Derivatives of 2-oxo-N-(4-(pyrimidin-4-yloxy / thio)phenyl)-1,2-dihydropyridine-3-carboxamide for use as therapeutic protein kinase inhibitors

Abstract

Disclosed are 2-oxo-N-(4-(pyrimidin-4-yloxy / thio)phenyl)-1,2-dihydropyridine-3-carboxamide derivatives for use in the prevention and / or treatment of proliferative cell diseases and conditions, including cancer. The compounds are capable of inhibiting cell proliferation and are believed to induce apoptosis in cancer cells by inhibiting the activity of receptor tyrosine kinases (RTKs), such as TYRO3, AXL, MER, and / or MET. The compounds have the general structure I shown below: [Formula 1] JPEG2023532010000018.jpg56156

Description

[Technical Field]

[0001] The present disclosure relates to a novel class of inhibitors of protein kinases that are useful in the treatment of proliferative cell diseases and conditions, including cancer.

[0002] Priority document This application claims priority from Australian Provisional Patent Application No. 2020902392, entitled "Protein kinase inhibitors for therapy," filed July 10, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0003] There is an ongoing need to identify and develop new compounds for treating proliferative diseases and conditions, including cancer. Among the various "targets" for potential antiproliferative compounds, a group of enzymes known as receptor tyrosine kinases (RTKs) are being explored. RTKs are cell surface proteins that transmit signals from the cell surface environment to the cytoplasm and nucleus, regulating cellular events such as survival, growth, proliferation, differentiation, adhesion, and migration. Genetic dysfunction due to mutation or deletion can lead to the aberrant expression of protein kinases, which is associated with tumorigenesis and progression.

[0004] The TAM subfamily consists of three RTKs: TYRO3, AXL, and MER (Graham et al., Nat Rev Cancer 14:769-785, 2014; Linger et al., Adv Cancer Res 100:35-83, 2008). TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Two ligands, growth arrest specific 6 (GAS6) and protein S (PROS1), have been identified for TAM kinases. GAS6 can bind to and activate all three TAM kinases, while PROS1 is a ligand for MER and TYRO3 (Graham et al., supra). Activation of the TAM receptor leads to signaling in several growth-promoting pathways, including the PI3K / AKT, MAPK, and PKC pathways. Furthermore, TAM receptors are essential regulators of epithelial-mesenchymal transition (EMT), which leads to resistance to therapy, metastasis, and immune cell suppression, suggesting an important role for TAMs in cancer biology and therapy.

[0005] AXL (also known as UFO, ARK, JTK11, and TYRO7) was originally identified as a transforming gene from DNA of patients with chronic myeloid leukemia (O'Bryan et al., Mol Cell Biol 11:5016-5031, 1991; Graham et al., supra). GAS6 binds to AXL, subsequently autophosphorylating and activating the AXL kinase (Stitt TN et al., Cell 80(4):661-670, 1995; Li et al., Oncogene 1;28(39):3442-3455, 2009). AXL activates several downstream signaling pathways, including PI3K / AKT, Raf / MAPK, and PKC (Feneyrolles et al., Mol Cancer Ther 13:2141-2148, 2014). Overexpression of AXL has been shown to be a key risk factor for acute myeloid leukemia (Hong CC et al., Cancer Lett 268(2):314-324, 2008), breast cancer (Berclaz G et al., Ann Oncol 12(6):819-824, 2001; Zhang YX et al., Cancer Res 68(6):1905-1915, 2008; Gjerdrum C et al., Proc Natl Acad Sci USA 107(3):1124-1129, 2010), gastric (Wu CW et al., Anticancer Res 22(2B):1071-1078, 2002), and lung cancer (Shieh YS et al., Neoplasia 7(12):1058-1064, 2005), melanoma (Quong RY et al., Melanoma Res 4(5):313-319, 1994), osteosarcoma (Han J et al., Biochem Biophys Res Commun 435(3):493-500, 2013), and renal cell carcinoma (Gustafsson A et al., Clin Cancer Res 15(14):4742-4749, 2009). More recently, the AXL receptor has been found to mediate resistance to several different cancer therapies, including chemotherapy, radiation, and inhibitors of EGFR and PI3K.Therefore, targeting AXL may be a promising strategy for the treatment of various malignancies.

[0006] MER kinase (also known as MERTK, EYK, RYK, RP38, NYK, and TYRO12) was originally identified as a phosphoprotein from a lymphoblastoid expression library (Graham et al., Oncogene 10:2349-2359, 1995). Both GAS6 and PROS1 can bind to MER and induce phosphorylation and activation of MER kinase. Similar to AXL, activation of MER also induces downstream signaling pathways, including PI3K / AKT and Raf / MAPK. Aberrant expression of MER in various malignant tumors, such as melanoma (Schlegel et al., J Clin Invest 123(5):2257-2267, 2013), gastric cancer (Yi et al., Oncotarget 8(57):96656-96667, 2017), leukemia (Linger et al., Blood 122(9):1599-1609, 2013; Lee-Sherick et al., Oncogene 32(46):5359-5368, 2013), and lung cancer (Xie et al., Oncotarget 6(11):9206-9219, 2015), plays a crucial role in the carcinogenesis process.

[0007] TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, and ETK2) was originally identified through PCR-based cloning studies (Lai et al., Neuron 6:691-670, 1991). Both ligands, GAS6 and PROS1, can bind to and activate TYRO3. TYRO3 appears to play important roles in immunity, phagocytosis, hemostasis, and neurological diseases. Overexpression of TYRO3 and its ligands has been shown in a wide range of cancers and correlates with poor prognosis in various tumor types. Through AKT / NFκB signaling, TYRO3 exerts pro-survival effects and promotes cancer cell proliferation (Crosier et al., Leuk Lymphoma 18:443-449, 1995). TYRO3 and AXL protein levels are undetectable in normal thyroid cells but are significantly upregulated and activated in thyroid cancer cells (Avilla et al., Cancer Res 71:1792-1804, 2011). Activated TYRO3 promotes cancer cell survival, invasion, migration, proliferation, and transformation. TYRO3 has also been shown to promote chemoresistance in breast cancer (Ekyalongo et al., Anticancer Res 34:3337-3345, 2014) and ovarian cancer (Lee et al., Mol Med Rep 12:1485-1492, 2015). TYRO3 promotes phagocytosis and inhibits inflammation, enabling resistance to antitumor treatments for further cancer progression (Liu et al., J Immunother 35:299-308, 2012). Taken together, the studies suggest that inhibition of TYRO3 and its signaling pathways may have therapeutic effects in cancer treatment.

[0008] TAM inhibition not only has direct activity against neoplastic cells but also activates anti-cancer immune responses (Akalu YT et al. Immunol Rev 276(1):165-177, 2017). Therefore, TAM inhibitors represent an attractive approach for cancer treatment. Furthermore, TAM inhibitors can be combined with other targeted therapies, chemotherapy, radiation, or immunotherapy agents to achieve maximum efficacy in the clinic (Yokoyama et al., Cancer Res 79:1996-2008, 2019).

[0009] MET, also known as the N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene, is a proto-oncogene that encodes the receptor tyrosine kinase c-MET for hepatocyte growth factor (HGF) (Bladt et al., Nature 376:768-771, 1995; Sattler et al., Curr Oncol Rep 102-108, 2007). HGF binding leads to the dimerization and autophosphorylation of c-MET, which activates MAPK, PI3K, SRC, and STAT signaling pathways (Ma et al., Cancer Metastasis Rev 309-325, 2003). Ectopic MET expression is widely observed in various malignancies, particularly in non-small cell lung cancer, gastrointestinal cancer, and hepatocellular carcinoma (Ichimura et al., Jpn J Cancer Res 87:1063-1069, 1996; Siegfried et al., Ann Thorac Surg 66:1915-1918, 1998; Goyal et al., Clin Cancer Res 19:2310-2318, 2013; Hack et al., Oncotarget 5:2866-2880, 2014). Therefore, MET has become an attractive target for cancer therapy and drug development.

[0010] The present application now identifies a novel class of compounds for use in the prevention and / or treatment of proliferative diseases and conditions, including cancer. Without being bound by theory, it is believed that these novel compounds can inhibit cell proliferation, therapeutic resistance, metastasis, and immune cell suppression by inhibiting the activity of one or more protein kinases, such as RTKs, and in particular one or more TAM and / or MET family protein kinases, and / or mutant forms thereof. Summary of the Invention

[0011] The present invention relates to compounds of formula I: [ka] [In the formula, X is O or S; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are H, alkyl, and alkyl-R, respectively. 12 , aryl, aryl-R 12 , aralkyl, aralkyl-R 12 , alicyclic, heterocyclic, halogen, NO2, CN, CF3, O-CF3, OH, O-alkyl, COR 12 , COOR 12 , O-aryl, OR 12 , amino, NH-alkyl, NH-aryl, N-(alkyl)2, N-(aryl)2, N-(alkyl)(aryl), NH-R 12 , NH-alkyl-N(alkyl)2, N-(R 12 )(R 13 ), N-(alkyl)(R 12 ), N-(aryl)(R 12 ), COOH, CONH2, CONH-alkyl, CONH-aryl, CONH-alicyclic, CON-(alkyl)(R 12), CON(aryl)(R 12 ), CONH-R 12 , CON-(R 12 )(R 13 ), S-alkyl, SO3H, SO2-alkyl, SO2-alkyl-R 12 , SO2-aryl, SO2-aryl-R 12 , SO2NH2, SO2NH-R 12 , SO2N-(R 12 )(R 13 ), CO-alkyl, CO-alkyl-R 12 , CO-aryl, and CO-aryl-R 12 wherein the alkyl, aryl, aralkyl, alicyclic, and heterocyclic groups are independently selected from the group consisting of C 1-6 Alkyl, OC 1-6 may be optionally substituted with one or more groups selected from alkyl, CN, OH, NH2, COOH, CONH2, CF3, OCF3, and halogen; In the formula, R 12 and R 13 is COOH, SO3H, OSO3H, SONHCH3, SONHCH2CH3, SO2CH3, SO2CH2CH3, PO3H2, and OPO3H2, mono-, di-, and polyhydroxylated alicyclic groups, di- or polyhydroxylated aliphatic or aryl groups, and one or more C 1-6 are independently selected from N-, O-, and / or S-containing heterocyclic groups optionally substituted with alkyl, hydroxyl, carbonyl, amino, or alkoxy groups, wherein said N-, O-, and / or S-containing heterocyclic groups can optionally be attached to the remainder of the compound via an alkyl, amine, alkoxy, or ketone bridge; R 1 , R 2 and R 3 At least two of are other than H, and R 11 is phenyl-R 14 is selected from where R 14 is C 1-6 Alkyl, OC 1-6is selected from alkyl, CN, OH, NH2, COOH, CONH2, CF3, OCF3, and halogen. or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0012] In a second aspect, the present disclosure provides the use of a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating cancer or another proliferative cell disease or condition.

[0013] In a third aspect, the present disclosure provides a method of treating cancer, or another proliferative cell disease or condition, in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier, diluent and / or excipient.

[0014] In a fourth aspect, the present disclosure provides the use of a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for treating cancer or another proliferative cell disease or condition.

[0015] In a fifth aspect, the present disclosure provides a pharmaceutical composition or medicament comprising a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0016] In a sixth aspect, the present disclosure provides a method of regulating protein kinase activity in a cell, comprising introducing into or contacting said cell with an effective amount of a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present application now identifies a novel class of pyrimidin-2-amine derivatives, in particular derivatives of 2-oxo-N-(4-(pyrimidin-4-yloxy / thio)phenyl)-1,2-dihydropyridine-3-carboxamide, that have desired biological activity and are suitable for use in the prevention and / or treatment of proliferative cell diseases and conditions, including cancer (e.g., the compounds can inhibit cell proliferation and induce apoptosis in cancer cells by inhibiting the activity of receptor tyrosine kinases (RTKs), such as TYRO3, AXL, MER, and / or MET).

[0018] According to a first aspect, the present disclosure provides a compound of formula I, as shown below: [ka] [In the formula, X is O or S; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are H, alkyl, and alkyl-R, respectively. 12 , aryl, aryl-R 12 , aralkyl, aralkyl-R 12 , alicyclic, heterocyclic, halogen, NO2, CN, CF3, O-CF3, OH, O-alkyl, COR 12 , COOR 12 , O-aryl, OR 12 , amino, NH-alkyl, NH-aryl, N-(alkyl)2, N-(aryl)2, N-(alkyl)(aryl), NH-R 12 , NH-alkyl-N(alkyl)2, N-(R 12 )(R 13 ), N-(alkyl)(R 12 ), N-(aryl)(R 12), COOH, CONH2, CONH-alkyl, CONH-aryl, CONH-alicyclic, CON-(alkyl)(R 12 ), CON(aryl)(R 12 ), CONH-R 12 , CON-(R 12 )(R 13 ), S-alkyl, SO3H, SO2-alkyl, SO2-alkyl-R 12 , SO2-aryl, SO2-aryl-R 12 , SO2NH2, SO2NH-R 12 , SO2N-(R 12 )(R 13 ), CO-alkyl, CO-alkyl-R 12 , CO-aryl, and CO-aryl-R 12 wherein the alkyl, aryl, aralkyl, alicyclic, and heterocyclic groups are independently selected from the group consisting of C 1-6 Alkyl, OC 1-6 may be optionally substituted with one or more groups selected from alkyl, CN, OH, NH2, COOH, CONH2, CF3, OCF3, and halogen; In the formula, R 12 and R 13 is COOH, SO3H, OSO3H, SONHCH3, SONHCH2CH3, SO2CH3, SO2CH2CH3, PO3H2, and OPO3H2, mono-, di-, and polyhydroxylated alicyclic groups, di- or polyhydroxylated aliphatic or aryl groups, and one or more C 1-6 are independently selected from N-, O-, and / or S-containing heterocyclic groups optionally substituted with alkyl, hydroxyl, carbonyl, amino, or alkoxy groups, wherein said N-, O-, and / or S-containing heterocyclic groups can optionally be attached to the remainder of the compound via an alkyl, amine, alkoxy, or ketone bridge; R 1 , R 2 and R 3 At least two of are other than H, and R 11 is phenyl-R 14 is selected from where R14 is C 1-6 Alkyl, OC 1-6 is selected from alkyl, CN, OH, NH2, COOH, CONH2, CF3, OCF3, and halogen. or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0019] In some embodiments, when present, R 12 and / or R 13 The group(s) can provide the compound of formula I with at least one water-soluble group. The presence of at least one water-soluble group can improve in vivo absorption and oral bioavailability.

[0020] In some embodiments, when present, R 12 and / or R 13 The group(s) include N-, O-, and / or S-containing heterocyclic group(s) (optionally substituted with one or more hydroxyl, amino, or alkoxy groups) that may be attached to the remainder of the compound by an alkyl bridge (e.g., -CH2, or -CH2CH2- bridge), an amine bridge (e.g., -NH-, -NH-CH2, and -NH-CH2CH2-), an alkoxy bridge (e.g., -O-CH2- and -O-CH2CH2-), or a ketone bridge (e.g., a -C(=O)- bridge). For example, when a compound is an NH-R 12 When it contains a group, R 12 can be, for example, an N-, O-, and / or S-containing heterocyclic group (optionally substituted with one or more hydroxyl, amino, or alkoxy groups) attached to the remainder of the compound by a -CH-, or -CHCH alkyl bridge.

[0021] The compounds of Formula I have been found to have antiproliferative activity and are therefore believed to be useful in the treatment of proliferative cell diseases and conditions, such as cancer, leukemia, lymphoma, and other diseases and conditions associated with uncontrolled cell proliferation (or, in other words, requiring cell cycle control), including some cardiovascular diseases or conditions such as restenosis and cardiomyopathy, some autoimmune diseases such as glomerulonephritis and rheumatoid arthritis, skin conditions such as psoriasis, and fungal or parasitic diseases. As used herein, an antiproliferative effect within the scope of the present disclosure can be demonstrated by the ability to inhibit cell proliferation in an in vitro whole cell assay. Example(s) of such an assay, including methods of implementation, are described in more detail in Example 2 provided herein below.

[0022] In a second aspect, the present disclosure provides the use of a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating cancer or another proliferative cell disease or condition.

[0023] In a third aspect, the present disclosure provides a method of treating cancer, or another proliferative cell disease or condition, in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier, diluent and / or excipient.

[0024] In a fourth aspect, the present disclosure provides the use of a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for treating cancer or another proliferative cell disease or condition.

[0025] In a fifth aspect, the present disclosure provides a pharmaceutical composition or medicament comprising a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0026] In a sixth aspect, the present disclosure provides a method of regulating protein kinase activity in a cell, comprising introducing into or contacting said cell with an effective amount of a compound defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0027] Preferably, the method of the sixth aspect regulates the activity of one or more protein kinases selected from RTKs, and in particular one of the TAM and / or MET family protein kinases.

[0028] A number of terms are used herein that are well known to those of skill in the art. Nevertheless, for the sake of clarity, many of these terms are defined below.

[0029] As used herein, the term "treating" includes prevention as well as the alleviation of established symptoms of a condition. Thus, the act of "treating" a disease or condition therefore includes (1) preventing or delaying the appearance of clinical symptoms of the disease or condition in a subject afflicted with or susceptible to the disease or condition; (2) inhibiting the disease or condition (i.e., halting, reducing, or delaying the progression of the disease or condition, or (in the case of maintenance treatment) its recurrence, or at least one clinical or subclinical symptom thereof); and (3) alleviating or attenuating the disease or condition (i.e., causing regression of the disease or condition, or at least one clinical or subclinical symptom thereof).

[0030] As used herein, the term "alkyl" includes both straight-chain and branched alkyl groups having from 1 to 8 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like).

[0031] As used herein, the term "aryl" refers to a substituted (mono- or poly) or unsubstituted monoaromatic or polyaromatic group, which may be fused or unfused. Thus, the term includes groups having 6 to 10 carbon atoms (e.g., phenyl, naphthyl, etc.). It should also be understood that the term "aryl" is synonymous with the term "aromatic."

[0032] As used herein, the term "aralkyl" is used to combine the terms alkyl and aryl described above.

[0033] The term "aliphatic" has its ordinary meaning in the art and includes non-aromatic groups such as alkanes, alkenes, and alkynes, and substituted derivatives thereof. This term includes groups having 1 to 8 carbon atoms.

[0034] As used herein, the term "alicyclic" means a cyclic aliphatic group.

[0035] The term "halogen" means fluoro, chloro, bromo, and iodo.

[0036] As used herein, the term "heterocyclic" refers to a saturated or unsaturated cyclic group containing one or more heteroatoms in the ring system (e.g., a system containing one or more rings (mono- or poly-)), and where more than one ring is present, the rings can be fused and / or unfused. Thus, the term covers saturated heterocyclic groups such as pyrrolidinyl, morpholinyl, aziridine, and piperazine, as well as heterocyclic groups (such as "heteroaryl" groups such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyrimidyl, 5-indolyl, furan, thiophene, and thiazole), where at least one ring of the ring system contains, as ring members, 1 to 4 heteroatoms selected from N, O, and S (i.e., contains at least one heterocyclic ring), and the nitrogen and sulfur atoms can be oxidized and the nitrogen atom(s) can be quaternized. Heterocyclic groups can be attached to the remainder of the molecule through a ring carbon or ring heteroatom, or, if the ring system is polycyclic, e.g., bicyclic, tricyclic, or a fused ring system, through any ring of the ring system.

[0037] As used herein, the term "derivative" includes any chemical modification of an element. Examples of such chemical modifications are replacement of hydrogen with a halogen, alkyl, acyl, or amino group.

[0038] As used herein, the phrase "manufacturing a medicament" includes the direct use of one or more of the compounds of formula I as a medicament or at any stage in the manufacture of a medicament comprising one or more of the compounds of formula I.

[0039] Some compounds of Formula I can exist as single stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are encompassed within the scope of the present disclosure. Such isomeric forms, such as diastereomers, enantiomers, and geometric isomers, can be separated by physical and / or chemical methods known to those skilled in the art.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of a compound of Formula I, including pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of a compound of Formula I can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid. Further information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995.

[0041] The term "solvate" means any form of a compound of formula I resulting from solvation with a suitable solvent. Such forms can be, for example, crystalline solvates or complexes that can form between a solvent and a dissolved compound.

[0042] The term "prodrug" refers to a compound that undergoes conversion to a compound of Formula I in a biological system, usually by metabolic means (e.g., by hydrolysis, reduction, or oxidation). For example, an ester prodrug of a compound of Formula I containing a hydroxyl group can be converted to a compound of Formula I in vivo by hydrolysis. Suitable esters of a compound of Formula I containing a hydroxyl group can be, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-p-hydroxynaphthonate, gentisate, isethionate, di-p-toluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. As another example, ester prodrugs of compounds of Formula I containing a carboxy group can be converted in vivo to compounds of Formula I by hydrolysis. Examples of ester prodrugs include those described by Leinweber FJ, Drug Metab Rev 18:379-439 (1987). Similarly, acyl prodrugs of compounds of Formula I containing an amino group can be converted in vivo to compounds of Formula I by hydrolysis. Examples of prodrugs for these and other functional groups, including isopropyl amines, are provided in Prodrugs: Challenges and Rewards, Valentino J Stella (ed.), Springer, 2007.

[0043] In the case of compounds of Formula I that are solid, it will be understood by those of skill in the art that the compound (or a pharmaceutically acceptable salt, solvate, or prodrug thereof) may exist in different crystalline or polymorphic forms, all of which are encompassed within the scope of this disclosure.

[0044] The term "therapeutically effective amount," or "effective amount," is an amount sufficient to produce a beneficial or desired clinical result. A therapeutically effective amount can be administered in one or more administrations. Typically, a therapeutically effective amount is sufficient to treat, or otherwise alleviate, ameliorate, stabilize, reverse, slow, or delay the progression of, a disease or condition, such as, for example, cancer or another proliferative cell disease or condition. By way of example only, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, can comprise from about 0.1 to about 250 mg / kg body weight / day, more preferably from about 0.1 to about 100 mg / kg body weight / day, and still more preferably from about 0.1 to about 25 mg / kg body weight / day. Notwithstanding the above, however, it will be understood by those skilled in the art that a therapeutically effective amount may vary and may depend on a variety of factors, including the activity of the particular compound (or salt, solvate, or prodrug thereof), the metabolic stability and length of action of the particular compound (or salt, solvate, or prodrug thereof), age, weight, sex, health, route and time of administration, excretion rate of the particular compound (or salt, solvate, or prodrug thereof), and the severity of, for example, cancer or other proliferative cell disease or condition being treated.

[0045] The compounds of Formula I, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, are capable of inhibiting protein kinases, particularly RTKs, and can exhibit high selectivity for (i.e., inhibit) TYRO3, AXL, MER, and / or MET over other protein kinases. As such, the compounds of Formula I, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, which are believed to inhibit at least TYRO3, AXL, MER, and / or MET, find utility in both in vitro and in vivo applications (e.g., in vitro cell-based assays) and as the basis of therapeutic methods for treating cancer or another proliferative cell disease or condition in a subject.

[0046] Compounds of formula I may be prepared by the method of formula (e.g., R12 , and / or R 13 The compound may have at least one water-soluble group (provided by the formula (I)). The term "water-soluble group" will be well understood by those skilled in the art to refer to any polar functional group that can ionize or form hydrogen bonds with water molecules (i.e., compared to the water solubility of the corresponding compound lacking the water-soluble group), thereby increasing the water solubility of the compound. Examples of suitable water-soluble groups, as well as methods and considerations for introducing them, are described, for example, in Fundamentals of Medicinal Chemistry by Gareth Thomas (publisher: John Wiley & Sons).

[0047] R is preferably 0 or 1, such that the compounds of formula (I) contain di- or tri-substituted pyrimidine groups. 1 , R 2 and R 3 At least two of these are other than H.

[0048] In some embodiments, R 1 , R 2 and R 3 is H, alkyl (e.g., C 1-6 Alkyl or, preferably, C, such as methyl, ethyl, and C(CH3)2. 1-3 alkyl), CN, CF3, amino (e.g., NH2), O-alkyl (e.g., O-CH3, etc.) 1-3 alkyl), NH-alkyl (e.g., NH-C such as NH(C5H9) (i.e., NH-cyclopentyl) 1-6 Alkyl or NH-C such as NH-CH3 1-3 alkyl), S-alkyl (e.g., SC 1-6 Alkyl or, preferably, SC, such as S—CH3 and S—CH(CH3)2. 1-3 alkyl), and halogen (preferably F, Br, or Cl).

[0049] R 1 is H, methyl, etc. 1-3It is preferably alkyl or amino (eg, NH2).

[0050] R 2 is H, methyl, etc. 1-3 It is preferably alkyl or amino (eg, NH2).

[0051] R 3 is H, methyl, etc. 1-3 It is preferably alkyl, O-alkyl (eg, O-CH3), or halogen (preferably F or Cl).

[0052] In some embodiments, R 4 , R 5 , R 6 and R 7 is H, alkyl (e.g., C 1-6 Alkyl or, preferably, C, such as methyl, ethyl, and C(CH3)2. 1-3 alkyl), CN, CF3, amino (e.g., NH2), O-alkyl (e.g., O-CH3, etc.) 1-3 alkyl), NH-alkyl (e.g., NH-C such as NH(C5H9) (i.e., NH-cyclopentyl) 1-6 Alkyl or NH-C such as NH-CH3 1-3 alkyl), S-alkyl (e.g., SC 1-6 Alkyl or, preferably, SC, such as S-CH3 and SCH(CH3)2. 1-3 alkyl), and halogen (preferably F, Br, or Cl).

[0053] R 4 , R 5 , R 6 and R 7 are preferably independently selected from H and halogen (preferably F). 4 , R 5 , R 6 and R 7 Preferably, at least one of

[0054] In some preferred embodiments, R 4 , R 5 , R 6 and R 7 One or two of the groups are halogen (preferably F).

[0055] In some other preferred embodiments, R 4 , R 5 , R 6 and R 7 are all H.

[0056] In some embodiments, R 8 , R 9 and R 10 is H, alkyl (e.g., C 1-6 Alkyl or, preferably, C, such as methyl, ethyl, and C(CH3)2. 1-3 alkyl), CN, CF3, amino (e.g., NH2), O-alkyl (e.g., O-CH2CH3, etc.) 1-3 alkyl), NH-alkyl (e.g., NH-C such as NH(C5H9) (i.e., NH-cyclopentyl) 1-6 Alkyl or NH-C such as NH-CH3 1-3 alkyl), S-alkyl (e.g., SC 1-6 Alkyl or, preferably, SC, such as S—CH3 and S—CH(CH3)2. 1-3 alkyl), and halogen (preferably F, Br, or Cl).

[0057] R 8 is H, C such as methyl 1-3 Alkyl or OC such as O-CH2CH3 1-3 It is preferably alkyl.

[0058] Preferably, R 9 and R 10 At least one, and more preferably both, of is H.

[0059] In some preferred embodiments, R 11is phenyl-R 14 where R 14 is C 1-3 Alkyl, OC 1-3 It is selected from alkyl, CF3, OCF3, and halogen (preferably F).

[0060] In some particularly preferred embodiments, R 11 is phenyl-R 14 where R 14 is selected from CH3, OCH3, CF3, OCF3, F, and Cl. In such embodiments, R 11 The phenyl is preferably substituted in only one position, preferably at the carbon atom in the 4-position.

[0061] In some preferred embodiments, compounds of Formula I exhibit antiproliferative activity in human cell lines as measured by cytotoxicity assays. Preferably, the compounds have an IC of less than 10 μM, and even more preferably less than 5 μM, as measured by standard cell viability assays. 50 Indicates the value.

[0062] In some preferred embodiments, the compounds of Formula I exhibit an IC50 activity against one or more protein kinases as measured by any standard assay known to those of skill in the art. Preferably, the compounds exhibit an IC50 activity against one or more protein kinases of less than 1 μM, or less than 0.5 μM, and more preferably even less than 0.1 μM, as measured by the kinase assay described in Example 2 below. 50 Indicates the value.

[0063] Specific examples of compounds according to the first aspect are shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0064] The compounds (and pharmaceutically acceptable salts, solvates, and prodrugs thereof) can be administered in combination with one or more additional agent(s) for treating cancer or another proliferative disease or condition. For example, the compounds can be used in combination with other anti-cancer agents to simultaneously inhibit two or more cancer signaling pathways, making cancer cells more sensitive to anti-cancer therapy (e.g., treatment with other anti-cancer agents, chemotherapy, radiation therapy, or a combination thereof). Thus, the compounds of Formula I can be used in combination with one or more of the following categories of anti-cancer agents: Other antiproliferative / antineoplastic agents used in medical oncology, such as alkylating agents (e.g., cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., antifolates such as gemcitabine and fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, fludarabine, and hydroxyurea); antitumor antibiotics (e.g., Adriamycin, anthracyclines such as vincristine, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin; antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids including taxol and taxotere, and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin); Cytostatics, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and inhibitors of 5α-reductase, such as finasteride; anti-invasive agents (e.g., c-Src kinase family inhibitors such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Publication No. WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib), and bosutinib (SKI-606)), as well as metalloproteinase inhibitors including marimastat, inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase; Inhibitors of growth factor function (e.g., growth factor antibodies and growth factor receptors such as the anti-erbB2 antibody trastuzumab (Herceptin™), the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab (Erbitux, C225), and any of the growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology / haematology, 2005, Vol. 54, pp 11-29). Such inhibitors include inhibitors of the epidermal growth factor family (e.g., N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774), and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI EGFR family tyrosine kinase inhibitors such as erbB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., sorafenib (BAY 43-9006), tipifarnib (R115777), and farnesyltransferase inhibitors, including lonafarnib (SCH66336), inhibitors of cell signaling via MEK and / or AKT kinase, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; tyrosine kinase inhibitors such as Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, and AX39459), and cyclin-dependent kinase inhibitors such as CDK2 and / or CDK9 inhibitors; antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™), and VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034), and 4-(4-fluoro-2-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 of International Patent Publication No. WO 00 / 47212), as described in International Patent Publication Nos. WO 97 / 22596, WO 97 / 30035, WO 00 / 47212, and WO 00 / 47212; compounds such as those disclosed in WO 97 / 32856 and WO 98 / 13354, as well as compounds that act by other mechanisms (e.g., linomide, an inhibitor of integrin αvβ3 function, and angiostatin); vascular damaging agents, such as combretastatin A4 and compounds disclosed in International Patent Publications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434, and WO 02 / 08213; Endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan; Antisense therapeutics, for example directed against the targets mentioned above, e.g., ISIS 2503, anti-ras antisense; approaches to increase patient resistance to chemotherapy or radiation therapy, such as gene therapy approaches, including approaches to replace ectopic genes, such as ectopic p53, or ectopic BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase enzymes, and multidrug resistance gene therapy; and Immunotherapeutic approaches, including ex vivo and in vivo approaches to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor, approaches to reduce T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies.

[0065] When used in combination with other anticancer agents, the compound of Formula I and the other anticancer agent can be administered in the same pharmaceutical composition or in separate pharmaceutical compositions. When administered in separate pharmaceutical compositions, the compound and the other anticancer agent can be administered simultaneously or sequentially in any order (e.g., within a few seconds or minutes, or even within a few hours (e.g., 2 to 48 hours)).

[0066] The compounds of Formula I are typically applied to treat cancer or another proliferative cell disease or condition in human subjects, but the subjects can also be selected from, for example, livestock animals (e.g., cows, horses, pigs, sheep, and goats), companion animals (e.g., dogs and cats), and exotic animals (e.g., non-human primates, tigers, elephants, etc.).

[0067] Cancers and other proliferative cell disorders and conditions treatable according to the present disclosure include biliary tract cancer, brain tumors and other cancers of the central nervous system (CNS) (including glioblastoma and medulloblastoma), neuroblastoma, breast cancer, cervical cancer, ovarian cancer (including those arising from epithelial, stromal, germ, and mesenchymal cells), choriocarcinoma, colorectal cancer, endometrial cancer, liver cancer, lung cancer, esophageal cancer, gastric cancer, hematological tumors (acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML), as well as acute myeloid leukemia (AML), multiple myeloma, AIDS-related leukemia, and adult T-cell leukemia. lymphomas (including non-Hodgkin's lymphoma, Hodgkin's disease, and lymphocytic lymphoma), intraepithelial neoplasia (including Bowen's disease and Paget's disease), oral cancer (including squamous cell carcinoma), pancreatic cancer, sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), testicular cancer (including embryonal tumors such as seminoma, nonseminomatous teratoma, and choriocarcinoma), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma), and renal cancer (including adenocarcinoma and Wilms' tumor).

[0068] In some embodiments, compounds of Formula I are used to treat cancer or other conditions that depend on TAM and / or MET activation, where TAM and / or MET activation can be controlled by gene amplification or TAM and / or MET mutations.

[0069] The compounds of formula I can be formulated with pharmaceutically acceptable carriers, diluents, and / or excipients to form pharmaceutical compositions. Examples of suitable carriers and diluents are well known to those skilled in the art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA 1995. Examples of suitable excipients for the various different forms of pharmaceutical compositions described herein can be found in Handbook of Pharmaceutical Excipients, 2000, edited by A. Wade and P. J. Weller. ndEdition, (1994). Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Examples of suitable diluents include ethanol, glycerol, and water. The selection of carrier, diluent, and / or excipient can be made according to the intended route of administration and standard pharmaceutical practice.

[0070] Pharmaceutical compositions containing a compound of Formula I can further contain any suitable binder, lubricant, suspending agent, coating agent, and solubilizer. Examples of suitable binders include starch, gelatin, glucose, anhydrous lactose, fast-flowing lactose, β-lactose, natural sugars such as corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Preservatives, stabilizers, dyes, and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0071] Pharmaceutical compositions containing compounds of Formula I can be administered orally, rectally, intravaginally, parenterally, intramuscularly, intraperitoneally, intraarterially, intrathecally, intrabronchially, subcutaneously, intradermally, intravenously, nasally, buccally, or sublingually. For oral administration, compressed tablets, pills, tablets, gellues, drops, and capsules can be used in particular. For other administration forms, pharmaceutical compositions can include solutions or emulsions that are injectable intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally, or intramuscularly and are prepared from sterile or sterilizable solutions. Pharmaceutical compositions containing compounds of Formula I can also be in the form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions, or powders. Pharmaceutical compositions can be formulated in unit dosage form (i.e., in the form of individual portions containing a single dose or a multiple or subunit of a single dose).

[0072] The compounds of formula I can be provided as pharmaceutically acceptable salts, including, for example, suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al., J Pharm Sci 66:1-19 (1977). For example, salts are formed with strong inorganic acids such as mineral acids (e.g., sulfuric acid, phosphoric acid, or hydrohalic acid); with strong organic carboxylic acids such as unsubstituted or substituted (e.g., by halogen) alkanecarboxylic acids of 1 to 4 carbon atoms, such as acetic acid; with saturated or unsaturated dicarboxylic acids (e.g., oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid); with hydroxycarboxylic acids (e.g., ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid); with amino acids (e.g., aspartic acid or glutamic acid); with benzoic acid; or with organic sulfonic acids (e.g., unsubstituted or substituted (C1-C4)-alkyl or aryl sulfonic acids, such as methane or p-toluenesulfonic acid, e.g., by halogen).

[0073] The compound of formula I can be provided in its various crystalline forms, polymorphic forms, and hydrated (anhydrous) forms. In this regard, it is well known to those skilled in the art that the compound can be isolated in any of such forms by minor variations in purification and / or isolation techniques from solvents used in the synthetic preparation of such compound.

[0074] The present disclosure further provides methods for synthesizing compounds according to Formula I, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0075] With respect to the description of the synthetic methods that follow, and in the referenced synthetic methods used to prepare starting materials, it will be understood by those skilled in the art that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment, and work-up procedure, can be readily selected. Furthermore, it will be understood by those skilled in the art that the functional groups present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0076] The necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with variations of the following exemplary processes and in the following examples. Alternatively, the necessary starting materials are available by procedures similar to those described within the skill of the art. Furthermore, it will be understood that during the synthesis of compounds, within the processes described below, or during the synthesis of particular starting materials, it may be desirable to protect certain substituents to prevent their undesired reaction. Those skilled in the art will readily understand when such protection is necessary and how such protecting groups are installed and subsequently removed. Examples of protecting groups are described, for example, in *Protective Groups in Organic Synthesis* by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method known to those skilled in the art as appropriate for removing the protecting group in question, and such methods will be selected to effect removal of the protecting group with minimal interference with groups elsewhere in the molecule. Thus, when reactants contain groups such as amino, carboxyl, or hydroxyl, it may be desirable to protect the group in some of the reactions mentioned herein.

[0077] Synthetic methods for preparing compounds of Formula I will be readily apparent to those skilled in the art.

[0078] However, in a further aspect of the disclosure, there is provided a method of synthesizing a compound of formula I (or a pharmaceutically acceptable salt, solvate, or prodrug thereof), said method comprising: a) a compound of formula A [ka] [In the formula, X is O or S; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R7 is as defined above for formula I.] with a suitable 2-oxo-1,2-dihydropyridine-3-carboxylic acid derivative with which a compound of formula B is reacted; [ka] [In the formula, R 8 , R 9 , R 10 and R 11 is as defined above for Formula I.] and, if necessary, b) removing any protecting groups present and / or forming a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0079] Still in a further aspect of the disclosure, there is provided a method of synthesizing a compound of formula I (or a pharmaceutically acceptable salt, solvate, or prodrug thereof), said method comprising: a) a compound of formula B [ka] [In the formula, R 8 , R 9 , R 10 and R 11 is as defined above for formula I.] is reacted with a compound having formula C: [ka] [In the formula, R 4 , R 5 , R 6 and R 7 is as defined above for formula I.] providing a compound of formula D; [ka] b) reacting a compound of formula D with a halogenated pyrimidine and, if necessary, c) removing any protecting groups present and / or forming a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0080] The coupling reaction of the compounds of formula A and formula B can be carried out in the presence of a suitable solvent or solvent mixture. Those skilled in the art will be able to readily select a suitable solvent or solvent mixture for use in this reaction. Examples of suitable solvents include acetonitrile, halogenated solvents, etc.

[0081] Furthermore, one skilled in the art would be able to select appropriate reaction conditions for use in the coupling reaction of compounds of Formula A and Formula B. However, typically, the reaction will be carried out under anhydrous conditions and in the presence of an inert atmosphere, such as argon or nitrogen. The reaction can also be carried out at room temperature or at elevated temperatures for a suitable period of time, for example, from 30 minutes to 48 hours.

[0082] The resulting compounds can be isolated and purified using techniques well known to those skilled in the art.

[0083] An example of a particularly suitable method for synthesizing compounds of the present disclosure is shown in Scheme 1 below. Scheme 1 [ka] Here, typical reaction conditions are: (a) appropriate halogenated pyrimidine, K2CO3 or Cs2CO3, DMF, room temperature to 80°C, 12 to 24 hours; (b) appropriate boronic acid, Cu(CH3CO2)2, pyridine, room temperature; (c) LiOH, THF / MeOH / H2O (2:2:1), room temperature to 80°C, 12 to 24 hours; (d) NaClO2, NaH2PO4, 2-methyl-2-butene, THF / t-butanol / H2O (1:1:1), 0°C to room temperature, 0.5 to 2 hours; and (e) HATU, DIPEA, room temperature, 2 to 4 hours; or SOCl2, DIPEA, 0°C to room temperature, 0.5 to 2 hours.

[0084] The present disclosure will now be described with reference to the following non-limiting examples and the accompanying drawings. [Example]

[0085] Example 1 Synthesis overview 1 H and 13 C NMR spectra were obtained at 298 K (unless otherwise stated) on a Bruker AVANCE III HD 500 spectrometer (at 500.20 MHz). 1 H and 125.79MHz 13 C) and analyzed using Bruker Topspin 3.2 software. 1 H NMR signals are reported as chemical shift values ​​δ (ppm), multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets, ddd = doublet of doublet of doublets, m = multiplet, and br = broad), relative integrals, coupling constants J (Hz), and assignments. High-resolution mass spectra were recorded on an AB SCIEX TripleTOF 5600 mass spectrometer (Concord, ON, Canada), and ionization of all samples was performed using electrospray ionization (ESI).

[0086] General synthetic procedure: To a solution of carboxylic acid B (1.15 equiv.) and HATU (1.2 equiv.) in DCM under N2, DIPEA (1.2 equiv.) was added, and the reaction mixture was stirred at room temperature for 15 min. Next, a solution of the appropriate arylamine A (1 equiv.) in DCM was added, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated NH4Cl solution. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel). The resulting product was dissolved in a solution of DCM / TFA (1:1), and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in DCM and washed with 1 M NaOH solution. The organic phase was dried over MgSO4 and concentrated under reduced pressure to give the desired compound.

[0087] Example N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (1) A mixture of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 3.27 mmol), 4-fluorophenylboronic acid (1.37 g, 9.80 mmol), copper(II) acetate (1.19 g, 6.55 mmol), DCM (25 mL), and pyridine (1.1 mL, 13.7 mmol) was stirred at room temperature under air for 18 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 1 M hydrochloric acid (50 mL). The organic phase was washed with brine (50 mL), dried over MgSO4, and concentrated. The residue was purified by flash chromatography (silica, PE grading to EtOAc) to give methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate as a white solid (394 mg, 49%). 1H NMR(MeOD)δ 3.78 (s, 3H), 6.45 (t, 1H, J = 7.0 Hz), 7.20 (t, 2H, J = 8.0 Hz), 7.38 (m, 2H), 7.81 (d, 1H, J = 6.5 Hz), 8.23 ​​(d, 1H, J = 7.0 Hz). HRMS m / z 248.0841[M+H] + .

[0088] Next, HO (1 mL) was added to a solution of methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 2.02 mmol) and lithium hydroxide (100 mg, 4.18 mmol) in THF / MeOH (1:1, 4 mL). After stirring for 3 h, the reaction mixture was quenched with 1 M hydrochloric acid (2 mL) and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 1 M hydrochloric acid. The aqueous phase was extracted with EtOAc (2 × 50 mL). The organic extracts were combined, dried under MgSO and concentrated under reduced pressure to give 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid as a white solid (463 mg, 98%). 1 H NMR(DMSO)δ 6.79 (t, 1H, J = 7.0 Hz), 7.43 (t, 2H, J = 8.5 Hz), 7.62 (dd, 2H, J = 8.5 & 8.5 Hz), 8.21 (d, 1H, J = 6.5 Hz), 8.49 (d, 1H, J = 7.0 Hz). HRMS m / z 240.0853[M+H] + .

[0089] To a mixture of 6-chloro-5-fluoropyrimidin-4-amine (500 mg, 3.39 mmol), EtN (1 mL, 7.17 mmol), and DMAP (80 mg, 0.655 mmol) in DCM (20 mL) was added a solution of di-tert-butyl dicarbonate (1.50 g, 6.87 mmol) in DCM (2 mL). After stirring at room temperature for 12 hours, the reaction mixture was washed with 0.1 M hydrochloric acid. The organic phase was dried over MgSO and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, PE increasing to PE:EtOAc = 7:3) to give 6-chloro-5-fluoro-N,N-tert-butoxycarbonylpyrimidin-4-amine as a white solid (808 mg, 69%). 1 H NMR(DMSO)δ 1.42 (s, 18H), 8.94 (s, 1H).

[0090] Next, 4-amino-2-fluorophenol (307 mg, 2.42 mmol) was added to a mixture of 6-chloro-5-fluoro-N,N-tert-butoxycarbonylpyrimidin-4-amine (700 mg, 2.01 mmol) and cesium carbonate (790 mg, 2.42 mmol) in DMF (5 mL), and the reaction mixture was stirred at room temperature for 12 hours. After concentration under reduced pressure, HO was added to the residue and extracted with DCM (3 × 50 mL). The combined organic phase was dried over MgSO, concentrated, and purified by flash chromatography (silica, gradient from PE to PE:EtOAc = 2:3) to give 6-(4-amino-2-fluorophenoxy)-5-fluoro-N,N-tert-butoxycarbonylpyrimidin-4-amine as a pale pink powder (418 mg, 47%). 1 H NMR(CDCl3)δ 1.48 (s, 18H), 3.80 (s, 2H), 6.50 (m, 2H), 7.03 (t, 1H, J = 8.5 Hz), 8.39 (s, 1H). HRMS m / z 439.1923[M+H] + .

[0091] A mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.429 mmol), DIPEA (100 μL, 0.574 mmol), and HATU (170 mg, 0.447 mmol) in DCM (3 mL) was stirred at room temperature for 15 minutes. Next, a solution of 6-(4-amino-2-fluorophenoxy)-5-fluoro-N,N-tert-butoxycarbonylpyrimidin-4-amine (160 mg, 0.365 mmol) in DCM (3 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. DCM (150 mL) was added to the reaction mixture, and saturated NH4Cl solution was added (50 mL). The organic phase was dried over MgSO4, concentrated, and purified by flash chromatography (silica, PE gradient to EtOAc). The resulting product was treated with DCM / TFA (1:1, 6 mL) for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and washed with 1 M NaOH solution. The organic phase was dried over MgSO and concentrated under reduced pressure to give N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (4) as a white solid (126 mg, 76%). 1 H NMR(CDCl3)δ 5.03 (s, 2H), 6.61 (t, 1H, J = 7.0 Hz), 7.27 (t, 2H, J = 8.5 Hz), 7.34 (d, 1H, J = 9.0 Hz), 7.40 (m, 2H), 7.61 (dd, 1H, J = 2.0 & 6.5 Hz), 7.92 (dd, 1H, J = 2.0 & 12.5 Hz), 7.96 (s, 1H), 8.74 (dd, 1H, J = 2.0 & 7.5 Hz), 11.95 (s, 1H). HRMS m / z 454.1190[M+H] +

[0092] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (2)

[0093] A solution of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (600 mg, 1.67 mmol) in toluene (5 mL) was treated with thionyl chloride (5 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL), and a solution of 6-(4-amino-2-fluorophenoxy)-5-chloro-N,N-tert-butoxycarbonylpyrimidin-4-amine (476 mg, 1.05 mmol), DIPEA (0.4 mL), DMF (0.3 mL), and THF (5 mL) was added in an ice bath. After 5 minutes, the reaction mixture was stirred for an additional 30 minutes at room temperature. The reaction mixture was quenched with saturated NaHCO3 solution (20 mL), and the suspension was extracted with EtOAc (2 × 100 mL). The organic phase was dried over MgSO4, concentrated and purified by flash chromatography (silica, gradient from PE to EtOAc:PE=1:1) to give N-(4-((5-chloro-6-(di-tert-butoxycarbonylamino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamide as a pale yellow powder (378 mg, 36%). 1 H NMR(CDCl3)δ 1.45 (s, 18H), 7.12 (d, 1H, J = 7.0 Hz), 7.22 (m, 3H), 7.36 (m, 3H), 7.90 (d, 1H, J = 12.0 Hz), 8.50 (s, 1H), 11.58 (s, 1H). MS m / z 796.3[M+H]+.

[0094] Next, to a solution of N-(4-((5-chloro-6-(di-tert-butoxycarbonylamino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamide (228 mg, 0.286 mmol) in anhydrous EtOH (10 mL) was added sodium ethoxide (30 mg, 0.441 mmol) and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was quenched with water (20 mL) and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in DCM / TFA (1:1, 6 mL) and the mixture was stirred for 48 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with 1 M NaOH solution (20 mL). The organic phase was dried, concentrated, and purified by flash chromatography (silica, grading from EtOAc to EtOAc:MeOH=95.5) to produce the title compound (1) as a white solid (24 mg, 16%). 1 H NMR(CDCl3)δ 1.57 (t, 3H, J = 7.0 Hz), 4.35 (q, 2H, J = 7.0 Hz), 5.34 (s, 2H), 6.34 (d, 1H, J = 8.0 Hz), 7.10 (t, 1H, J = 8.5 Hz), 7.25 (m, 5H), 7.35 (m, 2H), 7.49 (d, 1H, J = 8.0 Hz), 7.90 (dd, 1H, J = 1.5 & 12.5 Hz), 8.06 (s, 1H), 11.52 (s, 1H). HRMS m / z 514.1260[M+H]+.

[0095] N-(4-((6-amino-5-chloropyrimidin-4-yl-)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (3) was prepared as a white solid (132 mg, 75%) by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.429 mmol) with 6-(4-amino-2-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (170 mg, 0.374 mmol). 1 H NMR(CDCl3)δ 5.25 (s, 2H), 6.54 (t, 1H, J = 7.0 Hz), 7.22 (m, 2H), 7.28 (d, 1H, J = 9.5 Hz), 7.34 (m, 2H), 7.55 (d, 1H, J = 6.5 Hz), 7.85 (d, 1H, J = 12.5 Hz), 8.00 (s, 1H), 8.67 (d, 1H, J = 7.5 Hz), 11.88 (s, 1H). HRMS m / z 470.1326[M+H] + .

[0096] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (4) was obtained as a white solid (131 mg, 79%) from the reaction of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.429 mmol) and 6-(4-aminophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (160 mg, 0.366 mmol). 1H NMR(CDCl3)δ 5.30 (s, 2H), 6.60 (t, 1H, J = 7.0 Hz), 7.12 (d, 2H, J = 8.5 Hz), 7.26 (m, 2H), 7.41 (m, 2H), 7.60 (d, 1H, J = 6.5 Hz), 7.79 (d, 2H, J = 8.5 Hz), 8.09 (s, 1H), 8.75 (d, 1H, J = 7.0 Hz), 11.86 (s, 1H). HRMS m / z 452.0980[M+H] + .

[0097] Treatment of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.429 mmol) with 5-chloro-6-(3,4-difluorophenoxy)-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (170 mg, 0.374 mmol) gave N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (5) as a pale yellow solid (156 mg, 89%). 1 H NMR(CDCl3)δ 5.34 (s, 2H), 6.59 (t, 1H, J = 7.0 Hz), 6.98 (m, 2H), 7.24 (m, 2H), 7.41 (m, 2H), 7.61 (d, 1H, J = 6.5), 8.10 (s, 1H), 8.60 (m, 1H), 8.73 (d, 1H, J = 7.0 Hz), 12.03 (s, 1H). HRMS m / z 470.0718[M+H] + .

[0098] Treatment of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (130 mg, 0.557 mmol) with 6-(4-aminophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (200 mg, 0.476 mmol) gave N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (6) as a beige powder (143 mg, 69%). 1 H NMR (CDCl3) δ 5.04 (s, 2H), 6.59 (t, 1H, J = 7.0 Hz), 7.13 (d, 2H, J = 9.0 Hz), 7.41 (m, 2H), 7.60 (dd, 1H, J = 1.5 & 6.5 Hz), 7.78 (d, 2H, J = 9.0 Hz), 7.98 (s, 1H), 11.85 (s, 1H) (two proton signals obscured by CDCl3 peaks). HRMS m / z 436.1112 [M+H] + .

[0099] Following the general synthetic procedure, N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (7) was prepared as a yellow powder (138 mg, 83%) by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.429 mmol) with 6-(4-amino-3-fluorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (160 mg, 0.365 mmol). 1H NMR(CDCl3)δ 5.10 (s, 2H), 6.58 (t, 1H, J = 7.0 Hz), 6.99 (m, 2H), 7.24 (m, 2H), 7.41 (m, 2H), 7.60 (d, 1H, J = 6.5 Hz), 7.99 (s, 1H), 8.59 (m, 1H), 8.73 (s, 1H), 12.02 (s, 1H). HRMS m / z 454.1018[M+H] + .

[0100] N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydropyridine-3-carboxamide (8) was prepared as a white powder (72 mg, 61%) by treating 2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydropyridine-3-carboxylic acid (78 mg, 0.261 mmol) with 6-(4-amino-2-fluorophenoxy)-5-fluoro-di-tert-butoxycarbonylpyrimidin-4-amine (100 mg, 0.228 mmol). 1 H NMR(DMSO)δ 6.74 (t, 1H, J = 7.0 Hz), 7.33 (m, 3H), 7.42 (d, 1H, J = 9.0 Hz), 7.60 (d, 2H, J = 8.5 Hz), 7.71 (d, 2H, J = 8.5 Hz), 7.82 (s, 1H), 7.93 (d, 1H, J = 12.5 Hz), 8.17 (d, 1H, J = 6.5 Hz), 8.59 (d, 1H, J = 7.0 Hz), 12.01 (s, 1H). HRMS m / z 520.1341[M+H] + .

[0101] N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide (9) was prepared as a white powder (85 mg, 74%) by treating 2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid (74 mg, 0.261 mmol) with 6-(4-amino-2-fluorophenoxy)-5-fluoro-di-tert-butoxycarbonylpyrimidin-4-amine (100 mg, 0.228 mmol). 1 H NMR(DMSO)δ 6.78 (t, 1H J = 7.0 Hz), 7.33 (m, 3H), 7.40 (d, 1H, J = 9.0 Hz), 7.81 (m, 3H), 7.92 (d, 1H, J = 12.5 Hz), 7.98 (d, 2H, J = 8.0 Hz), 8.18 (d, 1H, J = 6.5 Hz), 8.60 (d, 1H, J = 7.5 Hz), 11.97 (s, 1H). HRMS m / z 504.1380[M+H] + .

[0102] Treatment of 2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydropyridine-3-carboxylic acid (55 mg, 0.184 mmol) with 6-(4-amino-2-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (70 mg, 0.160 mmol) gave N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydropyridine-3-carboxamide (10) as a white powder (37 mg, 43%). 1H NMR(CDCl3)δ 5.35 (s, 2H), 6.63 (t, 1H, J = 7.0 Hz), 7.16 (t, 1H, J = 8.5 Hz), 7.34 (d, 1H, J = 8.5 Hz), 7.43 (d, 2H, J = 8.5 Hz), 7.48 (d, 2H, J = 8.5 Hz), 7.61 (d, 1H, J = 6.0 Hz), 7.92 (d, 1H, J = 12.0 Hz), 8.07 (s, 1H), 8.75 (d, 1H, J = 7.0 Hz), 11.90 (s, 1H). HRMS m / z 536.0856[M+H] + .

[0103] Treatment of 2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid (52 mg, 0.184 mmol) with 6-(4-amino-2-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (70 mg, 0.160 mmol) gave N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide (11) as a yellow powder (23 mg, 28%). 1 H NMR(DMSO)δ 6.77 (t, 1H, J = 7.0 Hz), 7.32 (t, 1H, J = 8.5 Hz), 7.40 (d, 1H, J = 9.0 Hz), 7.82 (d, 2H, J = 8.0 Hz), 7.95 (m, 4H), 8.18 (d, 1H, J = 6.5 Hz), 8.60 (d, 1H, J = 7.0 Hz), 11.97 (s, 1H). HRMS m / z 520.1093[M+H] + .

[0104] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2,3-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (13) was prepared as a white powder (237 mg, 73%) by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (178 mg, 0.763 mmol) with 6-(4-amino-2,3-difluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (314 mg, 0.664 mmol). 1 H NMR(DMSO)δ 6.74 (t, 1H, J = 7.0 Hz), 7.25 (t, 1H, J = 8.0 Hz), 7.43 (t, 2H, J = 9.0 Hz), 7.61 (m, 2H), 7.98 (s, 1H), 8.15 (dd, 1H, J = 2.0 & 6.5 Hz), 8.26 (t, 1H, J = 7.5 Hz), 8.61 (dd, 1H, J = 2.0 & 7.5 Hz), 12.31 (s, 1H). MS m / z 488.14

[0105] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxamide (15) was prepared as a white powder (73 mg, 71%) by treating 2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxylic acid (58 mg, 0.253 mmol) with 6-(4-amino-3-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (100 mg, 0.220 mmol). 1H NMR(DMSO)δ 2.40 (s, 3H), 6.72 (t, 1H, J = 7.0 Hz), 7.05 (d, 1H, J = 9.0 Hz), 7.29 (dd, 1H, J = 2.0 & 11.5 Hz), 7.38 (m, 4H), 7.98 (s, 1H), 8.10 (dd, 1H, J = 2.0 & 6.5 Hz), 8.47 (t, 1H, J = 9.0 Hz), 8.59 (dd, 1H, J = 2.0 & 7.5 Hz), 12.25 (s, 1H). MS m / z 466.31

[0106] N-(4-((6-amino-5-chloropyrimidin-4-yl)thio)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (17) was prepared as a pale yellow powder (67 mg, 19%) by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (191 mg, 0.819 mmol) with 6-((4-amino-2-fluorophenyl)thio)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (335 mg, 0.711 mmol). 1 H NMR(DMSO)δ 6.73 (t, 1H, J = 7.0 Hz), 7.43 (m, 3H), 7.53 (t, 1H, J = 8.0 Hz), 7.61 (m, 2H), 7.92 (d, 1H, J = 11.0 Hz), 8.00 (s, 1H), 8.14 (dd, 1H, J = 1.5 & 6.5 Hz), 8.58 (dd, 1H, J = 1.5 & 7.0 Hz), 12.19 (s, 1H). MS m / z 486.26.

[0107] Following the general procedure, N-(4-((6-amino-5-fluoropyrimidin-4-yl)thio)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (19) was prepared as a beige powder (66 mg, 21%) by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (183 mg, 0.785 mmol) with 6-((4-amino-2-fluorophenyl)thio)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (311 mg, 0.684 mmol). 1 H NMR(DMSO)δ 6.73 (t, 1H, J = 7.0 Hz), 7.28 (s, 2H), 7.43 (m, 3H), 7.57 (t, 1H, J = 8.5 Hz), 7.61 (m, 2H), 7.92 (m, 2H), 8.14 (dd, 1H, J = 2.0 & 6.5 Hz), 8.59 (dd, 1H, J = 2.0 & 7.5 Hz), 12.19 (s, 1H). MS m / z 470.09.

[0108] Following the general synthetic procedure, N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (20) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (135 mg, 0.579 mmol) with 6-(4-amino-2,5-difluorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (229 mg, 0.502 mmol) to yield a white powder (159 mg, 67%). 1H NMR(DMSO)δ 6.74 (t, 1H, J = 7.0 Hz), 7.37 (s, 2H), 7.43 (t, 1H, J = 8.5 Hz), 7.60 (m, 3H), 7.84 (s, 1H), 8.15 (dd, 1H, J = 2.0 & 6.5 Hz), 8.47 (m, 1H), 8.61 (dd, 1H, J = 2.0 & 7.0 Hz), 12.38 (s, 1H). MS m / z 472.29.

[0109] Following the general synthetic procedure, N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (21) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (122 mg, 0.523 mmol) with 6-(4-amino-2,5-difluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (216 mg, 0.457 mmol) to yield a white powder (157 mg, 70%). 1 H NMR(DMSO)δ 6.75 (t, 1H, J = 7.0 Hz), 7.43 (t, 2H, J = 9.0 Hz), 7.59 (m, 3H), 7.98 (s, 1H), 8.15 (dd, 1H, J = 2.0 & 6.5 Hz), 8.47 (m, 1H), 8.61 (dd, 1H, J = 2.0 & 7.5 Hz), 12.37 (s, 1H). MS m / z 488.14.

[0110] Following the general synthetic procedure, N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (22) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.858 mmol) with 6-(4-amino-2-chlorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (338 mg, 0.743 mmol) to yield a white powder (265 mg, 76%). 1 H NMR(DMSO)δ 6.73 (t, 1H, J = 7.0 Hz), 7.30 (s, 2H), 7.34 (d, 1H, J = 9.0 Hz), 7.42 (t, 2H, J = 8.5 Hz), 7.55 (dd, 1H, J = 2.0 & 8.5 Hz), 7.61 (m, 2H), 7.80 (s, 1H), 8.12 (m, 2H), 8.58 (dd, 1H, J = 1.5 & 7.5 Hz), 12.04 (s, 1H). HRMS m / z 470.15.

[0111] Following the general synthetic procedure, N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (23) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (154 mg, 0660 mmol) with 6-(4-amino-2-chlorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (270 mg, 0.573 mmol) to yield a white powder (229 mg, 82%). 1H NMR(DMSO)δ 6.72 (t, 1H, J = 7.0 Hz), 7.32 (d, 1H, J = 9.0 Hz), 7.42 (t, 2H, J = 8.5 Hz), 7.56 (dd, 1H, J = 2.5 & 9.0 Hz), 7.61 (m, 2H), 7.94 (s, 1H), 8.12 (m, 2H), 8.58 (dd, 1H, J = 2.0 & 7.5 Hz), 12.04 (s, 1H). MS m / z 486.12.

[0112] Following the general synthetic procedure, N-(4-((2-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (24) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (78 mg, 0.334 mmol) with 4-(4-amino-2-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-2-amine (133 mg, 0.292 mmol) to yield a white powder (30 mg, 22%). 1 H NMR(DMSO)δ 6.72 (t, 1H, J = 7.0 Hz), 6.90 (s, 2H), 7.36 (t, 1H, J = 8.5 Hz), 7.42 (m, 3H), 7.60 (m, 2H), 7.94 (dd, 1H, J = 2.0 & 12.5 Hz), 8.13 (dd, 1H, J = 2.0 & 6.5 Hz), 8.58 (dd, 1H, J = 2.0 & 7.5 Hz), 12.34 (s, 1H). MS m / z 470.15.

[0113] Following the general synthetic procedure, N-(4-((2-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (25) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (107 mg, 0.459 mmol) with 4-(4-amino-3-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-2-amine (181 mg, 0.398 mmol) to yield a yellow powder (73 mg, 39%). 1 H NMR(DMSO)δ 6.73 (t, 1H, J = 7.0 Hz), 6.87 (s, 2H), 7.11 (d, 1H, J = 9.0 Hz), 7.37 (dd, 1H, J = 2.5 & 11.5 Hz), 7.43 (t, 2H, J = 8.5 Hz), 7.61 (m, 2H), 8.13 (dd, 1H, J = 2.0 & 6.5 Hz), 8.21 (s, 1H), 8.46 (t, 1H, J = 9.0 Hz), 8.60 (dd, 1H, J = 2.0 & 7.5 Hz), 12.18 (s, 1H). MS m / z 470.15.

[0114] Following the general synthetic procedure, N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (33) was prepared by treating 1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (63 mg, 0.252 mmol) with 6-(4-amino-3-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (100 mg, 0.220 mmol) to yield a white powder (68 mg, 64%). 1H NMR(DMSO)δ 6.74 (t, 1H, J = 7.0 Hz), 7.05 (d, 1H, J = 9.0 Hz), 7.29 (dd, 1H, J = 2.0 & 11.5 Hz), 7.62 (m, 4H), 7.98 (s, 1H), 8.13 (dd, 1H, J = 2.0 & 6.5 Hz), 8.46 (t, 1H, J = 9.0 Hz), 8.60 (dd, 1H, J = 2.0 & 7.0 Hz), 12.17 (s, 1H). MS m / z 486.25.

[0115] Following the general synthetic procedure, N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (34) was prepared by treating 1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (65 mg, 0.260 mmol) with 6-(4-amino-2-fluorophenoxy)-5-fluoro-N,N-tert-butoxycarbonylpyrimidin-4-amine (100 mg, 0.228 mmol) to yield a white powder (76 mg, 71%). 1 H NMR(DMSO)δ 6.73 (t, 1H, J = 7.0 Hz), 7.36 (m, 4H), 7.59 (d, 2H, J = 8.5 Hz), 7.66 (d, 2H, J = 8.5 Hz), 7.82 (s, 1H), 7.92 (dd, 1H, J = 2.0 & 12.5 Hz), 8.13 (dd, 1H, J = 2.0 & 6.5 Hz), 8.58 (dd, 1H, J = 2.0 & 7.0 Hz), 12.02 (s, 1H). MS m / z 470.29.

[0116] Following the general synthetic procedure, N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxamide (35) was prepared by treating 2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxylic acid (60 mg, 0.262 mmol) with 6-(4-amino-2-fluorophenoxy)-5-fluoro-N,N-tert-butoxycarbonylpyrimidin-4-amine (100 mg, 0.228 mmol) to yield a white powder (74 mg, 72%). 1 H NMR(DMSO)δ 6.71 (t, 1H, J = 7.0 Hz), 7.35 (m, 8H), 7.82 (s, 1H), 7.92 (dd, 1H, J = 2.0 & 12.5 Hz), 8.09 (dd, 1H, J = 2.0 & 6.5 Hz), 8.57 (dd, 1H, J = 2.0 & 7.5 Hz), 12.12 (s, 1H). MS m / z 450.33

[0117] Following the general synthetic procedure, 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (67 mg, 0.287 mmol) was reacted with N 4 -(4-a-amino-2-fluorophenyl)-5-chloro-N 6 ,N 6 N-(4-((6-amino-5-chloropyrimidin-4-yl)amino)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (36) was prepared by treatment with -di-tert-butoxycarbonylpyrimidine-4,6-diamine (113 mg, 0.249 mmol) to yield a yellow powder (61 mg, 52%). 1H NMR(DMSO)δ 6.76 (m, 3H), 7.33 (d, 1H, J = 5.0 Hz), 7.45 (m, 3H), 7.63 (m, 2H), 7.85 (s, 2H), 8.15 (m, 1H), 8.29 (s, 1H), 8.61 (m, 1H), 12.04 (s, 1H). MS m / z 469.10.

[0118] Following the general synthetic procedure, N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (37) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (167 mg, 0.716 mmol) with 6-(4-amino-3-chlorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (294 mg, 0.624 mmol) to yield an off-beige powder (281 mg, 93%). 1 H NMR(DMSO)δ 6.72 (t, 1H, J = 7.0 Hz), 7.21 (dd, 1H, J = 2.5 & 9.0 Hz), 7.43 (m, 3H), 7.61 (m, 2H), 7.98 (s, 1H), 8.12 (dd, 1H, J = 2.0 & 6.5 Hz), 8.57 (d, 1H, J = 9.0 Hz), 8.62 (dd, 1H, J = 2.0 & 7.0 Hz), 12.31 (s, 1H). HRMS m / z 486.0530.

[0119] Following the general synthetic procedure, N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-2-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (38) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (81 mg, 0.347 mmol) with 6-(4-amino-3-chlorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (137 mg, 0.301 mmol) to yield a white powder (86 mg, 61%). 1 H NMR(DMSO)δ 6.72 (t, 1H, J = 7.0 Hz), 7.23 (dd, 1H, J = 2.0 & 9.0 Hz), 7.28 (s, 2H), 7.43 (t, 2H, J = 8.5 Hz), 7.48 (d, 1H, J = 2.5 Hz), 7.61 (m, 2H), 7.85 (s, 1H), 8.12 (dd, 1H, J = 1.5 & 7.0 Hz), 8.57 (d, 1H, J = 9.0 Hz), 8.62 (dd, 1H, J = 1.5 & 7.5 Hz), 12.30 (s, 1H). HRMS m / z 470.0826.

[0120] N-(4-((6-amino-5-chloropyrimidin-4-yl)thio)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (39)

[0121] A mixture of 3-fluoro-4-nitrophenol (2.00 g, 12.7 mmol) and DABCO (2.84 g, 25.3 mmol) in anhydrous DMF (10 mL) was treated with dimethylthiocarbamoyl chloride (2.36 g, 19.1 mmol), and the mixture was stirred at 50 °C for 4 hours under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 1 M hydrochloric acid (50 mL). The organic phase was washed with brine (50 mL), dried, concentrated, and purified by flash chromatography (silica, PE gradient from PE: EtOAc = 1:1) to give O-(3-fluoro-4-nitrophenyl) dimethylcarbamothioate as an orange powder (2.172 g, 70%). 1 H NMR(CDCl3)δ 3.36 (s, 3H), 3.45 (s, 3H), 7.05 (m, 2H), 8.13 (t, 1H, J = 8.5 Hz).

[0122] A solution of O-(3-fluoro-4-nitrophenyl)dimethylcarbamothioate (1.00 g, 4.99 mmol) in NMP (10 mL) was heated at 180 °C for 20 minutes under microwave irradiation. The reaction mixture was concentrated using a Genevac centrifugal evaporator. The residue was purified by flash chromatography (silica, PE elution gradient from PE: EtOAc = 1:1) to give S-(3-fluoro-4-nitrophenyl)dimethylcarbamothioate as an orange powder (871 mg, 87%). 1 H NMR(CDCl3)δ 2.83 (s, 6H), 7.40 (d, 1H, J = 8.5 Hz), 7.50 (d, 1H, J = 11.0 Hz), 8.03 (t, 1H, J = 8.0 Hz).

[0123] Next, iron powder (571 mg, 10.2 mmol) was added to a solution of S-(3-fluoro-4-nitrophenyl)dimethylcarbamothioate (500 mg, 2.05 mmol) in MeOH / CHCOOH (1:1, 10 mL). After stirring at 50 °C for 2 h under N, the iron was removed and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in DCM (100 mL), and 1 M NaOH solution was added (50 mL). The precipitate was removed by centrifugation. The aqueous layer was extracted with DCM (50 mL). The combined organic layers were dried and concentrated to give S-(4-amino-3-fluorophenyl)dimethylcarbamothioate (419 mg, 96%) as a pale yellow solid, which was used in the subsequent reaction without further purification.

[0124] A mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (524 mg, 2.25 mmol), HATU (892 mg, 2.35 mmol), and DIPEA (0.60 mL, 3.44 mmol) in DCM (10 mL) was stirred at room temperature for 15 minutes. A solution of S-(4-amino-3-fluorophenyl)dimethylcarbamothioate (419 mg, 1.96 mmol) in DCM (5 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. After dilution with DCM (150 mL), saturated NH4Cl solution (50 mL) was added. The organic phase was separated, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, PE to EtOAc gradient) to give S-(3-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)dimethylcarbamothioate as a yellow solid (702 mg, 84%). 1H NMR (CDCl3) δ 3.05 (m, 6H), 6.58 (t, 1H, J = 7.0 Hz), 7.40 (m, 2H), 7.60 (dd, 1H, J = 2.0 & 6.5 Hz), 8.60 (t, 1H, J = 8.0 Hz), 8.72 (dd, 1H, J = 2.0 & 7.5 Hz), 12.13 (s, 1H) (one proton signal obscured by a CDCl3 peak).

[0125] A mixture of S-(3-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)dimethylcarbamothioate (700 mg, 1.63 mmol) in THF / MeOH / HO (2:2:1, 25 mL) was treated with lithium hydroxide (80 mg, 3.34 mmol), and the reaction mixture was stirred at 80° C. for 15 h. After concentration, 1 M hydrochloric acid was added to the residue, and the mixture was extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (50 mL), and concentrated to give N-(2-fluoro-4-mercaptophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide as a yellow powder (510 mg, 87%). 1 H NMR(DMSO)δ 5.68 (s, 1H), 6.72 (t, 1H, J = 7.0 Hz), 7.13 (d, 1H, J = 8.5 Hz), 7.29 (dd, 1H, J = 1.5 & 11.5 Hz), 7.42 (m, 3H), 7.59 (m, 3H), 8.12 (dd, 1H, J = 2.0 & 6.5 Hz), 8.34 (t, 1H, J = 8.5 Hz), 8.57 (dd, 1H, J = 2.0 & 7.5 Hz), 12.15 (s. 1H).

[0126] Finally, a mixture of N-(2-fluoro-4-mercaptophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (216 mg, 0.603 mmol), 5,6-dichloro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine (200 mg, 0.549 mmol), and cesium carbonate (215 mg, 0.660 mmol) in DMF (5 mL) was stirred at room temperature for 12 hours. After concentration, the residue was dissolved in DCM (100 mL) and washed with water (25 mL). The organic phase was dried over MgSO and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, gradient from PE to PE:EtOAc = 1:4). The resulting product was treated with TFA in CHCl (1:1, 6 mL) for 4 hours at room temperature. After concentration, the residue was dissolved in DCM (50 mL) and washed with 1 M NaOH solution (20 mL). The organic phase was dried over MgSO and concentrated to give N-(4-((6-amino-5-chloropyrimidin-4-yl)thio)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (48) as a beige powder (134 mg, 50%). 1 H NMR(DMSO)δ 6.74 (t, 1H, J = 7.0 Hz), 7.41 (m, 3H), 7.54 (dd, 1H, J = 2.0 & 11.0 Hz), 7.61 (m, 2H), 8.03 (s, 1H), 8.15 (dd, 1H, J = 2.0 & 6.5 Hz), 8.56 (t, 1H, J = 8.5 Hz), 8.62 (dd, 1H, J = 2.0 & 7.5 Hz), 12.38 (d, 1H, J = 2.0 Hz). HRMS m / z 486.0598.

[0127] Example 2 Biological activity Kinase assay Percent inhibition and / or IC20 were measured using a filter-binding radiometric kinase activity assay (Kinase Profiler™) from Eurofins Discovery. 50Briefly, optimal concentrations of TYRO3, AXL, MER, and MET human kinases were incubated in 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 250 μM of specific substrates (i.e., TYRO3: KVEKIGEGTYGVVYK (SEQ ID NO: 1); AXL: KKSRGDYMTMQIG (SEQ ID NO: 2); MER: GGMEDIYFEFMGGKKK (SEQ ID NO: 3), and Met: KKKGQEEEYVFIE (SEQ ID NO: 4), respectively), with an apparent K for ATP of 15 μM. m (AXL / MET: 90 μM, and Mer / TYRO3: 45 μM) in 10 mM magnesium acetate [γ -33 The reaction mixture was incubated with [P]-ATP and test compound. The reaction was initiated by adding the Mg / ATP mixture. After a 40-minute incubation at room temperature, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. 10 μL of the reaction mixture was then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol before drying and scintillation counting. IC values ​​were determined by fitting a sigmoidal dose-response curve to a plot of the assay readout versus inhibitor concentration. 50 All fits were calculated with GraphPad Prism software (San Diego, CA, United States of America). i The values ​​were calculated as IC using the Cheng Prusoff equation (Cheng Y et al., Biochem Pharmacol 22(23):3099-3108, 1973). 50 derived from the value.

[0128] Inhibition of CDK and FLT3 was measured using the ADP Glo kinase assay previously described in International Patent Publication No. 2017 / 020065. The results are shown in Table 2.

[0129] Proliferation assay As previously reported (Wang S et al., J Med Chem 47:1662-1675, 2004, and Diab S et al., CheMedChem 9:962-972, 2014), the compound of Example 1 was subjected to standard resazurin and MTT assays in solid tumor and leukemia cancer cell lines, respectively. The results are shown in Table 2. [Table 2]

[0130] Throughout the following specification and claims, unless the context requires otherwise, the words "comprise" and "include" and variations such as "comprising" and "including" will be understood to mean the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0131] The reference to any prior art in this specification is not, and should not be construed as, an admission in any way that such prior art forms part of the general common knowledge.

[0132] Those skilled in the art will understand that the present disclosure is not limited to use in the particular applications described. The present disclosure is also not limited to its preferred embodiments with respect to the specific elements and / or features described or illustrated herein. It will also be understood that the present disclosure is not limited to the described embodiment(s), but that various rearrangements, modifications, and substitutions are possible without departing from the scope of the present disclosure, as described and defined in the following claims.

Claims

1. A compound of formula I, 【Chemical 1】 [In the formula, X is O or S; R 1 is H; R 2 and R 3 are independently selected from alkyl, CN, CF 3 , O-alkyl, amino, NH-alkyl, S-alkyl, and halogen; R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ are H, alkyl, and alkyl-R １２ , aryl, aryl-R １２ , aralkyl, aralkyl-R １２ , alicyclic, heterocyclic, halogen, NO ２ , C.N., C.F. ３ , O-CF ３ , OH, O-alkyl, COR １２ , COOR １２ , O-aryl, O-R １２ , amino, NH-alkyl, NH-aryl, N-(alkyl) ２ , N-(aryl) ２ , N-(alkyl)(aryl), NH—R １２ , NH-alkyl-N(alkyl) ２ , N-(R １２ ) (R １３ ), N-(alkyl)(R １２ ), N-(aryl)(R １２ ), COOH, CONH ２ , CONH-alkyl, CONH-aryl, CONH-alicyclic, CON-(alkyl)(R １２ ), CON(aryl)(R １２ ), CONH-R １２ , CON-(R １２ ) (R １３ ), S-alkyl, SO ３ H, SO ２ -Alkyl, SO ２ -Alkyl-R １２ , S.O. ２ -aryl, SO ２ -aryl-R １２ , S.O. ２ NH ２ , S.O. ２ NH-R １２ , S.O. ２ N-(R １２ ) (R １３ ), CO-alkyl, CO-alkyl-R １２ , CO-aryl and CO-aryl-R １２ wherein said alkyl, said aryl, said aralkyl, said alicyclic, and said heterocyclic groups are independently selected from the group consisting of C １－６ Alkyl, O-C １－６ Alkyl, CN, OH, NH ２ , COOH, CONH ２ , C.F. ３ , OCF ３ and halogen; In the formula, R １２ and R １３ COOH, SO ３ H, OSO ３ H,SONHCH ３ ,SONHCH ２ CH ３ , S.O. ２ CH ３ , S.O. ２ CH ２ CH ３ , P.O. ３ H ２ , and OPO ３ H ２ , mono-, di-, and polyhydroxylated alicyclic groups, di- or polyhydroxylated aliphatic or aryl groups, and one or more C １－６ are independently selected from N-, O-, and / or S-containing heterocyclic groups optionally substituted with alkyl, hydroxyl, carbonyl, amino, or alkoxy groups, wherein said N-, O-, and / or S-containing heterocyclic groups can optionally be attached to the remainder of the compound via an alkyl, amine, alkoxy, or ketone bridge; and R １１ is phenyl substituted with halogen. Or a pharmaceutically acceptable salt or solvate thereof.

2. R 2 and R 3 are C 1-6 alkyl, CN, CF ３ , N.H. ２ , O-C １－６ Alkyl, NH—C １－６ Alkyl, S-C １－６ 10. The compound of claim 1, wherein each of the groups is independently selected from the group consisting of alkyl, and halogen.

3. The compound according to claim 1, wherein R 2 is C 1-3 alkyl or NH 2.

4. The compound according to claim 1, wherein R 3 is C 1-3 alkyl, O—C 1-3 alkyl, or halogen.

5. R ４ , R ５ , R ６ and R ７ But H, C １－６ Alkyl, CN, CF ３ , N.H. ２ , O-C １－６ Alkyl, NH—C １－６ Alkyl, S-C １－６ The compound of any one of claims 1 to 4, wherein each of the groups is independently selected from the group consisting of alkyl and halogen.

6. R ４ , R ５ , R ６ and R ７ The compound of claim 5 , wherein is independently selected from H and halogen.

7. R ４ , R ５ , R ６ and R ７ The compound according to any one of claims 1 to 6, wherein at least one of

8. R ４ , R ５ , R ６ and R ７ The compound according to any one of claims 1 to 6, wherein one or two of are halogen.

9. R ４ , R ５ , R ６ and R ７ The compound of claim 5 , wherein all are H.

10. R ８ , R ９ and R １０ But H, C １－６ Alkyl, CN, CF ３ , N.H. ２ , O-C １－６ Alkyl, NH—C １－６ Alkyl, S-C １－６ The compound of any one of claims 1 to 9, wherein each of the groups is independently selected from the group consisting of alkyl and halogen.

11. R ８ H, C １－３ Alkyl, or O—C １－３ The compound of any one of claims 1 to 10, which is alkyl.

12. R ９ and R １０ The compound according to any one of claims 1 to 11, wherein at least one of

13. R １１ The compound of any one of claims 1 to 12, wherein is phenyl substituted with F or Cl.

14. R １１ The compound of claim 13, wherein is fluorophenyl.

15. The compound of claim 1 selected from the group consisting of: N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-2,3-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2,3-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((2-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.

16. The compound of claim 1 selected from the group consisting of: N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)amino)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-((6-amino-5-chloropyrimidin-4-yl)thio)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.

17. 20. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, or solvate thereof, in the manufacture of a medicament for treating cancer or another proliferative cell disease or condition.

18. A pharmaceutical composition or medicament comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent, and / or excipient.

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