TITLE: FLUORINATED 2,4-DIAMINOPYRIMIDINE COMPOUNDS AS MER TYROSINE KINASE (MERTK) INHIBITORS AND USES THEREOF

RELATED APPLICATIONS

[0001 ] The present application claims the benefit of priority from copending United States provisional patent application S.N. 62/528,495 filed on July 4, 2017 and co-pending United States provisional patent application S.N. 62/630,938 filed on February 15, 2018, the contents of both of which are incorporated herein by reference in their entirety.

FIELD

[0002] 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.

BACKGROUND

[0003] Receptor tyrosine kinases (RTKs) are frequently ectopically expressed, overexpressed, or hyperactivated in tumor cells and are therefore attractive targets for cancer therapy. 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

II I (FNIII) motifs which function to detect phosphatidylserine (PtdSer) in conjunction with growth arrest-specific protein 6 (GAS6) or vitamin K- dependent protein S (PROS1 ). Normally located on the intracellular leaf of lipid membranes, phosphatidylserine becomes externalized when cells undergo apoptosis, on virus envelopes, and upon platelet aggregation.

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. In addition to their similar extracellular domains, 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.

[0004] A diverse array of cellular functions are mediated by TAM RTKs. For instance, 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. To illustrate the points mentioned above, 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.

[0005] 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. Specifically, TAM receptor signaling can be associated with three hallmark characteristics of cancerous cells: tissue invasion, sustained angiogenesis and evasion of apoptosis. Remarkably, 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. Furthermore, the co-expression of 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.

[0006] 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. This class of inhibitors is by far the largest and potentially the least selective, as the ATP-binding site is highly conserved amongst kinases. 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.

[0007] As a consequence of playing key roles in autoimmunity, viral infection as well as oncogenesis and drug resistance, 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.

[0008] 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].

[0009] The best-studied 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. In the brain, 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 ].

[0010] An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity. These mechanisms may be innate, adaptive, or acquired [Curr Oncol Rep 2017 19: 19].

[001 1 ] 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]. In certain cases, inhibition of MERTK has restored sensitivity to chemotherapeutics such as erlotinib in EGFR driven NSCLC [Onco ta rget 2015, 6(1 1 ): 9206-9019]. 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.

[0012] The compound MRX-6313 (also known as UNC2025) has been reported as MERTK inhibitor (Zhang, W., et al. J. Med. Chem. 2014, 57, 7031 - 7041 ).

MRX-6313

[0013] 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).

MRX-2863

[0014] 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.

[0015] Despite the fact that 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]. However, 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.

SUMMARY

[0016] The Applicants have found that a class of fluorinated 2,4- diaminopyrimidine compounds have potency and selectivity against MERTK. Therefore, compounds of Formula I have been prepared and found to be useful as MERTK inhibitors. It has surprisingly been found that fluoro-substitition in either the R ¹ or R ² positions in representative compounds of the application provides compounds with improved pharmacokinetic properties, such as oral bioavailability (%F), half-life, and Cmax.compared to non-fluorosubstitued analogs.

[0017] Accordingly, the present application includes a compound of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:

wherein: R ¹ is selected from Ci-6alkyl, Ci-6alkylene-0-Ci-6alkyl, C3-iocycloalkyl, C3- loheterocycloalkyl, C6-ioaryl and Cs-ioheteroaryl;

R ² selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C3- loheterocycloalkyl, C6-ioaryl, Cs-ioheteroaryl, Ci-6alkyleneC3-iocycloalkyl, Ci- 6alkyleneC3-ioheterocycloalkyl, Ci-6alkyleneC5-ioheteroaryl and Ci-6alkyleneC6- ioaryl, each of which is unsubstituted or substituted with one or two substituents independently selected from halo, S02NR ⁵ R ⁶ , C(0)NR ⁵ R ⁶ , =0, CN, Z'Ci-ealkyl, Z'Ci-ealkyleneCN, Z'Ci-ealkyleneOR ⁵ , Z'Ci-6alkyleneNR ⁵ R ⁶ , Z'C3-iocycloalkyl, Z'C3-ioheterocycloalkyl, Z'C6-ioaryl and Z'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;

all alkyl, aryl, cycloalkyl and alkylene groups are optionally fluoro-substituted; and

at least one of R ¹ and R ² comprises a CFH2, CF2H or CF3 group.

[0018] In some embodiments, 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:

I-B

wherein:

R ¹ , R ² , R ³ and R ⁴ are as defined in Formula I above.

[0019] The present application also includes a composition comprising one or more compounds of the application and a carrier. In an embodiment, the composition is a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.

[0020] 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.

[0021 ] In a further embodiment, the compounds of the application are used as medicaments. Accordingly, the application also includes a compound of the application for use as a medicament.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] In an embodiment, the disease, disorder or condition mediated by MERTK protein inhibition, or treatable by inhibition of MERTK, is a neoplastic disorder. In an embodiment, 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.

[0026] In an embodiment, the disease, disorder or condition mediated by MER protein inhibition, or treatable by inhibition of MERTK, is cancer.

[0027] In an embodiment, 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. In another embodiment, the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by MERTK is proliferative activity in a cell. [0028] 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.

[0029] In a further embodiment 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. In another embodiment, 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.

[0030] 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.

[0031 ] The application additionally provides a process for the preparation of compounds of Formula I. General and specific processes are discussed in more detail and set forth in the Examples below.

[0032] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating embodiments of the application are given by way of illustration only, since various changes and modifications within the spirit and scope of the application will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The application will be described in greater detail herein below with reference to the drawings in which: [0034] Figure 1 shows the results from the maximum tolerated dose study in mice (Example 19) which compares MRX-2843 and exemplary compound I-87.

DETAILED DESCRIPTION

I. Definitions

[0035] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the application herein described for which they are suitable as would be understood by a person skilled in the art. Unless otherwise specified within this application or unless a person skilled in the art would understand otherwise, the nomenclature used in this application generally follows the examples and rules stated in "Nomenclature of Organic Chemistry" (Pergamon Press, 1979), Sections A, B, C, D, E, F, and H. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001 , Advanced Chemistry Development, Inc., Toronto, Canada.

[0036] The term "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.

[0037] The term "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.

[0038] As used in the present application, the singular forms "a", "an" and "the" include plural references unless the content clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to present certain aspects with one compound, or two or more additional compounds.

[0039] In embodiments comprising an "additional" or "second" component, such as an additional or second compound, 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.

[0040] In understanding the scope of the present application, the term "comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives.

[0041 ] The term "consisting" and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps.

[0042] The term "consisting essentially of", as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and/or steps.

[0043] The term "suitable" as used herein 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.

[0044] In embodiments of the present application, 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.

[0045] 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.

[0046] 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.

[0047] Terms of degree such as "substantially", "about" and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.

[0048] The term "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. For example, the term 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.

[0049] The term "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". For example, the term C2-6alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms.

[0050] The term "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". For example, the term C2-6alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.

[0051 ] The term "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. For example, the term 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.

[0052] The term "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". For example, the term C3-iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0053] The term "aryl" as used herein, whether it is used alone or as part of another group, refers to carbocyclic groups containing at least one aromatic ring. In an embodiment of the application, the aryl group contains from 6, 9 or 10 carbon atoms, such as phenyl, indanyl or naphthyl.

[0054] The term "heterocycloalkyl" as used herein, whether it is used alone or as part of another group, 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.

[0055] The term "heteroaryl" as used herein, whether it is used alone or as part of another group, 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. When 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.

[0056] 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.

[0057] A first ring being "fused" with a second ring means the first ring and the second ring share two adjacent atoms there between.

[0058] A first ring being "bridged" with a second ring means the first ring and the second ring share two non-adjacent atoms there between.

[0059] A first ring being "spirofused" with a second ring means the first ring and the second ring share one atom there between.

[0060] The term "halo" as used herein refers to a halogen atom and includes fluoro, chloro, bromo and iodo.

[0061 ] The term "optionally substituted" refers to groups, structures, or molecules that are either unsubstituted or are substituted with one or more substituents.

[0062] The term "fluorosubstituted" refers to the substitution of one or more, including all, hydrogens in a referenced group with fluorine.

[0063] The symbol " ·™ ^« " is used herein to represent the point of attachment of a group to the remainder of a molecule or chemical formula.

[0064] The term "protecting group" or "PG" and the like as used herein 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. 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. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 ^rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0065] The term "cell" as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.

[0066] The term "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.

[0067] The term "pharmaceutically acceptable" means compatible with the treatment of subjects, for example humans.

[0068] The term "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.

[0069] The term "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.

[0070] 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. Illustrative of such 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. In general, 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.

[0071 ] 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. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. [See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 -19]. 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.

[0072] 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.

[0073] The term "solvate" as used herein 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".

[0074] The term "inert organic solvent" as used herein 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.

[0075] The term "treating" or "treatment" as used herein and as is well understood in the art, 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. For example, 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. For example, in some embodiments, the compounds of the application may be administered at least once a week. In some embodiments, 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. In another embodiment, 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.

[0076] "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.

[0077] The term "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.

[0078] 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.

[0079] The term "mediated by MERTK" as used herein means that 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. These diseases respond favourably when MER activity associated with the disease is blocked by one or more of the compounds of the application.

[0080] As used herein, the term "effective amount" or "therapeutically 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. For example in the context of treating a disease, disorder or condition mediated by MERTK protein inhibition or treatable by inhibition of MERTK, 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. When the disease is cancer, amounts that are effective can cause a reduction in the number, growth rate, size and/or distribution of tumours.

[0081 ] 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. [0082] The term "neoplastic disorder" as used herein 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. The term "neoplasm" as used herein 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.

[0083] The term "cancer" as used herein 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 Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplasia Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor. Metastases of the aforementioned cancers can also be treated in accordance with the methods described herein.

Compounds and Compositions of the Application

[0084] 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. In particular, 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.

[0085] Accordingly, the present application includes a compound of Formula I or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:

wherein:

R ¹ is selected from Ci-6alkyl, Ci-6alkylene-0-Ci-6alkyl, C3-iocycloalkyl, C3- -loheterocycloalkyl, C6-ioaryl and Cs-ioheteroaryl;

R ² selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C3- -loheterocycloalkyl, C6-ioaryl, Cs-ioheteroaryl, Ci-6alkyleneC3-iocycloalkyl, Ci- 6alkyleneC3-ioheterocycloalkyl, Ci-6alkyleneC5-ioheteroaryl and Ci-6alkyleneC6- -loaryl, each of which is unsubstituted or substituted with one or two substituents independently selected from halo, S02NR ⁵ R ⁶ , C(0)NR ⁵ R ⁶ , =0, CN, Z'Ci-ealkyl, Z'Ci-ealkyleneCN, Z'Ci-ealkyleneOR ⁵ , Z'Ci-6alkyleneNR ⁵ R ⁶ , Z'C3-iocycloalkyl, Z'C3-ioheterocycloalkyl, Z'C6-ioaryl and Z'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;

all alkyl, aryl, cycloalkyl and alkylene groups are optionally fluoro-substituted; and

at least one of R ¹ and R ² comprises a CFH2, CF2H or CF3 group.

[0086] In some embodiments, R ¹ is selected from Ci-6alkyl, Ci-6alkylene- 0-Ci-6alkyl, Ci-6alkyleneC3-6cycloalkyl and C6-ioaryl, each of which is optionally

fluorosubstituted. In some embodiments 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. In some emebodiments, 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. In some emebodiments, R ¹ is

R* R ^b

fr R ⁹ y R ^R ? , wherein one of R ^a and R ^b is CH3 and R ^c and R ^d are both H and

at least two of R ^e , R ^f and R ^g is F. In some embodiments R ¹ is or In some embodiments R ¹ in some

embodiments, R ¹ is

[0087] In some embodiments, R ² is selected from Ci-6alkyl, C3- locycloalkyl, C3-6heterocycloalkyl, phenyl, Cs-6heteroaryl, Ci-6alkyleneC3- 6cycloalkyl, Ci-6alkyleneC3-6heterocycloalkyl, Ci-6alkyleneC5-6heteroaryl and Ci-6alkylenephenyl, each of which is unsubstituted or substituted with one or two substituents independently selected from halo, S02NR ⁵ R ⁶ , C(0)NR ⁵ R ⁶ , =0, CN, Z'Ci-ealkyl, Z'Ci-ealkyleneCN, Z'Ci-ealkyleneOR ⁵ , Z'Ci- 6alkyleneNR ⁵ R ⁶ , Z'C3-6cycloalkyl, Z'C3-6heterocycloalkyl, Z'phenyl and Z'Cs- 6heteroaryl.

[0088] In some embodiments, Z is selected from a direct bond and NH.

[0089] In some embodiments, 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).

embodiments R ² is _ wherein Cy ¹ is selected from Cs-

6heteroaryl and phenyl, and X ¹ is selected from O, S, NH, NCH3 and

NCH2CH2OCF2H and the Ci-6alkylene is optionally substituted with one =0. In some embodiments Cy ¹ is selected from thiophenyl, furanyl, pyridinyl and phenyl. i (CH ₂ )o-i

[0091] some embodiments, R ² , wherein Cy ² is selected from Cs-6heteroaryl, C5-6heterocycloalkyl, phenyl and C3-6cycloalkyl, each of which is optionally substituted with 1 -3, or 1 -2, substituents selected from F, =0, Ci-6alkyl, Ci-6fluoroalkyl, OCi-6alkyl, OCi-6fluoroalkyl, Ci- 6alkyleneOCi-6fluoroalkyl, Ci-6alkyleneCN, Ci-6alkyleneN(Ci-6alkyl)2, Ci- 6alkyleneNH2, Co-6alkyleneC3-6cycloalkyl, C(0)Ci-6alkyl, C(0)Co-6alkyleneC3- ecycloalkyl, C(0)Co-6alkyleneOCi-6fluoroalkyl, C(0)Ci-efluoroalkyl, C(0)Ci- ealkenyl, SO2NH2, SCfcCi-ealkyl, SCfcCwcycloalkyl, C(0)NHCi-6alkyl, and C(0)NHC3-6cycloalkyl. In some embodiments Cy ² is selected from cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, cyclopropyl, pyrazolyl, piperidinyl, pyrrolidinyl, piperazinyl, pyridinyl, dihydropyridinyl, tetrahydopyridinyl, tetrahydrofuranyl, dihydrothiopyranyl, dihydropyranyl, oxetanyl, isoxazolyl and phenyl, each of which is optionally substituted with 1 -2 F or 1 substituent selected from =0, Ci-6alkyl, Ci-6fluoroalkyl, OCi-6alkyl, OCi-6fluoroalkyl, Ci- 6alkyleneOCi-6fluoroalkyl, Ci-6alkyleneCN, Ci-6alkyleneN(Ci-6alkyl)2, Ci- 6alkyleneNH2, Co-6alkyleneC3-6cycloalkyl, C(0)Ci-6alkyl, C(0)Co-6alkyleneC3- ecycloalkyl, C(0)Co-6alkyleneOCi-6fluoroalkyl, C(0)Ci-efluoroalkyl, C(0)Ci- ealkenyl, SO2NH2, SCfcCi-ealkyl, SCfcCwcycloalkyl, C(0)NHCi-ealkyl, and C(0)NHC3-6cycloalkyl.

[0092] In some embodiments, 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.

[0093] In some embodiments, 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.

[0094] In some embodiment, Z is NH or a direct bond and R ² is or

comprises a group that is substituted with In some embodiments 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

a group that is substitu ted with

[0095] In some embodiments, Q is C(O).

[0096] In some embodiments, Q and R ³ are joined to form an alkenylene bridge that together with the atoms therebetween, result in 5 membered unsaturated ring.

[0097] In some embodiments, 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 _¾ \— / -OH . In some embodiments R ⁴ is

V

\— '-OH . In some embodiments, R ⁴ is -\-( \— ' ) _" OH In some embodiments, R ⁴ is unsubstituted C5-6heterocycloalkyl. In some embodiments, 4 is tetrahydrofuranyl or tetrahydropyranyl. In some embodiments, R ⁴ is

[0098] In some embodiments, 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

I ^Ri \ ^Rh some emebodiments, 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. In some

R ^k are both H and at least two of R ¹ , R ^m and R ⁿ is F. In some embodiments R ⁸ is or . In some embodiments R ⁸ is . in

some embodiments, R ⁸ is

[0099] In some embodiments, R ⁷ is selected from H and Ci- ₄ alkyl;

[00100] In some embodiments, 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.

[00101 ] In some embodiments, 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:

l-A

l-B

wherein:

R ¹ , R ² , R ³ and R ⁴ are as defined above.

[00102] In some embodiments, the compound of the present application is selected from the compounds listed below, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:

31

51

52

53

54 or a pharmaceutically acceptable salt, solvate and/or prodrug thereof.

[00103] 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.

[00104] 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. [00105] 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.

[00106] 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. For oral therapeutic administration, 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. In the case of tablets, 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). The tablets may be coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed- release, formulations. Examples of 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. liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. 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. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch.

[00107] 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. When 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. If desired, 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). Useful diluents include lactose and high molecular weight polyethylene glycols.

[00108] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[00109] 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. A person skilled in the art would know how to prepare 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. For ocular administration, 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. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[001 10] 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. Alternatively, 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.

[001 1 1 ] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.

[001 12] For intranasal administration or administration by inhalation, 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. Alternatively, 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. Where 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. In the case of a pressurized aerosol, 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) for use in 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.

[001 13] 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.

[001 14] 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.

[001 15] Compounds of the application may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide- phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, 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.

[001 16] 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. Depending on the mode of administration, 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.

[001 17] 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. When used in combination with other agents useful in treating diseases, disorders or conditions mediated by MERTK protein inhibition, or that are treatable by inhibition of MERTK, it is an embodiment that the compounds of the application are administered contemporaneously with those agents. As used herein, "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. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a non-contemporaneous fashion. In an embodiment, 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. Accordingly, 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.

[001 18] 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 μg/cc to about 1000 g/cc, or about 0.1 μg/cc to about 100 μg/cc. As a representative example, 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. For parenteral administration, 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. For oral administration, 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. For administration in suppository form, 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. In an embodiment of the application, 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.

[001 19] To be clear, in the above, the term "a compound" also includes embodiments wherein one or more compounds are referenced.

III. Methods and Uses of the Application

[00120] The compounds of the application have been shown to be capable of inhibiting MERTK activity, such as MERTK protein activity.

[00121 ] Accordingly, 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.

[00122] As 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.

[00123] 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.

[00124] 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.

[00125] In an embodiment, the disease, disorder or condition is a neoplastic disorder. Accordingly, 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. In an embodiment, 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.

[00126] Compounds of the application have been demonstrated to be effective against a panel of human tumor cell line. Therefore in another embodiment of the present application, the disease, disorder or condition that is treated by inhibition MERTK is cancer. Accordingly, 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. In an embodiment, the compound is administered for the prevention of cancer in a subject such as a mammal having a predisposition for cancer.

[00127] In an embodiment, the cancer is selected from a cancer of the skin, blood, prostate, colorectum, pancreas, kidney, ovary, breast, for example mammary, liver, tongue and lung. In another embodiment, the cancer is selected from leukaemia, lymphoma, non-Hodgkin's lymphoma and multiple myeloma. In a further embodiment of the present application, the cancer is selected from leukemia, melanoma, lung cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer and kidney cancer.

[00128] In an embodiment, 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. In another embodiment, the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by inhibition of MERTK is proliferative activity in a cell. Accordingly, 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.

[00129] 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.

[00130] Accordingly, 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. In an embodiment, 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. [00131 ] further embodiment, 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. In another embodiment, 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.

[00132] In some embodiments, the subject is a mammal. In some embodiments, the subject is human.

IV. Preparation of Compounds of the Application

[00133] Compounds of the present application can be prepared by various synthetic processes. The choice of particular structural features and/or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula I is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art. In the Schemes below showing the preparation of compounds of the application, all variables are as defined in Formula I, unless otherwise stated,

[00134] In some embodiments, 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. In some embodiments, the amines B are used in the form of an acid addition salt, such as a hydrochloride salt.

A

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 .

Scheme 2

[00136] In some embodiments 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.

Scheme 3

[00137] 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.

[00138] 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.

[00139] The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, 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.

[00140] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. For example, 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).

[00141 ] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York, (1999). It is also to be understood that 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. References and descriptions of other suitable transformations are given in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations" R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March, 4th ed. McGraw Hill (1992) or, "Organic Synthesis", Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[00142] The following non-limiting examples are illustrative of the present application:

EXAMPLES

General methods

[00143] All starting materials used herein were commercially available or earlier described in the literature. The ¹ H and ¹³ C NMR spectra were recorded either on Bruker 300, Bruker DPX400 or Varian +400 spectrometers operating at 300, 400 and 400 MHz for ¹ H NMR respectively, using TMS or the residual solvent signal as an internal reference, in deuterated chloroform as solvent unless otherwise indicated. All reported chemical shifts are in ppm on the delta- scale, and the fine splitting of the signals as appearing in the recordings is generally indicated, for example as s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m: multiplet. Unless otherwise indicated, in the tables below, ¹ H NMR data was obtained at 400 MHz, using CDC as the solvent.

[00144] Purification of products was carried out using Chem Elut Extraction Columns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPE Columns (Varian, cat # 12256018; 12256026; 12256034) or by flash chromatography in silica-filled glass columns.

Example 1(a): Preparation of (N-cyclohexyl-2-[2-

(difluoromethoxy)ethylamino]-4-[(4-hydroxycyclohexyl)amin o]

pyrimidine-5-carboxamide) (1-1 )

[00145] To a stirred suspension of 2-chloro-N-cyclohexyl-4-[(4- hydroxycyclohexyl)amino]pyrimidine-5-carboxamide (Compound A-1 , 0.100 g, 0.283 mmol) and 2-(difluoromethoxy)ethylammonium chloride (0.167 g, 1 .13 mmol) in ACN (3 ml_) was added DIPEA (0.182 g, 1 .41 mmol). The mixture was stirred at 90°C and reaction progress monitored by LC/MS. Once complete (~16h), the reaction was diluted with EtOAc and washed with water, followed by brine. The organic phase was dried with MgS0 ₄ , filtered and concentrated in vacuo. The crude reaction mixture was triturated with Et ₂ 0 to afford 1-1 (0.100 mg, 0.234 mmol, 83% yield) as a white solid: ¹ H NMR: (400 MHz, d6-DMSO) δ 8.88 (s, 1 H), 8.37 (s, 1 H), 7.82 (d, J = 8 Hz, 1 H), 7.22 (s, 1 H), 6.67 (t, J = 76 Hz, 1 H), 4.56 (d, J = 8 Hz, 1 H), 3.99-3.89 (m, 2H), 3.87-3.78 (m, 1 H), 3.73-3.62 (m, 1 H), 3.53-3.43 (m, 3H), 1 .99-1 .89 (m, 2H), 1 .88-1 .65 (m, 6H), 1 .65-1 .51 (m, 1 H), 1 .37-1 .16 (m, 8H), 1 .18-1 .02 (m, 1 H).

MS: 428.2 (MH+). [00146] In a like manner, the following additional compound was prepared:

(b) N-cyclohexyl-2-[[(1 S)-2-(difluoromethoxy)-1 -methyl -ethyl]amino]-4-[(4 hydroxycyclohexyl)amino] pyrimidine-5-carboxamide (I-2)

I-2

[00147] 49% yield; ¹ H NMR: (400 MHz, d6-DMSO) δ 8.87 (s, 1 H), 8.37 (s, 1 H), 7.82 (d, J = 8 Hz, 1 H), 7.10 (s, 1 H), 6.67 (t, J = 76 Hz, 1 H), 4.55 (d, J = 4 Hz, 1 H), 4.31 -4.03 (m, 1 H), 3.97-3.77 (m, 2H), 3.75-3.60 (m, 2H), 3.51 -3.42 (m, 1 H), 2.00-1 .87 (m, 2H), 1 .87-1 .66 (m, 5H), 1 .64-1 .55 (m, 1 H), 1 .33-1 .12 (m, 9H).

Example 2: N-cyclohexyl-2-[[(1 R)-2-(difluoromethoxy)-1 -methyl- ethyl]amino]-4-[(4-hydroxycyclohexyl)amino]pyrimidine-5-carb oxamide

(1-14)

[00148] To a stirred suspension of 2-chloro-N-cyclohexyl-4-[(4- hydroxycyclohexyl)amino]pyrimidine-5-carboxamide (Compound A-1 , 0.100 g, 0.283 mmol) and [(1 R)-2-(difluoromethoxy)-1 -methyl-ethyl]ammonium chloride (0.183 g, 1 .13 mmol) in DMF (2 ml_) was added K2CO3 (0.313 g, 2.27 mmol). The mixture was stirred at 90°C and reaction progress monitored by LC/MS. Once complete (~16h), the reaction was diluted with EtOAc and washed with water (2x), followed by brine. The organic phase was dried with MgS0 ₄ , filtered, and concentrated then chromatographed (0-50% EtOAc in hexanes) to afford B-3 (0.057 g, 0.129 mmol, 47% yield) as a white solid.

¹ H NMR: (400 MHz, d6-DMSO) δ 8.85 (s, 1 H), 8.36 (s, 1 H), 7.82 (d, J = 8 Hz, 1 H), 7.05 (s, 1 H), 6.66 (t, J = 76 Hz, 1 H), 4.60 (d, J = 4 Hz, 1 H), 4.28-4.03 (m, 2H), 3.97-3.76 (m, 3H), 3.75-3.56 (m, 5H), 2.00-1 .87 (m, 2H), 1 .87-1 .77 (m, 2H), 1 .77-1 .67 (m, 3H), 1 .63-1 .55 (m, 1 H), 1 .33-1 .12 (m, 9H).

Example 3: Preparation 2-[2-(Difluoromethoxy)ethylamino]-N-[(4- fluorophenyl)methyl]-4-[(4-hydroxycyclohexyl)amino]pyrimidin e-5- carboxamide (I-8)

a. CS2CO3, DMA; b. LiOH, MeOH, THF, H2O; c. HBTU, DIPEA, DMF.

(a) Methyl 2-[2-(difluoromethoxy)ethylamino]-4-[(4-hydroxycyclohexyl)- amino]pyrimidine-5-carboxylate (Compound D-1 )

[00149] To a stirred solution of methyl 2-chloro-4-[(4- hydroxycyclohexyl)amino]pyrimidine-5-carboxylate (C-1 , 100 mg, 3.49 mmol) in DMA (6 mL) was added 2-(difluoromethoxy)ethanamine hydrochloride (154 mg, 1 .05 mmol) followed by cesium carbonate (684 mg, 2.1 mmol) and the resulting mixture was stirred overnight at 90 °C. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate (1x) and brine (1x). The organic phase was dried over anhydrous sodium sulfate, filtered and chromatographed in 0 - 80% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo giving the desired product as a white solid. LCMS: 97%, m/z 361 .4 (MH ⁺ ). This compound was used directly in the subsequent step.

(b) 2-[2-(Difluoromethoxy)ethylamino]-4-[(4-hydroxycyclohexyl)- amino]pyrimidine-5-carboxylic acid (E-1 ):

[00150] To a stirred solution of methyl 2-[2-(difluoromethoxy)ethylamino]- 4-[(4-hydroxycyclohexyl)amino]pyrimidine-5-carboxylate (D-1 , 1 .6 g, 4.44 mmol) in methanol (16 mL) and THF (16 mL) was added lithium hydroxide (0.73 g, 31 .1 mmol) as a solution in water (16 mL) and the resulting mixture was stirred at 55 °C for 90 min. The mixture was concentrated in vacuo to remove methanol and THF, cooled to 0 °C and treated with 3 N HCI to adjust the pH to 2-3. The resulting suspension was filtered; the filter cake was rinsed with water and ether then dried in the oven giving the desired product as a white solid (1 .5 g, 92%). This material was used directly in the subsequent step. ¹ H NMR (400 MHz, d6-DMSO) δ 12.49 (brs, 1 H), 8.39 (s, 1 H), 8.24 (d, J = 8 Hz, 1 H), 7.65- 7.58 (m, 1 H), 6.69 (t, J = 76 Hz, 1 H), 4.58 (brs, 1 H), 4.01 -3.82 (m, 3H), 3.58- 3.41 (m, 3H), 2.03-1 .89 (m, 2H), 1 .89-1 .75 (m, 2H), 1 .35-1 .18 (m, 4H).

(c) 2-[2-(Difluoromethoxy)ethylamino]-N-[(4-fluorophenyl)methyl] -4- [(4-hydroxycyclohexyl)amino]pyrimidine-5-carboxamide (I-8)

[00151 ] To a stirred suspension of 2-[2-(difluoromethoxy)ethylamino]-4- [(4-hydroxycyclohexyl)-amino]pyrimidine-5-carboxylic acid (E-1 , 0.312 mmol) and (4-fluorophenyl)methanamine (0.468 mmol) in DMF (2 ml_) was added HBTU (142 mg, 0.375 mmol) followed by DIPEA (162 μΙ_, 0.936 mmol) and the resulting solution was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with NaHC03 (1 x) and brine (2x). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0 - 100% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo then stirred in hexanes; the resulting suspension was filtered to give the desired product as a white solid (74%).

[00152] H NMR (400 MHz, d6-DMSO) δ 8.83 (brs, 1 H), 8.70 (brs, 1 H), 8.43 (s, 1 H), 7.38-7.27 (m, 3H), 7.19-7.10 (m, 2H), 6.68 (t, J = 76 Hz, 1 H), 4.56 (d, J = 4 Hz, 1 H), 4.36 (d, J = 8 Hz, 2H), 3.99-3.89 (m, 2H), 3.88-3.78 (m, 1 H), 3.56-3.41 (m, 3H), 2.00-1 .88 (m, 2H), 1 .87-1 .77 (m, 2H), 1 .32-1 .16 (m, 4H)..

[00153] In a similar manner, using the above procedures, the following compounds of Formula I were prepared:

N-[4-

(difluoromethoxy)cycl

ohexyl]-2-[2-

(difluoromethoxy)ethyl

White solid 50 amino]-4-[(4- hy d roxy cy cl o h exy I )

-4 amino]- pyrimidine-5- carboxamide

¹ H NMR (400 MHz, d6-DMSO) δ 8.85 (brs, 1H), 8.37 (s, 1H), 7.86 (brs, 1H), 7.25 (brs, 1H), 6.72 (t, J = 78 Hz, 1H), 6.68 (t, J = 76 Hz, 1H), 4.56 (d, J = 4 Hz, 1H), 4.07-3.98 (m, 1H), 3.97-3.88 (m, 2H), 3.88-3.77 (m, 1H), 3.77-3.62 (m, 1H), 3.54-3.40 (m, 3H), 2.03-1.88 (m, 4H), 1.88-1.77 (m, 4H), 1.52-1.33 (M, 4H), 1.32-1.16 (m, 4H).

2-[2-

(difluoromethoxy)ethyl

amino]-4-[(4- hy d roxy cy cl o h exy I ) a m

White solid 74 ino]-N-[[4-

(morpholinomethyl)ph

-5 enyl]methyl]pyrimidin

e-5-carboxamide

¹ H NMR (400 MHz, d6-DMS0) δ 8.86 (brs, 1H), 8.68 (brs, 1H), 8.43 (s, 1H), 7.29-7.21 (m, 4H), 7.14 (brs, 1H), 6.68 (t, J = 76 Hz, 1H), 4.56 (d, J = 4 Hz, 1H), 4.36 (d, J = 4 Hz, 2H), 3.94 (s, 2H), 3.83 (brs, 1H), 3.60-3.53 (m, 4H), 3.53-3.41 (m, 5H), 2.37-2.29 (m, 4H), 1.99-1.89 (m, 2H), 1.87- 1.78 (m, 2H), 1.31-1.18 (m, 4H).

benzene- sulfonamide

tert-butyl (3S)-3-[[2- [2-

(difluoromethoxy)ethyl

^H ° ^" C1 -V amino]-4-[(4-

White solid quant hy d roxy cy cl o h exy I ) a m

F ^H ino]pyrimidine-5- carbonyl]amino]pyrroli

1-19 dine-1-carboxylate

¹ H NMR (400 MHz, d6-DMSO) δ 8.78 (brs, 1H), 8.41 (s, 1H), 8.12 (brs, 1H), 7.31 (brs, 1H), 6.68 (t, J = 76 Hz, 1H), 4.56 (d, J = 4 Hz, 1H), 4.37- 4.27 (m, 1H), 3.99-3.89 (m, 2H), 3.89-3.78 (m, 1H), 3.54-3.42 (m, 4H), 3.43-3.48 (m, 2H), 3.31-3.21 (m, 1H), 3.19-3.07 (m, 1H), 2.10-2.00 (m, 1 H), 1.99-1.90 (m, 2H), 1.90-1.77 (m, 2H), 1.41 (s, 9H), 1.32-1.20 (m, 4H). tert-butyl 3-[[2-[2-

(difluoromethoxy)ethyl

amino]-4-[(4- hy d roxy cy cl o h exy I ) a m

White solid quant ino]pyrimidine-5- carbonyl]amino]azetid

I-20 ine-1-carboxylate

¹ H NMR (400 MHz, d6-DMS0) δ 8.76 (brs, 1H), 8.56 (brs, 1H), 8.42 (s, 1 H), 7.35 (brs, 1 H), 6.68 (t, J = 76 Hz, 1 H), 4.56 (d, J = 4 Hz, 1 H), 4.57- 4.50 (m, 1H), 4.12-4.02 (m, 2H), 3.99-3.89 (m, 2H), 3.88-3.75 (m, 3H), 3.56-3.41 (m, 3H), 1.98-1.87 (m, 2H), 1.86-1.77 (m, 2H), 1.39 (s, 9H), 1.32-1.16 (m, 4H).

carboxamide

carboxamide ¹ H NMR: (400 MHz, d6-DMSO) δ 8.84-8.66 (m, 2H), 8.53-8.39 (m, 1 H),

7.78 (d, J = 8 Hz, 2H), 7.45 (d, J = 8 Hz, 2H), 7.35-7.22 (m, 5H), 7.15-7.07

(m, 2H), 4.56 (d, J = 4 Hz, 1 H), 4.44 (d, J = 8 Hz, 2H), 3.91 -3.77 (m, 1 H),

3.52-3.36 (m, 2H), 2.86-2.77 (m, 2H), 2.03-1.87 (m, 2H), 1.87-1.77 (m, 2H),

1.33-1.14 (m, 4H).

2-[[(1 S)-2-

(difluoromethoxy)-l- methyl-ethyl]amino]-

4-[(4- hydroxycyclohexyl)am White solid 30 ino]-N-[(4- sulfamoylphenyl)meth

-69 yl]pyrimidine-5- carboxamide

H NMR: (400 MHz, d6-DMSO) δ 8.84-8.67 (m, 2H), 8.46 (s, 1 H), 7.77 (d,

J = 8 Hz, 2H), 7.45 (d, J = 8 Hz, 2H), 7.31 (s, 2H), 7.20-7.10 (brs, 1 H), 6.68

(t, J = 76 Hz, 1 H), 4.54 (d, J = 4 Hz, 1 H), 4.44 (d, J = 4 Hz, 2H), 4.20-4.07

(m, 1 H), 3.99-3.76 (m, 2H), 3.76-3.65 (m, 1 H), 3.48-3.38 (m, 1 H), 1.98-1.86

(m, 2H), 1.85-1 .73 (m, 2H), 1.30-1.10 (m, 7H).

isopropyl (3S)-3-[[2- [[(1 S)-2-

(difluoromethoxy)-l- methyl-ethyl]amino]- 4-[(4- White solid quant hydroxycyclohexyl)am

ino]pyrimidine-5- carbonyl]amino]pyrroli

-70 dine-1-carboxylate

H NMR: (400 MHz, d6-DMSO) δ 8.85-8.62 (m, 2H), 8.41 (s, 1 H), 8.13 (s,

1 H), 7.25-7.1 1 (m, 1 H), 6.67 (t, J = 76 Hz, 1 H), 4.81 -4.71 (m, 1 H), 4.59-

4.52 (m, 1 H), 4.39-4.19 (m, 2H), 4.18-4.02 (m, 1 H), 3.97-3.75 (m, 2H), 3.77-

3.64 (m, 1 H), 3.61-3.40 (m, 4H), 3.24-3.10 (m, 1 H), 2.1 1-1.99 (m, 1 H), 2.00-

1.88 (m, 2H), 1.88-1 .74 (m, 3H), 1 .31-1.20 (bs, 3H), 1.20-1 .09 (m, 8H).

N-cyclopropyl-2- [[(1 S)-2-

HO (difluoromethoxy)-l -

\^ ' NH O » methyl-ethyl]amino]- Foamy

23 4-[(4- solid

-89

ί ^H hydroxycyclohexyl)am

ino]pyrimidine-5- carboxamide

MS: m/z: 400.3 (MH ⁺ )

[4-[[5-[2-

(difluoromethoxy)ethyl

carbamoyl]-2-[[(1 S)-2- (difluoromethoxy)-l -

White solid 75 methyl--95 ^H ethyl]amino]pyrimidin- 4-yl]amino]cyclohexyl]

acetate

MS: m/z: 496.3 (MH ⁺ )

Example 4: 2-[2-(difluoromethoxy)ethylamino]-4-[(4- hydroxycyclohexyl)amino]-N-[(3S)-3-piperidyl]pyrimidine-5-ca rboxamide

(1-47)

[00154] To a stirred solution of tert-butyl (3S)-3-[[2-[2-

(difluoromethoxy)ethylamino]-4-[(4-hydroxycyclohexyl)amin o]pyrimidine-5- carbonyl]amino]piperidine-1-carboxylate (270 mg, 0.549 mmol) in MeOH (2 ml_) was added hydrochloric acid (cone, aq., 229 μΙ_, 2.74 mmol) and the resulting mixture was stirred at 60 °C for 3 h. The mixture was diluted with saturated sodium carbonate and extracted with DCM (1 x 20 ml_, 4 x5 ml_). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo then triturated with diethyl ether and hexanes. The suspension was filtered to give the desired product as a white solid (202 mg, 92%). LCMS: 98%, m/z: 429.3 (MH+).

[00155] H NMR: (400 MHz, d6-DMSO) 58.88-8.70 (m, 1H), 8.38 (s, 1H), 7.79-7.71 (m, 1 H), 7.30-7.20 (m, 1 H), 6.67 (t, J = 74 Hz, 1 H), 4.56 (d, J = 4 Hz, 1H), 3.97-3.88 (m, 2H), 3.87-3.77 (m, 1H), 3.76-3.64 (m, 1H), 3.53-3.40 (m, 3H), 2.93-2.86 (m, 1H), 2.81-2.73 (m, 1H), 2.42-2.30 (m, 2H), 2.01-1.88 (m, 2H), 1.87-1.75 (m, 3H), 1.64-1.55 (m, 1H), 1.43-1.33 (m, 2H), 1.33-1.19 (m, 4H), 0.90-0.80 (m, 1H).

[00156] In a like manner, using the above procedure, the following compounds of Formula I were prepared.

2-[2-(difluoromethoxy)ethylamino]-4- [(4-hydroxycyclohexyl)amino]-N-

White solid 72 [(3R)-3-piperidyl]pyrimidine-5- carboxamide

H NMR: (400 MHz, d6-DMSO) δ 8.88-8.70 (m, 1H), 8.38 (s, 1H), 7.79-7.71 (m, 1H),-49

7.30-7.20 (m, 1H), 6.67 (t, J = 74 Hz, 1H), 4.56 (d, J = 4 Hz, 1H), 3.97-3.88 (m, 2H), 3.87-3.77 (m, 1H), 3.76-3.64 (m, 1H), 3.53-3.40 (m, 3H), 2.93-2.86 (m, 1H), 2.81-2.73 (m, 1H), 2.42-2.30 (m, 2H), 2.01-1.88 (m, 2H), 1.87-1.75 (m, 3H), 1.64-1.55 (m, 1H), 1.43-1.33 (m, 2H), 1.33-1.19 (m, 4H), 0.90-0.80 (m, 1H). MS: 429.3 (MH ⁺ ).

2-[2-(difluoromethoxy)ethylamino]-4- [(4-hydroxycyclohexyl)amino]-N-

White solid 15 [(3R)-3-piperidyl]pyrimidine-5- carboxamide

-35 ¹ H NMR: (400 MHz, d6-DMSO) δ 8.87 (brs, 1H), 8.38 (s, 1H), 7.85 (d, J = 8 Hz, 1H), 7.10 (brs, 1H), 6.67 (t, J = 76 Hz, 1H), 4.55 (d, J = 4 Hz, 1H), 4.19-4.03 (m, 1H), 3.97- 3.77 (m, 2H), 3.76-3.65 (m, 2H), 3.50-3.38 (m, 3H), 2.93 (d, J = 12 Hz, 1H), 2.47-2.40 (m, 3H), 2.00-1.87 (m, 2H), 1.86-1.77 (m, 1H), 1.70-1.62 (m, 2H), 1.41-1.14 (m, 7H). MS: 443.3 (MH+)

2-[[(1 S)-2-(difluoromethoxy)-1 -

^H°' U — NH 0 methyl-ethyl]amino]-4-[(4-

White solid 49

F O X j ^H hydroxycyclohexyl)amino]-N-(4- F ^H piperidyl)pyrimidine-5-carboxamide

-36 ¹ H NMR: (400 MHz, d6-DMSO) δ 8.88-8.67 (m, 1H), 8.37 (s, 1H), 8.13-7.94 (m, 1H), 7.22-7.08 (m, 1H), 6.67 (t, J = 76 Hz, 1H), 4.55 (s, 1H), 4.37-4.07 (m, 2H), 3.99-3.76 (m, 2H), 3.76-3.65 (m, 1H), 3.57-3.29 (m, 6H), 2.03-1.87 (m, 2H), 1.87-1.76 (m, 2H), 1.71-1.51 (m, 1H), 1.34-1.08 (m, 7H).

MS: 429.3 (MH+)

N-(azetidin-3-yl)-2-[2- (difluoromethoxy)ethylamino]-4-[(4--50 White Solid 70 hydroxycyclohexyl)amino]pyrimidine- 5-carboxamide ¹ H NMR: (400 MHz, d6-DMSO) δ 9.71 -9.22 (m, 2H), 9.16 (brs, 1 H), 8.88-8.71 (m, 1 H), 8.58 (s, 1 H), 6.69 (t, J = 76 Hz, 1 H), 4.79-4.68 (m, 1 H), 4.65-4.58 (m, 1 H), 4.14-4.01 (m, 3H), 3.99-3.89 (m, 2H), 3.89-3.78 (m, 1 H), 3.58-3.41 (m, 3H), 1 .99-1 .87 (m, 2H), 1 .87-1 .76 (m, 2H), 1 .33-1 .17 (m, 4H).

Example 5: N-[(3S)-1-(cyclopropanecarbonyl)-3-piperidyl]-2-[2- (difluoromethoxy)ethylamino]-4-[(4- hydroxycyclohexyl)amino]pyrimidine-5-carboxamide (I-56)

[00157] To a stirred solution of 2-[2-(difluoromethoxy)ethylamino]-4-[(4- hydroxycyclohexyl)amino]-N-[(3S)-3-piperidyl]pyrimidine-5-ca rboxamide (100 mg, 0.233 mmol) and cyclopropane carboxylic acid (20 mg, 0.233 mmol) in DMF (1 ml_) was added HBTU (132 mg, 0.350 mmol) followed by DI PEA (60 mg, 0.467 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate and washed with saturated sodium bicarbonate (1x) and brine (1x). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0 - 5% methanol in ethyl acetate. The product containing fractions were concentrated in vacuo and triturated with diethyl ether and hexanes giving the desired product as a white solid (75 mg, 64 %). LCMS: 98%, m/z 497.2 (MH ⁺ ).

[00158] ¹ H NMR: (400 MHz, d6-DMSO) 5 8.90-8.66 (m, 1 H), 8.39 (s, 1 H), 7.99-7.86 (m, 1 H), 7.34-7.21 (m, 1 H), 6.68 (t, J = 76 Hz, 1 H), 4.56 (d, J = 4 Hz, 1 H), 4.36-4.25 (m, 1 H), 4.00-3.89 (m, 2H),3.88-3.74 (m, 2H), 3.73-3.58 (m, 1 H), 3.54-3.39 (m, 2H), 3.29-3.14 (m, 1 H), 3.13-2.95 (m, 1 H), 2.94-2.80 (m, 1 H), 2.03-1 .67 (m, 6H), 1 .66-1 .38 (m, 2H), 1 .35-1 .19 (m, 4H), 0.91 -0.80 (m, 1 H), 0.79-0.56 (m, 4H).

[00159] In a like manner, using the above procedure, the following additional compounds of Formula I were prepared.

5-carboxamide

5-carboxamide

5-carboxamide

5-carboxamide

Example 6 N-[1 -[2-(difluoromethoxy)ethyl]-4-piperidyl]-2-[[(1 S)-2- (difluoromethoxy)-l -methyl -ethyl]amino]-4-[(4- hydroxycyclohexyl)amino]- pyrimidine-5-carboxamide (1-38)

[00160] To a stirred suspension of 2-[[(1 S)-2-(difluoromethoxy)-1 -methyl- ethyl]amino]-4-[(4-hydroxycyclohexyl)amino]-N-(4-piperidyl)p yrimidine-5- carboxamide dihydrochloride (51 mg, 0.1 mmol) and potassium carbonate (75 mg, 0.54 mmol) in ACN (2 ml_) was added 2-(difluoromethoxy)ethyl 4- methylbenzenesulfonate (80 mg, 0.3 mmol) followed by DIPEA (300 μΙ_) and the resulting mixture was stirred at 80 °C for 2 h then at room temperature overnight. The mixture was then diluted with ethyl acetate and washed with brine (2x). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0-10% (2M Nh in MeOH) in 1 : 1 ethyl acetate:dichloromethane. The product containing fractions were concentrated in vacuo giving the desired product as a white solid (20 mg, 32 %). LCMS: m/z 536.3 (MH ⁺ ).

[00161 ] ¹ H NMR: (400 MHz, d6-DMSO) 5 8.90-8.72 (m, 1 H), 8.38 (s, 1 H), 7.93-7.81 (m, 1 H), 7.18-7.06 (m, 1 H), 6.67 (t, J = 76 Hz, 1 H), 4.56 (d, J = 4 Hz, 1 H), 4.30-4.04 (m, 2H), 3.99-3.75 (m, 3H), 3.75-3.56 (m, 2H), 3.54-3.36 (m, 2H), 3.20-2.80 (m, 2H), 2.67-2.51 (m, 2H), 2.16-1 .88 (m, 3H), 1 .87-1 .63 (m, 3H), 1 .60-1 .42 (m, 2H), 1 .35-1 .1 1 (m, 8H).

[00162] In a like manner, using the above procedure, the following additional compounds of Formula I were prepared. Cpd AppearYield

Structure Nomenclature

ID ance (%)

2-(butylamino)-N-[1- [2-(difluoromethoxy)

^ΗΟ η ethyl]-4-piperidyl]-4- [(4- White solid 15 hydroxycyclohexyl)a

H

mino]pyrimidine-5-

1-13

carboxamide

H NMR: (400 MHz, d6-DMS0) δ 8.86-8.71 (m 1H), 8.36 (s, 1H), 7.87-7.75 (m, 1 H), 7.25-7.03 (m, 1 H), 6.68 (t, J = 76 Hz, 1 H), 4.56 (d, J = 4 Hz, 1 H), 3.98- 3.75 (m, 3H), 3.75-3.60 (m, 1H), 3.50-3.36 (m, 2H), 3.28-3.17 (m, 2H), 2.97- 2.80 (m, 2H), 2.62-2.53 (m, 2H), 2.17-1.88 (m, 4H), 1.88-1.78 (m, 2H), 1.78- 1.61 (m, 2H), 1.58-1.43 (m, 3H), 1.37-1.15 (m, 6H), 0.95-0.84 (m, 3H).

N-[(3S)-1-

(cyclopropylmethyl)- pyrrolidin-3-yl]-2-

[[(1S)-2-

(difluoromethoxy)-l-

White solid 15 methyl-ethyl]amino]-

I ^H 4-[(4-hydroxy- cyclohexyl)amino]py

I-58

rimidine-5- carboxamide

H NMR: (400 MHz, d6-DMSO) δ 8.82 (m, 1H), 8.42 (s, 1H), 8.19-8.03 (m, 1H), 7.25-7.06 (m, 1H), 6.67 (t, J = 76 Hz, 1H), 4.56 (d, J = 4 Hz, 1H), 4.40- 4.21 (m, 2H), 4.19-4.02 (m, 1H), 3.97-3.77 (m, 2H), 3.78-3.64 (m, 1H), 3.53- 3.37 (m, 2H), 2.99-2.78 (m, 1H), 2.78-2.61 (m, 1H), 2.42-2.21 (m, 2H), 2.19- 2.04 (m, 1H), 2.02-1.88 (m, 2H), 1.88-1.67 (m, 3H), 1.35-1.07 (m, 7H), 0.97- 0.79 (m, 1H), 0.54-0.39 (m, 2H), 0.21-0.03 (m, 2H).

Example 7: 4-[[2-[2-(difluoromethoxy)ethylamino]-5-[5- (morpholinomethyl)-2-thienyl]pyrimidin-4-yl]amino]cyclohexan ol (1-24)

(a) 4-[[5-bromo-2-[2-(difluoromethoxy)ethylamino]pynmidin-4- yl]amino]cyclohexanol

[00163] To a stirred suspension of 4-[(5-bromo-2-chloro-pyrimidin-4- yl)amino]cyclohexanol (800 mg, 2.61 mmol) and 2- (difluoromethoxy)ethanamine hydrochloride (1 .16 g, 7.83 mmol) in dioxane (10 ml_) was added potassium carbonate (2.16 g, 15.66 mmol) and the resulting mixture was stirred at 60-70 °C for 3 d. The mixture was colled to room temperature and filtered to remove solids and the filtrate was concentrated in vacuo and chromatographed in 0-60% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo then stirred in hexanes. The resulting suspension was fitered to give the desired product (510 mg, white solid). H NMR: (400 MHz, d6-DMSO) δ 7.83 (s, 1 H), 6.89-6.77 (m, 1 H), 6.66 (t, J = 76 Hz, 1 H), 6.18-6.05 (m, 1 H), 4.62 (d, J = 4 Hz, 1 H), 3.91 (t, J = 6 Hz, 2H), 3.90-3.78 (m, 1 H), 3.46-3.34 (m, 2H), 1 .89-1 .74 (m, 4H), 1 .50-1 .35 (m, 2H), 1 .29-1 .15 (m, 2H).

(b) 4-[[2-[2-(difluoromethoxy)ethylamino]-5-[5-(morpholinomethyl )-2- thien l]pyrimidin-4-yl]amino]cyclohexanol (I-

[00164] 4-[[5-bromo-2-[2-(difluoromethoxy)ethylamino]pyrimidin-4- yl]amino]cyclohexanol (75 mg, 0.196 mmol), 4-[[5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-thienyl]methyl]morpholine (73 mg, 0.236 mmol), sodium carbonate (62.6 mg, 0.590 mmol) and tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.0197 mmol) were charged to a flask and purged with nitrogen. Dioxane (2 mL) and water (0.5 mL) were added and the resulting mixture was stirred at 90 °C for 2 h. The mixture was diluted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo then chromatographed in 1 :4:5 (2 N NH3 in MeOH): DCM : EtOAc. The product containing fractions were concentrated in vacuo giving a foamy solid (90 mg). 1 H NMR: (400 MHz, d6-DMSO) δ 7.73 (s, 1 H), 6.95 (d, J = 4 Hz, 1 H), 6.91 (d, J = 4 Hz, 1 H), 6.89-6.82 (m, 1 H), 6.69 (t, J = 76 Hz, 1 H), 5.80-5.69 (m, 1 H), 4.54 (d, J = 4 Hz, 1 H), 3.95 (t, J = 6 Hz, 2H), 3.92-3.83 (m, 1 H), 3.66 (s, 2H), 3.63-3.54 (m, 4H), 3.53-3.43 (m, 2H), 3.45-3.43 (m, 1 H), 2.47-2.38 (m, 4H), 1 .93-1 .76 (m, 4H), 1 .40-1 .17 (m, 4H).

[00165] In a like manner, using the above procedure, the following additional compounds of Formula I were prepared.

Cpd AppearYield

Structure Nomenclature

ID ance (%)

4-[[2-[2-

(difluoromethoxy)et

hylamino]-5-[4-[(4- methylpiperazin-1 -

White solid 82% yl)methyl]phenyl]py

rimidin-4-

I-23 yl]amino]cyclohexa

nol

H NMR: (400 MHz, d6-DMSO) δ 7.59 (s, 1 H), 7.33 (d, J = 8 Hz, 2H), 7.26 (d, J = 8 Hz, 2H), 6.70-6.63 (m, 1 H), 6.68 (t, J = 76 Hz, 1 H), 5.58-5.48 (m, 1 H), 4.58 (d, J = 4 Hz, 1 H), 3.93 (t, J = 8 Hz, 2H), 3.92-3.82 (m, 1 H), 3.53- 3.44 (m, 5H), 2.46-2.22 (m, 8H), 2.15 (s, 3H), 1 .90-1 .75 (m, 4H), 1 .33-1 .15 (m, 4H).

Example 8: 4-[2-[[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]amino]-5-[4-

[(dimethylamino)methyl]phenyl]pyrrolo[2,3-d]pyrimidin-7- yl]cyclohexanol

(a) 7-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]-N-[(1 S)-2- (difluoromethoxy) -1-methyl-ethyl]pyrrolo[2,3-d]pyrimidin-2-amine

[00166] Tert-butyl-[4-(2-chloropyrrolo[2,3-d]pyhmidin-7-yl)cyclohexo xy]- dimethyl-silane (15.26 g, 41 .7 mmol), cesium carbonate (54 g, 167 mmol), BINAP (2.39 g, 3.84 mmol), (2S)-1 -(difluoromethoxy)propan-2-amine trifluoroacetate (14 g, 58.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.43 g, 3.836 mmol) were charged to a RBF with a stir bar under an inert atmosphere of nitrogen. Dioxane (140 ml_) was added and the resulting mixture was stirred at 90 °C overnight. The mixture was then diluted with ethyl acetate and washed with brine (2x). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0-30% ethyl acetate in hexanes. The produt containing fractions were concentrated in vacuo giving the desired product as an orange oil (15 g, 80%). H NMR: (400 MHz, d6-DMSO) δ 8.49 (s, 1 H), 7.18 (d, J = 4 Hz, 1 H), 6.69 (t, J = 76 Hz, 1 H), 6.61 (d, J = 8 Hz, 1 H), 6.32 (d, J = 4 Hz, 1 H), 4.44-4.34 (m, 1 H), 4.27-4.15 (m, 1 H), 4.02-3.91 (m, 1 H), 3.79-3.67 (m, 2H), 2.02-1 .78 (m, 6H), 1 .51 -1 .34 (m, 2H), 1 .20 (d, J = 8 Hz, 1 H), 0.88 (s, 9H), 0.07 (s, 6H).

(b) 5-bromo-7-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]-N-[(1 S)-2- (difluoromethoxy)-l -methyl -ethyl]pyrrolo[2,3-d]pyrimidin-2 -amine

butyl(dimethyl)silyl]oxycyclohexyl]-N-[(1 S)-2-(difluoromethoxy)-1 -methyl- ethyl]pyrrolo[2,3-d]pyrimidin-2-amine (12.9 g, 28 mmol) in DCM (280 mL) cooled to -20 °C was added NBS (4.04 g, 23 mmol) portionwise over 20 min. The mixture was concentrated onto silica gel and chromatographed in 0-20% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo giving the desired product as a white solid (5.0 g, 40%).

¹ H NMR: (400 MHz, d6-DMSO) δ 8.40 (s, 1 H), 7.42 (s, 1 H), 6.98 (brs, 1 H), 6.70 (t, J = 78 Hz, 1 H), 4.48-4.34 (m, 1 H), 4.30-4.15 (m, 1 H), 4.02-3.91 (m, 1 H), 3.82-3.66 (m, 2H), 2.03-1 .78 (m, 6H), 1 .51 -1 .34 (m, 2H), 1 .20 (d, J = 8 Hz, 1 H), 0.87 (s, 9H), 0.07 (s, 6H).

(c) 4-[5-bromo-2-[[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]amino] pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanol

[00168] To a stirred solution of 5-bromo-7-[4-[tert- butyl(dimethyl)silyl]oxycyclohexyl]-N-[(1 S)-2-(difluoromethoxy)-1 -methyl- ethyl]pyrrolo[2,3-d]pyrimidin-2-amine (2.0 g, 3.75 mmol) in THF (10 ml_) was added TBAF (1 .0 M in THF, 4 ml_, 4 mmol) and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with brine (1x), 1 : 1 brine:water (2x) and brine (1x). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 20-50% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo giving a sticky foam (1 .4 g, 90 %). ¹ H NMR: (400 MHz, d6-DMSO) δ 8.39 (s, 1 H), 7.42 (s, 1 H), 6.96 (d, J = 8 Hz, 1 H), 6.69 (t, J = 74 Hz, 1 H), 4.68 (d, J = 4 Hz, 1 H), 4.46-4.34 (m, 1 H), 4.29-4.16 (m, 1 H),4.01 -3.91 (m, 1 H), 3.78- 3.69 (m, 1 H), 3.57-3.44 (m, 1 H), 1 .98-1 .78 (m, 6H), 1 .40-1 .25 (m, 2H).

(d) 4-[2-[[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]amino]-5-[4-

[(dimethylamino)methyl]phenyl]pyrrolo[2,3-d]pyrimidin-7- yl]cyclohexanol

[00169] 4-[5-bromo-2-[[(1 S)-2-(difluoromethoxy)-1 -methyl- ethyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanol (648 mg, 1 .54 mmol), N,N-dimethyl-1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methanamine (484 mg, 1 .86 mmol), potassium carbonate (320 mg, 2.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (89 mg, 0.77 mmol) were charged to a RBF with a stir bar under an inert atmosphere of nitrogen. Dioxane (10 ml_) and water (2 ml_) were added and the resulting mixture was stirred at 100 °C for 5 h. The mixture was diluted with ethyl acetate and washed with brine (3x). The organic phase was dried, filtered and concentrated in vacuo, triturated with diethyl ether and filtered. The filtrate was concentrated in vacuo then chromatographed in 0-100% THF in ethyl acetate giving the desired product as a pale solid (440 mg, 60%). Example 9: N-[(1S)-2-(difluoromethoxy)-1 -methyl-ethyl]-5-[4-

[(dimethylamino)methyl]phenyl]-7-[(3R)-tetrahydrofuran-3- yl]pyrrolo[2,3- d]pyrimidin-2-amine

(a) 2-chloro-7-[(3R)-tetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidi ne

To a stirred suspension of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13 mmol) and triphenylphosphine (3.76 g, 14.3 mmol) was added (3S)-tetrahydrofuran- 3-ol (1 .15 ml_, 14.3 mmol) followed by diisopropyl azodicarboxylate (2.82 ml_, 14.3 mmol), dropwise over a period of 5 min. The resulting mixture was stirred at room temperature for 3 h. The mixture was then diluted with ethyl acetate and washed with brine (1x), water (1 x) and brine (1x). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0-50% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo then stirred in diethyl ether; filtered to collect desired product as a white solid (1 .5 g, 51 %). H NMR (400 MHz, d6-DMSO) δ 8.93 (s, 1 H), 7.68 (d, J = 4 Hz, 1 H), 6.74 (d, J = 4 Hz, 1 H), 5.46-5.39 (m, 1 H), 4.15-4.07 (m, 1 H), 4.00- 3.93 (m, 1 H), 3.92-3.80 (m, 2H), 2.58-2.47 (m, 1 H), 2.18-2.10 (m, 1 H).

(b) N-[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]-7-[(3R)-tetrahydrofuran-3- l]pyrrolo[2,3-d]pyrimidin-2-amine

2-chloro-7-[(3R)-tetrahydrofuran-3-yl]pyrrolo[2,3-d]pyhmi dine (1 .0 g, 4.47 mmol), (2S)-1 -(difluoromethoxy)propan-2-amine trifluoroacetate (2.14 g, 8.94 mmol), BINAP (278 mg, 0.447 mmol) and cesium carbonate (17.8 mmol) were charged to a RBF with stirbar; flask was flushed with nitrogen.

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%). ¹ H NMR (400 MHz, d6-DMSO) δ 8.52 (s, 1 H), 7.12 (d, J = 4 Hz, 1 H), 6.73-6.66 (brs, 1 H), 6.69 (t, J = 76 Hz, 1 H), 6.36 (d, J = 4 Hz, 1 H), 5.26-5.18 (m, 1 H), 4.31 -4.19 (m, 1 H), 4.1 1 -4.03 (m, 1 H), 3.99-3.91 (m, 2H), 3.87-3.80 (m, 2H), 3.79-3.72 (m, 1 H), 2.49-2.36 (m, 1 H), 2.20-2.10 (m, 1 H), 1 .21 (d, J = 8 Hz, 3H).

(c) tert-butyl N-[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]-N-[7-[(3R)- tetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidin-2-yl]carbamate

To a stirred solution of N-[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]-7-[(3R)- tetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidin-2-amine (1 .1 g, 3.52 mmol) in THF (10 mL) was added sodium hydride (60 wt. % in mineral oil, 169 mg, 4.23 mmol) followed by di-tert-butyl dicarbonate (922 mg, 4.23 mmol) and the resulting mixture was stirred at 60 °C overnight. The mixture was quenched with methanol and concentrated onto silica gel; chromatographed in 0-60% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo giving the desired product as a pale yellow oil (1 .4 g, quantitative). ¹ H NMR (400 MHz, d6-DMSO) δ 8.95 (s, 1 H), 7.66 (d, J = 4 Hz, 1 H), 6.70 (t, J = 76 Hz, 1 H), 6.68 (d, J = 4 Hz, 1 H), 5.42-5.33 (m, 1 H), 4.63-4.54 (m, 1 H), 4.23- 4.15 (m, 1 H), 4.15-4.07 (m, 1 H), 4.04-3.96 (m, 2H), 3.92-3.82 (m, 2H), 2.57- 2.47 (m, 1 H), 2.26-2.16 (m, 1 H), 1 .35 (s, 9H), 1 .12 (d, J = 4 Hz, 3H). (d) tert-butyl N-[5-bromo-7-[(3R)-tetrahydrofuran-3-yl]pyrrolo[2,3- d]pyrimidin-2-yl]-N-[(1S)-2-(difluoromethoxy)-1 -methyl -ethyl]carba mate

tert-butyl N-[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]-N-[7-[(3R)- tetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidin-2-yl]carbamate (1 .4 g, 3.94 mmol) was stirred in ethyl acetate and cooled to -20 °C. The mixture was treated with n-bromosuccinimide (604 mg, 3.94 mmol) then warmed slowly to room temperature. After 45 min, TLC analysis shows that the reactin is complete. The mixture was concentrated onto silica gel then chromatographed in 0-40% ethyl acetate in hexanes; the product containing fractions were concentrated in vacuo giving the desired product as a clear oil (1 .6 g, 96%). ¹ H NMR (400 MHz, d6-DMSO) δ 8.88 (s, 1 H), 7.88 (s, 1 H), 6.68 (t, J = 76 Hz, 1 H), 5.42-5.34 (m, 1 H), 4.66-4.56 (m, 1 H), 4.23-4.08 (m, 2H), 4.03-3.93 (m, 2H), 3.93-3.80 (m, 2H), 2.55-2.45 (m, 1 H), 2.29-2.18 (m, 1 H), 1 .37 (s, 9H), 1 .14 (d, J = 8 hz, 3H).

(e) tert-butyl N-[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]-N-[5-[4-

[(dimethylamino)methyl]phenyl]-7-[(3R)-tetrahydrofuran-3- yl]pyrrolo[2,3- d] rimidin-2-yl]carbamate

tert-butyl N-[5-bromo-7-[(3R)-tetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimi din-2-yl]- N-[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]carbamate (800 mg, 1 .6 mmol), N,N-dimethyl-1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methanamine (549 mg, 2.1 mmol), potassium carbonate (442 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol) were charged to a RBF with stirbar and purged with nitrogen. Dioxane (10 mL) and water (2 mL) was added and the resulting mixture was stirred for 5 h at 90 °C. The mixture was diluted with ethyl acetate and washed with brine (1 x). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0-10% (2 M Nhb in MeOH) in 1 : 1 ethyl acetate:dichloromethane. The product containing fractions were concentrated in vacuo giving the desired product as a foam (710 mg, 80%). ¹ H NMR (400 MHz, d6-DMSO) δ 9.31 (s, 1 H), 8.02 (s, 1 H), 7.78 (d, J = 8 Hz, 2H), 7.38 (d, J = 8 Hz, 2H), 6.88 (brs, 1 H), 6.71 (t, J = 76 Hz, 1 H), 5.47-5.38 (m, 1 H), 4.68- 4.57 (m, 1 H), 4.26-4.14 (m, 2H), 4.06-3.99 (m, 2H), 3.99-3.93 (m, 1 H), 3.93- 3.85 (m, 1 H), 3.42 (s, 2H), 2.61 -2.53 (m, 1 H), 2.38-2.27 (m, 1 H), 2.17 (s, 6H), 1 .38 (s, 6H), 1.15 (d, J = 8 Hz, 3H).

(f) N-[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]-5-[4-

[(dimethylamino)methyl]phenyl]-7-[(3R)-tetrahydrofuran-3- yl]pyrrolo[2,3- d rimidin-2-amine

To a stirred solution of tert-butyl N-[(1 S)-2-(difluoromethoxy)-1 -methyl-ethyl]-N- [5-[4-[(dimethylamino)methyl]phenyl]-7-[(3R)-tetrahydrofuran -3-yl]pyrrolo[2,3- d]pyrimidin-2-yl]carbamate (700 mg, 1 .28 mmol) in DCM (4 mL) was added TFA (4 mL) and the resulting mixture was stirred at room temperature for 2.5 h. The mixture was diluted with ethyl acetate and washed with NaOH/brine (2x). THe organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0-5% (2 M NH3 in MeOH) in 1 : 1 ethyl acetate:dichloromethane. The product containing fractions were concentrated in vacuo giving the desired product as a pale oil (380 mg, 66%). ¹ H NMR (400 MHz, d6-DMSO) δ 8.89 (s, 1 H), 7.65 (d, J = 8 Hz, 2H), 7.52 (s, 1 H), 7.32 (d, J = 8 Hz, 2H), 6.91-6.84 (brs, 1H), 6.70 (t, J = 78 Hz, 1H), 5.32-5.22 (m, 1H), 4.34-4.22 (m, 1H), 4.18-4.09 (m, 1H), 4.03-3.94 (m, 2H), 3.94-3.83 (m, 2H), 3.82-3.74 (m, 1H), 3.39 (s, 2H), 2.51-2.40 (m, 1H), 2.34-2.19 (m, 1H), 2.17 (s, 6H), 1.23 (d, J = 8 Hz, 3H).

In a like manner, using the above procedueres, the following additional compounds of Formula I were prepared:

yl]cyclohexanol

yl]cyclohexanol

(d, J

4.69 (m, =

yl]cyclohexanol

yl]cyclohexanol

OH 1 H-pyridin-2-one

d]pyrimidin-2-amine ¹ H NMR (400 MHz, d6-DMSO) δ 8.89 (s, 1 H), 7.66 (d, J = 8 Hz, 2H), 7.51 (s, 1 H), 7.32 (d, J = 8 Hz, 2H), 6.90-6.83 (brs, 1 H), 6.70 (t, J = 76 Hz, 1 H), 5.32- 5.23 (m, 1 H), 4.34-4.21 (m, 1 H), 4.m, 1 H), 4.18-4.08 (m, 1 H), 4.04-3.94 (m, 2H), 3.94-3.84 (m, 2H), 3.83-3.75 (m, 1 H), 3.39 (s, 2H), 2.48-2.40 (m, 1 H), 2.28-2.19 (m, 1 H), 2.17 (s, 6H), 1.23 (d, J = 8 Hz, 3H).

Biological Testing

Example 10: MER and AXL protocols:

Compound Preparation and Assay Controls

[00170] All compounds are prepared to 50x final assay concentration in 100% DMSO. This working stock of the compound was added to the assay well as the first component in the reaction, followed by the remaining components as detailed in the general assay protocols below. In the standard KinaseProfiler service, there was no pre-incubation step between the compound and the kinase prior to initiation of the reaction. Positive control wells contained all components of the reaction, except the compound of interest; however, DMSO (at a final concentration of 2%) was included in these wells to control for solvent effects. Blank wells contained all components of the reaction, with a reference inhibitor replacing the compound of interest. This abolished kinase activity and established the base-line (0% kinase activity remaining). Note that for lipid kinase assays, the blank wells were generated by omitting the enzyme (rather than by including a reference inhibitor to abolish the signal).

Mer (h)

[00171 ] Mer (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 mM NaCI, 250 μΜ 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 μΙ_ 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)

[00172] Axl (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μΜ 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 μΙ_ 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.

[00173] 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.

Table 1

-21 A C-22 A 53%-23 C 92%-24 B 93%-25 A 78%-26 A 84%-27 B 85%-28 B 89%-29 A 84%-30 B 88%-31 B 95%-32 A 89%-33 A 77%-34 A 64%-35 A 85%-36 A 88%-37 A 78%-38 A 93%-39 A 99%-40 A 84%-41 A 72%-43 B 37%-44 A 80%-45 B 92%-46 A 77%-47 A 38%-49 B 62%-50 B 80%-51 A 93%-52 B 110%-53 A 101%-54 B 108%-55 A 102%-56 B 88%-57 B 49%-58 A 104%-59 A 111%-60 A 100%-61 A 108%-62 A 107%-63 A 49%-64 A 46% 1-65 A 104%

1-66 A 72%

1-67 A 39%

1-69 A 39%

1-70 A 70%

1-71 A 74%

1-72 A 26%

1-73 A 96%

1-74 B 91%

1-75 A 70%

1-76 A B

1-77 A 3%

1-78 B 118%

1-79 B 113%

1-80 B 107%

1-81 B 103%

1-82 B 94%

1-83 A 88%

1-84 B 105%

1-85 A 37%

1-86 A B

1-87 A B

1-88 A 48%

1-89 B 100%

1-90 A 28%

1-91 A C

1-92 A 11%

1-93 A 65%

1-94 A 70%

1-95 B 90%

1-96 A 49%

1-97 A 19%

1-98 A 39%

1-99 A 52%-100 A 55%-101 B 84%-102 A 19%-103 C 96%-104 A 40%-105 A 35%-106 A 55%-107 A 33% 1-108 A 69%

1-109 A 43%

1-110 A 30%

1-111 A 4%

1-112 A 3%

1-113 A 10%

1-114 A 13%

1-115 A 15%

1-116 A 11%

1-117 A 13%

1-118 B 75%

1-119 C 96%

1-120 A 48%

1-121 B 58%

Example 11 : Flt3, TrkA, Mlk3, and Sik3 Binding Assay Protocols:

Compound Preparation and Assay Controls

[00174] All compounds were prepared to 50x final assay concentration in 100% DMSO. This working stock of the compound was added to the assay well as the first component in the reaction, followed by the remaining components as detailed in the general assay protocols below. In the standard KinaseProfiler service, there was no pre-incubation step between the compound and the kinase prior to initiation of the reaction. Positive control wells contained all components of the reaction, except the compound of interest; however, DMSO (at a final concentration of 2%) was included in these wells to control for solvent effects. Blank wells contained all components of the reaction, with a reference inhibitor replacing the compound of interest. This abolished kinase activity and established the base-line (0% kinase activity remaining).

Assay Protocol

[00175] 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 μΙ_ 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.

[00176] Capacity for Flt3, TrkA, Mlk3, and Sik3 inhibition were assayed and the results are presented as an ICso in Table 2.

Table 2

Example 12: Evaluation of P-gp efflux

[00177] P-glycoprotein (Pgp) 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.

Protocol

[00178] Human, epithelial Caco-2 cells (CRL-2102 (C2BBe1 )) were seeded at a density of 40,000 cells/well, on high-density PET membrane inserts (1 .0 μιη pore size, 0.31 cm ² surface area) and utilized on day 21 or 22 days (post-seeding). At this stage of growth, cell monolayers were fully polarized and differentiated.

[00179] 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 μΜ metoprolol (positive control), 5 μΜ atenolol (negative control) and 100 μΜ lucifer yellow. The buffer in the receiver chamber also contained 1 % bovine serum albumin (BSA). The dosing solution concentration was 5 μΜ in the assay buffer. Digoxin (20 μΜ) was used as Pgp substrate control. [00180] For suspected Pgp substrate, 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 μΜ with compound at 5 μΜ.

[00181 ] Cell monolayers were dosed on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37°C in a shaker (65 rpm). Samples were taken from the donor and receiver chambers at 120 minutes. Each determination was performed in duplicate.

[00182] 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.

Results

[00183] Results are shown in Table 3.

Table 3: Permeability results compared to benchmark drugs (MRX-6313) in Caco-2 cell line

Example 13: Human and Mouse Microsomal Stability

Protocol

[00184] For Phase I analysis, representative compounds of the application (10 mM stock in DMSO) were incubated at a final concentration of 1 μΜ (this concentration was assumed to be well below the Km values to ensure linear reaction conditions). Working stocks were initially diluted to a concentration of 40.0 μΜ in 0.1 M potassium phosphate buffer before addition to the reaction vials. Pooled mouse (CD-1 , male) or human (50 donors) liver microsomes were utilized at a final concentration of 0.5 mg/ml. Duplicate wells were used for each time point (0 and 30 minutes). Reactions were carried out at 37°C in a shaker, and the final concentration of DMSO was kept constant at 0.01 %. The final volume for each reaction was 100 μΙ_, which includes the addition of an NADPH-Regeneration solution (NRS) mix. 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. Upon completion of the 30 minute time point, reactions were terminated by the addition of 1 .5-volumes (150 μΙ_) 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 μΙ_ of supernatant was subsequently transferred to a new 96 well microplate for LC/MS analysis.

[00185] 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.

„. . . Area count o f t=20 min .

00186 % remaining = x 100

Area count of t=0 min

Results & Discussion

[00187] 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

Example 14: CYP450 Inhibition

Experimental Procedure:

[00188] Prepare 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 μΜ. Transfer 1 μΙ_ 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 μΜ. All experiments are performed in duplicate.

Table 5. CYP450 Control Compounds

CYP Isoform Control Compound

CYP 1A2 furafylline

CYP 3A4 ketoconazole

CYP 2C9 sulfaphenazole

CYP 2C19 N-3-benzylnirvanol

CYP 2D6 quinidine

Results

[00189] Results for representative compounds of the application are presented in Table 6. Table 6. MERTK Inhibitor CYP450 Inhibition

Example 15: In Vivo Pharmacokinetics

[00190] 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.

[00191 ] Ninety-six (96) male CD-1 mice (25-30 g) from Charles River Laboratories were acclimatized for a minimum of 5 days prior to use. Animals dosed orally were deprived of food overnight and fed ~2 h following dosing.

[00192] Administered compounds were suspended in the following formulations: Table 7. Formulation conditions for MERTK inhibitors

[00193] Only animals in good health were used for dosing. Since the effects of the test article on the animals may not be known, animals were closely observed for 1 h following dosing and at each sample collection time point for the remainder of the study. The observations included: grooming, eating, drinking, level of activity, depth and frequency of breathing and gait. Any adverse reactions to the administration of the test material were noted. Mice experiencing a severe level of pain or were humanely euthanized using isoflurane anesthesia followed by cardiac puncture.

[00194] Blood was collected for each time point (0.0833, 0.25, 0.5, 1 , 2, 4, 6 & 8 h) via cardiac puncture (three mice per time-point). Approximately 0.6 mL of blood was collected into 0.8 mL K2EDTA coated tubes. Blood tubes were centrifuged at 3200 x g for 5 min at 4°C and plasma transferred into 1 .5 mL microfuge tubes. One vial of plasma was collected for each time point. [00195] 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.

[00196] Results are shown in Table 8.

Table 8:. Pharmacokinetic parameters for MERTK inbitors

Example 16: hERG mediated Cardiotoxicity

[00197] Compound affinity for hERG was tested using an automated patch-clamp system. CHO-K1 (Chinese 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 μΜ) are used for IC50 determination. After whole cell configuration is achieved (intracellular solution (mM): 130 KCI, 10 NaCI, 1 MgC , 10 EGTA, 5 MgATP, 10 HEPES (pH adjusted to 7.2 with KOH) and extracellular solution (mM): 137 NaCI, 4 KCI, 1 .8 CaCI ₂ , 1 MgCI ₂ , 10 D(+)-Glucose, 10 HEPES (pH adjusted to 7.4 with NaOH)), the cell is held at - 80 mV. A 50 ms pulse to -40 mV is delivered to measure the leaking current, which is subtracted from the tail current on-line. Then 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. Then 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.

[00198] 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).

Results

[00199] Results for representative compounds of the application are presented in Table 9.

Table 9. hERG inhibition constants for selected MERTK inhibitors

1-75 >100

1-85 70

1-97 >100

1-102 >100

Example 17: Inhibition of efferocytosis by MERTK inhibitors

[00200] 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.

[00201 ] After incubation, 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.

[00202] 10μΜ stocks of MERTK inhibitor solutions in X-VIVO 15 + 20ng/ml_ rhM-CSF were serially diluted and added to the primed macrophages. The MERTK inhibitor treated macrophages were incubated for 30 min. under standard conditions before the addition of heat shocked Jurkat cells. Heat shock was accomplished by incubating Jurkat cells at 60 °C for 5 min. These cells were transferred to an incubator (37 °C in an atmosphere of 5% CO2) and permitted to rest for 1 hour. Heat shocked Jurkats were added to inhibitor treated MDM cells such that a 5: 1 ratio of target to primed macrophage ratio was achieved. Upon the introduction of Jurkat cells, the plate was swirled gently to mix its contents, covered with foil, and then incubated at 37 °C in an atmosphere of 5% CO2 for 2 hours.

[00203] After incubating, each well was washed with 200 μΙ_ 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.

[00204] The washed MDM cell pellet was resuspended in 25 μΙ_ 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 μΙ_ 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 μΙ_ of BD Stabalizing Fixative and the plate wraped with foil and refrigerated overnight. Percent efferocytosis was determined on a FACSVerse instrument the following day.

Results

[00205] Results for representative compounds of the application are presented in Table 10.

Table 10. MERTK inhibitor efferocytosis assay results

Example 18. Maximum Tolerated Dose Study in mice (QD)

[00206] 7-9 week-old C57BL/6 female mice were dosed orally with MRX- 2843 (50mg/kg or 75mg/kg, or 120mg/kg) or I-87 (50mg/kg or 75mg/kg, or 120mg/kg) or I-76 (75mg/kg) or vehicle (0.5% Tween-80 in H20) once per day for a total of 4 days with n=3-4 mice per group. Mice were weighed and survival (study endpoint: bodyweight loss of 20% or more) was tracked on day 0, 1 , 2, 3, 7, 8, 9, 10. Results:

[00207] Doses up to 75 mg/kg QD were well tolerated for MRX-2843 (benchmark compound) and 1-87. Significant weight loss was observed in animals treated with 120 mg/kg of MRX-2843 under the same dosing method (PO) and regime (QD x 1 a day x 4 days). Representative data is illustrated in Fig. 1 .

[00208] While the present application has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

[00209] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.