016-11-17 2020-06-17 The University of North Carolina at Chapel Hill Analogues d'alkyle pyrrolopyrimidine et leurs procédés de préparation et d'utilisation
WO2020205967A1 (fr) * 2019-04-02 2020-10-08 Meryx, Inc. Polymorphes d'un inhibiteur de kinase, compositions pharmaceutiques contenant un tel composé, procédés de préparation et utilisations
WO2023235925A1 (fr) * 2022-06-07 2023-12-14 Monash University Composés à activité mertk
CN117865941A (zh) * 2024-03-13 2024-04-12 上海方予健康医药科技有限公司 取代哌啶化合物及其制备方法和应用

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WO2015157127A1 (fr) * 2014-04-11 2015-10-15 The University Of North Carolina At Chapel Hill Utilisations thérapeutiques de composés sélectionnés de pyrimidine ayant une activité tyrosine kinase antimère
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WO2016165205A1 (fr) * 2015-04-14 2016-10-20 中国科学院合肥物质科学研究院 Nouvel inhibiteur de kinase bcr-abl

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3541391A4 (fr) * 2016-11-17 2020-06-17 The University of North Carolina at Chapel Hill Analogues d'alkyle pyrrolopyrimidine et leurs procédés de préparation et d'utilisation
WO2020205967A1 (fr) * 2019-04-02 2020-10-08 Meryx, Inc. Polymorphes d'un inhibiteur de kinase, compositions pharmaceutiques contenant un tel composé, procédés de préparation et utilisations
WO2023235925A1 (fr) * 2022-06-07 2023-12-14 Monash University Composés à activité mertk
CN117865941A (zh) * 2024-03-13 2024-04-12 上海方予健康医药科技有限公司 取代哌啶化合物及其制备方法和应用

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