A derivative of 2-oxo-N-(4-(pyrimidin-4-yloxy / thio)phenyl)-1,2-dihydropyridine-3-carboxamide used as a protein kinase inhibitor for therapeutic purposes.

Abstract

A 2-oxo-N-(4-(pyrimidin-4-yloxy / thio)phenyl)-1,2-dihydropyridine-3-carboxamide derivative is disclosed for the prevention and / or treatment of proliferative cell diseases and disorders, including cancer. The compound is believed to 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. The compound has the following general formula I:

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a new class of protein kinase inhibitors useful for the treatment of proliferative cell diseases and conditions, including cancer.

[0002] PRIORITY DOCUMENT

[0003] This application claims priority from Australian provisional patent application number 2020902392 filed 10 July 2020 entitled “Protein kinase inhibitors for therapy”, the contents of which are hereby incorporated by reference in their entirety. BACKGROUND

[0004] There is an ongoing need to identify and develop new compounds for the treatment of proliferative diseases and conditions, including cancer. Among the many “targets” of potential anti-proliferative compounds under investigation are a group of enzymes known as receptor tyrosine kinases (RTKs). RTKs are cell surface proteins that transmit signals from the extracellular environment to the cytoplasm and nucleus to regulate cellular events such as survival, growth, proliferation, differentiation, adhesion and migration. Impaired function of genes resulting from mutation or deletion can lead to abnormal expression of protein kinases, which in turn leads to tumour formation and progression.

[0005] The TAM subfamily consists of three RTKs, namely 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 characterised by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Two ligands for TAM kinases have been identified, growth-arrest-specific 6 (GAS6) and protein S (PROS1). 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 TAM receptors leads to signalling along several pro-growth pathways such as the PI3K / AKT, MAPK and PKC pathways. Furthermore, TAM receptors are essential regulators of epithelial-mesenchymal transition (EMT), which leads to therapy resistance, metastasis and immune cell suppression, suggesting that TAMs play an important role in cancer biology and therapy.

[0006] AXL (also known as UFO, ARK, JTK11, and TYRO7) was initially identified as a transforming gene from DNA of patients with chronic myeloid leukemia (O'Bryan et al., Mol Cell Bi ol 11:5016-5031, 1991; Graham et al., ibid.). GAS6 binds to AXL, which then autophosphorylates and activates 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). AXL overexpression has been detected in most human cancers, including acute myeloid leukemia (Hong CC et al., Cancer Lett 268(2):314-324, 2008), breast cancer (Berclaz G et al., Ann Onc ol 12(6):819-824, 2001; Zhang YX et al., Cancer Res 68(6):1905-1915, 2008; Gjerdrum C et al., ProcNatl Acad Sci USA 107(3):1124-1129, 2010), gastric cancer (Wu CW et al., Anticancer Res 22(2B):1071-1078, 2002), lung cancer (Shieh YS et al., Neoplasia 7(12):1058-1064, 2005), and melanoma (Quong RY et al., Melanoma Res 2008). 4(5):313-319,1994), osteosarcoma (Han J et al., Biochem Biophys Res Commun 435(3):493-500,2013), renal cell carcinoma (Gustafsson A et al., Clin Cancer Res 15(14):4742-4749,2009), etc. Recently, AXL receptor-mediated resistance to several different cancer therapies (including chemotherapy, radiotherapy, and inhibitors of EGFR and PI3K) has been discovered. Therefore, targeting AXL may be a promising strategy for treating a variety of malignancies.

[0007] MER kinases (also known as MERTK, EYK, RYK, RP38, NYK, and TYRO12) were initially identified as phosphorylated proteins 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 kinases. Like AXL, MER activation also transmits downstream signaling pathways, including PI3K / AKT and Raf / MAPK. Aberrant expression of MER in various malignant tumors, such as melanoma (Schlegel et al., J ClinInvest 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., Onco gene 32(46):5359–5368,2013), and lung cancer (Xie et al., Oncotarget 6(11):9206–9219,2015), plays a key role in tumorigenesis.

[0008] TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, ETK2) was initially 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 a crucial role in immunity, phagocytosis, hemostasis, and neuronal diseases. Overexpression of TYRO3 and its ligands has been shown in various cancers and is associated with poor prognosis in multiple tumor types. Through AKT / NFκB signaling, TYRO3 exerts a pro-survival effect and promotes cancer cell growth (Crosier et al., Leuk Lymphoma 18:443–449, 1995). Protein levels of TYRO3 and AXL 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, allowing resistance to antitumor therapies to further promote cancer progression (Liu et al., J Immunother 35:299–308, 2012). In summary, these studies suggest that inhibiting TYRO3 and its signaling pathways may have therapeutic benefits in cancer treatment.

[0009] TAM inhibition not only has direct activity against neoplastic cells but also activates anticancer immune responses (Akalu YT et al. Immunol Rev 276(1):165–177, 2017), thus representing an attractive approach for cancer treatment. Furthermore, TAM inhibitors can be combined with other targeted therapies, chemotherapy, radiation, or immunotherapies to achieve maximum efficacy in clinical settings (Yokoyama et al., Cancer Res 79:1996-2008, 2019).

[0010] MET, also known as the N-methyl-N'-nitrosoguanidine human osteosarcoma transforming gene, is a proto-oncogene encoding c-MET, the receptor tyrosine kinase of 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 c-MET dimerization and autophosphorylation, which in turn activates the MAPK, PI3K, SRC, and STAT signaling pathways (Ma et al., Cancer Metastasis Rev 309-325, 2003). Aberrant MET expression is widely present in various malignant tumors, particularly 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 ThoracSurg 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 treatment and drug development.

[0011] The applicant has now identified a new class of compounds for the prevention and / or treatment of proliferative diseases and disorders, including cancer. While not wishing to be bound by theory, it is believed that these new compounds can inhibit cell proliferation, treat resistance, metastasis, and suppress immune cells by inhibiting the activity of one or more protein kinases, such as RTKs, particularly one or more TAM and / or MET family protein kinases, and / or their mutant forms. Summary of the Invention

[0012] This invention relates to a compound of formula I:

[0013]

[0014] in:

[0015] X is either O or S;

[0016] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10Each is independently selected from the following groups: H, alkyl, alkyl-R 12 aryl, aryl-R 12 Aryl, Aryl-R 12 Alicyclic groups, heterocyclic groups, halogens, 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 The alkyl, aryl, aralkyl, alicyclic, and heterocyclic groups may optionally be substituted by one or more groups selected from the group consisting of: C 1-6 Alkyl, OC 1-6 Alkyl groups, CN, OH, NH2, COOH, CONH2, CF3, OCF3, and halogens;

[0017] Where R 12 and R 13 Independently selected from COOH, SO3H, OSO3H, SONHCH3, SONHCH2CH3, SO2CH3, SO2CH2CH3, PO3H2 and OPO3H2, monohydroxylated, dihydroxylated and polyhydroxylated alicyclic groups, dihydroxylated or polyhydroxylated aliphatic groups or aryl groups, and optionally converted by one or more C 1-6A heterocyclic group containing N, O, and / or S, substituted with an alkyl, hydroxyl, carbonyl, amino, or alkoxy group, wherein the N, O, and / or S heterocyclic group may optionally be connected to the remainder of the compound via an alkyl, amine, alkoxy, or ketone bridge, wherein R 1 R 2 and R 3 At least two of them are not H; and

[0018] R 11 Selected from phenyl-R 14 ,

[0019] Where R 14 Selected from C 1-6 Alkyl, OC 1-6 Alkyl groups, CN, OH, NH2, COOH, CONH2, CF3, OCF3, and halogens;

[0020] Or a pharmaceutically acceptable salt, solvate, or prodrug.

[0021] In a second aspect, this disclosure provides the use of a compound as defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the treatment of cancer or another proliferative cell disease or disorder.

[0022] In a third aspect, this disclosure provides a method for treating a subject with cancer or another proliferative cell disease or disorder, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, solvate, or prodrug as defined in the first aspect, the compound or a pharmaceutically acceptable salt, solvate, or prodrug optionally combined with a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0023] In a fourth aspect, this disclosure provides the use of a compound as defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for the treatment of cancer or another proliferative cell disease or disorder.

[0024] In a fifth aspect, this disclosure provides a pharmaceutical composition or medicament comprising a compound as defined in the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent and / or excipient.

[0025] In a sixth aspect, this disclosure provides a method for regulating protein kinase activity in cells, comprising introducing an effective amount of a compound as defined in the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof into the cells, or contacting the cells with an effective amount of a compound as defined in the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof. Detailed Implementation

[0026] The applicant has now identified a new class of pyrimidine-2-amine derivatives suitable for the prevention and / or treatment of proliferative cell diseases and disorders (including cancer), particularly derivatives of 2-oxo-N-(4-(pyrimidin-4-yloxy / thio)phenyl)-1,2-dihydropyridine-3-carboxamide, which have the desired biological activity (e.g., the compound 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).

[0027] According to the first aspect, this disclosure provides a compound of formula I shown below:

[0028]

[0029] in:

[0030] X is either O or S;

[0031] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10 Each is independently selected from the following groups: H, alkyl, alkyl-R 12 aryl, aryl-R 12 Aryl, Aryl-R 12 Alicyclic groups, heterocyclic groups, halogens, 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 The alkyl, aryl, aralkyl, alicyclic, and heterocyclic groups may optionally be substituted by one or more groups selected from the group consisting of: C 1-6 Alkyl, OC 1-6 Alkyl groups, CN, OH, NH2, COOH, CONH2, CF3, OCF3, and halogens;

[0032] Where R 12 and R 13 Independently selected from COOH, SO3H, OSO3H, SONHCH3, SONHCH2CH3, SO2CH3, SO2CH2CH3, PO3H2 and OPO3H2, monohydroxylated, dihydroxylated and polyhydroxylated alicyclic groups, dihydroxylated or polyhydroxylated aliphatic groups or aryl groups, and optionally converted by one or more C 1-6 A heterocyclic group containing N, O, and / or S, substituted with an alkyl, hydroxyl, carbonyl, amino, or alkoxy group, wherein the N, O, and / or S heterocyclic group may optionally be connected to the remainder of the compound via an alkyl, amine, alkoxy, or ketone bridge, wherein R 1 R 2 and R 3 At least two of them are not H; and

[0033] R 11 Selected from phenyl-R 14 ,

[0034] Where R 14 Selected from C 1-6 Alkyl, OC 1-6 Alkyl groups, CN, OH, NH2, COOH, CONH2, CF3, OCF3, and halogens;

[0035] Or a pharmaceutically acceptable salt, solvate, or prodrug.

[0036] In some implementations, when present, one or more R 12 and / or R 13 The group may provide at least one water-solubilizing group for the compound of formula I. The presence of said at least one water-solubilizing group may enhance in vivo absorption and oral bioavailability.

[0037] In some implementations, when present, one or more R 12 and / or R 13 The group comprises one or more N, O, and / or S-containing heterocyclic groups (optionally substituted with one or more hydroxyl, amino, or alkoxy groups) connected to the remainder of the compound via 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., -C(=O)- bridge). For example, when the compound contains NH-R 12 When the group is R 12 It may be an N, O and / or S heterocyclic group (optionally substituted with one or more hydroxy, amino or alkoxy groups) connected to the rest of the compound via, for example, -CH2- or -CH2CH2- alkyl bridges.

[0038] Compounds of Formula I have been found to possess antiproliferative activity and are therefore considered for the treatment of proliferative cell diseases and disorders, such as cancer, leukemia, lymphoma, and other diseases and disorders associated with uncontrolled cell proliferation (or, in other words, the need for cell cycle control), for example, some cardiovascular diseases or disorders such as restenosis and cardiomyopathy, some autoimmune diseases (such as glomerulonephritis and rheumatoid arthritis), dermatological disorders (such as psoriasis), and fungal or parasitic conditions. As used herein, the antiproliferative effect within the scope of this disclosure can be demonstrated by the ability to inhibit cell proliferation in an in vitro whole-cell assay. One or more examples of such an assay (including the method for performing it) are described in more detail in Example 2 provided below.

[0039] In a second aspect, this disclosure provides the use of a compound as defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the treatment of cancer or another proliferative cell disease or disorder.

[0040] In a third aspect, this disclosure provides a method for treating a subject with cancer or another proliferative cell disease or disorder, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, solvate, or prodrug as defined in the first aspect, the compound or a pharmaceutically acceptable salt, solvate, or prodrug optionally combined with a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0041] In a fourth aspect, this disclosure provides the use of a compound as defined in the first aspect, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for the treatment of cancer or another proliferative cell disease or disorder.

[0042] In a fifth aspect, this disclosure provides a pharmaceutical composition or medicament comprising a compound as defined in the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent and / or excipient.

[0043] In a sixth aspect, this disclosure provides a method for regulating protein kinase activity in cells, comprising introducing an effective amount of a compound as defined in the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof into the cells, or contacting the cells with an effective amount of a compound as defined in the first aspect or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0044] Preferably, the method of the sixth aspect modulates the activity of one or more protein kinases selected from RTKs, particularly one or more TAM and / or MET family protein kinases.

[0045] This patent specification uses many terms that are well known to those skilled in the art. However, for clarity, some of these terms are defined below.

[0046] As used herein, the term “treatment” includes preventing and treating a disease as well as alleviating the established symptoms of a disease. Therefore, acts of “treating” a disease or ailment thus include: (1) preventing or delaying the development of clinical symptoms of the disease or ailment in subjects who have or are susceptible to the disease or ailment; (2) suppressing the disease or ailment (i.e., curbing, reducing or delaying the development of the disease or ailment or its recurrence (in the case of maintenance treatment)) or at least one of its clinical or subclinical symptoms; and (3) alleviating or slowing the disease or ailment (i.e., causing the disease or ailment or at least one of its clinical or subclinical symptoms to subside).

[0047] As used herein, the term "alkyl" includes straight-chain and branched alkyl groups having 1 to 8 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, etc.).

[0048] As used herein, the term "aryl" refers to a substituted (mono- or poly-substituted) or unsubstituted monocyclic aromatic group or polycyclic aromatic group, wherein the polycyclic aromatic group may be fused or unfused. Therefore, 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."

[0049] As used herein, the term "aralkyl" is used as a combination of the terms alkyl and aryl as defined above.

[0050] The term "aliphatic" has its normal meaning in this field and includes non-aromatic groups such as alkanes, alkenes, and alkynes, as well as their substituted derivatives. The term includes groups having 1 to 8 carbon atoms.

[0051] As used in this article, the term "alicyclic" refers to cyclic aliphatic groups.

[0052] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0053] As used herein, the term "heterocyclic (group)" refers to a saturated or unsaturated cyclic group containing one or more heteroatoms in a cyclic system (e.g., a system containing one or more rings (monocyclic or polycyclic)), wherein the rings may be fused and / or unfused when more than one ring is present. Thus, the term encompasses saturated heterocyclic groups such as pyrrolidinyl, morpholinyl, aziridine, and piperazine, and unsaturated heterocyclic groups ("heteroaryl" groups such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyrimidinyl, 5-indolyl, furan, thiophene, and thiazole, etc.); and wherein at least one ring of the cyclic system contains one to four heteroatoms selected from N, O, and S as ring members (i.e., it contains at least one heterocycle), and wherein nitrogen and sulfur atoms may be oxidized, and one or more nitrogen atoms may be quaternized. Heterocyclic groups can be attached to the rest of the molecule via cyclic carbons or cyclic heteroatoms, and if the ring system is, for example, a polycyclic system such as a bicyclic, tricyclic, or fused-ring system, the heterocyclic group can be attached to any ring of that ring system.

[0054] As used herein, the term "derivative" includes any chemical modification of an entity. Examples of such chemical modifications include the substitution of hydrogen with a halogen group, alkyl group, acyl group, or amino group.

[0055] As used herein, the phrase “manufacturing of a drug” includes using one or more compounds of Formula I directly as a drug, or at any stage of the manufacture of a drug comprising one or more compounds of Formula I.

[0056] 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 included within the scope of this disclosure. These isomeric forms, such as diastereomers, enantiomers, and geometric isomers, can be isolated by physical and / or chemical methods known to those skilled in the art.

[0057] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound retaining Formula I that provides the desired biological activity, including pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds 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 acids, and sulfonic 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, alkyl sulfonic acids, and aryl sulfonic acids. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences (19th edition, Mack Publishing Co., Easton, PA 1995).

[0058] The term "solvent" refers to any form of a compound of formula I produced by solvation with a suitable solvent. This form can be, for example, a crystalline solvate or a complex that can be formed between the solvent and the dissolved compound.

[0059] The term "prodrug" refers to a compound that is typically converted into a compound of formula I within a biological system via metabolic means (e.g., by hydrolysis, reduction, or oxidation). For example, an ester prodrug of a formula I compound containing a hydroxyl group can be converted into a compound of formula I via in vivo hydrolysis. Suitable esters of formula I compounds containing hydroxyl groups can be, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bis-p-hydroxynaphthyl esters, gestisates, ethanesulfonates, di-p-toluyl tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylaminosulfonates, and quinates. As another example, an ester prodrug of a formula I compound containing a carboxyl group can be converted into a compound of formula I via in vivo hydrolysis. Examples of ester prodrugs include those described in Leinweber FJ, Drug Metab Rev 18:379-439 (1987). Similarly, acyl prodrugs of Formula I containing an amino group can be converted into compounds of Formula I through in vivo hydrolysis. Examples of these and other prodrugs with functional groups (including amines) are provided in Prodrugs: Challenges and Rewards, Valentino J Stella (ed.), Springer, 2007.

[0060] When the compound of Formula I is a solid, those skilled in the art will understand that the compound (or its pharmaceutically acceptable salt, solvate, or prodrug) may exist in different crystalline or polymorphic forms, all of which are covered within the scope of this disclosure.

[0061] The term "therapeutic effective amount" or "effective amount" is an amount sufficient to produce a beneficial or desired clinical outcome. A therapeutic effective amount may be administered in one or more doses. Generally, a therapeutic effective amount is sufficient to treat a disease or condition, or otherwise alleviate, improve, stabilize, reverse, slow, or delay the progression of a disease or condition such as cancer or another proliferative cell disease or condition. For example only, a therapeutic effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof may include between about 0.1 mg / kg body weight / day and about 250 mg / kg body weight / day, more preferably between about 0.1 mg / kg body weight / day and about 100 mg / kg body weight / day, and even more preferably between about 0.1 mg / kg body weight / day and about 25 mg / kg body weight / day. However, those skilled in the art will understand that the therapeutically effective dose can vary and depend on a variety of factors, including the activity of the particular compound (or its salts, solvates or prodrugs), the metabolic stability and duration of action of the particular compound (or its salts, solvates or prodrugs), age, weight, sex, health, route and time of administration, the excretion rate of the particular compound (or its salts, solvates or prodrugs), and the severity of, for example, the cancer or other proliferative cell disease or ailment to be treated.

[0062] Compounds of Formula I, along with their pharmaceutically acceptable salts, solvates, and prodrugs, are capable of inhibiting protein kinases, particularly RTK, and can exhibit higher selectivity for (i.e., inhibition of) TYRO3, AXL, MER, and / or MET than other protein kinases. Therefore, compounds of Formula I, along with their pharmaceutically acceptable salts, solvates, and prodrugs, are believed to be effective in both in vitro and in vivo applications (e.g., in vitro cell-based assays) and form the basis of treatments for cancer or other proliferative cell diseases or disorders in subjects.

[0063] Compounds of Formula I may contain at least one water-solubilizing group (e.g., derived from R...). 12 and / or R 13(Provided). Those skilled in the art will fully understand that the term "water-solubilizing group" refers to any polar functional group that ionizes or is capable of forming hydrogen bonds with water molecules, thereby increasing the water solubility of a compound (i.e., the water solubility relative to a corresponding compound lacking a water-solubilizing group). Examples of suitable water-solubilizing groups and methods for introducing them, as well as considerations, are described, for example, in *Fundamentals of Medicinal Chemistry* by Gareth Thomas (published by John Wiley & Sons).

[0064] R 1 R 2 and R 3 At least two of them are not H; such that the compound of formula (I) contains a di- or tri-substituted pyrimidine group.

[0065] In some implementation schemes, R 1 R 2 and R 3 Independently selected from the group consisting of: H, alkyl (e.g., C) 1-6 Alkyl, or preferably C 1-3 Alkyl groups such as methyl, ethyl, and C(CH3)2), CN, CF3, amino (e.g., NH2), O-alkyl (e.g., OC) 1-3 Alkyl groups such as O-CH3), NH-alkyl groups (e.g., NH-C) 1-6 Alkyl groups such as NH(C5H9) (i.e., NH-cyclopentyl), or preferably NH-C 1-3 Alkyl groups such as NH-CH3), S-alkyl groups such as SC 1-6 Alkyl, or preferably SC 1-3 Alkyl groups such as S-CH3 and S-CH(CH3)2 and halogens (preferably F, Br or Cl).

[0066] Preferably, R 1 For H, C 1-3 Alkyl groups such as methyl or amino groups (e.g., NH2).

[0067] Preferably, R 2 For H, C 1-3 Alkyl groups such as methyl or amino groups (e.g., NH2).

[0068] Preferably, R 3 For H, C 1-3 Alkyl (such as methyl), O-alkyl (e.g. O-CH3), or halogen (preferably F or Cl).

[0069] In some implementation schemes, R 4 R 5 R 6 and R7 Independently selected from the group consisting of: H, alkyl (e.g., C) 1-6 Alkyl, or preferably C 1-3 Alkyl groups such as methyl, ethyl, and C(CH3)2), CN, CF3, amino (e.g., NH2), O-alkyl (e.g., OC) 1-3 Alkyl groups such as O-CH3), NH-alkyl groups (e.g., NH-C) 1-6 Alkyl groups such as NH(C5H9) (i.e., NH-cyclopentyl), or preferably NH-C 1-3 Alkyl groups such as NH-CH3), S-alkyl groups such as SC 1-6 Alkyl or preferably SC 1-3 Alkyl groups such as S-CH3 and SCH(CH3)2 and halogens (preferably F, Br or Cl).

[0070] Preferably, R 4 R 5 R 6 and R 7 Independently selected from H and halogens (preferably F). Furthermore, preferably, R 4 R 5 R 6 and R 7 At least one of them is H.

[0071] In some preferred embodiments, R 4 R 5 R 6 and R 7 One or both of them are halogens (preferably F).

[0072] In some other preferred embodiments, R 4 R 5 R 6 and R 7 All are H.

[0073] In some implementation schemes, R 8 R 9 and R 10 Independently selected from the group consisting of: H, alkyl (e.g., C) 1-6 Alkyl, or preferably C 1-3 Alkyl groups such as methyl, ethyl, and C(CH3)2), CN, CF3, amino (e.g., NH2), O-alkyl (e.g., OC) 1-3 Alkyl groups such as O-CH2CH3), NH-alkyl groups (e.g., NH-C) 1-6 Alkyl groups such as NH(C5H9) (i.e., NH-cyclopentyl), or preferably NH-C 1-3 Alkyl groups such as NH-CH3), S-alkyl groups such as SC1-6 Alkyl, or preferably SC 1-3 Alkyl groups such as S-CH3 and S-CH(CH3)2 and halogens (preferably F, Br or Cl).

[0074] Preferably, R 8 For H, C 1-3 Alkyl (such as methyl), or OC 1-3 Alkyl groups (such as O-CH2CH3).

[0075] Preferably, R 9 and R 10 At least one of them, and more preferably both, is H.

[0076] In some preferred embodiments, R 11 phenyl-R 14 , where R 14 Selected from C 1-3 Alkyl, OC 1-3 Alkyl groups, CF3, OCF3, and halogens (preferably, F).

[0077] In some particularly preferred embodiments, R 11 phenyl-R 14 , where R 14 Selected from CH3, OCH3, CF3, OCF3, F, and Cl. In such embodiments, R 11 The phenyl group is preferably substituted at only one position, and preferably at the carbon atom at position 4.

[0078] In some preferred embodiments, the compound of formula I exhibits antiproliferative activity in human cell lines, as measured by a cytotoxicity assay. Preferably, the compound exhibits an IC50 concentration of less than 10 μM, and even more preferably less than 5 μM. 50 Values, such as those measured using standard cell viability assays.

[0079] In some preferred embodiments, the compound of Formula I inhibits one or more protein kinases, as measured by any standard assay known to those skilled in the art. Preferably, the compound exhibits an IC50 of less than 1 μM or less than 0.5 μM, more preferably less than 0.1 μM, as measured by the kinase assay described in Example 2 below. 50 value.

[0080] Specific examples of compounds according to the first aspect are listed in Table 1 below.

[0081] Table 1. Chemical structures of the selected compounds disclosed herein.

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] The compound (and its pharmaceutically acceptable salts, solvates, and prodrugs) may be administered in combination with one or more additional agents for the treatment of cancer or another proliferative disease or disorder. For example, the compound may be used in combination with other anticancer agents to simultaneously inhibit more than one cancer signaling pathway, thereby making cancer cells more sensitive to anticancer therapies (e.g., treatment with other anticancer agents, chemotherapy, radiotherapy, or combinations thereof). Therefore, the compound of Formula I may be used in combination with one or more of the following classes of anticancer agents:

[0089] • Other antiproliferative / anti-proliferative drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolate agents, such as fluoropyrimidines like 5-fluorouracil and nitrofluoridine, raltitrexed, methotrexate, cytosine arabinoside, fludarabine, and hydroxyurea); and antitumor antibiotics (e.g., anthracyclines, such as doxorubicin). Bleomycin, doxorubicin, doxorubicin, epirubicin, idarubicin, mitomycin C, sclerosingin, and sclerosingin; antimitotic agents (e.g., vinca alkaloids, such as vincristine, vinblastine, vinorelbine, and vinorelbine, as well as taxanes, including paclitaxel and doxorubicin and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxin, such as etoposide and teniposide, acridine, topotecan, and camptothecin);

[0090] • Cell inhibitors, such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), anti-androgens (e.g., bicalutamide, flutamide, nilumet, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductases such as finasteride;

[0091] • Anti-invasive agents (e.g., c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyaniline)-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}thiazolyl-5-carboxamide (dasatinib) and bosutinib (SKI-606)), as well as metalloproteinase inhibitors including mamastine, inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase;

[0092] • Inhibitors of growth factor function (e.g., growth factor antibodies and growth factor receptor antibodies, such as anti-erbB2 antibody trastuzumab (Herceptin)) TMAnti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab (Erbitux, C225), and any growth factor or growth factor receptor antibody disclosed in Stern et al., Critical reviews in oncology / haematology, 2005, Vol. 54, pp. 11-29. Such inhibitors also include tyrosine kinase inhibitors such as epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI 774), and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI). 1033), ERB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin-like 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., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, including sorafenib (BAY)). 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; 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;

[0093] • Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin)). TM) 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-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidone-1-ylpropoxy)quinazoline (AZD2171; Example 240 in International Patent Publication No. WO 00 / 47212), such as compounds disclosed in International Patent Publications Nos. WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354, as well as compounds that act through other mechanisms (e.g., linolamine, an inhibitor of integrin αvβ3 function and angiostatin);

[0094] • Vascular damaging agents, such as Combretastatin A4 and compounds disclosed in International Patent Publication Nos. WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[0095] • Endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan;

[0096] • Antisense therapies, such as those targeting the targets listed above, such as ISIS 2503, which is an anti-ras antisense;

[0097] Gene therapy approaches include, for example, replacing abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2), GDEPT (gene-guided enzyme prodrug therapy) approaches (such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase), and approaches to improve patient tolerance to chemotherapy or radiation therapy (such as multidrug resistance gene therapy); and

[0098] • Immunotherapy approaches include, for example, in vitro and in vivo approaches that increase the immunogenicity of the patient’s tumor cells (such as transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factors), approaches that reduce T cell dysfunction, approaches that use transfected immune cells such as dendritic cells transfected with cytokines, approaches that use tumor cell lines transfected with cytokines, and approaches that use anti-idiotype antibodies.

[0099] When used in combination with other anticancer agents, the compounds of Formula I and the other anticancer agents may be administered in the same pharmaceutical composition or in separate pharmaceutical compositions. If administered in separate pharmaceutical compositions, the compounds and the other anticancer agents may be administered simultaneously or in any order (e.g., within seconds, minutes, or even hours, e.g., 2 to 48 hours).

[0100] Compounds of Formula I are typically used to treat cancer or another proliferative cell disease or disorder in human subjects. However, the subject may also be selected from, for example, livestock (e.g., cattle, horses, pigs, sheep, and goats), companion animals (e.g., dogs and cats), and wild animals (e.g., non-human primates, tigers, elephants, etc.).

[0101] Cancers and other proliferative cell diseases and disorders that can be treated according to this disclosure include biliary tract cancer, brain cancer and other cancers of the central nervous system (CNS) (including glioblastoma and medulloblastoma), neuroblastoma, breast cancer, cervical cancer, ovarian cancer (including those caused by epithelial cells, stromal cells, germ cells and mesenchymal cells), choriocarcinoma, colorectal cancer, endometrial cancer, liver cancer, lung cancer, esophageal cancer, gastric cancer, hematologic vegetations (including acute lymphoblastic leukemia (ALL)), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), multiple myeloma, AIDS-related leukemia and adult T-cell leukemia lymphoma, lymphoma (including non-Hodgkin lymphoma, Hodgkin's disease and lymphocytic lymphoma), intraepithelial vegetations (including Bowen's disease and Paget's disease) Diseases including oral cancer (including squamous cell carcinoma), pancreatic cancer, prostate cancer, sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basophilic carcinoma, and squamous cell carcinoma), testicular cancer (including germ tumors such as seminoma, non-seminomatous tumor, teratoma, and choriocarcinoma), stromal tumors, germ cell tumors, thyroid cancer (including adenocarcinoma and medullary carcinoma), and kidney cancer (including adenocarcinoma and Wilms' tumor).

[0102] In some implementations, compounds of Formula I are used to treat cancers or other diseases that depend on TAM and / or MET activation, wherein TAM and / or MET activation can be regulated by gene amplification or activated TAM and / or MET mutant forms.

[0103] Compounds of Formula I can be formulated into pharmaceutical compositions having pharmaceutically acceptable carriers, diluents, and / or excipients. 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 forms of pharmaceutical compositions described herein can be found in Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), by Awade and PJ Weller. Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Examples of suitable diluents include ethanol, glycerol, and water. The carrier, diluent, and / or excipient can be selected according to the intended route of administration and standard pharmaceutical practice.

[0104] Pharmaceutical compositions containing compounds of Formula I may also include any suitable binders, lubricants, suspending agents, coating agents, and solubilizers. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethyl cellulose, 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, esters of sorbic acid and p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0105] Pharmaceutical compositions comprising a compound of formula I can be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intra-arterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal, or sublingual administration. For oral administration, compressed tablets, pills, tablets, gels, drops, and capsules are particularly suitable. For other forms of administration, the pharmaceutical composition may comprise a solution or emulsion prepared from a sterile or sterile solution that can be injected intravenously, intra-arterially, intrathecally, subcutaneously, intradermally, intraperitoneally, or intramuscularly. Pharmaceutical compositions comprising a compound of formula I may also be in the form of suppositories, vaginal suppositories, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions, or powders. The pharmaceutical composition may be formulated in unit dosage forms (i.e., in the form of discrete portions containing a unit dose, or multiple unit doses, or unit dose subunits).

[0106] Compounds of Formula I may be provided as pharmaceutically acceptable salts, including, for example, suitable acid addition salts or base salts of the compound. A review of suitable pharmaceutical salts can be found in Berge et al., J Pharm Sci 66:1-19 (1977). Salts are formed, for example, from the following substances: strong inorganic acids such as mineral acids (e.g., sulfuric acid, phosphoric acid, or hydrohalic acid); strong organic carboxylic acids such as unsubstituted or (e.g., halogenated) substituted alkane carboxylic acids of 1 to 4 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids (e.g., oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid); hydroxycarboxylic acids (e.g., ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid); amino acids (e.g., aspartic acid or glutamic acid); benzoic acid; or organic sulfonic acids (e.g., unsubstituted or (C1-C4)-alkyl or aryl sulfonic acids substituted, for example, with halogens), such as methanesulfonic acid or p-toluenesulfonic acid).

[0107] Compounds of Formula I can be provided in their various crystalline, polymorphic, anhydrous, or hydrated forms. In this respect, it is well known to those skilled in the art that chemical compounds in any of these forms can be isolated by slightly altering the purification method and / or by separating them from the solvents used in the synthetic preparation of such compounds.

[0108] This disclosure also provides a method for synthesizing a compound according to formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0109] Regarding the description of the synthetic methods and reference synthetic methods for preparing the starting materials described below, those skilled in the art will understand that all suggested reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, and duration of experimental and post-treatment procedures, can be readily selected. Furthermore, those skilled in the art will understand that the functional groups present on various parts of the molecule must be compatible with the reagents and reaction conditions used.

[0110] The necessary starting materials can be obtained through standard procedures in organic chemistry. The preparation of such starting materials is described in conjunction with representative process variations, as illustrated in the examples below. Alternatively, the necessary starting materials can be obtained through procedures similar to those exemplified and which are within the general technical scope of those skilled in the art. Furthermore, it should be understood that during the synthesis of compounds, in the processes described below, or in the synthesis of certain starting materials, it may be desirable to protect certain substituents from undesirable reactions. Those skilled in the art will readily recognize when such protection is needed, how to place such protecting groups in their proper positions, and subsequently remove them. 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 well known to those skilled in the art suitable for removing the protecting groups in question, chosen to achieve removal of the protecting groups with minimal interference to groups elsewhere in the molecule. Thus, if the reactants include groups such as amino, carboxyl, or hydroxyl, protecting such groups may be desirable in some of the reactions mentioned herein.

[0111] The synthetic methods for preparing compounds of formula I are obvious to those skilled in the art.

[0112] However, in a further aspect of this disclosure, a method for synthesizing a compound of formula I (or a pharmaceutically acceptable salt, solvate, or prodrug thereof) is provided, wherein the method comprises:

[0113] a) Compounds of formula A:

[0114]

[0115] in

[0116] X is either O or S;

[0117] R 1 R 2 R 3 R 4 R 5 R 6 and R 7 As defined above for Formula I, reaction with a suitable 2-oxo-1,2-dihydropyridine-3-carboxylic acid derivative yields a compound of Formula B:

[0118]

[0119] Where R 8 R9 R 10 and R 11 As defined above for Equation I, and if necessary

[0120] b) Remove any existing protecting groups, and / or form a pharmaceutically acceptable salt, solvate, or prodrug.

[0121] In another aspect of this disclosure, a method is provided for synthesizing a compound of formula I (or a pharmaceutically acceptable salt, solvate, or prodrug thereof), wherein the method comprises:

[0122] a) Compounds of formula B:

[0123]

[0124] Where R 8 R 9 R 10 and R 11 As defined above for formula I, it reacts with compounds having formula C:

[0125]

[0126] Where R 4 R 5 R 6 and R 7 As defined above for formula I, we obtain the compound of formula D.

[0127]

[0128] b) React the compound of formula D with a halopyrimidine, and if necessary

[0129] c) Remove any existing protecting groups, and / or form a pharmaceutically acceptable salt, solvate, or prodrug.

[0130] The coupling reaction between 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 this reaction. Examples of suitable solvents include acetonitrile, halogenated solvents, etc.

[0131] Furthermore, those skilled in the art will be able to select suitable reaction conditions for the coupling reaction of compounds of formulas A and 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 time period, such as 30 minutes to 48 hours.

[0132] The resulting compound can be separated and purified using techniques well known to those skilled in the art.

[0133] An example of a particularly suitable method for synthesizing the disclosed compound is shown in Scheme 1 below.

[0134] Option 1

[0135]

[0136] The general reaction conditions are as follows: (a) appropriate halopyrimidine, K2CO3 or Cs2CO3, DMF, room temperature - 80°C, 12-24 hours; (b) appropriate boric acid, Cu(CH3CO2)2, pyridine, room temperature; (c) LiOH, THF / MeOH / H2O (2:2:1), room temperature - 80°C, 12-24 hours; (d) NaClO2, NaH2PO4, 2-methyl-2-butene, THF / tert-butanol / H2O (1:1:1), 0°C - room temperature, 0.5-2 hours; and (e) HATU, DIPEA, room temperature, 2-4 hours; or SOCl2, DIPEA, 0°C - room temperature, 0.5-2 hours.

[0137] The present disclosure is described below with reference to the following non-limiting examples and accompanying drawings.

[0138] Example

[0139] Example 1 Synthesis

[0140] General Principles

[0141] 1 H and 13 C10 NMR spectra were recorded at 298 K (unless otherwise noted) on a Bruker AVANCE III HD 500 spectrometer. 1 H at 500.20MHz and 13 C at 125.79MHz, and analyzed using Bruker Topspin 3.2 software. 1 HNMR signals were represented by chemical shift values ​​δ (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doubletuplets, dt = doubletuplets, td = tripletuplets, ddd = doubletuplets, m = multiply, br = broad peak), relative integral, coupling constant J (Hz), and assignment report. High-resolution mass spectra were recorded on an AB SCIEX TripleTOF 5600 mass spectrometer (Concord, ON, Canada), and all samples were ionized using ESI.

[0142] General synthetic procedure: DIPEA (1.2 equivalents) was added to a solution of carboxylic acid B (1.15 equivalents) and HATU (1.2 equivalents) in DCM under N2 atmosphere, and the reaction mixture was stirred at room temperature for 15 minutes. Then, a suitable solution of arylamine A (1 equivalent) in DCM was added, and the reaction mixture was stirred at room temperature for 4 hours. 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 rapid chromatography (silica gel). The resulting product was dissolved in a DCM / TFA (1:1) solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in DCM and washed with 1M NaOH solution. The organic phase was dried over MgSO4 and concentrated under reduced pressure to give the desired compound.

[0143] Example

[0144] N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (1)

[0145] 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) in DCM (25 mL) and pyridine (1.1 mL, 13.7 mmol) was stirred at room temperature in the presence of air for 18 hours. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 1 M HCl aqueous solution (50 mL). The organic phase was washed with brine (50 mL), dried over MgSO4, and concentrated. The residue was purified by rapid chromatography (silica, PE inclined to EtOAc) to give methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate as a white solid (394 mg, 49%). 1 H NMR (MeOD) δ3.78 (s, 3H), 6.45 (t, 1H, J = 7.0Hz), 7.20 (t, 2H, J = 8.0Hz), 7.38 (m, 2H), 7.81 (d, 1H, J = 6.5Hz), 8.23 ​​(d, 1H, J = 7.0Hz). HRMS m / z 248.0841[M+H] + .

[0146] Then, H₂O (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 hours, the reaction mixture was quenched with 1 M HCl in water (2 mL) and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 1 M HCl aqueous solution. The aqueous phase was extracted with EtOAc (2 × 50 mL). The organic extracts were combined, dried over MgSO₄ 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 HNMR (DMSO) δ6.79 (t, 1H, J = 7.0Hz), 7.43 (t, 2H, J = 8.5Hz), 7.62 (dd, 2H, J = 8.5 & 8.5Hz), 8.21 (d, 1H, J = 6.5Hz), 8.49 (d, 1H, J = 7.0Hz). HRMS m / z240.0853[M+H] + .

[0147] A solution of di-tert-butyl dicarbonate (1.50 g, 6.87 mmol) in DCM (2 mL) was added to a mixture of 6-chloro-5-fluoropyrimidin-4-amine (500 mg, 3.39 mmol), Et3N (1 mL, 7.17 mmol), and DMAP (80 mg, 0.655 mmol) in DCM (20 mL). After stirring at room temperature for 12 hours, the reaction mixture was washed with 0.1 M HCl aqueous solution. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by rapid chromatography (silica, PE ramp to PE:EtOAc = 7:3) to give 6-chloro-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidin-4-amine as a white solid (808 mg, 69%). 1 HNMR(DMSO)δ1.42(s,18H),8.94(s,1H).

[0148] Then, 4-amino-2-fluorophenol (307 mg, 2.42 mmol) was added to a mixture of 6-chloro-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-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, H2O was added to the residue, and the mixture was extracted with DCM (3 × 50 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by rapid chromatography (silica, PE ramp to PE:EtOAc = 2:3) to give 6-(4-amino-2-fluorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine as a light pink powder (418 mg, 47%). 1 H NMR (CDCl3) δ1.48 (s, 18H), 3.80 (s, 2H), 6.50 (m, 2H), 7.03 (t, 1H, J = 8.5Hz), 8.39 (s, 1H). HRMS m / z 439.1923[M+H] + .

[0149] 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 min. Then, a solution of 6-(4-amino-2-fluorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (160 mg, 0.365 mmol) in DCM (3 mL) was added, and the reaction mixture was stirred at room temperature for 4 h. DCM (150 mL) was added to the reaction mixture, and the mixture was washed with saturated NH4Cl solution (50 mL). The organic phase was dried over MgSO4, concentrated, and purified by rapid chromatography (silica, PE ramp to EtOAc). The resulting product was treated with DCM / TFA (1:1, 6 mL) for 2 h. 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 MgSO4 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), a white solid (126 mg, 76%). 1H NMR(CDCl3)δ5.03(s,2H),6.61(t,1H,J=7.0Hz),7.27(t,2H,J=8.5Hz),7.34(d,1H,J=9.0Hz),7.40(m,2H),7.6 1(dd,1H,J=2.0&6.5Hz),7.92(dd,1H,J=2.0&12.5Hz),7.96(s,1H),8.74(dd,1H,J=2.0&7.5Hz),11.95(s,1H). HRMS m / z 454.1190[M+H] +

[0150] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (2)

[0151] 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 added to a solution of 6-(4-amino-2-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (476 mg, 1.05 mmol), DIPEA (0.4 mL), DMF (0.3 mL), and THF (5 mL) in an ice bath. After 5 minutes, the reaction mixture was stirred at room temperature for another 30 minutes. 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 rapid chromatography (silica, PE uplift to EtOAc:PE = 1:1) to obtain 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, a light yellow powder (378 mg, 36%). 1 H NMR (CDCl3) δ1.45 (s, 18H), 7.12 (d, 1H, J = 7.0Hz), 7.22 (m, 3H), 7.36 (m, 3H), 7.90 (d, 1H, J = 12.0Hz), 8.50 (s, 1H), 11.58 (s, 1H). MS m / z 796.3[M+H]+.

[0152] Then, sodium ethoxide (30 mg, 0.441 mmol) was added 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), and the reaction mixture was stirred at room temperature for 12 hours. 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 × 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 at room temperature for 48 hours. 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 rapid chromatography (silica, EtOAc up to EtOAc:MeOH = 95:5) to give the title compound (1) as a white solid (24 mg, 16%). 1 H NMR (CDCl3) δ1.57 (t, 3H, J = 7.0Hz), 4.35 (q, 2H, J = 7.0Hz), 5.34 (s, 2H), 6.34 (d, 1H, J = 8.0Hz), 7.10 (t, 1H, J = 8. 5Hz),7.25(m,5H),7.35(m,2H),7.49(d,1H,J=8.0Hz),7.90(dd,1H,J=1.5&12.5Hz),8.06(s,1H),11.52(s,1H). HRMS m / z514.1260[M+H]+.

[0153] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.429 mmol) was prepared 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-butoxycarbonylpyrimidine-4-amine (170 mg, 0.374 mmol) to obtain a white solid (132 mg, 75%). 1H NMR(CDCl3)δ5.25(s,2H),6.54(t,1H,J=7.0Hz),7.22(m,2H),7.28(d,1H,J=9.5Hz),7.34(m,2H) ,7.55(d,1H,J=6.5Hz),7.85(d,1H,J=12.5Hz),8.00(s,1H),8.67(d,1H,J=7.5Hz),11.88(s,1H). HRMS m / z 470.1326[M+H] + .

[0154] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.429 mmol) was obtained by reacting 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (160 mg, 0.366 mmol) with 6-(4-aminophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (160 mg, 0.366 mmol), as a white solid (131 mg, 79%). 1 H NMR(CDCl3)δ5.30(s,2H),6.60(t,1H,J=7.0Hz),7.12(d,2H,J=8.5Hz),7.26(m,2H),7.41(m,2H) ,7.60(d,1H,J=6.5Hz),7.79(d,2H,J=8.5Hz),8.09(s,1H),8.75(d,1H,J=7.0Hz),11.86(s,1H). HRMS m / z 452.0980[M+H] + .

[0155] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.429 mmol) was prepared as a pale yellow solid (156 mg, 89%) by treating 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-butoxycarbonylpyrimidine-4-amine (170 mg, 0.374 mmol). 1H NMR(CDCl3)δ5.34(s,2H),6.59(t,1H,J=7.0Hz),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 = 7.0Hz), 12.03 (s, 1H). HRMS m / z470.0718[M+H] + .

[0156] N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (130 mg, 0.557 mmol) was obtained as a beige powder (143 mg, 69%) by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (6) with 6-(4-aminophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (200 mg, 0.476 mmol). 1 ¹H 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 are masked by the CDCl₃ peak). HRMS m / z 436.1112 [M+H] + .

[0157] N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.429 mmol) was obtained by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (7) with 6-(4-amino-3-fluorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (160 mg, 0.365 mmol) according to a general synthetic procedure, yielding a yellow powder (138 mg, 83%). 1 H NMR(CDCl3)δ5.10(s,2H),6.58(t,1H,J=7.0Hz),6.99(m,2H),7.24(m,2H),7.41(m ,2H),7.60(d,1H,J=6.5Hz),7.99(s,1H),8.59(m,1H),8.73(s,1H),12.02(s,1H). HRMS m / z 454.1018[M+H]+ .

[0158] N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydropyridine-3-carboxylic acid (78 mg, 0.261 mmol) was prepared as a white powder (72 mg, 61%) by treating 2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydropyridine-3-carboxamide with 6-(4-amino-2-fluorophenoxy)-5-fluoro-di-tert-butoxycarbonylpyrimidine-4-amine (100 mg, 0.228 mmol). 1 H NMR(DMSO)δ6.74(t,1H,J=7.0Hz),7.33(m,3H),7.42(d,1H,J=9.0Hz),7.60(d,2H,J=8.5Hz),7.71(d,2H,J =8.5Hz), 7.82 (s, 1H), 7.93 (d, 1H, J = 12.5Hz), 8.17 (d, 1H, J = 6.5Hz), 8.59 (d, 1H, J = 7.0Hz), 12.01 (s, 1H). HRMS m / z520.1341[M+H] + .

[0159] N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid (74 mg, 0.261 mmol) was prepared as a white powder (85 mg, 74%) by treating 2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide (9) with 6-(4-amino-2-fluorophenoxy)-5-fluoro-di-tert-butoxycarbonylpyrimidine-4-amine (100 mg, 0.228 mmol). 1 H NMR(DMSO)δ6.78(t,1H J=7.0Hz),7.33(m,3H),7.40(d,1H,J=9.0Hz),7.81(m,3H),7.92(d,1H,J=12.5Hz) ,7.98(d,2H,J=8.0Hz),8.18(d,1H,J=6.5Hz),8.60(d,1H,J=7.5Hz),11.97(s,1H). HRMS m / z504.1380[M+H] + .

[0160] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydropyridine-3-carboxylic acid (55 mg, 0.184 mmol) was prepared as a white powder (37 mg, 43%) by treating 2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydropyridine-3-carboxamide (10) with 6-(4-amino-2-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (70 mg, 0.160 mmol). 1 H NMR(CDCl3)δ5.35(s,2H),6.63(t,1H,J=7.0Hz),7.16(t,1H,J=8.5Hz),7.34(d,1H,J=8.5Hz),7.43(d,2H,J=8.5Hz),7 .48(d,2H,J=8.5Hz), 7.61(d,1H,J=6.0Hz), 7.92(d,1H,J=12.0Hz), 8.07(s,1H), 8.75(d,1H,J=7.0Hz), 11.90(s,1H). HRMS m / z 536.0856[M+H] + .

[0161] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid (52 mg, 0.184 mmol) was obtained as a yellow powder (23 mg, 28%) by treating 2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide with 6-(4-amino-2-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (70 mg, 0.160 mmol). 1 H NMR(DMSO)δ6.77(t,1H,J=7.0Hz),7.32(t,1H,J=8.5Hz),7.40(d,1H,J=9.0Hz),7.82(d ,2H,J=8.0Hz),7.95(m,4H),8.18(d,1H,J=6.5Hz),8.60(d,1H,J=7.0Hz),11.97(s,1H). HRMS m / z 520.1093[M+H] + .

[0162] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2,3-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (178 mg, 0.763 mmol) 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-butoxycarbonylpyrimidine-4-amine (314 mg, 0.664 mmol). 1 H NMR(DMSO)δ6.74(t,1H,J=7.0Hz),7.25(t,1H,J=8.0Hz),7.43(t,2H,J=9.0Hz),7.61(m,2H),7.98(s ,1H),8.15(dd,1H,J=2.0&6.5Hz),8.26(t,1H,J=7.5Hz),8.61(dd,1H,J=2.0&7.5Hz),12.31(s,1H). MSm / z 488.14

[0163] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxylic acid (58 mg, 0.253 mmol) was prepared as a white powder (73 mg, 71%) by treating 2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxylic acid (15) with 6-(4-amino-3-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (100 mg, 0.220 mmol). 1 H NMR(DMSO)δ2.40(s,3H),6.72(t,1H,J=7.0Hz),7.05(d,1H,J=9.0Hz),7.29(dd,1H,J=2.0&11.5Hz),7.38(m,4 H),7.98(s,1H),8.10(dd,1H,J=2.0&6.5Hz),8.47(t,1H,J=9.0Hz),8.59(dd,1H,J=2.0&7.5Hz),12.25(s,1H). MSm / z 466.31

[0164] N-(4-((6-amino-5-chloropyrimidin-4-yl)thio)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (191 mg, 0.819 mmol) was prepared as a light yellow powder (67 mg, 19%) by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (17) with 6-((4-amino-2-fluorophenyl)thio)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (335 mg, 0.711 mmol). 1 H NMR(DMSO)δ6.73(t,1H,J=7.0Hz),7.43(m,3H),7.53(t,1H,J=8.0Hz),7.61(m,2H),7.92(d,1H, J=11.0Hz), 8.00(s,1H), 8.14(dd,1H,J=1.5&6.5Hz), 8.58(dd,1H,J=1.5&7.0Hz), 12.19(s,1H). MS m / z 486.26.

[0165] N-(4-((6-amino-5-fluoropyrimidin-4-yl)thio)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (183 mg, 0.785 mmol) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (19) with 6-((4-amino-2-fluorophenyl)thio)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (311 mg, 0.684 mmol) according to a general synthetic procedure, yielding a beige powder (66 mg, 21%). 1 H NMR(DMSO)δ6.73(t,1H,J=7.0Hz),7.28(s,2H),7.43(m,3H),7.57(t,1H,J=8.5Hz),7.61(m ,2H),7.92(m,2H),8.14(dd,1H,J=2.0&6.5Hz),8.59(dd,1H,J=2.0&7.5Hz),12.19(s,1H). MS m / z470.09.

[0166] N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (135 mg, 0.579 mmol) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (20) with 6-(4-amino-2,5-difluorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (229 mg, 0.502 mmol) according to a general synthetic procedure, yielding a white powder (159 mg, 67%). 1 H NMR(DMSO)δ6.74(t,1H,J=7.0Hz),7.37(s,2H),7.43(t,1H,J=8.5Hz),7.60(m,3H),7.84(s ,1H),8.15(dd,1H,J=2.0&6.5Hz),8.47(m,1H),8.61(dd,1H,J=2.0&7.0Hz),12.38(s,1H). MS m / z 472.29.

[0167] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (122 mg, 0.523 mmol) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (216 mg, 0.457 mmol) with 6-(4-amino-2,5-difluorophenyl)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (216 mg, 0.457 mmol) according to a general synthetic procedure, yielding a white powder (157 mg, 70%). 1 H NMR(DMSO)δ6.75(t,1H,J=7.0Hz),7.43(t,2H,J=9.0Hz),7.59(m,3H),7.98(s,1H), 8.15(dd,1H,J=2.0&6.5Hz), 8.47(m,1H), 8.61(dd,1H,J=2.0&7.5Hz), 12.37(s,1H). MS m / z488.14.

[0168] N-(4-(((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.858 mmol) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (22) with 6-(4-amino-2-chlorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (338 mg, 0.743 mmol) according to a general synthetic procedure, yielding a white powder (265 mg, 76%). 1 H NMR (DMSO) δ6.73 (t, 1H, J = 7.0Hz), 7.30 (s, 2H), 7.34 (d, 1H, J = 9.0Hz), 7.42 (t, 2H, J = 8.5Hz), 7.55 (dd ,1H,J=2.0&8.5Hz),7.61(m,2H),7.80(s,1H),8.12(m,2H),8.58(dd,1H,J=1.5&7.5Hz),12.04(s,1H). HRMS m / z 470.15.

[0169] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (154 mg, 0.660 mmol) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (23) with 6-(4-amino-2-chlorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (270 mg, 0.573 mmol) according to a general synthetic procedure, yielding a white powder (229 mg, 82%). 1 H NMR(DMSO)δ6.72(t,1H,J=7.0Hz),7.32(d,1H,J=9.0Hz),7.42(t,2H,J=8.5Hz),7.56(dd,1H,J= 2.5&9.0Hz),7.61(m,2H),7.94(s,1H),8.12(m,2H),8.58(dd,1H,J=2.0&7.5Hz),12.04(s,1H). MS m / z486.12

[0170] N-(4-(((2-amino-5-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (78 mg, 0.334 mmol) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (24) with 4-(4-amino-2-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-2-amine (133 mg, 0.292 mmol) according to a general synthetic procedure, yielding a white powder (30 mg, 22%). 1 H NMR(DMSO)δ6.72(t,1H,J=7.0Hz),6.90(s,2H),7.36(t,1H,J=8.5Hz),7.42(m,3H),7.60(m,2H),7. 94(dd,1H,J=2.0&12.5Hz), 8.13(dd,1H,J=2.0&6.5Hz), 8.58(dd,1H,J=2.0&7.5Hz), 12.34(s,1H). MSm / z 470.15.

[0171] N-(4-(((2-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (107 mg, 0.459 mmol) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (25) with 4-(4-amino-3-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-2-amine (181 mg, 0.398 mmol) according to a general synthetic procedure, yielding a yellow powder (73 mg, 39%). 1 H NMR(DMSO)δ6.73(t,1H,J=7.0Hz),6.87(s,2H),7.11(d,1H,J=9.0Hz),7.37(dd,1H,J=2.5&11.5Hz),7.43(t,2H,J=8.5Hz) ,7.61(m,2H),8.13(dd,1H,J=2.0&6.5Hz),8.21(s,1H),8.46(t,1H,J=9.0Hz),8.60(dd,1H,J=2.0&7.5Hz),12.18(s,1H). MS m / z 470.15.

[0172] N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (63 mg, 0.252 mmol) was prepared by treating 1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (33) with 6-(4-amino-3-fluorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (100 mg, 0.220 mmol) according to a general synthetic procedure, yielding a white powder (68 mg, 64%). 1 H NMR(DMSO)δ6.74(t,1H,J=7.0Hz),7.05(d,1H,J=9.0Hz),7.29(dd,1H,J=2.0&11.5Hz),7.62(m,4H),7.9 8(s,1H),8.13(dd,1H,J=2.0&6.5Hz),8.46(t,1H,J=9.0Hz),8.60(dd,1H,J=2.0&7.0Hz),12.17(s,1H). MS m / z 486.25

[0173] N-(4-(((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (65 mg, 0.260 mmol) 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-di-tert-butoxycarbonylpyrimidine-4-amine (100 mg, 0.228 mmol) according to a general synthetic procedure, yielding a white powder (76 mg, 71%). 1 H NMR (DMSO) δ6.73 (t, 1H, J = 7.0Hz), 7.36 (m, 4H), 7.59 (d, 2H, J = 8.5Hz), 7.66 (d, 2H, J = 8.5Hz), 7.82 (s, 1H ), 7.92(dd,1H,J=2.0&12.5Hz), 8.13(dd,1H,J=2.0&6.5Hz), 8.58(dd,1H,J=2.0&7.0Hz), 12.02(s,1H). MS m / z470.29

[0174] N-(4-(((6-amino-5-fluoropyrimidin-4-yl)oxy)-3-fluorophenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxylic acid (60 mg, 0.262 mmol) was prepared by treating 2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3-carboxylic acid (35) with 6-(4-amino-2-fluorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (100 mg, 0.228 mmol) according to a general synthetic procedure, yielding a white powder (74 mg, 72%). 1 H NMR(DMSO)δ6.71(t,1H,J=7.0Hz),7.35(m,8H),7.82(s,1H),7.92(dd,1H,J=2.0& 12.5Hz), 8.09(dd,1H,J=2.0&6.5Hz), 8.57(dd,1H,J=2.0&7.5Hz), 12.12(s,1H). MS m / z 450.33

[0175] By using N according to the general synthesis procedure 4 -(4-amino-2-fluorophenyl)-5-chloro-N 6 N 6 - Di-tert-butoxycarbonylpyrimidine-4,6-diamine (113 mg, 0.249 mmol) was used to treat 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (67 mg, 0.287 mmol) to prepare N-(4-((6-amino-5-chloropyrimidin-4-yl)amino)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (36), yielding a yellow powder (61 mg, 52%). 1 H NMR(DMSO) δ6.76(m,3H),7.33(d,1H,J=5.0Hz),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.

[0176] N-(4-(((6-amino-5-chloropyrimidin-4-yl)oxy)-2-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (167 mg, 0.716 mmol) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (37) with 6-(4-amino-3-chlorophenoxy)-5-chloro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (294 mg, 0.624 mmol) according to a general synthetic procedure, yielding a light yellow powder (281 mg, 93%).1 H NMR(DMSO)δ6.72(t,1H,J=7.0Hz),7.21(dd,1H,J=2.5&9.0Hz),7.43(m,3H),7.61(m,2H),7.98(s, 1H), 8.12(dd,1H,J=2.0&6.5Hz), 8.57(d,1H,J=9.0Hz), 8.62(dd,1H,J=2.0&7.0Hz), 12.31(s,1H). HRMS m / z 486.0530.

[0177] N-(4-(((6-amino-5-fluoropyrimidin-4-yl)oxy)-2-chlorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (81 mg, 0.347 mmol) was prepared by treating 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (38) with 6-(4-amino-3-chlorophenoxy)-5-fluoro-N,N-di-tert-butoxycarbonylpyrimidine-4-amine (137 mg, 0.301 mmol) according to a general synthetic procedure, yielding a white powder (86 mg, 61%). 1 H NMR(DMSO)δ6.72(t,1H,J=7.0Hz),7.23(dd,1H,J=2.0&9.0Hz),7.28(s,2H),7.43(t,2H,J=8.5Hz),7.48(d,1H,J=2.5Hz) ,7.61(m,2H),7.85(s,1H),8.12(dd,1H,J=1.5&7.0Hz),8.57(d,1H,J=9.0Hz),8.62(dd,1H,J=1.5&7.5Hz),12.30(s,1H). HRMS m / z 470.0826.

[0178] N-(4-((6-amino-5-chloropyrimidin-4-yl)thio)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (39)

[0179] 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 HCl aqueous solution (50 mL). The organic phase was washed with brine (50 mL), dried, concentrated, and purified by rapid chromatography (silica, PE ramp to PE:EtOAc = 1:1) to give O-(3-fluoro-4-nitrophenyl)dimethylthiocarbamate as an orange powder (2.172 g, 70%). 1 H NMR (CDCl3) δ3.36 (s, 3H), 3.45 (s, 3H), 7.05 (m, 2H), 8.13 (t, 1H, J = 8.5Hz).

[0180] A solution of O-(3-fluoro-4-nitrophenyl)dimethylthiocarbamate (1.00 g, 4.99 mmol) in NMP (10 mL) was heated at 180 °C for 20 min under microwave irradiation. The reaction mixture was concentrated using a Genevac centrifugal evaporator. The residue was purified by rapid chromatography (silica, PE ramp to PE:EtOAc = 1:1) to give S-(3-fluoro-4-nitrophenyl)dimethylthiocarbamate as an orange powder (871 mg, 87%). 1 H NMR (CDCl3) δ2.83 (s, 6H), 7.40 (d, 1H, J = 8.5Hz), 7.50 (d, 1H, J = 11.0Hz), 8.03 (t, 1H, J = 8.0Hz).

[0181] Then, iron powder (571 mg, 10.2 mmol) was added to a solution of S-(3-fluoro-4-nitrophenyl)dimethylthiocarbamate (500 mg, 2.05 mmol) in MeOH / CH3COOH (1:1, 10 mL). After stirring at 50 °C under N2 for 2 hours, 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 (50 mL) was added. 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)dimethylthiocarbamate (419 mg, 96%) as a pale yellow solid, which was used in subsequent reactions without further purification.

[0182] 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. S-(4-amino-3-fluorophenyl)dimethylthiocarbamate (419 mg, 1.96 mmol) was added to DCM (5 mL), and the reaction mixture was stirred at room temperature for 4 hours. After dilution with DCM (150 mL), a 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 rapid chromatography (silica gel, PE up to EtOAc) to give S-(3-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbamate)phenyl)dimethylthiocarbamate, as a yellow solid (702 mg, 84%). 1 H 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 was masked by the CDCl3 peak).

[0183] A mixture of S-(3-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)dimethylthiocarbamate (700 mg, 1.63 mmol) in THF / MeOH / H2O (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 hours. After concentration, the residue was added to a 1 M HCl aqueous solution and extracted with EtOAc (3 × 50 mL). The extracts were combined, 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)δ5.68(s,1H),6.72(t,1H,J=7.0Hz),7.13(d,1H,J=8.5Hz),7.29(dd,1H,J=1.5&11.5Hz),7.42(m,3 H),7.59(m,3H),8.12(dd,1H,J=2.0&6.5Hz),8.34(t,1H,J=8.5Hz),8.57(dd,1H,J=2.0&7.5Hz),12.15(s.1H).

[0184] 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-butoxycarbonylpyrimidine-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 MgSO4 and concentrated under reduced pressure. The residue was purified by rapid chromatography (silica, PE ramp to PE:EtOAc = 1:4). The resulting product was treated with TFA (1:1, 6 mL) in CH2Cl2 at room temperature for 4 hours. 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 MgSO4 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)δ6.74(t,1H,J=7.0Hz),7.41(m,3H),7.54(dd,1H,J=2.0&11.0Hz),7.61(m,2H),8.03(s,1H), 8.15(dd,1H,J=2.0&6.5Hz), 8.56(t,1H,J=8.5Hz), 8.62(dd,1H,J=2.0&7.5Hz), 12.38(d,1H,J=2.0Hz). HRMS m / z486.0598.

[0185] Example 2 Bioactivity

[0186] Kinase assay

[0187] The inhibition percentage and / or IC50 were determined using a filter-binding radiometric kinase activity assay (Kinase Profiler™) from Eurofins Discovery. 50Values. In short, the apparent K values ​​of optimized concentrations of TYRO3, AXL, MER, and MET human kinases were obtained by reacting them with 8 mM MOPS at pH 7.0, 0.2 mM EDTA, 250 μM specific substrates (i.e., TYRO3: KVEKIGEGTYGVVYK (SEQ ID NO:1); AXL: KKSRGDYMTMQIG (SEQ ID NO:2); MER: GG MEDIYFEFMGGKKK (SEQ ID NO:3); and Met: KKKGQEEEY VFIE (SEQ ID NO:4)), 10 mM magnesium acetate, and ATP. m [γ within 15 μM] -33 [P]-ATP (AXL / MET: 90 μM and Mer / TYRO3 45 μM) was incubated together with the test compound. The reaction was initiated by adding the Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL of the reaction mixture was then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 minutes each, washed once with methanol, and then dried and scintillation counted. The IC50 was obtained by fitting an S-shaped dose-response curve to a graph of the measured reading versus inhibitor concentration. 50 Values. All fits were calculated using GraphPad Prism software (San Diego, CA, USA). Values ​​were obtained from IC using the Cheng Prusoff equation (Cheng Y et al., Biochem Pharmacol 22(23):3099–3108, 1973). 50 Value Export K i value.

[0188] Inhibition of CDK and FLT3 was determined using the ADP-Glo ​​kinase assay, as previously described in International Patent Publication No. WO2017 / 020065. The results are shown in Table 2.

[0189] Proliferation assay

[0190] 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 compounds from Example 1 were subjected to standard rexazuril and MTT assays, respectively, against solid tumor and leukemia cancer cell lines. The results are shown in Table 2.

[0191] Table 2 Enzyme and cell activities of exemplary compounds

[0192]

[0193] Throughout the specification and the accompanying claims, unless the context otherwise requires, the words “comprise” and “include”, as well as variations such as “comprising” and “including”, shall be understood to imply inclusion of the stated whole or group of wholes, but not to exclude any other whole or group of wholes.

[0194] Any references to prior art in this specification are not and should not be construed as an admission that such prior art is part of common general knowledge.

[0195] Those skilled in the art will understand that this disclosure is not limited in its use to the specific applications described. Nor is this disclosure limited in its preferred embodiments by the specific elements and / or features described or depicted herein. It should also be understood that this disclosure is not limited to the one or more embodiments disclosed, but is open to various rearrangements, modifications, and substitutions without departing from the scope of this disclosure as set forth and defined by the appended claims.

[0196]

[0197] sequence list <110> Aucentra Therapeutics Pty Ltd <120> A derivative of 2-oxo-N-(4-(pyrimidin-4-yloxy / thio)phenyl)-1,2-dihydropyridine-3-carboxamide used as a protein kinase inhibitor for therapeutic purposes. <130> 55362PCT <150> AU 2020902392 <151> 2020-07-09 <160> 4 <170> PatentIn version 3.5 <210> 1 <211> 15 <212> PRT <213> Homo sapiens <400> 1 Lys Val Glu Lys Ile Gly Glu Gly Thr Tyr Gly Val Val Tyr Lys 1 5 10 15 <210> 2 <211> 13 <212> PRT <213> Homo sapiens <400> 2 Lys Lys Ser Arg Gly Asp Tyr Met Thr Met Gln Ile Gly 1 5 10 <210> 3 <211> 16 <212> PRT <213> Homo sapiens <400> 3 Gly Gly Met Glu Asp Ile Tyr Phe Glu Phe Met Gly Gly Lys Lys Lys 1 5 10 15 <210> 4 <211> 13 <212> PRT <213> Homo sapiens <400> 4 Lys Lys Lys Gly Gln Glu Glu Glu Tyr Val Phe Ile Glu 1 5 10

Claims

1. A compound of Formula I: wherein: X is O; R 1 is H; R 2 is amino; R 3 R is halogen; R 4 , R 5 , R 6 , and R 7 are each H; or are each independently selected from H or F, but one of R 4 , R 5 , R 6 , and R 7 is F, or R 4 and R 6 are both F and R 5 and R 7 are both H; R 8 , R 9 , and R 10 are each independently selected from H or O-C 1-6 alkyl; and R 11 is phenyl-R 14 wherein R 14 is halogen; or a pharmaceutically acceptable salt thereof; and the compound of Formula I is not N-(4-((6-amino-5-fluoropyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, or N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.

2. The compound of claim 1, wherein R 3 is CI or F.

3. The compound of claim 1, wherein R 4 is F, R 5 , R 6 and R 7 are each H; or R 5 is F, R 4 , R 6 and R 7 are each H.

4. The compound of claim 1, wherein R 4 , R 5 , R 6 , and R 7 are each H.

5. The compound of claim 1, wherein R 4 and R 6 are F, and R 5 and R 7 are both H.

6. The compound of claim 1, wherein R 8 is H or O-C 1-3 alkyl.

7. The compound of claim 1, wherein R 9 and at least one of R 10 is H.

8. The compound of claim 1, wherein R 14 selected from CI or F.

9. The compound of claim 8, wherein, R 11 is fluorophenyl.

10. The compound of claim 1, wherein 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)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-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.

11. The compound of claim 1, wherein The compound is N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.

12. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer or another proliferative cell disease or condition.

13. A pharmaceutical composition or medicament comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and / or excipient.

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