Pyrimidinedione compounds as AXL, C-MET, and MER inhibitors and methods of use thereof

Abstract

Provided are inhibitors of AXL, Mer, and / or c-Met of formula (I) or a pharma- ceutically acceptable salt thereof: JPEG2025506739000292.jpg62113 (In the formula, R 1 , R 2 , R 3 , G, and Q are as described herein. Also provided is a method for treating or preventing AXL, Mer, and / or c-Met mediated diseases using an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. When AXL, MER, and / or c-Met are inhibited, the compound or a pharma-ceutically acceptable salt thereof can resensitize cancer cells, such as non-small cell lung cancer cells, that have increased resistance to anticancer drugs.

Description

[Technical Field]

[0001] Cross-reference to prior application This application claims the benefit of U.S. Provisional Patent Application No. 63 / 310,840, filed February 16, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Background of the Invention Receptor tyrosine kinases (RTKs) are transmembrane proteins that transduce signals from the extracellular environment to the cytoplasm and nucleus to regulate normal cellular processes, including survival, growth, differentiation, adhesion, and motility. Overexpression or activation of RTKs is associated with cellular transformation, tumorigenesis, and metastasis and is involved in the pathogenesis of various cancers.

[0003] TAM receptors are expressed in various cells and tissues. AXL is a member of the TAM RTK family, including TYR03 and Mer, originally identified as a transforming gene expressed in cells from patients with chronic myeloid leukemia (O'Bryan et al., Mol. Cell Biol., 1991, 11, 5016-5031) and chronic myeloproliferative disorder (Janssen et al., Oncogene, 1991, 6(11), 2113-2120). AXL contributes to at least three of the six fundamental mechanisms of cancer malignancy by promoting cancer cell migration and invasion, participating in tumor angiogenesis, and facilitating cancer cell survival and tumor growth (Holland et al., Cancer Res., 2005, 65(20), 9294-9303; Tai et al., Oncogene, 2008, 27, 4044-4055; Li et al., Oncogene, 2009, 28, 3442-3455; and Mudduluru et al., Mol. Cancer Res., 2010, 8(2), 159-169).

[0004] Furthermore, overexpression of AXL has also been implicated in asthma, pain, and dermatitis (Shibata et al., J Immunol, 2014, 192(8), 3569-3581; Liang et al., Molecular Pain, 2020, 16, 1-13; and Bauer et al., J Exp Med, 2012, 209(11), 2033-2047).

[0005] Overexpression of c-MET is associated with the development and poor prognosis of a wide range of solid tumors, including breast, prostate, thyroid, lung, gastric, colorectal, pancreatic, renal, ovarian, and uterine cancers, malignant gliomas, uveal melanomas, and bone and soft-tissue sarcomas (Jiang et al., Critical Reviews in Oncology / Hematology, 2005, 53(1), 35-69).

[0006] Given the roles of AXL, Mer, and c-MET in various diseases, there remains a need for the development of agents that act as inhibitors of AXL, Mer, and / or c-Met to therapeutically treat such diseases. Summary of the Invention

[0007] Brief Summary of the Invention The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0008] [ka]

[0009] (In the formula, R 1 , R 2 , R 3 , G, and Q are as described herein).

[0010] The present invention further provides a method for treating or preventing an AXL-, Mer-, and / or c-Met-mediated disease in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0011] The present invention provides a method for inhibiting AXL, Mer, and / or c-Met enzymes in a cell, comprising administering to the cell a compound of formula (I) or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0012] A brief description of some perspectives of the drawing [Figure 1] FIG. 1 is a chemical synthesis of N-(4-(2-amino-3-(3-oxo-3-(piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 2] FIG. 2 is a chemical synthesis of N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-oxoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 3] FIG. 3 is a chemical synthesis of (E)-N-(4-(2-amino-3-(3-oxo-3-(piperazin-1-yl)prop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 4]FIG. 4 is a chemical synthesis of (E)-N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-oxoprop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 5] FIG. 5 is a chemical synthesis of N-(4-(2-amino-3-cyanopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 6] FIG. 6 is a chemical synthesis of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 7] FIG. 7 is a chemical synthesis of N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluoropentenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 8] FIG. 8 is a chemical synthesis of N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 9] FIG. 9 is a chemical synthesis of N-(4-(2-amino-3-(pyridin-2-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 10] FIG. 10 is a chemical synthesis of N-(4-(2-amino-3-(4-phenoxyphenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 11] FIG. 11 is a chemical synthesis of N-(4-(2-amino-3-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 12] FIG. 12 is a chemical synthesis of N-(4-(2-amino-3-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 13] FIG. 13 is a chemical synthesis of N-(4-(2-amino-3-((1-propyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 14] FIG. 14 is a chemical synthesis of N-(4-(2-amino-3-(3-morpholino-3-oxoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 15] FIG. 15 is a chemical synthesis of N-(4-(2-amino-3-(piperidin-4-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 16] FIG. 16 is a chemical synthesis of N-(4-(2-amino-3-((1-(2-methoxyethyl)piperidin-4-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 17] FIG. 17 is a chemical synthesis of N-(4-(2-amino-3-(3-piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 18] FIG. 18 is a chemical synthesis of N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)prop-1-ylny)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 19] FIG. 19 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 20] FIG. 20 is a chemical synthesis of N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-methylbut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 21]FIG. 21 is a chemical synthesis of N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-oxopropyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 22] FIG. 22 is a chemical synthesis of N-(4-(2-amino-3-phenylpyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 23] FIG. 23 is a chemical synthesis of N-(4-(2-amino-3-((1-methylpiperidin-4-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 24] FIG. 24 is a chemical synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 25] FIG. 25 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 26]FIG. 26 is a chemical synthesis of N-(4-(2-amino-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 27] FIG. 27 is a chemical synthesis of N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 28] FIG. 28 is a chemical synthesis of N-(4-(2-amino-3-(3-(1-(2-methoxyethyl)piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 29] FIG. 29 is a chemical synthesis of N-(4-(2-amino-3-(3-(1-isopropylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxmide in one embodiment of the present invention. [Figure 30] FIG. 30 is a chemical synthesis of N-(4-((2-amino-3-(3-methyl-3-morpholinobut-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 31]FIG. 31 is a chemical synthesis of N-(4-((2-amino-3-(3-morpholinoprop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 32] FIG. 32 is a chemical synthesis of N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 33] FIG. 33 is a chemical synthesis of N-(4-((2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 34] FIG. 34 is a chemical synthesis of N-(4-((2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 35] FIG. 35 is a chemical synthesis of N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 36] FIG. 36 is a chemical synthesis of N-(4-((2-amino-3-(3-methyl-3-morpholinobut-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 37] FIG. 37 is a chemical synthesis of N-(4-((2-amino-3-(3-morpholinoprop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 38] FIG. 38 is a chemical synthesis of N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 39] FIG. 39 is a chemical synthesis of N-(4-((2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 40] FIG. 40 is a chemical synthesis of N-(4-((2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 41] FIG. 41 is a chemical synthesis of N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 42] FIG. 42 is a chemical synthesis of N-(4-((2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. [Figure 43] FIG. 43 is a chemical synthesis of N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. [Figure 44] FIG. 44 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. [Figure 45] FIG. 45 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. [Figure 46]FIG. 46 is a chemical synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. [Figure 47] FIG. 47 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 48] FIG. 48 is a chemical synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 49] FIG. 49 is a chemical synthesis of N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 50] FIG. 50 is a chemical synthesis of N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 51]FIG. 51 is a chemical synthesis of N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 52] FIG. 52 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 53] FIG. 53 is a chemical synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 54] FIG. 54 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 55] Figure 55 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 56]FIG. 56 is a chemical synthesis of N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 57] FIG. 57 is a chemical synthesis of N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 58] FIG. 58 is a chemical synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 59] FIG. 59 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 60] FIG. 60 is a chemical synthesis of N-(4-(2-amino-3-(3-(methyl-3-morpholinebut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 61]Figure 61 is a chemical synthesis of N-(4-((2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 62] FIG. 62 is a chemical synthesis of N-(4-(2-amino-3-(3-piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 63] Figure 63 is a chemical synthesis of N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 64] FIG. 64 is a chemical synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 65] Figure 65 is a chemical synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 66]Figure 66 is a chemical synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 67] FIG. 67 is a chemical synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. [Figure 68] Figure 68 is a chemical synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description of the Invention A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0014] [ka]

[0015] (In the formula, R 1 is H, alkyl, haloalkyl, halo, or CN; R 2 is H, alkyl, haloalkyl, halo, or CN; R 3 is H or halo; Q is H, CN, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl, wherein said alkenyl or alkynyl is -CH=CR4 (CX') m (CH2) n NR 5 R 6 , -C≡C(CX') m (CH2) n NR 5 R 6 , -CH=CR 4 (CX') m (CH2) n CHR 5 R 6 , -C≡C(CX') m (CH2) n CHR 5 R 6 , -CH=CR 4 (CX') m (CH2) n NR 7 OR 8 , and -C≡C(CX') m (CH2) n NR 7 OR 8 Selected from the group consisting of: where: R 4 is hydrogen or halo; X' is H2, (C 1-6 alkyl)2, or =O; m is 0 or 1; n is 0 or 1 to 3; -NR 5 R 6 either forms a 4- to 7-membered heterocyclic ring or does not form a ring structure, and the heterocyclic ring is either a heteroaryl ring or a heterocyclyl ring; -NR 5 R 6 When forms a 4- to 7-membered heterocyclic ring, the 4- to 7-membered heterocyclic ring is 5 R 6 and an optional second heteroatom in addition to the nitrogen, and optionally substituted with one or more substituents independently selected from the group consisting of linear C1-C6 alkyl, branched C3-C6 alkyl, hydroxy, C1-C6 alkoxyalkyl, carboxylic acid, linear C1-C4 alkylcarboxylic acid, and branched C3-C4 alkylcarboxylic acid; -NR 5 R 6 does not form a ring structure, R 5 is selected from the group consisting of hydrogen, linear C1-C6 alkyl, and branched C3-C6 alkyl, and R 6 is selected from the group consisting of hydrogen, linear C1-C6 alkyl optionally substituted with at least one fluoro or at least one hydroxy, branched C3-C6 alkyl optionally substituted with at least one fluoro or at least one hydroxy, and cycloalkyl optionally substituted with at least one fluoro or at least one hydroxy; -CHR 5 R 6 either forms a 4- to 7-membered heterocyclic ring or does not form a ring structure, and the heterocyclic ring is either a heteroaryl ring or a heterocyclyl ring; -CHR 5 R 6 forms a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle contains one or two heteroatoms and is optionally substituted with one or more substituents independently selected from the group consisting of linear C1-C6 alkyl, branched C3-C6 alkyl, hydroxy, C1-C6 alkoxyalkyl, carboxylic acid, linear C1-C4 alkylcarboxylic acid, and branched C3-C4 alkylcarboxylic acid; -CHR 5 R 6 does not form a ring structure, R 5 is selected from the group consisting of hydrogen, linear C1-C6 alkyl, and branched C3-C6 alkyl, and R 6 is selected from the group consisting of hydrogen, linear C1-C6 alkyl optionally substituted with at least one fluoro or at least one hydroxy, branched C3-C6 alkyl optionally substituted with at least one fluoro or at least one hydroxy, and cycloalkyl optionally substituted with at least one fluoro or at least one hydroxy; -NR 7 OR 8 does not form a ring structure, and R 7is selected from the group consisting of hydrogen, linear C1-C6 alkyl, and branched C3-C6 alkyl, and R 8 is selected from the group consisting of hydrogen, linear C1-C6 alkyl optionally substituted with at least one fluoro, hydroxy, or alkoxy group, branched C3-C6 alkyl optionally substituted with at least one fluoro, hydroxy, or alkoxy group, and cycloalkyl optionally substituted with at least one fluoro, hydroxy, or alkoxy group; G is

[0016] [ka]

[0017] (In the formula, R 9 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or heteroarylalkyl, where the heteroaryl group of the heteroarylalkyl can be substituted or ubsubstituted; R 10 is H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl, alkenyl or alkynyl, where the alkyl, alkenyl or cycloalkyl can be substituted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino (wherein the alkyl groups of the dialkylamino can be the same or different), heteroaryl, substituted heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl (wherein the alkyl groups of the dialkylcarbamoyl can be the same or different), and heterocyclylcarbonyl; and Y is N, CH, or C-alkyl).

[0018] Pyrimidinedione inhibitors are useful in treating a variety of diseases and disorders associated with AXL, Mer, and / or c-Met without the need for special modes of administration.

[0019] In some embodiments of Formula (I), R 1 and R 2 are both hydrogen.

[0020] In some embodiments of Formula (I), R 3 is a halo.

[0021] In some embodiments of Formula (I), Q is CN, halo, optionally substituted phenyl, optionally substituted heterocyclyl, or -CH=CR 4 (CX') m (CH2) n NR 5 R 6 , -C≡C(CX') m (CH2) n NR 5 R 6 , -CH=CR 4 (CX') m (CH2) n CHR 5 R 6 , -C≡C(CX') m (CH2) n CHR 5 R 6 , -CH=CR 4 (CX') m (CH2) n NR 7 OR 8 , and -C≡C(CX') m (CH2) n NR 7 OR 8 is an alkenyl or alkynyl moiety selected from the group consisting of where: R 4 is hydrogen or halo; X' is H2, (C 1-6 alkyl)2, or =O; m is 0 or 1; n is 0 or 1; -NR 5 R 6 is morpholinyl, piperazinyl, or piperidinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of a nitrogen protecting group, alkyl, hydroxy, alkoxy, and alkoxyalkyl; -CHR 5 R 6 is tetrahydropyranyl, morpholinyl, piperazinyl, or piperidinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of a nitrogen protecting group, alkyl, hydroxy, alkoxy, and alkoxyalkyl; R 7 is selected from the group consisting of hydrogen, linear C1-C6 alkyl, and branched C3-C6 alkyl, and R 8 is selected from the group consisting of linear C1-C6 alkyl optionally substituted with at least one alkoxy group and branched C3-C6 alkyl optionally substituted with at least one alkoxy group.

[0022] In some embodiments of Formula (I), R 9 is phenyl substituted with alkyl, haloalkyl, halogen, and / or CN; and either (i) Y is CH or (ii) Y is N.

[0023] In some embodiments, the compound of formula (I) has formula (Ib):

[0024] [ka]

[0025] (In the formula,

[0026] [ka]

[0027] is a compound of formula (I) where -C≡C- or -CH=CH-.

[0028] In some embodiments of Formula (Ib), R 1 and R 2 are both hydrogen.

[0029] In some embodiments of Formula (Ib), R 3 is a halo.

[0030] In some embodiments of Formula (Ib), X' is H, (C alkyl), or =0; and -NR 5 R 6 is morpholinyl, piperazinyl, or piperidinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of a nitrogen protecting group (e.g., tert-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl (Cbz), acetyl, trifluoroacetamide, phthalimide, benzyl, trityl, benzylideneamine, or tosyl), alkyl, hydroxy, alkoxy, and alkoxyalkyl.

[0031] In some embodiments of Formula (Ib), R 9 is phenyl substituted with alkyl, haloalkyl, halo, and / or CN; and either (i) Y is CH or (ii) Y is N.

[0032] In some embodiments, the compound of formula (I) has formula (Ic):

[0033] [ka]

[0034] (In the formula,

[0035] [ka]

[0036] is a compound of formula (I) where -C≡C- or -CH=CH-.

[0037] In some embodiments of Formula (Ic), R 1 and R 2 are both hydrogen.

[0038] In some embodiments of Formula (Ic), R 3 is a halo.

[0039] In some embodiments of Formula (Ic), X' is H, (C alkyl), or =0; R 7 is selected from the group consisting of linear C1-C6 alkyl and branched C3-C6 alkyl, and R 8 is selected from the group consisting of straight chain C1-C6 alkyl and branched C3-C6 alkyl.

[0040] In some embodiments of Formula (Ic), R 9 is phenyl substituted with alkyl, haloalkyl, halo, and / or CN; and either (i) Y is CH or (ii) Y is N.

[0041] Exemplary compounds of formula (I), including compounds of formula (Ib) and (Ic), are set forth below in the Examples. Pharmaceutically acceptable salts of these exemplary compounds are also contemplated. In particular, compounds of formula (I) are

[0042] [ka]

[0043] [ka]

[0044] [ka]

[0045] [ka]

[0046] [ka]

[0047] [ka]

[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] [ka]

[0052] [ka]

[0053] or a pharmaceutically acceptable salt thereof.

[0054] In any of the above embodiments, the term "alkyl" connotes a straight or branched chain alkyl substituent containing from, for example, about 1 to about 8 carbon atoms, e.g., about 1 to about 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like. This definition also applies whenever "alkyl" occurs as part of a group, such as in, for example, C3-C6 cycloalkylalkyl, hydroxyalkyl, haloalkyl (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl), cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, arylalkyl, and the like. Alkyl can be substituted or unsubstituted as described herein. When alkyl is an alkylene chain (e.g., -(CH2) n Even in the case of -), the alkyl group can be substituted or unsubstituted. Examples of substituted alkylene chains include -CH2CH2-methoxy.

[0055] In any of the above embodiments, the term "alkenyl" as used herein refers to a straight-chain alkenyl substituent containing, for example, about 2 to about 8 carbon atoms (branched alkenyl is about 3 to about 8 carbon atoms), for example, about 3 to about 6 carbon atoms (branched alkenyl is about 3 to about 6 carbon atoms). According to one embodiment, the alkenyl group is a C2-C4 alkenyl. Examples of alkenyl groups include ethenyl, allyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, and the like. Alkenyl can be substituted or unsubstituted as described herein.

[0056] In any of the above embodiments, the term "alkynyl," as used herein, refers to a straight-chain alkenyl substituent containing at least one carbon-carbon triple bond and, for example, from about 2 to about 8 carbon atoms (branched alkynyls are from about 4 to about 12 carbon atoms), for example, from about 2 to about 6 carbon atoms (branched alkynyls can be from about 4 to about 8 carbon atoms), for example, from about 2 to about 4 carbon atoms. Examples of such substituents include propynyl, propargyl, n-butynyl, pentynyl, isopentynyl, hexynyl, octynyl, and the like. Alkynyl can be substituted or unsubstituted as described herein.

[0057] In any of the above embodiments, the term "cycloalkyl" as used herein refers to a cyclic alkyl moiety containing, for example, 3 to 6 carbon atoms or 5 to 6 carbon atoms. Examples of such moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl can be substituted or unsubstituted as described herein.

[0058] In any of the above embodiments, the term "hydroxy" refers to the group --OH.

[0059] In any of the above embodiments, the term "alkoxy" includes straight or branched chain alkyl groups attached to a divalent oxygen. Alkyl groups are as described herein.

[0060] In any of the above embodiments, the term "halo" refers to a halogen radical selected from fluoro, chlorobromo, and iodo.

[0061] In any of the above embodiments, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having one, two, or three aromatic rings, such as phenyl, naphthyl, anthracenyl, or biphenyl. As generally understood in the art, the term "aryl" refers to an unsubstituted or substituted aromatic carbocyclic moiety and includes monocyclic and polycyclic aromatic compounds such as phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like. Aryl moieties generally contain, for example, 6 to 30 carbon atoms, 6 to 18 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. The term aryl is understood to include carbocyclic moieties that are planar and contain 4n+2 π-electrons (where n=1, 2, or 3) according to Hückel's rule. This definition also applies whenever "aryl" occurs as part of a group such as, for example, in haloaryl (e.g., monohaloaryl, dihaloaryl, and trihaloaryl), arylalkyl, etc. Aryl can be substituted or unsubstituted as described herein.

[0062] In any of the above embodiments, the term "heteroaryl" refers to aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups having at least one heteroatom (O, S, or N) in at least one of the rings. Each ring of a heteroatom-containing heteroaryl group may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. A bicyclic or tricyclic heteroaryl group must contain at least one fully aromatic ring, but the other fused ring(s) may be aromatic or non-aromatic. Heteroaryl groups can be bonded at any available nitrogen or carbon atom of any ring. Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl. Heteroaryl can be substituted or unsubstituted as described herein.

[0063] The term "heterocyclyl" refers to stable, saturated or partially unsaturated monocyclic, bicyclic, and spirocyclic ring systems containing 3 to 7 ring-membered carbon atoms and other atoms selected from nitrogen, sulfur, and / or oxygen. In one embodiment, the heterocyclyl is a 5-, 6-, or 7-membered monocyclic ring and contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocyclyl can be attached to the parent structure through a carbon atom or any heteroatom (e.g., a nitrogen atom) of the heterocyclyl that results in a stable structure. Examples of such heterocyclyl rings are isoxazolyl, thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, oxazolyl, and morpholinyl. Preferably, the heterocyclyl is piperazinyl, piperidinyl, or morpholinyl. The heterocyclyl can be substituted or unsubstituted as described herein.

[0064] In other embodiments, any non-hydrogen substituent (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocyclyl) can be an optionally substituted moiety. Substituted moieties typically contain at least one substituent (e.g., 1, 2, 3, 4, 5, 6, etc.) at any suitable position (e.g., 1-, 2-, 3-, 4-, 5-, or 6-position, etc.). When an aryl group is substituted with a substituent, e.g., halo, amino, alkyl, OH, alkoxy, and the like, a hydrogen on the aromatic ring is replaced with the substituent, and this can occur at any available hydrogen, e.g., 2-, 3-, 4-, 5-, and / or 6-position when the 1-position is the point of attachment of the aryl group in the compounds of the invention. Suitable substituents include, for example, halo, alkyl, alkenyl, alkynyl, hydroxy, nitro, cyano, amino, alkylamino, alkoxy, aryloxy, aralkoxy, carboxyl, carboxyalkyl, carboxyalkyloxy, amido, alkylamido, haloalkylamido, aryl, heteroaryl, and heterocyclyl, each of which is described herein.

[0065] In any of the above embodiments, whenever a range of numbers of atoms in a structure is given (e.g., C 1~12 , C 1~8 , C 1~6 , or C 1~4It is specifically contemplated that, for any group (e.g., alkyl, cycloalkyl, etc.) referred to herein, any subrange or individual number of carbon atoms falling within the recited range may also be used. That is, for example, recitation of a range of 1 to 8 carbon atoms (e.g., C1-C8), 1 to 6 carbon atoms (e.g., C1-C6), 1 to 4 carbon atoms (e.g., C1-C4), 1 to 3 carbon atoms (e.g., C1-C3), or 2 to 8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl, cycloalkyl, etc.) referred to herein is intended to encompass 1, 2, 3, 4, 5, 6, 7, and / or 8 carbon atoms, as appropriate, and any subrange thereof (e.g., 1 to 2, as appropriate). carbon atoms, 1 to 3 carbon atoms, 1 to 4 carbon atoms, 1 to 5 carbon atoms, 1 to 6 carbon atoms, 1 to 7 carbon atoms, 1 to 8 carbon atoms, 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 2 to 7 carbon atoms, 2 to 8 carbon atoms, 3 to 4 carbon atoms, 3 to 5 carbon atoms, 3 to 6 carbon atoms, 3 to 7 carbon atoms, 3 to 8 carbon atoms, 4 to 5 carbon atoms, 4 to 6 carbon atoms, 4 to 7 carbon atoms, 4 to 8 carbon atoms, etc.

[0066] The subscript "m" represents the number of (CX') repeat units. The subscript m can be either 0 or 1. When m is 0, then (CX') is not present in the molecule.

[0067] The subscript "n" represents the number of methylene (CH) repeat units. The subscript n can be either 0 or an integer from 1 to 3 (i.e., 1, 2, or 3). When n is 0, then the respective moiety does not contain any methylene repeat units.

[0068] In any embodiment herein, the phrase "salt" or "pharmaceutically acceptable salt" is intended to include non-toxic salts synthesized by conventional chemical methods from a parent compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For example, the salt can be selected from the group consisting of acetate, benzoate, besylate, bitartrate, bromide, carbonate, chloride, edetate, edisylate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, formate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, oxalate, pamoate, phosphate, diphosphate, salicylate, disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide, trifluoroacetate, and valerate salts.

[0069] The method described herein comprises administering a compound of formula (I) or its pharmaceutically acceptable salt in the form of a pharmaceutical composition.In particular, the pharmaceutical composition will comprise at least one compound of formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.The pharmaceutically acceptable excipients described herein, such as vehicles, adjuvants, carriers or diluents, are well known to those skilled in the art and are readily available to the general public.Typically, the pharmaceutically acceptable carrier is chemically inert to the active compound and does not have any adverse side effects or toxicity under the conditions of use.

[0070] The pharmaceutical compositions can be administered orally, sublingually, transdermally, subcutaneously, topically, by absorption through epithelial or mucocutaneous linings, intravenously, intranasally, intraarterially, intramuscularly, intratumorally, peritumorally, intraperitoneally, intrathecally, rectally, vaginally, or as an aerosol formulation. In some embodiments, the pharmaceutical compositions are administered orally or intravenously.

[0071] According to any of the embodiments, the compound of formula (I) or its pharmaceutically acceptable salt can be orally administered to a subject in need thereof. Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in a diluent, such as water, saline, or orange juice, and including additives such as cyclodextrins (e.g., α-, β-, or γ-cyclodextrin, hydroxypropylcyclodextrin) or polyethylene glycols (e.g., PEG400); (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient as a solid or granules; (c) powders; (d) suspensions in suitable liquids; and (e) suitable emulsions and gels. Liquid formulations can contain diluents, such as water and alcohols, e.g., ethanol, benzyl alcohol, and polyethylene alcohols, with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Capsule forms may be of the ordinary hard-shelled or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms may contain one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavorings, and pharmacologically compatible carriers. Lozenge forms may include pastiles containing the active ingredient in a flavoring, usually sucrose and acacia or tragacanth, and the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, etc., containing carriers known in the art in addition to the active ingredient.

[0072] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions which may include suspending agents, solubilizing agents, thickening agents, stabilizers, and preservatives. The compound of formula (I) or its salt may be administered in a physiologically acceptable diluent in a pharmaceutical carrier such as a sterile liquid or mixture of liquids including water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, ethers such as glycerol ketals, poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides, with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents, or emulsifying agents and other pharmaceutical adjuvants such as pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose.

[0073] Oils that can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oils. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal salts, ammonium salts, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium halides and alkylpyridinium halides; (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers; (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates and 2-alkyl-imidazoline quaternary ammonium salts; and (e) mixtures thereof.

[0074] Parenteral formulations will typically contain about 0.5 to about 25% by weight of the inhibitor in solution. Suitable preservatives and buffers can be used in such formulations. To minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide with hydrophobic bases formed by the condensation of propylene oxide with propylene glycol. Parenteral formulations can be presented in single- or multi-dose hermetically sealed containers, such as ampoules and vials, and for injectable solutions, can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, e.g., water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind described above.

[0075] The inhibitor can be made into an injectable formulation. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those skilled in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).

[0076] Topically applied compositions are generally in the form of liquids (e.g., mouthwashes), creams, pastes, lotions, and gels. Topical administration includes application to the oral mucosa, including the oral cavity, oral epithelium, palate, gums, and nasal mucosa. In some embodiments, the composition contains at least one active ingredient and a suitable vehicle or carrier. It may also contain other ingredients, such as anti-irritants. The carrier may be liquid, solid, or semi-solid. In some embodiments, the composition is an aqueous solution, such as a mouthwash. Alternatively, the composition may be a dispersion, emulsion, gel, lotion, or cream vehicle for the various ingredients. In one embodiment, the primary vehicle is water or a substantially neutral or substantially neutralized biocompatible solvent. The liquid vehicle may contain other materials, such as buffers, alcohol, glycerin, and mineral oil, along with various emulsifiers or dispersants known in the art, to achieve the desired pH, consistency, and viscosity. The composition can be prepared as a solid, such as powder or granules.The solid can be directly applied, or can be dissolved in water or a biocompatible solvent before use to form a solution that is substantially neutral or can be applied to the target site as a substantially neutral solution.In an embodiment of the present invention, the vehicle for topical application to the skin can include water, buffer solution, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oil, phosphoglycerides, collagen, gelatin and silicone-based materials.

[0077] The compound of formula (I) or its pharmaceutically acceptable salt, alone or in combination with other suitable components, can be made into aerosol formulations for administration via inhalation.These aerosol formulations can be placed into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen, etc.They can also be formulated as pharmaceuticals for non-pressurized preparations, such as in nebulizers or atomizers.

[0078] In accordance with the present invention, the dose administered to a subject, particularly a human or other mammal, should be sufficient to affect the desired response. Those skilled in the art will recognize that the dosage will depend on various factors, including the mammal's age, condition or disease state, disease predisposition, genetic defect(s), and body weight. The size of the dose will also be determined by the route, timing, and frequency of administration, as well as the existence, nature, and extent of any adverse side effects that may accompany the administration of the particular inhibitor and the desired effect. Those skilled in the art will recognize that various conditions or disease states may require long-term treatment, including multiple administrations.

[0079] The method of the present invention involves administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. "Effective amount" refers to an amount sufficient to show a significant, meaningful benefit in an individual, cell, or tissue. A meaningful benefit means that one or more symptoms of a disease or disorder (e.g., asthma, cancer) are prevented, reduced, stopped, or eliminated following administration of a compound of Formula (I), including a compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, thereby effectively treating the disease to at least some extent. For example, a meaningful benefit can be promoting at least one aspect of tumor cell cytotoxicity (e.g., inhibiting proliferation, inhibiting cancer cell survival, reducing proliferation, reducing tumor (e.g., solid tumor) size and / or mass), or treating, curing, preventing, delaying the onset, stopping, or ameliorating other related symptom(s) associated with a particular disease or disorder. The meaningful benefit observed in treated subjects can be up to any appropriate degree (10, 20, 30, 40, 50, 60, 70, 80, 90% or more).

[0080] The effective amount can vary depending on the desired biological effect in an individual, the condition to be treated, and / or the compound of formula (I), including the compound of formula (Ib) or (Ic), or its pharmaceutically acceptable salt, and the specific characteristics of the individual.In this regard, any appropriate dose of the compound of formula (I) or its pharmaceutically acceptable salt can be administered to a subject (e.g., a human) according to the disease or disorder to be treated (e.g., asthma, cancer).Various general considerations to be taken into account in determining the "effective amount" are known to those skilled in the art and are described, for example, in Gilman et al., eds., Goodman and Gilman's: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990; and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pa., 1990, each of which is incorporated herein by reference. The dose of a compound of Formula (I), including a compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, is desirably about 0.01 mg per kilogram (kg) of the subject's body weight (mg / kg) or more (e.g., about 0.05 mg / kg or more, 0.1 mg / kg or more, 0.5 mg / kg or more, 1 mg / kg or more, 2 mg / kg or more, 5 mg / kg or more, 10 mg / kg or more, 15 mg / kg or more, 20 mg / kg or more, 30 mg / kg or more, 40 mg / kg or more, or g or more, 50mg / kg or more, 75mg / kg or more, 100mg / kg or more, 125mg / kg or more, 150mg / kg or more, 175mg / kg or more, 200mg / kg or more, 225mg / kg or more, 250mg / kg or more, 275mg / kg or more, 300mg / kg or more, 325mg / kg or more, 350mg / kg or more, 375mg / kg or more, 400mg / kg or more, 425mg / kg or more, 450mg / kg or more, or 475mg / kg or more).Typically, the dose is about 500 mg / kg or less (e.g., about 475 mg / kg or less, about 450 mg / kg or less, about 425 mg / kg or less, about 400 mg / kg or less, about 375 mg / kg or less, about 350 mg / kg or less, about 325 mg / kg or less, about 300 mg / kg or less, about 275 mg / kg or less, about 250 mg / kg or less, about 225 mg / kg or less, about 200 mg / kg or less, about 175 mg / kg or less). g or less, about 150 mg / kg or less, about 125 mg / kg or less, about 100 mg / kg or less, about 75 mg / kg or less, about 50 mg / kg or less, about 40 mg / kg or less, about 30 mg / kg or less, about 20 mg / kg or less, about 15 mg / kg or less, about 10 mg / kg or less, about 5 mg / kg or less, about 2 mg / kg or less, about 1 mg / kg or less, about 0.5 mg / kg or less, or about 0.1 mg / kg or less). Any two of the foregoing endpoints can be used to define a closed-ended range, or a single endpoint can be used to define an open-ended range.

[0081] In one embodiment, the compound of formula (I) or a salt thereof inhibits one or more enzymes selected from AXL, Mer, and c-Met. Accordingly, the present invention provides a method for inhibiting AXL, Mer, and / or c-Met enzymes in cells, comprising administering a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to cells in need of such enzyme inhibition (e.g., cells overexpressing AXL, Mer, and / or c-Met). For example, the cells may be any cells that overexpress AXL, Mer, and / or c-Met and are associated with any suitable tissue, particularly tissues associated with diseases such as papillary thyroid cancer, pancreatic cancer, lung cancer, colon cancer, breast cancer, neuroblastoma, pain, cachexia (wasting syndrome), dermatitis, and asthma. The tissue may be derived, for example, from the thyroid, pancreas, lung, colon, breast, skin, or adrenal gland. According to one embodiment, the cells are cancer cells that overexpress AXL, Mer, and / or c-Met, such as cells from papillary thyroid carcinoma, pancreatic cancer, lung cancer, colon cancer, breast cancer, and neuroblastoma. In another embodiment, the cancer cells are non-small cell lung cancer cells.

[0082] Elevated levels of AXL, Mer, and c-Met are associated with certain diseases, and inhibiting one or more of AXL, Mer, and c-Met is believed to be a viable treatment for such diseases. That is, the present invention provides a method for treating or preventing AXL-, Mer-, and / or c-Met-mediated diseases in a subject with a compound of Formula (I). Generally, the compound of Formula (I) will be provided to the subject in the form of a pharmaceutical composition, as described herein. The type of disease to be treated or prevented is not particularly limited, but generally, the disease is characterized by elevated expression of AXL, Mer, and c-Met compared to normal tissue of the same type. In some embodiments, the disease is selected from the group consisting of papillary thyroid carcinoma, pancreatic cancer, lung cancer, colon cancer, breast cancer, neuroblastoma, pain, cachexia (wasting syndrome), dermatitis, and asthma. The method comprises administering a pharmaceutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. In some preferred embodiments of this method, the disease is lung cancer (eg, non-small cell lung cancer).

[0083] The present invention further provides a method for treating a subject having cancer cells that are resistant to an anticancer drug, comprising administering to the subject an effective amount of a compound of formula (I), including a compound of formula (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, and an anticancer drug, whereby the compound or a pharmaceutically acceptable salt thereof resensitizes the cancer cells to the anticancer drug.The cancer cells are the same as those described herein.In one embodiment, the cancer cells are selected from papillary thyroid carcinoma, pancreatic cancer, lung cancer, colon cancer, breast cancer, and neuroblastoma.In another embodiment, the cancer cells are non-small cell lung cancer cells.

[0084] In certain aspects of this method, a compound of Formula (I), including a compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, can be co-administered with an anti-cancer agent (e.g., a chemotherapeutic agent) and / or radiation therapy. In one aspect, the method comprises administering an amount of the compound or a salt thereof, preferably in the form of a pharmaceutical composition, that is effective to sensitize cancer cells to one or more treatment regimens (e.g., chemotherapy or radiation therapy). The term "co-administer" or "co-administration" refers to simultaneous or sequential administration. A compound can be administered prior to, simultaneously with, or after administration of another compound using any suitable time frame.

[0085] One or more, for example, two, three, or more, anti-cancer agents can be administered. In this regard, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of a compound of Formula (I), including a compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, and at least one anti-cancer agent (e.g., a chemotherapeutic agent).

[0086] Examples of anticancer drugs include platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin, dactinomycin), taxanes (e.g., paclitaxel, Taxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, pemetrexed, thioguanine, floxuridine, capecitabine, and methotrexate), nucleoside analogs (e.g., fludarabine, clofarabine, cladribine, pentostatin, nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine), proteosome inhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide) , DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vincristine, vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, sunitinib), monoclonal antibodies (e.g., rituximab, cetuximab, panitumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab), nitrosoureas (e.g., carmustine, fotemustine, and lomustine), enzyme inhibitors (e.g., L-asparagine), enzymes), biological agents (e.g., interferons and interleukins), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide, lenalidomide), steroids (e.g., prednisone, dexamethasone, and prednisolone), CDK4 / 6 inhibitors (e.g., abemaciclib, palbociclib, ribociclib), anticancer hormone agents (e.g., tamoxifen, fulvestrant, raloxifene, leuprolide, bicalutamide, granisetron, flutamide, goserelin), aromatase inhibitors (e.g., exemestane,letrozole, and anastrozole), arsenic trioxide, tretinoin, non-selective cyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory drugs, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin), selective cyclooxygenase-2 (COX-2) inhibitors, immune checkpoint inhibitors (e.g., anti-PD1, anti-CTLA4, and anti-PD-L1), cellular immunotherapy (e.g., chimeric antigen receptor T-cell therapy, tumor infiltrating lymphocyte therapy), or any combination thereof.

[0087] For purposes of the present invention, the term "subject" preferably refers to a mammal. Mammals include, but are not limited to, Rodents, such as mice, and Lagomorphs, such as rabbits. Preferably, the mammal is from the order Carnivora, including Felidae (cats) and Canidae (dogs). More preferably, the mammal is from the order Artiodactyla, including Bovine (cattle) and Swine (pigs), or Perissodactyla, including Equine (horses). Most preferably, the mammal is from the order Primates, Scrophulariformes, or Simioidea (monkeys) or from the order Anthropoidea (humans and apes). A particularly preferred mammal is a human.

[0088] The present invention is further illustrated by the following embodiments.

[0089] A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0090] [ka]

[0091] (In the formula, R 1 is H, alkyl, haloalkyl, halo, or CN; R 2 is H, alkyl, haloalkyl, halo, or CN; R 3is H or halo; Q is H, CN, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl, wherein said alkenyl or alkynyl is -CH=CR 4 (CX') m (CH2) n NR 5 R 6 , -C≡C(CX') m (CH2) n NR 5 R 6 , -CH=CR 4 (CX') m (CH2) n CHR 5 R 6 , -C≡C(CX') m (CH2) n CHR 5 R 6 , -CH=CR 4 (CX') m (CH2) n NR 7 OR 8 , and -C≡C(CX') m (CH2) n NR 7 OR 8 Selected from the group consisting of: where: R 4 is hydrogen or halo; X' is H2, (C 1-6 alkyl)2, or =O; m is 0 or 1; n is 0 or 1 to 3; -NR 5 R 6 either forms a 4- to 7-membered heterocyclic ring or does not form a ring structure, and the heterocyclic ring is either a heteroaryl ring or a heterocyclyl ring; -NR 5 R 6 When forms a 4- to 7-membered heterocyclic ring, the 4- to 7-membered heterocyclic ring is 5 R 6and an optional second heteroatom in addition to the nitrogen, and optionally substituted with one or more substituents independently selected from the group consisting of linear C1-C6 alkyl, branched C2-C6 alkyl, hydroxy, C1-C6 alkoxyalkyl, carboxylic acid, linear C1-C4 alkylcarboxylic acid, and branched C3-C4 alkylcarboxylic acid; -NR 5 R 6 does not form a ring structure, R 5 is selected from the group consisting of hydrogen, linear C1-C6 alkyl, and branched C3-C6 alkyl, and R 6 is selected from the group consisting of hydrogen, linear C1-C6 alkyl optionally substituted with at least one fluoro or at least one hydroxy, branched C3-C6 alkyl optionally substituted with at least one fluoro or at least one hydroxy, and cycloalkyl optionally substituted with at least one fluoro or at least one hydroxy; -CHR 5 R 6 either forms a 4- to 7-membered heterocyclic ring or does not form a ring structure, and the heterocyclic ring is either a heteroaryl ring or a heterocyclyl ring; -CHR 5 R 6 forms a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle contains one or two heteroatoms and is optionally substituted with one or more substituents independently selected from the group consisting of linear C1-C6 alkyl, branched C3-C6 alkyl, hydroxy, C1-C6 alkoxyalkyl, carboxylic acid, linear C1-C4 alkylcarboxylic acid, and branched C3-C4 alkylcarboxylic acid; -CHR 5 R 6 does not form a ring structure, R 5 is selected from the group consisting of hydrogen, linear C1-C6 alkyl, and branched C3-C6 alkyl, and R 6is selected from the group consisting of hydrogen, linear C1-C6 alkyl optionally substituted with at least one fluoro or at least one hydroxy, branched C3-C6 alkyl optionally substituted with at least one fluoro or at least one hydroxy, and cycloalkyl optionally substituted with at least one fluoro or at least one hydroxy; -NR 7 OR 8 does not form a ring structure, and R 7 is selected from the group consisting of hydrogen, linear C1-C6 alkyl, and branched C3-C6 alkyl, and R 8 is selected from the group consisting of hydrogen, linear C1-C6 alkyl optionally substituted with at least one fluoro, hydroxy, or alkoxy group, branched C3-C6 alkyl optionally substituted with at least one fluoro, hydroxy, or alkoxy group, and cycloalkyl optionally substituted with at least one fluoro, hydroxy, or alkoxy group; G is

[0092] [ka]

[0093] (In the formula, R 9 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or heteroarylalkyl, where the heteroaryl group of the heteroarylalkyl can be substituted or ubsubstituted; R 10is H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl, alkenyl or alkynyl, where the alkyl, alkenyl or cycloalkyl can be substituted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino (wherein the alkyl groups of the dialkylamino can be the same or different), heteroaryl, substituted heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl (wherein the alkyl groups of the dialkylcarbamoyl can be the same or different), and heterocyclylcarbonyl; and Y is N, CH, or C-alkyl).

[0094] 2.R 1 and R 2 The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein: are both hydrogen.

[0095] 3.R 3 The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is halo.

[0096] 4. Q is CN, halo, optionally substituted phenyl, optionally substituted heterocyclyl, or -CH=CR 4 (CX') m (CH2) n NR 5 R 6 , -C≡C(CX') m (CH2) n NR 5 R 6 , -CH=CR 4 (CX') m (CH2) n CHR 5 R 6 , -C≡C(CX') m (CH2) nCHR 5 R 6 , -CH=CR 4 (CX') m (CH2) n NR 7 OR 8 , and -C≡C(CX') m (CH2) n NR 7 OR 8 wherein R is an alkenyl or alkynyl moiety selected from the group consisting of 4 is hydrogen or halo; X' is H2, (C 1-6 alkyl)2, or ═O; m is 0 or 1; n is 0 or 1; —NR 5 R 6 is morpholinyl, piperazinyl, or piperidinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of a nitrogen protecting group, alkyl, hydroxy, alkoxy, and alkoxyalkyl; -CHR 5 R 6 is tetrahydropyranyl, morpholinyl, piperazinyl, or piperidinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of a nitrogen protecting group, alkyl, hydroxy, alkoxy, and alkoxyalkyl; R 7 is selected from the group consisting of hydrogen, linear C1-C6 alkyl, and branched C3-C6 alkyl, and R 8 is selected from the group consisting of linear C1-C6 alkyl optionally substituted with at least one alkoxy group and branched C3-C6 alkyl optionally substituted with at least one alkoxy group, or a pharmaceutically acceptable salt thereof.

[0097] 5.R 9 or a pharmaceutically acceptable salt thereof.

[0098] 6. The compound of formula (I) has the formula (Ib):

[0099] [ka]

[0100] (In the formula,

[0101] [ka]

[0102] or a pharmaceutically acceptable salt thereof.

[0103] 7.R 1 and R 2 The compound of embodiment 6, or a pharmaceutically acceptable salt thereof, wherein: are both hydrogen.

[0104] 8.R 3 The compound of embodiment 6 or 7, or a pharmaceutically acceptable salt thereof, wherein is halo.

[0105] 9. X' is H2, (C1-6 alkyl)2, or ═O; and -NR 5 R 6 is morpholinyl, piperazinyl, or piperidinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of a nitrogen protecting group, alkyl, hydroxy, alkoxy, and alkoxyalkyl, or a pharmaceutically acceptable salt thereof.

[0106] 10.R 9 or a pharmaceutically acceptable salt thereof.

[0107] 11. The compound of formula (I) has the formula (Ic):

[0108] [ka]

[0109] (In the formula,

[0110] [ka]

[0111] or a pharmaceutically acceptable salt thereof.

[0112] 12.R 1 and R 2 or a pharmaceutically acceptable salt thereof.

[0113] 13.R 3 13. The compound of embodiment 11 or 12, or a pharmaceutically acceptable salt thereof, wherein is halo.

[0114] 14. X' is H2, (C1-6 alkyl)2, or =O; R 7 is selected from the group consisting of linear C1-C6 alkyl and branched C3-C6 alkyl, and R 8 The compound of any one of embodiments 11-13, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of linear C1-C6 alkyl and branched C3-C6 alkyl.

[0115] 15.R 9 or a pharmaceutically acceptable salt thereof.

[0116] 16.

[0117]

change

[0118]

change

[0119]

change

[0120]

change

[0121]

change

[0122]

change

[0123]

change

[0124]

change

[0125]

change

[0126]

change

[0127]

change

[0128] or a pharmaceutically acceptable salt thereof.

[0129] 17. A pharmaceutical composition comprising at least one compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0130] 18. A method for treating or preventing an AXL-, Mer-, and / or c-Met-mediated disease in a subject, wherein the disease is selected from the group consisting of papillary thyroid cancer, pancreatic cancer, lung cancer, colon cancer, breast cancer, neuroblastoma, pain, cachexia, dermatitis, and asthma, the method comprising administering to a subject in need of such treatment a pharmaceutically effective amount of a compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof.

[0131] 19. The method of embodiment 18, wherein the lung cancer is non-small cell lung cancer.

[0132] 20. A method of inhibiting the AXL, Mer, and / or c-Met enzyme in a cell, the method comprising administering to a cell in need of such inhibition a pharmaceutically effective amount of a compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof.

[0133] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. [Example]

[0134] NMR spectra were recorded in CDCl3 and DMSO-d6 solutions in 5 mm OD tubes (Norell, Inc. 507-HP) at 30 °C. 1H spectra were collected on a Varian VNMRS-400 at 400 MHz. Chemical shifts (δ) are relative to tetramethylsilane (TMS = 0.00 ppm) and are expressed in ppm. LC / MS data were acquired on a FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 Series ion trap mass spectrometer (column: YMC Hydrosphere (C18, θ 4.6 × 50 mm, 3 μm, 120 Å, 40 °C) operated in ESI (+) ionization mode; flow rate = 1.0 mL / min, mobile phase = 0.01% heptafluorobutyric acid (HFBA) and 1.0% isopropyl alcohol (IPA) in water or CH3CN).

[0135] Intermediate Example 1 This example describes the synthesis of 1-morpholinoprop-2-yn-1-one (Intermediate 1).

[0136] [ka]

[0137] n-BuLi (2.5 M in hexane, 4.89 mL, 12.22 mmol) was slowly added to a solution of ethynyltrimethylsilane (1.45 mL, 10.18 mmol) in tetrahydrofuran (THF) (50 mL) at −78° C. The reaction mixture was stirred at the same temperature for 1 h, and morpholine-4-carbonyl chloride (1.27 mL, 11.20 mmol) was added. The reaction mixture was stirred at room temperature (rt) for another 2 h. Water was added to the reaction mixture and stirred for 10 min. Ethyl acetate (EtOAc) was poured into the mixture, and the separated organic layer was extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (hexane / EtOAc = 1 / 1) to give 1-morpholinoprop-2-yn-1-one (1.03 g, 73%) as an off-white solid. 1H-NMR (CDCl3, Varian, 400MHz): δ3.14 (1H, s), 3.64-3.69 (4H, m), 3.70-3.73 (2H, m), 3.77-3.79 (2H, m).

[0138] [ka]

[0139] Intermediate Example 2 This example describes the synthesis of 4-(prop-2-ynyl)morpholine (Intermediate 2).

[0140] [ka]

[0141] To a solution of morpholine (0.50 g, 5.74 mmol) in acetone (30.0 mL) was added 3-bromoprop-1-yne (0.82 g, 6.89 mmol) and potassium carbonate (1.03 g, 7.46 mmol). The reaction mixture was stirred at room temperature for 8 hours. The mixture was then cooled to 5°C and then cooled to 5°C. TM The residue was purified by column chromatography on SiO (hexane / EtOAc = 1 / 1) to give 4-(prop-2-ynyl)morpholine (370 mg, 52%) as a yellow oil. 1 H-NMR (CDCl3, Varian, 400MHz): δ2.27 (1H, s), 2.57 (4H, t, J = 4.8Hz), 3.29 (2H, t, J = 2.0Hz), 3.74 (4H, t, J = 4.4Hz).

[0142] [ka]

[0143] Intermediate Example 3 This example describes the synthesis of tert-butyl 4-(prop-2-ynyl)piperazine-1-carboxylate (Intermediate 3).

[0144] [ka]

[0145] To a mixture of tert-butyl piperazine-1-carboxylate (5.00 g, 26.8 mmol) and KCO (7.42 g, 53.7 mmol) in CHCN (140 mL) was added 3-bromoprop-1-yne (2.63 mL, 34.9 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then cooled to 50°C and cooled to 50°C. The resulting mixture was then ... TM The mixture was filtered through a pad (Sigma-Aldrich, St. Louis, MO), and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (hexane / EtOAc = 1 / 1) to give tert-butyl 4-(prop-2-ynyl)piperazine-1-carboxylate (5.39 g, 90%) as a yellow oil. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.46 (9H, s), 2.26 (1H, brs), 2.51 (4H, brs), 3.32 (2H, s), 3.47 (4H, t, J=4.4Hz).

[0146] [ka]

[0147] Intermediate Example 4 This example describes the synthesis of tert-butyl 4-propioloylpiperazine-1-carboxylate (Intermediate 4).

[0148] [ka]

[0149] To a solution of propiolic acid (0.67 g, 9.66 mmol) in dichloromethane (DCM) (22 mL) was added N,N'-dicyclohexylcarbodiimide (DCC) (1.76 mL, 9.66 mmol) at -5°C and stirred for 1 hour. To the reaction mixture were added tert-butyl piperazine-1-carboxylate (2.0 g, 10.74 mmol) and N,N-diisopropylethylamine (DIPEA) (5.75 mL, 32.2 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 5°C and cooled to 5°C. The resulting mixture was then cooled to 5°C and stirred for 1 hour. The resulting ... TM The residue was purified by column chromatography on SiO (hexane / EtOAc = 1 / 1) to give tert-butyl 4-propioloylpiperazine-1-carboxylate (1.09 g, 43%) as a white solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.47(9H,s),3.15(1H,s),3.43(2H,t,J=5.6Hz),3.49(2H,t,J=5.6Hz),3.61(2H,t,J=5.6Hz),3.74(2H,t,J=5.6Hz).

[0150] [ka]

[0151] Intermediate Example 5 This example describes the synthesis of tert-butyl 4-acryloylpiperazine-1-carboxylate (Intermediate 5).

[0152] [ka]

[0153] Triethylamine (TEA) (1.39 mL, 10.0 mmol) was added to a solution of acryloyl chloride (0.89 mL, 11.0 mmol) and tert-butyl piperazine-1-carboxylate in DCM (60 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and saturated NaHCO (aq). The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give tert-butyl 4-acryloylpiperazine-1-carboxylate (2.33 g, 97%) as a pale yellow solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.37(9H,s),3.35(8H,brs),5.36(1H,dd,J=10.4Hz),6.19(1H,dd,J=16.8Hz),6.48(1H,dd,J=16.8Hz).

[0154] [ka]

[0155] Intermediate Example 6 This example describes the synthesis of tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (Intermediate 6).

[0156] [ka]

[0157] To a solution of tert-butyl piperazine-1-carboxylate (0.50 g, 2.68 mmol), 3-chloro-3-methylbut-1-yne (0.39 mL, 3.50 mmol), and TEA (0.48 mL, 3.50 mmol) in tetrahydrofuran (THF) (10.0 mL) was added copper(I) chloride (0.02 g, 0.19 mmol) under a N atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Water-1N HCl (v / v = 2 / 1, 3.0 mL) was poured into the mixture, which was then extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (0.66 g, 97%) as an ivory solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.39 (6H, s), 1.46 (9H, s), 2.29 (1H, s), 2.58 (4H, m), 3.44-3.46 (4H, m).

[0158] [ka]

[0159] Intermediate Example 7 This example describes the synthesis of 4-(2-methylbut-3-yn-2-yl)morpholine (Intermediate 7).

[0160] [ka]

[0161] To a solution of morpholine (0.50 g, 5.74 mmol), 3-chloro-3-methylbut-1-yne (0.83 mL, 7.46 mmol), and TEA (1.0 mL, 7.46 mmol) in THF (10.0 mL) was added copper(I) chloride (0.04 g, 0.40 mmol) under a N atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Water-1N HCl (v / v=2 / 1, 3.0 mL) was poured into the mixture and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give 4-(2-methylbut-3-yn-2-yl)morpholine (0.66 g, 97%) as an ivory solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.38 (6H, s), 2.30 (1H, s), 2.62-2.64 (4H, m), 3.73-3.76 (4H, m).

[0162] [ka]

[0163] Intermediate Example 8 This example describes the synthesis of 1-methyl-4-(prop-2-ynyl)piperazine (Intermediate 8).

[0164] [ka]

[0165] To a solution of 1-methylpiperazine (3.80 mL, 33.7 mmol) and K2CO3 (4.70 g, 33.7 mmol) in acetone (40 mL) was added a solution of 3-bromoprop-1-yne (1.70 mL, 22.5 mmol) in acetone (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 hours and concentrated in vacuo. Water was poured into the residue and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 1-methyl-4-(prop-2-ynyl)piperazine (2.10 g, 45%) as a dark yellow oil. 1H-NMR (CDCl3, Varian, 400MHz): δ2.14-2.16 (1H, m), 2.19 (3H, s), 2.74-2.48 (8H, m), 3.17 (1H, d, J = 2.4Hz).

[0166] [ka]

[0167] Intermediate Example 9 This example describes the synthesis of 4-ethynyl-1-propyl-1H-pyrazole (Intermediate 9).

[0168] [ka]

[0169] Step A: 4-Iodo-1-propyl-1H-pyrazole

[0170] [ka]

[0171] A mixture of 4-iodo-1H-pyrazole (500 mg, 2.58 mmol) and K2CO3 (430 mg, 3.09 mmol) in dimethylfuran (DMF) (10 mL) was stirred at room temperature for 5 minutes. 1-Iodopropane (0.28 mL, 2.84 mmol) was added to the mixture, which was then stirred at room temperature for 17 hours. The reaction mixture was then cooled to 50°C and then cooled to 50°C. The resulting mixture was ... TM The mixture was filtered through a pad (Sigma-Aldrich, St. Louis, MO), and the filtrate was concentrated in vacuo. Water was added to the residue, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane / EtOAc = 7 / 3) to give -iodo-1-propyl-1H-pyrazole (430 mg, 71%) as a brown solid. 1H-NMR (CDCl3, Varian, 400MHz): δ0.61-0.67(3H,m), 1.57-1.67(2H,m), 3.81-3.86(2H,m), 7.22(1H,d,J=6.8Hz),7.75(1H,d,J=6.4Hz).

[0172] Step B: 1-Propyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole

[0173] [ka]

[0174] A mixture of 4-iodo-1-propyl-1H-pyrazole (430 mg, 1.82 mmol), ethynyltrimethylsilane (0.36 mL, 2.55 mmol), DIPEA (0.41 mL, 2.37 mmol), copper(I) iodide (21 mg, 0.11 mmol), PPh (96 mg, 0.36 mmol), and Pd(OAc) (29 mg, 0.13 mmol) in DMF (4 mL) was heated at 60 °C for 3 h under an Ar atmosphere. After cooling at room temperature, water was poured into the mixture, which was then extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (hexane / EtOAc = 9 / 1) to give 1-propyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole (260 mg, 69%) as a brown oil. 1 H-NMR (CDCl3, Varian, 400MHz): δ0.09(9H,s), 0.66(3H,t,J=5.4Hz), 1.59-1.68(2H,m), 3.81(2H,t,J=6.8Hz), 7.29(1H,s), 7.37(1H,s).

[0175] Step C: 4-ethynyl-1-propyl-1H-pyrazole

[0176] [ka]

[0177] To a solution of 1-propyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole (260 mg, 1.26 mmol) in MeOH (8 mL) was added K2CO3 (192 mg, 1.39 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 4-ethynyl-1-propyl-1H-pyrazole (120 mg, 71%) as a dark brown oil. 1 H-NMR (CDCl3, Varian, 400MHz): δ0.90(3H,t,J=7.6Hz),1.84-1.90(2H,m),3.01(1H,s),4.05(2H,t,J=7.2Hz),7.54(1H,s),7.61(1H,s).

[0178] [ka]

[0179] Intermediate Example 10 This example describes the synthesis of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10).

[0180] [ka]

[0181] Step A: Diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate

[0182] [ka]

[0183] To a solution of diethyl 2-(aminoethylene)malonate (500 mg, 2.67 mmol) in dichloroethane (13 mL) at room temperature was added 1-fluoro-4-isocyanatobenzene (318 μL, 2.80 mmol), followed by DIPEA (513 μL, 2.94 mmol). The reaction mixture was stirred at 100° C. for 8 hours and cooled to room temperature. The resulting precipitate was collected by filtration, washed with EtO, and dried under vacuum to give diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate (465 mg, 54%) as a yellow solid. 1 H-NMR(DMSO-d6,Varian,400MHz):δ1.22-1.29(6H,m),4.15(2H,q,J=7.2Hz),4.24(2H,q,J=7.2Hz), 7.17-7.21(2H,m),7.49-7.53(2H,m),8.46(1H,d,J=12.8Hz),10.41(1H,s),10.58(1H,d,J=12.4Hz).

[0184] Step B: Ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0185] [ka]

[0186] To a solution of diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate (465 mg, 1.43 mmol) in EtOH (7 mL) was added NaOEt (156 mg, 2.29 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was partitioned with EtOAc and 30% citric acid (aqueous) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was triturated with DCM and isopropyl ether (IPE) to give ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (342 mg, 86%) as a yellow solid. 1H-NMR (DMSO-d6, Varian, 400MHz): δ1.23 (3H, t, J = 7.2Hz), 4.18 (2H, q, J = 7.2Hz), 7.29-7.31 (4H, m), 8.25 (1H, s). * No NH peak was observed.

[0187] Step C: Ethyl 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0188] [ka]

[0189] To a solution of ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (342 mg, 1.23 mmol) in DMF (3 mL) was added KCO (340 mg, 2.46 mmol) followed by 2-iodopropane (246 μL, 2.46 mmol) at room temperature. The reaction mixture was stirred at 70 °C overnight and quenched with saturated NHCl solution (aqueous). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on SiO (hexane / EtOAc = 3 / 2) to give ethyl 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (276 mg, 70%) as a yellow solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.36(3H,t,J=7.2Hz),1.45(6H,d,J=6.8Hz),4.35(2H,q,J=7.2Hz),4.89-4.95(1H,m),7.17-7.18(4H,m),8.36(1H,s).

[0190] Step D: 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

[0191] [ka]

[0192] A mixture of ethyl 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (276 mg, 0.86 mmol) and HCl (1.08 mL, 4.31 mmol; 4 M solution in dioxane) in water (0.25 mL) was stirred at 70° C. overnight. After cooling at room temperature, water was added to the reaction mixture. The resulting precipitate was collected by filtration, washed with water and hexane, and dried under vacuum to give 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (202 mg, 80%) as a white solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.38 (6H, d, J=6.8Hz), 4.69-4.74 (1H, m), 7.30-7.35 (4H, m), 8.58 (1H, s). * No COOH peak was observed.

[0193] [ka]

[0194] Intermediate Example 11 This example describes the synthesis of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11).

[0195] [ka]

[0196] Step A: tert-butyl 4-chloropyridin-2-ylcarbamate

[0197] [ka]

[0198] To a solution of 4-chloropyridin-2-amine (3.00 g, 23.3 mmol) in THF (200 mL) was added NaHMDS (1 M in THF, 46.7 mL, 46.7 mmol) at −10° C. A solution of di-tert-butyl dicarbonate (5.09 g, 23.34 mmol) in THF (10 mL) was then added at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. Saturated NH4Cl was added to the reaction mixture and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-chloropyridin-2-ylcarbamate (5.00 g, 94%) as a brown solid, which was used in the next step without further purification. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.53 (9H, s), 6.95-6.97 (1H, m), 7.59 (1H, brs), 8.04 (1H, s), 8.13 (1H, d, J=5.6Hz).

[0199] Step B: tert-butyl 4-chloro-3-iodopyridin-2-ylcarbamate

[0200] [ka]

[0201] n-BuLi (2 M in hexane, 8.75 mL, 21.9 mmol) was added dropwise to a solution of tert-butyl 4-chloropyridin-2-ylcarbamate (2.00 g, 8.75 mmol) and tetramethylethylenediamine (TMEDA) (3.27 mL, 21.87 mmol) in THF (292 mL) at −78° C. for 30 minutes. The mixture was stirred at the same temperature for 1 hour, and then I (11.1 g, 43.7 mmol) in THF (100 mL) was added. After the addition was complete, the reaction mixture was stirred at −78° C. for 30 minutes and then warmed to room temperature. The mixture was treated with a solution of sodium bisulfite (16.0 g) in HO (100 mL), stirred for 30 minutes, and then extracted with EtOAc. The extract was washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on SiO.sub.2 (hexane / EtOAc=1 / 1) to give tert-butyl 4-chloro-3-iodopyridin-2-ylcarbamate (2.10 g, 68%) as a white solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.45 (9H, s), 7.48 (1H, d, J = 4.8Hz), 8.30 (1H, d, J = 4.8Hz), 9.48 (1H, s).

[0202] Step C: 4-chloro-3-iodopyridin-2-amine

[0203] [ka]

[0204] A suspension of tert-butyl 4-chloro-3-iodopyridin-2-ylcarbamate (2.10 g, 5.92 mmol) in HBr (10 mL, 5.92 mmol) was heated at 0 °C for 10 min to give a clear solution. After cooling at 0 °C, the reaction mixture was treated with crushed ice and basified with 6 M NaOH (aqueous). The precipitated product was collected by vacuum filtration, washed with water, and partially suctioned onto the funnel to give a white solid. The product was dissolved in THF, and the solution was dried over Na SO and concentrated in vacuo to give 4-chloro-3-iodopyridin-2-amine (1.50 g, quantitative) as a white solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ6.43 (2H, s), 6.72 (1H, d, J = 5.2Hz), 7.84 (1H, d, J = 5.2Hz).

[0205] Step D: 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine

[0206] [ka]

[0207] A mixture of 4-chloro-3-iodopyridin-2-amine (1.50 g, 5.89 mmol), 2-fluoro-4-nitrophenol (1.85 g, 11.8 mmol), DIPEA (1.54 mL, 8.84 mmol), and N-methylpyrrolidone (NMP) (8 mL) was placed in a glass pressure vessel and rapidly heated to 170 °C. Heating was continued for 18 h. After cooling at room temperature, the reaction mixture was dissolved in EtOAc and washed with saturated NaHCO solution (aqueous). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (hexane / EtOAc = 3 / 1) to give 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (1.48 g, 67%) as a pale yellow solid. 1H-NMR(DMSO-d6,Varian,400MHz):δ6.19(1H,d,J=5.6Hz),6.41(2H,s),7.33(1H,t ,J=8.6Hz),7.87(1H,d,J=5.6Hz),8.11-8.14(1H,m),8.40(1H,dd,J=2.4,10.4Hz).

[0208] Step E: 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine

[0209] [ka]

[0210] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (150 mg, 0.40 mmol) and SnCl (361 mg, 1.60 mmol) in EtOH (10 mL) was vigorously stirred at 90 °C for 2 h. After cooling at room temperature, the solvent was removed under reduced pressure and EtOAc was poured into the residue. The mixture was neutralized to pH 9 with saturated NaHCO (aq) and 2 N NaOH, and then CELITE TM The filtrate was extracted with EtOAc, dried over NaSO, and concentrated in vacuo to give 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (130 mg, 94%) as a yellow solid, which was used in the next step without further purification. 1 H-NMR(CDCl3,Varian,400MHz):δ3.78(2H,brs),5.08(2H,brs),5.87(1H,d,J=5.6Hz),6.44-6.53(2H,m),6.97(1H,t,J=8.8Hz),7.76(1H,d,J=5.6Hz)

[0211] Step F: N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0212] [ka]

[0213] To a mixture of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 11, 2.12 g, 7.24 mmol) and hexafluorophosphate (HATU) (3.03 g, 7.97 mmol), DIPEA (3.15 mL, 18.1 mmol) in DMF (18 mL) was added and stirred at room temperature for 1 hour. 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (2.50 g, 7.24 mmol) was added to the reaction mixture and stirred at room temperature for 3 hours. Water was poured into the reaction mixture. The resulting solid was collected by filtration, washed with water and ether, and dried under vacuum to give N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tettahydropyrimidine-5-carboxamide (3.60 g, 80%) as a beige solid, which was used in the next step without further purification. 1 H-NMR(CDCl3,Varian,400MHz):δ10.9(1H,s),8.68(1H,s),7.82-7.79(2H,m),7.26-7.25(4H,m),7.19(1H,d, J=9.2Hz), 6.95(1H,t,J=8.4Hz),6.02(1H,d,J=6.0Hz),5.09(2H,s),5.01-4.94(1H,m),1.49(6H,d,J=6.4Hz).

[0214] [ka]

[0215] Intermediate Example 12 This example describes the synthesis of tert-butyl 4-(3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)propioloyl)piperazine-1-carboxylate (Intermediate 12).

[0216] [ka]

[0217] Step A: tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)propioloyl)piperazine-1-carboxylate

[0218] [ka]

[0219] To a solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Step D of Intermediate 11, 1.00 g, 2.67 mmol), tert-butyl 4-propioloylpiperazine-1-carboxylate (Intermediate 4, 953 mg, 4.00 mmol), and TEA (1.49 mL, 10.7 mmol) in DMF (9 mL) was added copper(I) iodide (102 mg, 0.53 mmol) and Pd(PPh) (308 mg, 0.27 mmol) at room temperature under N. The reaction mixture was subjected to microwave irradiation at 90 °C for 1 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on SiO (EtOAc / MeOH=97 / 3) to give tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)propioloyl)piperazine-1-carboxylate (1.04 g, 80%) as a brown solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.47(9H,s),3.43(4H,brs),3.64(2Hbrs),3.73(2H,brs),5.35(2 H,brs),6.10(1H,d,J=6.0Hz),7.29(1H,d,J=8.4Hz),8.03(1H,d,J=6.0Hz),8.14(2H,t,J=10.4Hz).

[0220] Step B: tert-Butyl 4-(3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)propioloyl)piperazine-1-carboxylate

[0221] [ka]

[0222] A mixture of tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)propioloyl)piperazine-1-carboxylate (1.04 g, 2.14 mmol), zinc (1.40 g, 21.4 mmol), and ammonium chloride (1.15 g, 21.4 mmol) in THF / MeOH (v / v=1 / 1, 22 mL) was stirred at 60° C. for 45 minutes. The reaction mixture was filtered, and the filtrate was partitioned between EtOAc and saturated NaHCO (aq). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / MeOH=95 / 5) to give tert-butyl 4-(3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)propioloyl)piperazine-1-carboxylate (636 mg, 65%) as a yellow solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.46(9H,s),3.45(4H,brs),3.65(2Hbrs),3.81(2H,brs),3.85(2H,brs),5.22(2H,brs) ,5.98(1H,d,J=6.0Hz),6.45(1H,d,J=8.4Hz),6.51(1H,dd,J=11.6,2.4Hz),6.93(1H,t,J=8.4Hz),7.90(1H,d,J=6.0Hz).

[0223] [ka]

[0224] Intermediate Example 13 This example describes the synthesis of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (Intermediate 13).

[0225] [ka]

[0226] Step A: 4-Methylbenzenesulfonyl azide

[0227] [ka]

[0228] To a solution of 4-methylbenzene-1-sulfonyl chloride (5.0 g, 26.2 mmol) in acetone (65 mL) was added a solution of sodium azide (2.56 g, 39.3 mmol) in water (65 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. The acetone was removed in vacuo and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 4-methylbenzenesulfonyl azide (4.9 g, 95%) as a colorless oil. 1H-NMR (CDCl3, Varian, 400MHz): δ2.46 (3H, s), 7.39 (2H, d, J = 8.4 Hz), 7.82 (2H, d, J = 8.0 Hz).

[0229] Step B: 1-diazo-2-oxopropylphosphonic acid dimethyl ester

[0230] [ka]

[0231] To a stirred suspension of sodium hydride (4.9 g, 24.9 mmol) in toluene (50 mL) and THF (16 mL) was added a solution of dimethyl 2-oxopropylphosphonate (3.78 mL, 27.3 mmol) in toluene (6 mL) at 0 °C. A white solid formed, and stirring was continued for 1 h. A solution of 4-methylbenzenesulfonyl azide (1.19 g, 27.3 mmol) in toluene (10 mL) was added. The reaction mixture was stirred at room temperature for 12 h and then filtered through a pad of Celite. The filtrate was evaporated in vacuo to remove volatiles. The residue was purified by column chromatography on SiO (hexane / EtOAc = 1 / 1) to give dimethyl 1-diazo-2-oxopropylphosphonate (3.4 g, 71%) as a yellow oil. 1 H-NMR (CDCl3, Varian, 400MHz): δ2.16(3H,s), 3.73(3H,s), 3.76(3H,s).

[0232] Step C: tert-Butyl 4-(prop-2-ynyl)piperidine-1-carboxylate

[0233] [ka]

[0234] To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (3.3 g, 14.5 mmol) and potassium carbonate (4.01 g, 29.0 mmol) in MeOH (48 mL) was added dimethyl 1-diazo-2-oxopropylphosphonate (3.35 g, 17.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. The mixture was then extracted with EtOAc, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (hexane / EtOAc = 2 / 1) to afford tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (2.9 g, 89%) as a pale yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.02-1.16(2H,m),1.32(9H,s),1.38-1.56(1H,m),1.63(2H ,d,J=12.8Hz),1.87(1H,t,J=2.4Hz),2.01(2H,dd,J=2.2,6.6Hz),2.56(2H,s),3.98(2H,s).

[0235] [ka]

[0236] Intermediate Example 14 This example describes the synthesis of 1-methyl-4-(prop-2-ynyl)piperidine hydrochloride (Intermediate 14).

[0237] [ka]

[0238] Step A: 4-(prop-2-ynyl)piperidine hydrochloride

[0239] [ka]

[0240] A mixture of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.2 g, 5.37 mmol) and HCl (4 M in dioxane, 8.0 mL, 269 mmol) in DCM (20 mL) was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was triturated with ether. The precipitated solid was collected by filtration to give 4-(prop-2-ynyl)piperidine hydrochloride (739 mg, 86%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.34-1.44(2H,m),1.66-1.71(1H,m),1.79(2H,d,J=13.6Hz),2.14(2H ,dd,J=2.4,6.0Hz),2.79(2H,t,J=12.2Hz),2.88(1H,d,J=2.4Hz),3.20(2H,d,J=12.8Hz),8.78(1H,s).

[0241] Step B: 1-methyl-4-(prop-2-ynyl)piperidine hydrochloride

[0242] [ka]

[0243] A mixture of 4-(prop-2-ynyl)piperidine hydrochloride (739 mg, 4.63 mmol), formaldehyde (37 wt% in water, 0.26 mL, 6.94 mmol), sodium cyanoborohydride (582 mg, 9.26 mmol), and acetic acid (0.53 mL, 9.26 mmol) in MeOH (23 mL) was stirred at room temperature for 18 hours. The reaction mixture was quenched with NaHCO (aq), extracted with DCM, dried over NaSO, filtered, and concentrated in vacuo. The residue was triturated with HCl in ether. The precipitated solid was collected by filtration to give 1-methyl-4-(prop-2-ynyl)piperidine hydrochloride (410 mg, 51%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.73-1.83(2H,m),1.93-1.96(1H,m),1.98-2.09 (3H,m),2.22-2.24(2H,m),2.68-2.76(2H,m),2.78(3H,s),3.54(2H,d,J=12.0Hz).

[0244] [ka]

[0245] Intermediate Example 15 This example describes the synthesis of 1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 15).

[0246] [ka]

[0247] Step A: Diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate

[0248] [ka]

[0249] To a solution of diethyl 2-(aminoethylene)malonate (1.0 g, 5.34 mmol) in dichloroethane (1.5 mL) at room temperature was added 1-fluoro-4-isocyanatobenzene (0.64 mL, 5.61 mmol) followed by DIPEA (1.03 mL, 2.94 mmol). The reaction mixture was stirred at 100° C. for 6 hours and cooled to room temperature. The solvent was removed in vacuo. The resulting precipitate was collected by filtration, washed with EtO, and dried under vacuum to give diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate (776 mg, 44%) as a brown solid. 1H-NMR(DMSO-d6,Varian,400MHz):δ1.22-1.29(6H,m),4.15(2H,q,J=7.2Hz),4.24(2H,q,J=7.2Hz), 7.17-7.21(2H,m),7.49-7.53(2H,m),8.46(1H,d,J=12.8Hz),10.41(1H,s),10.58(1H,d,J=12.4Hz).

[0250] Step B: Ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0251] [ka]

[0252] To a solution of diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate (776 mg, 2.39 mmol) in EtOH (6 mL) was added NaOEt (261 mg, 3.83 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was partitioned between EtOAc and 1 M citric acid (aqueous) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO and concentrated in vacuo. The residue was triturated with diethyl ether and hexane to give ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (562 mg, 85%) as a yellow solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.23 (3H, t, J = 7.2Hz), 4.18 (2H, q, J = 7.2Hz), 7.29-7.31 (4H, m), 8.25 (1H, s). * No NH peak was observed.

[0253] Step C: Ethyl 1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0254] [ka]

[0255] To a solution of ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (510 mg, 1.83 mmol) in DMF (5 mL) was added KCO (507 mg, 3.67 mmol) followed by 2-chloro-N,N-dimethylacetamide (0.38 mL, 3.67 mmol) at room temperature. The reaction mixture was heated in a sealed tube at 70° C. overnight. The reaction mixture was diluted with EtOAc and then filtered through a Celite pad. The filtrate was washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (sole EtOAc) to afford 1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxyethyl (560 mg, 84%) as an off-white solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.33(3H,t,J=6.8Hz),3.01(3H,s),3.06(3H,s),4.29-4.35(2H,m),4.65(2H,s),7.12-7.25(4H,m),8.25(1H,s).

[0256] Step D: 1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

[0257] [ka]

[0258] A mixture of ethyl 1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (560 mg, 1.54 mmol) and HCl (4 M in dioxane, 1.93 mL, 7.71 mmol) in water (0.5 mL) was stirred at 70° C. overnight. After cooling at room temperature, water was added to the reaction mixture. The reaction mixture was extracted with DCM, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was triturated with hexane to give 1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (419 mg, 81%) as a white solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ2.84(3H,s), 2.97(3H,s), 4.85(2H,s), 7.29-7.31(4H,m), 8.65(1H,s), 12.58(1H,s).

[0259] [ka]

[0260] Intermediate Example 16 This example describes the synthesis of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 16).

[0261] [ka]

[0262] Step A: 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine

[0263] [ka]

[0264] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (1.04 g, 2.77 mmol) and SnCl (2.1 g, 11.09 mmol) in EtOH (27 mL) was vigorously stirred at 90 °C for 2 h. After cooling at room temperature, the solvent was removed under reduced pressure, and EtOAc was poured into the residue. The mixture was neutralized to pH 9 with 2 N NaOH solution and then filtered through a Celite pad. The filtrate was extracted with EtOAc, dried over NaSO, filtered, and concentrated in vacuo to give 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (914 mg, 96%) as a yellow solid, which was used in the next step without further purification. 1 H-NMR(CDCl3,Varian,400MHz):δ3.78(2H,brs),5.08(2H,brs),5.87(1H,d,J=5.6Hz),6.44-6.53(2H,m),6.97(1H,t,J=8.8Hz),7.76(1H,d,J=5.6Hz)

[0265] Step B: N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0266] [ka]

[0267] To a mixture of 1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 15, 194 mg, 0.58 mmol) and HATU (331 mg, 0.87 mmol), DIPEA (0.30 mL, 1.74 mmol) in DMF (5.8 mL) was added and stirred at room temperature for 10 minutes. 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (200 mg, 0.58 mmol) was added to the reaction mixture and stirred at room temperature overnight. Cold water was poured into the reaction mixture. The resulting solid was collected by filtration, washed with water and ether, and dried under vacuum to give N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (375 mg, 98%) as a beige solid, which was used for the next step without further purification. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ2.85(3H,s),3.00(3H,s),4.93(2H,s),5.79(1H,d,J=5.6Hz),6.23(2H,s),7.28-7 .23(1H,m),7.36-7.23(4H,m),7.46-7.44(1H,m),7.71(1H,d,J=5.6Hz),7.92-7.89(1H,m),8.75(1H,s),10.89(1H,s).

[0268] [ka]

[0269] Intermediate Example 17 This example describes the synthesis of 3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 17).

[0270] [ka]

[0271] Step A: Diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate

[0272] [ka]

[0273] To a solution of diethyl 2-(aminoethylene)malonate (3.0 g, 16.03 mmol) in dichloroethane (4.5 mL) at room temperature was added 1-fluoro-4-isocyanatobenzene (1.9 mL, 16.83 mmol) followed by DIPEA (3.08 mL, 17.63 mmol). The reaction mixture was stirred at 100° C. for 6 hours. After cooling to room temperature, the solvent was removed in vacuo. The resulting precipitate was collected by filtration, washed with EtO, and dried under vacuum to give diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate (1.79 g, 34%) as a brown solid. 1 H-NMR(DMSO-d6,Varian,400MHz):δ1.22-1.29(6H,m),4.15(2H,q,J=7.2Hz),4.24(2H,q,J=7.2Hz), 7.17-7.21(2H,m),7.49-7.53(2H,m),8.46(1H,d,J=12.8Hz),10.41(1H,s),10.58(1H,d,J=12.4Hz).

[0274] Step B: Ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0275] [ka]

[0276] To a solution of diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate (1.79 g, 5.54 mmol) in EtOH (14 mL) was added NaOEt (604 mg, 8.87 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was partitioned between EtOAc and 1 M citric acid (aqueous) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO and concentrated in vacuo. The residue was triturated with diethyl ether and hexane to give ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1.4 g, 91%) as a yellow solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.23 (3H, t, J = 7.2Hz), 4.18 (2H, q, J = 7.2Hz), 7.29-7.31 (4H, m), 8.25 (1H, s). * No NH peak was observed.

[0277] Step C: ethyl 3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0278] [ka]

[0279] To a solution of ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (600 mg, 2.15 mmol) in DMF (6 mL) at room temperature was added K2CO3 (596 mg, 4.31 mmol), followed by 24-(chloromethyl)-2-methylthiazole (0.5 mL, 4.31 mmol). The reaction mixture was heated in a sealed tube at 70 °C overnight. The reaction mixture was diluted with EtOAc and then filtered through a Celite pad. The filtrate was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc-hexane = 1 / 1 to EtOAc only) to give ethyl 3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (608 mg, 72%) as a yellow solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.24-1.20(3H,m),2.62(3H,s),4.16-4.21(2H,m),5.10(2H,s),7.26-7.28(4H,m),7.46(1H,s),8.73(1H,s).

[0280] Step D: 3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

[0281] [ka]

[0282] A mixture of ethyl 3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (608 mg, 1.56 mmol) and HCl (4 M in dioxane, 2.0 mL, 7.82 mmol) in water (0.5 mL) was stirred at 70° C. overnight. After cooling at room temperature, water was added to the reaction mixture. The reaction mixture was extracted with DCM, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was triturated with hexane to give 3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (565 mg, quantitative) as a white solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ2.62 (3H, s), 5.12 (2H, s), 7.27-7.35 (4H, m), 7.47 (1H, s), 8.83 (1H, s), 12.63 (1H, brs).

[0283] [ka]

[0284] Intermediate Example 18 This example describes the synthesis of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 18).

[0285] [ka]

[0286] To a mixture of 3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 17, 209 mg, 0.58 mmol) and HATU (331 mg, 0.87 mmol), DIPEA (0.30 mL, 1.74 mmol) in DMF (2 mL) was added and stirred at room temperature for 10 minutes. 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (200 mg, 0.58 mmol) was added to the reaction mixture and stirred at room temperature overnight. Cold water was poured into the reaction mixture. The resulting solid was collected by filtration, washed with water and ether, and dried under vacuum to give N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (318 mg, 80%) as a beige solid, which was used in the next step without further purification. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ2.66(3H,s),5.20(2H,s),5.78(1H,d,J=5.6Hz),6.19(2 H,s),7.45-7.22(7H,m),7.71(1H,d,J=6Hz),7.93-7.89(1H,m),8.83(1H,s),10.94(1H,s).

[0287] [ka]

[0288] Intermediate Example 19 This example describes the synthesis of 4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (Intermediate 19).

[0289] [ka]

[0290] Step A: Ethyl 4-(4-fluorophenyl)-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate

[0291] [ka]

[0292] A mixture of diethyl 2-oxomalonate (2.5 mL, 16.20 mmol) and N-(4-fluorophenyl)hydrazinecarbothioamide (3.0 g, 16.20 mmol) in EtOH (60 mL) was heated at reflux for 3 days (72 h). The mixture was cooled to room temperature, and the resulting precipitate was collected by filtration and dried under vacuum to give ethyl 4-(4-fluorophenyl)-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (2.88 g, 60%) as a white solid. 1 H-NMR(DMSO-d6,Varian,400MHz):δ1.25(3H,t,J=7.2Hz),4.27(2H,q,J=7.2Hz),7.31(4H,d,J=7.2Hz)

[0293] Step B: 4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate ethyl

[0294] [ka]

[0295] To a solution of ethyl 4-(4-fluorophenyl)-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (2.88 g, 9.78) in DMF (25 mL) and AcOH (10.64 mL, 186 mmol) was added HO (35% in water, 5.14 mL, 58.7 mmol). The mixture was stirred at room temperature for 2 days (48 h). The reaction mixture was extracted with EtOAc, water, and washed with brine. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude product was triturated with DCM and hexane to give ethyl 4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (2.40 g, 88%) as a white solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.24 (3H, t, J = 7.2Hz), 4.26 (2H, q, J = 7.2Hz).

[0296] Step C: Ethyl 4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate

[0297] [ka]

[0298] To a solution of ethyl 4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (2.40 g, 8.61 mmol) in DMF (20 mL) was added KCO (3.93 g, 28.4 mmol) and MeI (4.85 mL, 77.0 mmol). The mixture was stirred at 60 °C overnight. The residue was diluted with EtOAc and then filtered through a Celite pad and washed with EtOAc. The filtrate was washed with water and brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (hexane / EtOAc = 2 / 1) to give ethyl 4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (1.84 g, 73%) as a yellow solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.25 (3H, t, J = 7.2 Hz), 3.57 (3H, s), 4.28 (2H, q, J = 6.8 Hz), 7.33 (4H, d, J = 6.4 Hz).

[0299] Step D: 4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0300] [ka]

[0301] A mixture of ethyl 4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (1.74 g, 5.94 mmol) and HCl (4 M in dioxane, 7.43 mL, 29.7 mmol) in water (2 mL) was stirred at 70° C. for 2 days (48 hours). After cooling at room temperature, water was added to the reaction mixture. The resulting precipitate was collected by filtration, washed with water and hexane, and dried under vacuum to give 4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (1.57 g, quantitative) as a white solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ3.55 (3H, s), 7.32-7.34 (4H, m).

[0302] [ka]

[0303] Intermediate Example 20 This example describes the synthesis of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (Intermediate 20).

[0304] [ka]

[0305] To a mixture of 4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (Intermediate 19, 660 mg, 2.51 mmol) and HATU (1.43 g, 3.76 mmol), DIPEA (1.31 mL, 7.53 mmol) in DMF (13 mL) was added and stirred at room temperature for 10 minutes. 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (860 mg, 2.51 mmol) was added to the reaction mixture and stirred at room temperature overnight. Cold water was poured into the reaction mixture. The resulting solid was collected by filtration, washed with water and ether, and dried under vacuum to give N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (1.3 g, 88%) as a beige solid, which was used for the next step without further purification. 1 H-NMR(DMSO-d6,Varian,400MHz):δ3.65(3H,s),5.79(1H,d,J=5.6Hz),6.25(2H,brs),7.28- 7.38(5H,m),7.49-7.52(1H,m),7.71(1H,d,J=5.6Hz),7.88(1H,d,J=12.4Hz),10.87(1H,s).

[0306] [ka]

[0307] Intermediate Example 21 This example describes the synthesis of 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 21).

[0308] [ka]

[0309] A mixture of ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1.0 g, 3.59 mmol) and HCl (4 M in dioxane, 4.49 mmol) in water (1.2 mL) was stirred at 70° C. overnight. After cooling at room temperature, water was added to the reaction mixture. The resulting precipitate was collected by filtration, washed with water and hexane, and dried under vacuum to give 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (776 mg, 86%) as a beige solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ7.27-7.36 (4H, m), 8.35 (1H, s), 12.30 (1H, brs), 12.54 (1H, brs).

[0310] [ka]

[0311] Intermediate Example 22 This example describes the synthesis of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 22).

[0312] [ka]

[0313] To a mixture of 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 21, 636 mg, 2.54 mmol) and HATU (1.45 g, 3.82 mmol), DIPEA (1.33 mL, 7.63 mmol) in DMF (11 mL) was added and stirred at room temperature for 10 minutes. 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (877 mg, 2.54 mmol) was added to the reaction mixture and stirred at room temperature overnight. Water was poured into the reaction mixture. The resulting solid was collected by filtration, washed with water and ether, and dried under vacuum to give N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.31 g, 89%) as a yellow solid, which was used in the next step without further purification. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ5.80(1H,d,J=5.6Hz),6.21(2H,s),7.28-7.23(1H,t,J=8. 8Hz),7.45-7.32(5H,m),7.73(1H,d,J=5.2Hz),7.92-7.89(1H,m),8.44(1H,s),10.96(1H,s). * No NH peak was observed.

[0314] [ka]

[0315] Intermediate Example 23 This example describes the synthesis of 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 23).

[0316] [ka]

[0317] Step A: Ethyl 3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0318] [ka]

[0319] To a mixture of ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1.0 g, 3.59 mmol), K2CO3 (993 mg, 7.19 mmol) in DMF (10 mL) was added 4-bromotetrahydro-2H-pyran (809 μL, 7.19 mmol). The mixture was heated in a sealed tube at 100 °C overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through a Celite pad. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO 2 (hexane / EtOAc=1 / 1) to give ethyl 3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (457 mg, 35%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.36(3H,t,J=6.8Hz),1.93-1.98(4H,m),3.50-3.58(2H,m) ,4.13-4.16(2H,m),4.35(2H,q,J=6.8Hz),4.75-4.83(1H,m),7.17-7.19(4H,m),8.36(1H,s)

[0320] Step B: 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

[0321] [ka]

[0322] A mixture of ethyl 3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (457 mg, 1.26 mmol) and HCl (4 M in dioxane, 1.58 mL, 6.32 mmol) in water (1 mL) was stirred at 70° C. overnight. After cooling at room temperature, water was added to the reaction mixture. The reaction mixture was extracted with DCM, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was triturated with hexane to give 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (282 mg, 67%) as a beige solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.94-1.99(4H,m),3.49-3.56(2H,m),4.13-4 .16(2H,m),4.75-4.83(1H,m),7.22-7.26(4H,m),8.58(1H,s),12.28(1H,brs).

[0323] [ka]

[0324] Intermediate Example 24 This example describes the synthesis of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 24).

[0325] [ka]

[0326] To a mixture of 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 23, 273 mg, 0.82 mmol) and HATU (466 mg, 1.23 mmol), DIPEA (0.43 mL, 2.45 mmol) in DMF (8 mL) was added and stirred at room temperature for 10 minutes. 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (282 mg, 0.82 mmol) was added to the reaction mixture and stirred at room temperature overnight. Water was poured into the reaction mixture. The resulting solid was collected by filtration, washed with water and ether, and dried under vacuum to give N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (490 mg, 91%) as an ivory solid, which was used for the next step without further purification. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.83-1.88(2H,m),1.96-2.03(2H,m),3.35-3.45(2H,m),3.96-3.98(2H,m),4.60-4.64(1H,m),5.78(1H,d,J=6. 0Hz),6.19(2H,s),7.24(1H,t,J=8.8Hz),7.31-7.35(2H,m),7.38-7.45(3 H,m),7.71(1H,d,J=5.6Hz),7.90-7.94(1H,m),8.61(1H,s),10.94(1H,s).

[0327] [ka]

[0328] Intermediate Example 25 This example describes the synthesis of 3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 25).

[0329] [ka]

[0330] Step A: Diethyl 2-((3-cyclohexylureido)methylene)malonate

[0331] [ka]

[0332] A mixture of diethyl 2-(aminomethylene)malonate (3.0 g, 16.03 mmol), DIPEA (3.36 mL, 19.23 mmol), and isocyanatocyclohexane (2.25 mL, 17.63 mmol) in DCE (160 mL) was refluxed for 48 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / hexane = 1 / 1) to give diethyl 2-((3-cyclohexylureido)methylene)malonate (4.00 g, 80%) as a yellow oil. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.10-1.24(11H,m),1.49-1.52(1H,m),1.60-1.70(2H,m),1.71-1.80(2H,m),3.47(1H ,brs)4.09(2H,q,J=7.0Hz),4.17(2H,q,J=6.9Hz),8.04(1H,d,J=7.6Hz),8.40(1H,d,J=13.2Hz),10.28(1H,d,J=12.8Hz).

[0333] Step B: Ethyl 3-cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0334] [ka]

[0335] A mixture of diethyl 2-((3-cyclohexylureido)methylene)malonate (1.10 g, 3.52 mmol) and NaOEt (359 mg, 5.28 mmol) in EtOH (35.2 mL) was refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with EtOAc and washed with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / hexane = 1 / 1) to give ethyl 3-cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (320 mg, 34%) as a white solid. 1 H-NMR(DMSO-d6,Varian,400MHz):δ1.07-1.26(6H,m),1.47-1.50(2H,m),1.54-1.61(1H,m), 1.70-1.80(2H,m),2.20-2.30(2H,m),4.08(2H,q,J=7.2Hz),4.51-4.60(1H,m),8.05(1H,s).

[0336] Step C: Ethyl 3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0337] [ka]

[0338] A mixture of ethyl 3-cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (220 mg, 0.83 mmol), KCO (171 mg, 1.24 mmol), and iodoethane (80.0 μL, 0.99 mmol) in DMF (8.26 mL) was stirred at 70° C. for 6 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / hexanes = 1 / 1) to afford ethyl 3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (130 mg, 53%) as a yellow solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.16-1.30(9H,m),1.45-1.50(2H,m),1.55-1.64(1H,m),1.70-1.80 (2H,m),2.22-2.31(2H,m),3.82(2H,q,J=7.1Hz),4.16(2H,q,J=7.1Hz),4.60-4.66(1H,m),8.46(1H,s).

[0339] Step D: 3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

[0340] [ka]

[0341] A mixture of ethyl 3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (130 mg, 0.44 mmol) and LiOH (106 mg, 4.42 mmol) in EtOH (3.68 mL) and water (0.74 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and acidified with 1N aqueous HCl. The precipitated solid was collected by filtration and dried in vacuo to give 3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (110 mg, 94%) as a white solid, which was used in the next step without further purification. 1 H-NMR(DMSO-d6,Varian,400MHz):δ1.08-1.31(7H,m),1.56-1.62(2H,m),1.75-1.78(2H,m) ,2.21-2.30(2H,m),3.87(2H,q,J=7.1Hz),4.62-4.68(1H,m),8.67(1H,s),12.95(1H,brs).

[0342] [ka]

[0343] Intermediate Example 26 This example describes the synthesis of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 26).

[0344] [ka]

[0345] A mixture of 3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 26, 110 mg, 0.41 mmol), HATU (236 mg, 0.62 mmol), DIPEA (0.22 mL, 1.24 mmol), and 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (143 mg, 0.41 mmol) in DMF (4.13 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc and washed with brine. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / hexane=1 / 1) to give N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (180 mg, 73%) as a yellow solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.17-1.34(6H,m),1.55-1.61(3H,m),1. 78-1.80(2H,m),2.30-2.33(2H,m),3.91-3.99(2H,m),4.47-4.74(1H,m),5. 79(1H,d,J=5.6Hz),6.20(2H,s),7.26(1H,t,J=8.8Hz),7.45(1H,d,J=8.0Hz ),7.72(1H,d,J=5.6Hz),7.92(1H,d,J=14.8Hz),8.69(1H,s),11.15(1H,s).

[0346] Intermediate Example 27 This example describes the synthesis of 1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (intermediate 27).

[0347] [ka]

[0348] Step A: Ethyl 1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0349] [ka]

[0350] A mixture of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1.0 g, 5.43 mmol), K2CO3 (1.87 g, 13.6 mmol), and 3-iodoprop-1-ene (1.24 mL, 13.6 mmol) in DMF (54.3 mL) was heated at 80 °C for 6 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / hexane = 1 / 1) to give ethyl 1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1.1 g, 77%) as a yellow oil. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.22(3H,t,J=7.0Hz),4.18(2H,q,J=7.6Hz),4.38(2H,d,J=5.2Hz),4.4 7(2H,d,J=5.6Hz),5.07-5.09(2H,m),5.16-5.21(2H,m),5.73-5.83(1H,m),5.86-5.95(1H,m),8.48(1H,s)

[0351] Step B: 1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

[0352] [ka]

[0353] A mixture of ethyl 1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1.1 g, 4.16 mmol) and LiOH (997 mg, 41.6 mmol) in EtOH (41.6 mL) was stirred at room temperature for 18 hours. The reaction mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The separated organic layer was dried over NaSO, filtered, and concentrated in vacuo to give 1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (810 mg, 82%) as a yellow solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ4.41(2H,d,J=5.2Hz),4.50(2H,d,J=4.8Hz),5.07-5.11(2H,m),5.19-5.24(2H,m),5.76-5.94(2H,m),8.61(1H,s) * No protons from OH were observed.

[0354] [ka]

[0355] Intermediate Example 28 This example describes the synthesis of 1,3-diallyl-N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 28).

[0356] [ka]

[0357] A mixture of 1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (810 mg, 3.43 mmol), HATU (1.96 g, 5.14 mmol), DIPEA (1.78 mL, 10.29 mmol), and 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine (1.18 g, 3.43 mmol) in DMF (34.3 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc and washed with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / hexane=1 / 1) to give 1,3-diallyl-N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.5 g, 78%) as a yellow solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ4.48-4.52(2H,m),4.57(2H,d,J=5.6Hz),5.12-5.15(2H,m),5.22-5.27(2H,m),5.79(1H,d,J=5.2Hz),5.81- 5.92(2H,m)6.19(2H,s),7.27(1H,t,J=9.0Hz),7.45(1H,d,J=9.2Hz),7 .72(1H,d,J=5.2Hz),7.92(1H,d,J=15.2Hz),8.68(1H,s),11.05(1H,s).

[0358] Example 1 This example describes the synthesis of N-(4-(2-amino-3-(3-oxo-3-(piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 1.

[0359] [ka]

[0360] Step A: tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)propioloyl)piperazine-1-carboxylate

[0361] [ka]

[0362] To a degassed solution of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 8.40 g, 13.6 mmol), tert-butyl 4-propioloylpiperazine-1-carboxylate (Intermediate 4, 6.46 g, 27.1 mmol), copper(I) iodide (0.52 g, 2.71 mmol), and TEA (7.52 mL, 54.2 mmol) in DMF (45 mL) was added Pd(PPh) (1.57 g, 1.36 mmol) under an argon atmosphere. The reaction mixture was stirred at 90 °C overnight. After cooling to room temperature, EtOAc and saturated NH4Cl solution (aqueous) were added to the mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc / MeOH=97 / 3) to give tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)pyridin-3-yl)propioloyl)piperazine-1-carboxylate (5.20 g, 53%) as a dark brown form. 1H-NMR(CDCl3,Varian,400MHz):δ1.46(9H,s),1.51(6H,d,J=6.8Hz),3.45(4H,brs),3.65(2H,brs),3.82(2H,brs),4.96-4.99(1H,m),5.32(2H ,brs),5.97(1H,d,J=6.0Hz),7.11(1H,t,J=8.0Hz),7.23-7.27(5H,m), 7.85(1H,d,J=7.6Hz),7.91(1H,d,J=5.6Hz),8.69(1H,s),10.95(1H,s).

[0363] Step B: N-(4-(2-amino-3-(3-oxo-3-(piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0364] [ka]

[0365] To a solution of tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)propioloyl)piperazine-1-carboxylate (300 mg, 0.41 mmol) in DCM (8 mL) was added TFA (0.32 mL, 4.11 mmol) at 0° C. The mixture was stirred at room temperature for 18 hours. Excess TFA was removed by evaporation and DCM was poured into the residue. The mixture was neutralized with saturated NaHCO solution (aqueous). The separated aqueous layer was extracted with DCM and the combined organic layers were dried over NaSO, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=95 / 5) to give N-(4-(2-amino-3-(3-oxo-3-(piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (230 mg, 90%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.50(6H,d,J=6.8Hz),2.86(4H,brs),3.65(2H,brs),3.81(2H,brs),4.96-4.99(1H,m),5.32(2H,brs), 5.98(1H,d,J=6.4Hz),7.10(1H,t,J=8.8Hz),7.21-7.26(5H,m),7.84(1H,d,J=11.6Hz),7.91(1H,d,J=4.8Hz),8.68(1H,s),10.95(1H,s). * No NH peak was observed.

[0366] Example 2 This example describes the synthesis of N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-oxoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 2.

[0367] [ka]

[0368] A mixture of N-(4-(2-amino-3-(3-oxo-3-(piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 1, 30 mg, 0.05 mmol), 1-bromo-2-methoxyethane (5.37 μL, 0.06 mmol), potassium iodide (7.90 mg, 0.05 mmol), and KCO (6.59 mg, 0.09 mmol) in CHCN (1.0 mL) was heated at 90° C. for 18 hours. After cooling to room temperature, the reaction mixture was washed with saturated NaHCO (aq) and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=99 / 1) to give N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-oxoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (28 mg, 85%) as a yellow solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.51(6H,d,J=6.4Hz),2.50(4H,brs),2.59(2H,t, J=5.2Hz),3.34(3H,s),3.50(2H,t,J=5.2Hz),3.71(2H,brs),3.86(2H,brs),4.94- 5.01(1H,m),5.28(2H,brs),5.97(1H,d,J=6.0Hz),7.11(1H,t,J=8.4Hz),7.22-7.2 6(5H,m),7.84(1H,d,J=10.0Hz),7.90(1H,d,J=5.6Hz),8.68(1H,s),10.94(1H,s).

[0369] Example 3 This example describes the synthesis of (E)-N-(4-(2-amino-3-(3-oxo-3-(piperazin-1-yl)prop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 3.

[0370] [ka]

[0371] Step A: (E)-tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)acryloyl)piperazine-1-carboxylate

[0372] [ka]

[0373] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 200 mg, 0.32 mmol), tert-butyl 4-acryloylpiperazine-1-carboxylate (Intermediate 5, 116 mg, 0.48 mmol), PPh (3.62 mg, 0.02 mmol), TEA (90 μL, 0.70 mmol), and Pd(OAc) (3.62 mg, 0.02 mmol) in DMF (3.0 mL) was stirred at 90° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NH Cl solution (aqueous). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=9 / 1) to give tert-butyl (E)-4-(3-(2-amino-4-(2-fluoro-4-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)pyridin-3-yl)acryloyl)piperazine-1-carboxylate (140 mg, 59%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.47(9H,s),1.50(6H,d,J=6.4Hz),3.45(4H,d,J=4.4Hz),3.55(2H,s),3.70(2H,s),4.97-5.01(1H,m),6.04(1H, d,J=5.6Hz),7.07(1H,t,J=8.00Hz),7.15(2H,d,J=6.8Hz),7.18-7.27(5H ,m),7.71(1H,d,J=15.6Hz),7.82-7.85(2H,m),8.68(1H,s),10.9(1H,s). * No NH peak was observed.

[0374] Step B: (E)—N-(4-(2-amino-3-(3-oxo-3-(piperazin-1-yl)prop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0375] [ka]

[0376] To a solution of tert-butyl (E)-4-(3-(2-amino-4-(2-fluoro-4-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)acryloyl)piperazine-1-carboxylate (140 mg, 0.19 mmol) in DCM (2.2 ml) was added TFA (0.15 mL, 1.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (DCM / EtOAc=10 / 1) to give (E)-N-(4-(2-amino-3-(3-oxo-3-(piperazin-1)-yl)prop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (104 mg, 87%) as a yellow solid. 1H-NMR(CDCl3,Varian,400MHz):):δ1.50(6H,d,J=6.4Hz),2.89(4H,brs),3.55(2H,brs),3.71(2H,brs),4.96-5.01(1H,m),6.04(1H,d,J=6. 0Hz),7.07(1H,t,J=8.8Hz),7.17(2H,d,J=16.0Hz),7.25-7.26(6H,m),7.70(1H,d,J=15.6Hz),7.82-7.86(2H,m),8.68(1H,s),11.3(1H,s). * No NH peak was observed.

[0377] Example 4 This example describes the synthesis of (E)-N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-oxoprop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 4.

[0378] [ka]

[0379] A solution of (E)-N-(4-(2-amino-3-(3-oxo-3-(piperazin-1-yl)prop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 3, 90 mg, 0.14 mmol), 1-bromo-2-methoxyethane (14 μL, 0.14 mmol), potassium iodide (24 mg, 0.14 mmol), and KCO (20 mg, 0.14 mmol) in CHCN (2 mL) was heated to 90° C. for 18 hours. After cooling to room temperature, the reaction mixture was washed with saturated NaHCO (aq) and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=97 / 3) to give N-(4-(2-amino-3-(3-(4-(2-methoxyethyl))piperazin-1-yl)-3-oxoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (52 mg, 53%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.50(6H,d,J=6.8Hz),2.52(4H,brs),2.60(2H,t, J=5.6Hz),3.36(3H,s),3.51(2H,t,J=5.6Hz),3.62(2H,brs),3.78(2H,brs),4.96-4 .99(1H,m),6.03(1H,d,J=5.2Hz),7.07(1H,t,J=8.8Hz),7.17(2H,d,J=15.6Hz),7.2 5-7.26(5H,m),7.70(1H,d,J=15.6Hz),7.82-7.85(2H,m),8.68(1H,s),10.9(1H,s). * No NH peak was observed.

[0380] Example 5 This example describes the synthesis of N-(4-(2-amino-3-cyanopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 5.

[0381] [ka]

[0382] To a solution of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 200 mg, 0.32 mmol) in DMF (4.0 mL) was added dicyanozinc (76.0 mg, 0.65 mmol) and Pd(PPh3)4 (37.3 mg, 0.03 mmol). The reaction mixture was sealed and subjected to microwave irradiation at 90 °C for 8 h. The mixture was then cooled to 50°C for 1 hour. The resulting ... TM The mixture was filtered through a pad (Sigma-Aldrich, St. Louis, MO), and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=10 / 1). The product was purified by preparative LC to give N-(4-(2-amino-3-cyanopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (50.0 mg, 30%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.50(6H,d,J=6.4Hz),4.94-5.00(1H,m),5.28(2H,s),5.96(1H,d,J=6.0Hz),7.14( 1H,t,J=8.8Hz),7.24-7.26(4H,m),7.86(1H,dd,J=2.4Hz,12.0Hz),8.01(1H,d,J=6.0Hz),8.68(1H,s),10.9(1H,s). *No NH peak was observed.

[0383] Example 6 This example describes the synthesis of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 6.

[0384] [ka]

[0385] Step A: 3,4-Dichloropyridin-2-amine

[0386] [ka]

[0387] Hydrogen peroxide (1.49 mL, 15.6 mmol) was added to a solution of 4-chloropyridin-2-amine (2.00 g, 15.6 mmol) in concentrated HCl (11 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, basified to pH 10 by addition of Na2CO3, and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane / EtOAc = 2 / 1) to give 3,4-dichloropyridin-2-amine (594 mg, 23%) as a yellow solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ5.24 (2H, s), 6.75 (1H, d, J = 5.6Hz), 7.85 (1H, d, J = 5.2Hz).

[0388] Step B: 3-chloro-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine

[0389] [ka]

[0390] A solution of 3,4-dichloropyridin-2-amine (200 mg, 1.23 mmol) and 2-fluoro-4-nitrophenol (771 mg, 4.91 mmol) in NMP (3.0 mL) was stirred at 120 °C for 24 hours in a sealed tube. After cooling at room temperature, the reaction mixture was dissolved in EtOAc and washed with water. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (hexane / EtOAc = 1 / 1) to give 3-chloro-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (58 mg, 17%) as a yellow solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ5.19 (2H, s), 5.31 (1H, s), 6.23 (1H, d, J = 5.2 Hz), 7.19 (1 H, t, J = 8.4 Hz), 7.92 (1 H, d, J = 5.6 Hz), 8.11 (1 H, dd, J = 9.2, 20.0 Hz).

[0391] Step C: 4-(4-amino-2-fluorophenoxy)-3-chloropyridin-2-amine

[0392] [ka]

[0393] To a solution of 3-chloro-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (58.0 mg, 0.20 mmol) in EtOH (2.0 mL) was added tin(II) chloride dihydrate (185 mg, 0.82 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 1 hour. After cooling at room temperature, the solvent was removed in vacuo. The residue was dissolved in EtOAc, neutralized to pH 9 with 2N NaOH, and purified by CELITE. TMThe mixture was filtered through a pad (Sigma-Aldrich, St. Louis, MO) and the filtrate was extracted with EtOAc, dried over NaSO, filtered, and concentrated in vacuo to give 4-(4-amino-2-fluorophenoxy)-3-chloropyridin-2-amine (26.0 mg, 50%) as a brown solid, which was used for the next step without further purification. 1 H-NMR(CDCl3,Varian,400MHz):δ4.95(2H,s),6.01(1H,d,J=6.00Hz),6.44(1H,d,J =8.8Hz),6.50(1H,dd,J=2.4,11.8Hz),6.95(1H,t,J=8.8Hz),7.77(1H,d,J=6.0Hz). * No NH2 peak was observed.

[0394] Step D: N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0395] [ka]

[0396] A solution of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10, 40.0 mg, 0.14 mmol) in thionyl chloride (3.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the corresponding acyl chloride, which was used in the next reaction without further purification.

[0397] The acyl chloride obtained above was redissolved in DCM (2.0 mL), and 4-(4-amino-2-fluorophenoxy)-3-chloropyridin-2-amine (20.0 mg, 0.08 mmol) and TEA (22.0 μL, 0.16 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with water and extracted with DCM. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=10 / 1) to give N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (18 mg, 42%) as a pale yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.50(6H,d,J=6.4Hz),4.91-4.99(1H,m),6.03(1H,d,J=5.2Hz),7.11(2H ,t,J=8.4Hz),7.20-7.26(5H,m),7.79(1H,brs),7.84(1H,dd,J=2.0Hz,12.4Hz),8.68(1H,s),10.9(1H,s). * No NH peak was observed.

[0398] Example 7 This example describes the synthesis of N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluoropehynl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 7.

[0399] [ka]

[0400] Step A: 4-(2-fluoro-4-nitrophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

[0401] [ka]

[0402] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Step D of Intermediate 11, 0.20 g, 0.53 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.17 g, 0.80 mmol), KCO (0.22 g, 1.60 mmol), and Pd(PPh) (62 mg, 0.05 mmol) in 1,4-dioxane / HO (v / v = 2:1, 6.0 mL) was refluxed at 90 °C for 18 hours under an argon atmosphere. The mixture was poured into saturated NaHCO (aq) and then extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (DCM / MeOH=9 / 1) to give 4-(2-fluoro-4-nitrophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.14 g, 80%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ3.91(3H,s),4.90(2H,s),6.22(1H,d,J=5.6Hz),7.0 5(1H,t,J=8.6Hz),7.56(1H,s),7.64(1H,s),7.93(1H,d,J=5.6Hz),7.95-8.03(2H,m).

[0403] Step B: 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

[0404] [ka]

[0405] To a solution of 4-(2-fluoro-4-nitrophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.14 g, 0.42 mmol) in EtOH (5.0 mL) was added tin(II) chloride dihydrate (0.38 g, 1.70 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 1 h. After cooling at room temperature, the solvent was removed in vacuo and EtOAC was poured into the residue. The mixture was neutralized to pH 9.0 with saturated NaHCO3 (aq.) and 2N NaOH (aq.) and the resulting solution was purified by CELITE®. TM The mixture was filtered through a pad (Sigma-Aldrich, St. Louis, MO). The filtrate was extracted with EtOAc, and the combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.11 g, 86%) as a yellow form, which was used for the next step without further purification. 1 H-NMR(CDCl3,Varian,400MHz):δ3.96(3H,s),4.73(2H,brs),6.05(1H,d,J=6.0Hz),6.04-6.42( 1H,m),6.46-6.50(1H,m),6.87(1H,t,J=8.4Hz),7.66(1H,s),7.73(1H,s),7.80(1H,d,J=6.4Hz). * No NH2 peak was observed.

[0406] Step C: N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluoropehynl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0407] [ka]

[0408] A mixture of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10, 0.10 g, 0.36 mmol), HATU (0.15 g, 0.40 mmol), and DIPEA (0.16 mL, 0.91 mmol) in DMF (3.0 mL) was stirred at room temperature for 30 minutes. 4-(4-amino-2-fluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.11 g, 0.36 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluoropehynl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (0.14 g, 66%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.49(6H,d,J=6.8Hz),3.96(3H,s),4.93-5.00(1H,m),6.07(1H,d,J=5.6Hz),7.02( 1H,t,J=8.4Hz),7.18(1Hd,J=8.8Hz),7..24-7.25(4H,m),7.64(1H,s),7.75-7.84(3H,m),8.67(1H,s),10.87(1H,s). * No NH2 peak was observed.

[0409] Example 8 This example describes the synthesis of N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 8.

[0410] [ka]

[0411] Step A: 4-(2-fluoro-4-nitrophenoxy)-3-(prop-1-en-2-yl)pyridin-2-amine

[0412] [ka]

[0413] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Step D of Intermediate 11, 0.20 g, 0.53 mmol), potassium isopropenyltrifluoroborate (0.12 g, 0.80 mmol), NaCO (0.40 g, 3.73 mmol), and PdCl(dppf) (dppf: 1,1'-bis(diphenylphosphino)ferrocene) (44 mg, 0.05 mmol) in THF / HO (v / v = 1:1, 6.0 mL) was refluxed at 60 °C for 16 h under an argon atmosphere. The mixture was poured into saturated NaHCO (aq) and then extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane / EtOAc=1 / 4) to give 4-(2-fluoro-4-nitrophenoxy)-3-(prop-1-en-2-yl)pyridin-2-amine (0.15 g, 71%) as a yellow oil. 1 H-NMR(CDCl3,Varian,400MHz):δ2.05(3H,s),4.80(2H,s),5.08(1H,s),5.38(1H,s),6.16(1H, d,J=5.2Hz),7.12(1H,t,J=8.8Hz),7.91(1H,d,J=6.0Hz),8.01-8.05(1H,m),8.07-8.10(1H,m).

[0414] Step B: 4-(4-amino-2-fluorophenoxy)-3-isopropylpyridin-2-amine

[0415] [ka]

[0416] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-(prop-1-en-2-yl)pyridin-2-amine (110 mg, 0.38 mmol), platinum(IV) oxide (25 mg, 0.11 mmol), and 10% palladium on carbon (40 mg, 0.038 mmol) in EtOH / MeOH (v / v=1:2, 8.0 mL) was stirred under an H atmosphere at room temperature for 2 hours. The mixture was then purified by CELITE. TM Filtration through a pad (Sigma-Aldrich, St. Louis, MO), washing the filter cake with MeOH, and concentrating the filtrate in vacuo gave 4-(4-amino-2-fluorophenoxy)-3-isopropylpyridin-2-amine (63 mg, 63%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.38(6H,d,J=4.0Hz),3.18-3.30(1H,m),3.78(2H,s),4.51(2H,s),5.97(1H,d,J= 5.2Hz), 6.40(1H,dd,J=2.4Hz,8.4Hz),6.47(1H,dd,J=2.4Hz,11.8Hz),6.86(1H,t,J=8.8Hz),7.69(1H,d,J=6.0Hz).

[0417] Step C: N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0418] [ka]

[0419] A mixture of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10, 70 mg, 0.24 mmol), HATU (0.10 g, 0.26 mmol), and DIPEA (0.10 mL, 0.60 mmol) in DMF (2.0 mL) was stirred at room temperature for 30 minutes. 4-(4-amino-2-fluorophenoxy)-3-isopropylpyridin-2-amine (63 mg, 0.36 mmol) was added to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (47 mg, 36%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.40(6H,d,J=7.2Hz),1.50(6H,d,J=6.8Hz),4.47-4.52(1H,m),4.93-5.00(1H,m),6.00(1H,d,J=5.6Hz),7.03 (1H,t,J=8.4Hz),7.20(1H,d,J=8.0Hz),7.25(5H,d,J=6.0Hz),7.75(1H,d,J=6.0Hz),7.79(1H,dd,J=2.4Hz,12.6Hz),8.68(1H,s),10.87(1H,s). * No NH peak was observed.

[0420] Example 9 This example describes the synthesis of N-(4-(2-amino-3-(pyridin-2-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 9.

[0421] [ka]

[0422] Step A: 4-(2-fluoro-4-nitrophenoxy)-3-(pyridin-2-ylethynyl)pyridin-2-amine

[0423] [ka]

[0424] To a degassed solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Step D of Intermediate 11, 0.20 g, 0.53 mmol), 2-ethynylpyridine (0.10 mL, 1.06 mmol), CuI (20 mg, 0.10 mmol), and TEA (0.70 mL, 5.33 mmol) in THF (2.0 mL) was added Pd(PPh3)4 (20 mg, 0.1 mmol) under an argon atmosphere and stirred at 90 °C for 18 h. After cooling at room temperature, the mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (DCM / MeOH=9 / 1) to give 4-(2-fluoro-4-nitrophenoxy)-3-(pyridin-2-ylethynyl)pyridin-2-amine (0.12 g, 64%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ5.46(2H,s),6.16(1H,d,J=5.2Hz),7.24-7.27(2H,m),7.39(1 H,d,J=7.6H),7.65-7.69(1H,m),7.99(1H,d,J=5.2Hz),8.07-8.13(2H,m),8.59(1H,d,J=5.2H).

[0425] Step B: 4-(4-amino-2-fluorophenoxy)-3-(pyridin-2-ylethynyl)-pyridin-2-amine

[0426] [ka]

[0427] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-(pyridin-2-ylethynyl)pyridin-2-amine (0.12 g, 0.34 mmol), zinc (0.22 g, 3.43 mmol), and ammonium chloride (0.18 g, 3.43 mmol) in MeOH (2.0 mL) was stirred at 60° C. for 18 hours. The reaction mixture was filtered, and the residue was partitioned between EtOAc and saturated NaHCO (aqueous). The aqueous solution was extracted with EtOAc. The combined layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=95 / 5) to afford 4-(4-amino-2-fluorophenoxy)-3-(pyridin-2-ylethynyl)-pyridin-2-amine (23 mg, 20%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ5.42(2H,s),5.97(1H,dd,J=1.2Hz,6.0Hz),6.42-6.52(2H,m),6.97(1H,t,J=8. 4Hz), 7.22-7.26(1H,m),7.55(1H,d,J=8.0Hz),7.65-7.69(1H,m),7.84(1H,d,J=6.0.Hz),8.60(1H,d,J=5.2Hz). * No NH2 peak was observed.

[0428] Step C: N-(4-(2-amino-3-(pyridin-2-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0429] [ka]

[0430] A mixture of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10, 18 mg, 0.06 mmol), HATU (0.26 g, 0.07 mmol), and DIPEA (0.3 mL, 0.15 mmol) in DMF (1.0 mL) was stirred at room temperature for 30 minutes. 4-(4-amino-2-fluorophenoxy)-3-(pyridin-2-ylethynyl)-pyridin-2-amine (20 mg, 0.06 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(pyridin-2-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (16 mg, 43%) as a white solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ1.49(6H,d,J=6.8Hz),4.93-5.01(1H,m),5.99(1H,d,J=5.6Hz),7.12-7.18(2H,m),7.21- 7.24(7H,m),7.52(1H,d,J=7.6Hz),7.64-7.68(1H,m),7.81-7.88(2H,m),8.60(1H,d,J=4.4Hz),8.68(1H,s),10.9(1H,s).

[0431] Example 10 This example describes the synthesis of N-(4-(2-amino-3-(4-phenoxyphenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 10.

[0432] [ka]

[0433] Step A: 4-(2-fluoro-4-nitrophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine

[0434] [ka]

[0435] To a solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Step D of Intermediate 11, 0.30 g, 0.80 mmol) in dioxane / HO (v / v=10 / 1, 1.0 mL) was added 4-phenoxyphenylboronic acid (0.25 g, 1.20 mmol), Pd(OAc) (8.9 mg, 0.04 mmol), SPHOS (32 mg, 0.08 mmol), and KCO (0.33 g, 2.40 mmol) at room temperature under N. The reaction mixture was subjected to microwave irradiation at 90 °C for 20 min. After cooling at room temperature, NaSO was added to the mixture, which was subsequently purified by CELITE. TM The residue was filtered through a pad (Sigma-Aldrich, St. Louis, MO) and concentrated in vacuo. The residue was purified by MPLC (EtOAc / Hex=1 / 4 to MeOH) to give 4-(2-fluoro-4-nitrophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine (0.29 g, 88%) as a yellow solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ4.82 (2H, s), 6.27 (1H, d, J=6.0Hz), 6.98-7.09 (4H, m), 7.11-7.16 (2H, m), 7.29-7.37 (4H, m), 7.88-8.05 (3H, m).

[0436] Step B: 4-(4-amino-2-fluorophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine

[0437] [ka]

[0438] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine (0.29 g, 0.69 mmol), zinc (0.45 g, 6.95 mmol), and ammonium chloride (0.37 g, 6.95 mmol) in THF / MeOH (v / v=1 / 1, 8.0 mL) was stirred at 60° C. for 18 hours. The reaction mixture was filtered, and the residue was partitioned between EtOAc and saturated NaHCO (aqueous). The aqueous solution was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=95 / 5) to give 4-(4-amino-2-fluorophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine (0.26 g, 97%) as a yellow solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ6.97-7.04(6H,m), 7.08-7.14(2H,m), 7.31-7.37(6H,m). * No NH2 peak was observed.

[0439] Step C: N-(4-(2-amino-3-(4-phenoxyphenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0440] [ka]

[0441] A mixture of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10, 0.26 g, 0.67 mmol), HATU (0.28 g, 0.76 mmol), and DIPEA (0.30 mL, 1.67 mmol) in DMF (5.0 mL) was stirred at room temperature for 30 minutes. 4-(4-amino-2-fluorophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine (0.26 g, 0.67 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(4-phenoxyphenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (0.25 g, 56%) as a white solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.50(6H,d,J=6.4Hz),4.93-5.0(1H,m),6.26(1H,d,J=6.8Hz),7.04-7.14(5 H,m),7.20-7.26(8H,m),7.35-7.41(4H,m),7.72(1H,d,J=6.8Hz),7.87-7.87(1H,m),8.67(1H,s),10.99(1H,s).

[0442] Example 11 This example describes the synthesis of N-(4-(2-amino-3-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See FIG. 11.

[0443] [ka]

[0444] Step A: 3-(3,5-dimethylisoxazol-4-yl)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine

[0445] [ka]

[0446] To a solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Step D, Intermediate 11, 0.20 g, 0.53 mmol) in dioxane / HO (v / v=2 / 1, 6.0 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.17 g, 0.80 mmol) and KCO (0.22 g, 1.60 mmol). The mixture was degassed with argon, and Pd(PPh) (61 mg, 0.05 mmol) was added. The reaction mixture was stirred at 90 °C for 20 hours. After cooling to room temperature, the mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane / EtOAc=1 / 4) to give 3-(3,5-dimethylisoxazol-4-yl)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (0.13 g, 74%) as a yellow solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ2.19(3H,s),2.32(3H,s),4.70(2H,s),6.18(1H,d,J=4.4Hz),7.14-7.16(1H,m),7.18-7.33(2H,m),8.05(1H,brs).

[0447] Step B: 4-(4-amino-2-fluorophenoxy)-3-(3,5-dimethylisoxazol-4-yl)pyridin-2-amine

[0448] [ka]

[0449] To a solution of 3-(3,5-dimethylisoxazol-4-yl)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (0.13 g, 0.39 mmol) in EtOH (4.0 mL) was added tin(II) chloride dihydrate (0.09 g, 0.39 mmol). The reaction mixture was stirred at 80° C. for 2 hours. After cooling at room temperature, the solvent was concentrated in vacuo and dissolved in EtOAc. The organic layer was washed with water, dried over Na SO , filtered, and concentrated in vacuo to give 4-(4-amino-2-fluorophenoxy)-3-(3,5-dimethylisoxazol-4-yl)pyridin-2-amine (90 mg, 72%) as a brown solid, which was used for the next step without further purification. 1 H-NMR(CDCl3,Varian,400MHz):δ2.24(3H,s),2.36(3H,s),4.57(2H,s),5.94 (1H,d,J=8.4Hz),6.34-6.41(2H,m),6.80-6.84(1H,m),7.96(1H,d,J=4.8Hz). * No NH2 peak was observed.

[0450] Step C: N-(4-(2-amino-3-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0451] [ka]

[0452] A mixture of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10, 84 mg, 0.28 mmol), HATU (120 mg, 0.31 mmol), and DIPEA (125 μL, 0.71 mmol) in DMF (3.0 mL) was stirred at room temperature for 1 hour. 4-(4-amino-2-fluorophenoxy)-3-(3,5-dimethylisoxazol-4-yl)pyridin-2-amine (90 mg, 0.28 mmol) was added to the reaction mixture and stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (52 mg, 30%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.49(6H,d,J=6.8Hz),2.22(3H,s),2.57(3H,s),4.45(2H,s),4.96-4.98(1H,m),6.05(1H,d,J=6.4Hz),7.0 0(1H,t,J=6.4Hz),7.20(1H,d,J=9.6Hz),7.24-7.26(4H,m),7.79(1H,dd,J=2.4Hz,12.0Hz),7.94(1H,d,J=5.6Hz),8.67(1H,s),10.8(s,1H).

[0453] Example 12 This example describes the synthesis of N-(4-(2-amino-3-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 12.

[0454] [ka]

[0455] Step A: 4-(2-fluoro-4-nitrophenoxy)-3-(1-propyl-1H-pyrazol-4-yl)pyridin-2-amine

[0456] [ka]

[0457] To a degassed solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Step D of Intermediate 11, 200 mg, 0.533 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dixaborolan-yl)-1H-pyrazole (189 mg, 0.800 mmol) in 1,4-dioxane (4.0 mL) was added a degassed solution of KCO (221 mg, 1.60 mmol) in HO (2.0 mL) and Pd(PPh) (61 mg, 0.05 mmol). The reaction mixture was stirred at 90 °C for 18 h. After cooling at room temperature, saturated NaHCO (aq) was added to the mixture and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (DCM / MeOH=9 / 1) to give 4-(2-fluoro-4-nitrophenoxy)-3-(1-propyl-1H-pyrazol-4-yl)pyridin-2-amine (156 mg, 82%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ0.86(3H,t,J=7.6Hz),1.82-1.91(2H,m),4.08(2H,t,J=7.2Hz),4. 84(2H,s),6.30(1H,d,J=5.2Hz),7.02(1H,t,J=8.0Hz),7.58(1H,s),7.66(1H,s),7.96-8.04(3H,m).

[0458] Step B: 4-(4-amino-2-fluorophenoxy)-3-(1-propyl-1H-pyrazol-4-yl)pyridin-2-amine

[0459] [ka]

[0460] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-(1-propyl-1H-pyrazol-4-yl)pyridin-2-amine (156 mg, 0.43 mmol), zinc (285 mg, 4.37 mmol), and ammonium chloride (234 mg, 4.37 mmol) in THF / MeOH (v / v=1 / 1, 4.0 mL) was stirred at 60° C. for 18 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was partitioned between EtOAc and saturated NaHCO (aq). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc / MeOH=95 / 5) to give 4-(4-amino-2-fluorophenoxy)-3-(1-propyl-1H-pyrazol-4-yl)pyridin-2-amine (140 mg, 98%) as a yellow solid. 1 H-NMR(CD3OD,Varian,400MHz):δ0.93(3H,t,J=7.6Hz),1.88-1.97(2H,m),4.17(2H,t,J=7.2Hz),6.08(1H,d,J=6.4Hz),6. 49-6.55(2H,m),6.85-6.89(1H,m),7.54-7.57(1H,m),7.61-7.68(1H,m),7.70(1H,s),7.80(1H,d,J=6.0Hz),7.87(1H,s). * No NH2 peak was observed.

[0461] Step C: N-(4-(2-amino-3-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0462] [ka]

[0463] A mixture of 4-(4-amino-2-fluorophenoxy)-3-(1-propyl-1H-pyrazol-4-yl)pyridin-2-amine (65 mg, 0.20 mmol), 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10, 58 mg, 0.20 mmol), HATU (83 mg, 0.22 mmol), and DIPEA (0.09 mL, 0.50 mmol) in DMF (2.0 mL) was stirred at room temperature for 18 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg, 21%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ0.94(3H,t,J=13.2Hz),1.50(6H,d,J=6.4Hz),1.88-1.97(2H,m),4.13(2H,t,J=7.2Hz),4.93-5.0(1H,m),6. 11(1H,d,J=6.0Hz),7.02(1H,t,J=8.4Hz),7.18(1H,d,J=8.4Hz),7.24- 7.26(6H,m),7.67(1H,s),7.76-7.82(3H,m),8.67(1H,s),10.8(1H,s).

[0464] Example 13 This example describes the synthesis of N-(4-(2-amino-3-((1-propyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 13.

[0465] [ka]

[0466] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 290 mg, 0.47 mmol), 4-ethynyl-1-propyl-1H-pyrazole (Intermediate 9, 94 mg, 0.70 mmol), Pd(PPh) (54 mg, 0.05 mmol), copper(I) iodide (18 mg, 0.09 mmol), and TEA (0.26 mL, 1.87 mmol) in DMF (3.0 mL) was purged with N. The reaction mixture was stirred at 90 °C overnight. After cooling to room temperature, EtOAc and saturated NH Cl solution (aqueous) were added to the mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative LC to give N-(4-(2-amino-3-((1-propyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (35 mg, 12%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ0.91(3H,t,J=7.2Hz),1.49(6H,d,J=7.2Hz), 1.87(2H,t,J=7.2Hz),4.06(2H,t,J=6.8Hz),4.93-5.00(1H,m),5.20(2H,s),5. 99(1H,d,J=5.6Hz),7.08-7.15(1H,m),7.21(1H,d,J=8.4Hz),7.25-7.27(2H,m) ,7.53-7.56(3H,m),7.59(1H,s),7.79-7.84(2H,m),8.06(1H,s),10.91(1H,s).

[0467] Example 14 This example describes the synthesis of N-(4-(2-amino-3-(3-morpholino-3-oxoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 14.

[0468] [ka]

[0469] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 100 mg, 0.16 mmol), 1-morpholinoprop-2-yn-1-one (Intermediate 1, 22 mg, 0.16 mmol), Pd(PPh) (19 mg, 0.02 mmol), copper(I) iodide (6 mg, 0.03 mmol), and TEA (0.09 mL, 0.64 mmol) in DMF (1.0 mL) was purged with N. The reaction mixture was stirred at 90 °C for 5 h. After cooling at room temperature, EtOAc and saturated NH Cl solution (aqueous) were added to the mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (hexane / EtOAc = 1 / 9 to EtOAc) to give N-(4-(2-amino-3-(3-morpholino-3-oxoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10 mg, 10%) as a beige solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.50(6H,d,J=6.4Hz),1.63(2H,brs),3.67-3.68(6H,m),4.94-5.01(1H,m),5.25(2H,s), 5.98(1H,d,J=6.0Hz),7.21-7.26(4H,m),7.85(1H,dd,J=2.0Hz,12.2Hz),7.91(1H,d,J=5.6Hz),8.68(1H,s),10.9(1H,s). * No NH2 peak was observed.

[0470] Example 15 This example describes the synthesis of N-(4-(2-amino-3-(piperidin-4-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 15.

[0471] [ka]

[0472] Step A: tert-butyl 4-((2-amino-4-(2-fluoro-4-(3-(4-fluorophynl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)ethynyl)piperidine-1-carboxylate

[0473] [ka]

[0474] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 200 mg, 0.32 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (100 mg, 0.48 mmol), Pd(PPh) (37 mg, 0.03 mmol), copper(I) iodide (12 mg, 0.06 mmol), and TEA (0.18 mL, 1.3 mmol) in DMF (2 mL) was purged with N. The reaction mixture was stirred at 90 °C for 5 h. After cooling at room temperature, EtOAc and saturated NH Cl solution (aqueous) were added to the mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / Hex=9 / 1 to EtOAc) to give tert-butyl 4-((2-amino-4-(2-fluoro-4-(3-(4-fluorophynl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (150 mg, 66%) as a gray solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.45(9H,s),1.50(6H,d,J=6.8Hz),1.65-1. 72(3H,m).1.85-1.89(2H,m),3.20-3.27(2H,m),3.71-3.74(2H,m),4.95-4.9 8(1H,m),5.01(2H,s),5.99(1H,d,J=5.6Hz),7.08(1H,t,J=8.8Hz),7.21(1H, d,J=8.8Hz),7.24-7.26(4H,m),7.80-7.83(2H,m),8.68(1H,s),10.8(1H,s).

[0475] Step B: N-(4-(2-amino-3-(piperidin-4-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0476] [ka]

[0477] To a solution of tert-butyl 4-((2-amino-4-(2-fluoro-4-(3-(4-fluorophynl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)ethynyl)piperidine-1-carboxylate (150 mg, 0.21 mmol) in DCM (5.0 ml) was added TFA (0.16 mL, 2.14 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=95 / 5) to give N-(4-(2-amino-3-(piperidin-4-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (74 mg, 57%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.50(6H,d,J=6.8Hz),1.90-1.92(2H,m),2. 67-2.73(2H,m),2.81-2.83(1H,m),3.04-3.10(2H,m),4.74(4H,s),4.93-5.0 0(1H,m),5.03(1H,s),6.00(1H,d,J=6.0Hz),7.08(1H,t,J=8.8Hz),7.20(1H, d,J=8.8Hz),7.24-7.26(4H,m),7.79-7.82(1H,m),8.68(1H,s),10.8(1H,s).* No NH peak was observed.

[0478] Example 16 This example describes the synthesis of N-(4-(2-amino-3-((1-(2-methoxyethyl)piperidin-4-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 16.

[0479] [ka]

[0480] A mixture of N-(4-(2-amino-3-(piperidin-4-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 15, 30.0 mg, 0.05 mmol), 1-bromo-2-methoxyethane (5.6 μL, 0.06 mmol), potassium iodide (8.30 mg, 0.05 mmol), and KCO (6.90 mg, 0.05 mmol) in CHCN (2 mL) was heated at 80° C. overnight in a sealed vessel. After cooling at room temperature, EtOAc and water were poured into the reaction mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=95 / 5) to give N-(4-(2-amino-3-((1-(2-methoxyethyl)piperidin-4-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (18.0 mg, 55%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.49(6H,d,J=6.8Hz),1.78-1.84(2H,m),1.95-1.99(2H ,m),2.02(1H,s),2.29(2H,brs),2.55(2H,t,J=5.6Hz),2.76(2H,brs),3.34(3H,s),3.49( 2H,t,J=5.2Hz),4.93-5.00(1H,m),5.04(2H,s),5.98(1H,d,J=6.0Hz),7.09(1H,t,J=8.8H z),7.20(1H,d,J=8.4Hz),7.24-7.26(3H,m),7.79-7.83(2H,m),8.68(1H,s),10.8(1H,s). * No NH peak was observed.

[0481] Example 17 This example describes the synthesis of N-(4-(2-amino-3-(3-piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 17.

[0482] [ka]

[0483] Step A: tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)ypridin-3-yl)prop-2-ynyl)piperazine-1-carboxylate

[0484] [ka]

[0485] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 200 mg, 0.32 mmol), tert-butyl 4-(prop-2-ynyl)piperazine-1-carboxylate (Intermediate 3, 110 mg, 0.48 mmol), Pd(PPh) (37 mg, 0.03 mmol), copper(I) iodide (12 mg, 0.06 mmol), and TEA (0.18 mL, 1.3 mmol) in DMF (2 mL) was purged with N. The reaction mixture was stirred at 90 °C for 5 h. After cooling at room temperature, EtOAc and saturated NH4Cl solution (aqueous) were added to the mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc / MeOH=95 / 5) to give tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)ypridin-3-yl)prop-2-ynyl)piperazine-1-carboxylate (92 mg, 39%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.44(9H,s),1.49(6H,d,J=6.4Hz),2.56-2.58(4H,m),3.40-3.62(4H,m),3.71(2H,s),4.95-4.98(1H,m),5 .11(2H,s),5.97(1H,d,J=6.0Hz),7.07-7.12(1H,m),7.21(1H,d,J=8. 8Hz), 7.24-7.27 (3H, m), 7.81-7.84 (2H, m), 8.68 (1H, s), 10.9 (1H, s). * No NH peak was observed.

[0486] Step B: N-(4-(2-amino-3-(3-piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0487] [ka]

[0488] To a solution of tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)ypridin-3-yl)prop-2-ynyl)piperazine-1-carboxylate (90 mg, 0.13 mmol) in DCM (5.0 ml) was added TFA (96 μL, 1.26 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=95 / 5) to give N-(4-(2-amino-3-(3-piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (37 mg, 48%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.50(6H,d,J=6.4Hz),2.58(4H,brs),2.92(3H,t,J=4.8Hz),3.59(2H,s),4.93-5.00(1H,m ),5.07(2H,s),5.99(1H,d,J=5.6Hz),7.09(1H,t,J=8.4Hz),7.19-7.26(5H,m),7.80-7.83(2H,m),8.67(1H,s),10.9(1H,s). * No NH peak was observed.

[0489] Example 18 This example describes the synthesis of N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)prop-1-ylny)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 18.

[0490] [ka]

[0491] A mixture of N-(4-(2-amino-3-(3-piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 17, 27.0 mg, 0.04 mmol), 1-bromo-2-methoxyethane (4.91 μL, 0.05 mmol), potassium iodide (7.28 mg, 0.04 mmol), and KCO (6.06 mg, 0.04 mmol) in CHCN (1 mL) was heated at 80° C. overnight in a sealed vessel. After cooling at room temperature, EtOAc and water were poured into the reaction mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=95 / 5) to give N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)prop-1-ylny)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (5.7 mg, 19%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.49-1.60(8H,m),2.63-2.74(8H,m),3.34(3H,s),3.54(2H,brs),3.60(2H,s),4.95-4.99(1H ,m),5.09(2H,s),5.96(1H,d0,J=6.0Hz),7.10(1H,t,J=8.4Hz),7.24-7.26(3H,m),7.79-7.83(2H,m),8.68(1H,s),10.9(1H,s). * No NH2 peak was observed.

[0492] Example 19 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 19.

[0493] [ka]

[0494] Step A: tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate

[0495] [ka]

[0496] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 200 mg, 0.32 mmol), tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (Intermediate 6, 122 mg, 0.48 mmol), Pd(PPh) (37 mg, 0.03 mmol), copper(I) iodide (12 mg, 0.06 mmol), and TEA (0.18 mL, 1.3 mmol) in DMF (2 mL) was purged with N. The reaction mixture was stirred at 90 °C for 16 h. After cooling at room temperature, EtOAc and saturated NH4Cl solution (aqueous) were added to the mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (EtOAc to EtOAc / MeOH) to give tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (110 mg, 46%) as an ivory solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.43(9H,s),1.47-1.59(12H,m),2.62-2.64(4H,m),3.43-3.46(4H,m),4.93-5.00(1H,m),5.42(2H,br s),6.01(1H,d,J=6.0Hz),7.07(1H,t,J=8.8Hz),7.19(1H,d,J=1.2Hz),7.21-7.27(4H,m),7.71-7.87(2H,m),8.68(1H,s),10.9(1H,s).

[0497] Step B: N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0498] [ka]

[0499] To a solution of tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (110 mg, 0.15 mmol) in DCM (5.0 ml) was added TFA (0.11 mL, 1.48 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=95 / 5) to give N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl))but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (32 mg, 33%) as a pale yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.44(6H,s),1.48(6H,d,J=6.4Hz),2.63(4H,brs),2.92(4H,brs),4.93-4.97(1H,m),5.05(2H,s), 6.04(1H,d,J=6.0Hz),7.04(1H,t,J=8.4Hz),7.18(1H,d,J=8.4Hz),7.23-7.25(3H,m),7.78-7.83(2H,m),8.67(1H,s),10.8(1H,s).* No NH2 peak was observed.

[0500] Example 20 This example describes the synthesis of N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-methylbut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 20.

[0501] [ka]

[0502] A mixture of N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 19, 27.0 mg, 0.04 mmol), 1-bromo-2-methoxyethane (4.70 μL, 0.05 mmol), potassium iodide (7.00 mg, 0.04 mmol), and KCO (5.80 mg, 0.04 mmol) in CHCN (1 mL) was heated at 80° C. in a sealed vessel overnight. After cooling at room temperature, EtOAc and water were poured into the reaction mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=95 / 5) to give N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-methylbut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10 mg, 34%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ0.84-0.86(2H,m),1.46(6H,s),1.50(6H,d,J= 6.8Hz),2.57-2.60(4H,m),2.77(4H,brs),3.33(3H,s),3.48-3.51(2H,m),4.93 -5.00(1H,m),5.06(2H,s),6.02(1H,d,J=6.0Hz),7.07(1H,t,J=8.8Hz),7.19(1 H,d,J=8.0Hz),7.20-7.24(3H,m),7.79-7.82(2H,m),8.68(1H,s),10.8(1H,s). * No NH peak was observed.

[0503] Example 21 This example describes the synthesis of N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-oxopropyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 21.

[0504] [ka]

[0505] To a solution of N-(4-(2-amino-3-(3-(4-(2-methoxyethyl)piperazin-1-yl)-3-oxoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 4, 100.0 mg, 0.15 mmol) in methanol (3.0 mL) was added 10% palladium on carbon (11 mg, 10.2 μmol) at room temperature. The reaction mixture was stirred under an H atmosphere at room temperature for 5 hours. The mixture was purified by CELITE® HCl. TMThe mixture was filtered through a pad (Sigma-Aldrich, St. Louis, MO), and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=97 / 3) to give N-(4-(2-amino-3-(3-(4-(2-methoxyethyl))piperazin-1-yl)-3-oxopropyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10 mg, 10%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.50(6H,d,J=6.8Hz),2.35(2H,t,J=4.8Hz),2.42(2H,d,J=4.8Hz) ,2.54(2H,t,J=5.2Hz),2.72(2H,t,J=6.4Hz),3.01(2H,t,J=6.4Hz),3.34(3H,s),3.45-3.51(4H,m) ,3.64(2H,t,J=4.8Hz),4.93-5.00(1H,m),5.29(2H,s),5.94(1H,d,J=5.6Hz),7.06(1H,t,J=8.4Hz) ,7.20-7.26(4H,m),7.76(1H,d,J=6.0Hz),7.82(1H,dd,J=2.0Hz,12.2Hz),8.68(1H,s),10.9(1H,s). * No NH peak was observed.

[0506] Example 22 This example describes the synthesis of N-(4-(2-amino-3-phenylpyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 22.

[0507] [ka]

[0508] Step A: 4-(2-fluoro-4-nitrophenoxy)-3-phenylpyridin-2-amine

[0509] [ka]

[0510] To a solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Step D, Intermediate 11, 0.20 g, 0.53 mmol) in 1,4-dioxane / water (v / v=2 / 1, 6.0 mL) was added 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (163 mg, 0.80 mmol) and K2CO3 (221 mg, 1.60 mmol). The reaction mixture was degassed with argon, and Pd(PPh3)4 (62 mg, 0.05 mmol) was added and stirred at 90 °C for 18 h. After cooling at room temperature, the mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (EtOAc / hexane=2 / 3) to give 4-(2-fluoro-4-nitrophenoxy)-3-phenylpyridin-2-amine (147 mg, 85%) as a pale yellow solid. 1 H-NMR (CDCl3, Varian, 400MHz): δ4.65(2H,s),6.27(1H,d,J=6.0Hz),7.08(1H,t,J=8.4Hz),7.33-7.44(5H,m),7.98(2H,d,J=9.2Hz),8.02(1H,d,J=6.0Hz).

[0511] Step B: 4-(4-amino-2-fluorophenoxy)-3-phenylpyridin-2-amine

[0512] [ka]

[0513] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-phenylpyridin-2-amine (140 mg, 0.43 mmol), zinc (280 mg, 4.30 mmol), and NH4Cl (230 mg, 4.30 mmol) in THF / MeOH (v / v=1 / 1, 5.0 mL) was stirred at 60° C. for 18 hours. The reaction mixture was filtered, and the residue was partitioned between EtOAc and saturated NaHCO3 solution (aqueous). The aqueous solution was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc / MeOH=95 / 5) to afford 4-(4-amino-2-fluorophenoxy)-3-phenylpyridin-2-amine (110 mg, 87%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ3.76(2H,s),5.86(2H,s),6.12-6.15(1H,m),6.38-6.47(2H, m),6.83(1H,t,J=9.2Hz),7.41(3H,d,J=8.4Hz),7.49(2H,d,J=7.2Hz),8.00(1H,d,J=6.4Hz).

[0514] Step C: N-(4-(2-amino-3-phenylpyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0515] [ka]

[0516] A mixture of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10, 50 mg, 0.17 mmol), HATU (71 mg, 0.19 mmol), and DIPEA (74 μL, 0.42 mmol) was stirred at room temperature for 1 hour. 4-(4-amino-2-fluorophenoxy)-3-phenylpyridin-2-amine (50.0 mg, 0.17 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=95 / 5) to give N-(4-(2-amino-3-phenylpyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 16%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.48(6H,d,J=6.8Hz),4.53(2H,s),4.92-4.99(1H,m),6.09(1H,d,J=6.0Hz),7.01(1H,t,J=8.8Hz),7.16(1 H,d,J=8.8Hz),7.23-7.26(4H,m),7.33-7.40(1H,m),7.45-7.49(4H,m),7.73-7.76(1H,m),7.89(1H,d,J=4.0Hz),8.66(1H,s),10.8(1H,s).

[0517] Example 23 This example describes the synthesis of N-(4-(2-amino-3-((1-methylpiperidin-4-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 23.

[0518] [ka]

[0519] A mixture of N-(4-(2-amino-3-(piperidin-4-ylethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 15, 20 mg, 0.03 mmol) and formaldehyde (37%, 12.4 μL, 0.17 mmol) in MeOH (2.0 mL) was stirred at room temperature for 30 minutes. NaCNBH (21 mg, 0.33 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. The mixture was quenched with saturated NaHCO solution (aqueous) and diluted with DCM. The separated aqueous layer was extracted with DCM, and the combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=20 / 1) to give N-(4-(2-amino-3-((1-methylpiperidin-4-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (7.0 mg, 34%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.50(6H,d,J=6.4Hz),1.61(2H,s),1.74(2H,m),1.88-1.96(2H,m),2.25(3H,s),2.68(3H,brs),4.93-4.98 (1H,m),5.99(1H,d,J=5.6Hz),7.08(1H,t,J=8.8Hz),7.20(1H,d,J=8.4Hz),7.24-7.26(5H,m),7.79-7.82(2H,m),8.68(1H,s),10.8(1H,s).

[0520] Example 24 This example describes the synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 24.

[0521] [ka]

[0522] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 100 mg, 0.16 mmol), 4-(prop-2-ynyl)morpholine (Intermediate 2, 30 mg, 0.24 mmol), Pd(PPh) (19 mg, 0.016 mmol), copper(I) iodide (6.2 mg, 0.03 mmol), and TEA (0.09 mL, 0.65 mmol) in DMF (1.0 mL) was purged with N. The reaction mixture was stirred at 90 °C for 16 h. After cooling to room temperature, EtOAc and saturated NH Cl solution (aqueous) were added to the mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (EtOAc to EtOAc / MeOH) to give N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (46 mg, 46%) as an ivory solid. 1 H-NMR (CDCl3, Varian, 400 MHz): δ 1H-NMR(CDCl3,Varian,400MHz):δ1.49(6H,d,J=6.8Hz),2.61-2.63(4H,m),5.39(2H,s),3.73-3.75(4H,m),4.93-5.00(1H,m ),5.11(2H,s),5.98(1H,d,J=5.6Hz),7.09(1H,t,J=8.8Hz),7.02-7.26(5H,m),7.80-7.83(2H,m),8.68(1H,s),10.9(1H,s).

[0523] Example 25 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 25.

[0524] [ka]

[0525] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 50 mg, 0.08 mmol), 4-(2-methylbut-3-yn-2-yl)morpholine (Intermediate 7, 13 mg, 0.08 mmol), Pd(PPh) (9.3 mg, 0.008 mmol), copper(I) iodide (3.1 mg, 0.016 mmol), and TEA (45 μL, 0.32 mmol) in DMF (1.0 mL) was purged with N. The reaction mixture was stirred at 90 °C for 16 h. After cooling at room temperature, EtOAc and saturated NH4Cl solution (aqueous) were added to the mixture, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (EtOA / hexane = 9 / 1) to give N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (18 mg, 35%) as a yellow solid. 1 H-NMR (CDCl3, Varian, 400 MHz): δ 1 H-NMR(CDCl3,Varian,400MHz):δ1.46(6H,s),1.50(6H,d,J=6.8Hz),2.66-2.69(4H,m),3.72-3.75(4H,m),4.96-5.00(3H,m),6. 05(1H,d,J=5.6Hz),7.07(1H,t,J=8.4Hz),7.20(1H,d,J=8.8Hz),7.25-7.26(4H,m),7.79-7.85(2H,m),8.68(1H,s),10.9(1H,s).

[0526] Example 26 This example describes the synthesis of N-(4-(2-amino-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 26.

[0527] [ka]

[0528] Step A: 4-(2-fluoro-4-nitrophenoxy)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-2-amine

[0529] [ka]

[0530] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Step D of Intermediate 11, 200 mg, 0.53 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (Intermediate 8, 110 mL, 0.80 mmol), Pd(PPh) (62 mg, 53.0 μmol), and copper(I) iodide (20.0 mg, 0.10 mmol) in DMF (2.0 mL) was purged with N. The reaction mixture was stirred at 90 °C for 2 h. After cooling at room temperature, EtOAc and saturated NH Cl (aq) were poured into the residue, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by MPLC (EtOAc / MeOH) to give 4-(2-fluoro-4-nitrophenoxy)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-2-amine (139 mg, 67%) as a yellow solid. 1H-NMR(CDCl3,Varian,400MHz):δ2.68(3H,s),2.29-2.53(8H,m),3.51(2H,s),5.28(2H,s),6.20(1H, d,J=6.0Hz),7.37(1H,t,J=8.0Hz),8.04(1H,d,J=3.6Hz),8.05-8.06(1H,m),8.10(1H,d,J=11.6Hz).

[0531] Step B: 4-(4-amino-2-fluorophenyl)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-2-amine

[0532] [ka]

[0533] A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-2-amine (130 mg, 0.36 mmol), zinc (236 mg, 3.61 mmol), and NHCl (193 mg, 3.61 mmol) in THF-MeOH (v / v=1 / 1, 6 mL) was stirred at 60° C. for 18 hours. After cooling at room temperature, the solvent was evaporated in vacuo, and the residue was dissolved with EtOAc. The organic layer was washed with saturated NaHCO (aq), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (DCM / MeOH) to give 4-(4-amino-2-fluorophenyl)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-2-amine (49.0 mg, 39%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ2.29(3H,s),2.52(4H,brs),2.70(4H,brs),3.62(2H,s),5.09(2H,s),5.9 4(1H,d,J=6.0Hz),6.41-6.44(1H,m),6.49(1H,dd,J=11.8Hz),6.94(1H,t,J=8.4Hz),7.78(1H,d,J=5.6Hz). * No NH2 peak was observed.

[0534] Step C: N-(4-(2-amino-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0535] [ka]

[0536] A mixture of 4-(4-amino-2-fluorophenoxy)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-2-amine (42 mg, 0.12 mmol), 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Intermediate 10, 35 mg, 0.12 mmol), HATU (49.4 mg, 0.13 mmol), and DIPEA (52.0 μL, 0.30 mmol) in DMF (3.0 mL) was stirred at 50° C. for 1 h. After cooling at room temperature, EtOAc and saturated NH4Cl (aqueous) were poured into the residue, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (DCM / MeOH=100 / 1) to give N-(4-(2-amino-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (32 mg, 43%) as a white solid. 1H-NMR (DMSO-d6, Varian, 400MHz): δ1.42(6H,d,J=6.4Hz),2.12(3H,s),3.32(8H,s),3.53(2H,s),4.75-4.78(1H,m),5.89(1H,d,J=6.4Hz),6 .23(2H,s),7.25(1H,t,J=8.8Hz),7.35-7.37(2H,m),7.40-7.45(3H,m ),7.78(1H,d,J=6.0Hz),7.92-7.95(1H,m),8.67(1H,s).10.98(1H,s).

[0537] Example 27 This example describes the synthesis of N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 27.

[0538] [ka]

[0539] Step A: tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate

[0540] [ka]

[0541] A solution of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 11, 250 mg, 0.40 mmol), tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (135 mg, 0.61 mmol), TEA (0.23 mL, 1.62 mmol), and copper(I) iodide (15 mg, 0.08 mmol) in DMF (2.0 mL) was degassed with argon. Pd(PPh) (47 mg, 0.04 mmol) was added to the reaction mixture and stirred at 90 °C for 5 h. After cooling at room temperature, the mixture was dissolved in EtOAc and washed with saturated NH Cl solution (aqueous). The organic layer was dried over NaSO, filtered and concentrated in vacuo. The residue was purified by MPLC (hexane / EtOAc = 1 / 9) to give tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (180 mg, 62%) as a brown solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.44(9H,s),1.50(6H,d,J=6.4Hz),1.72-1. 73(3H,m),1.81(2H,d,J=13.2Hz),2.45(2H,d,J=6.4Hz),2.69(2H,brs),4.11( 2H,s),4.93-5.00(1H,m),5.06(2H,s),5.99(1H,s),7.08(1H,t,J=8.4Hz),7. 23(1H,d,J=8.0Hz),7.44(4H,s),7.80-7.83(2H,m),8.67(1H,s),10.9(1H,s).

[0542] Step B: N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0543] [ka]

[0544] To a solution of tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (180 mg, 0.25 mmol) in DCM (5.0 ml) was added TFA (0.19 mL, 2.52 mmol) at room temperature and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with saturated NaHCO3 solution (aqueous). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (DCM / MeOH=98 / 2) to give N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (136 mg, 88%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.49(6H,d,J=6.4Hz),1.64-1.74(1H,m),1.81(3H ,d,J=13.2Hz),2.43(2H,d,J=6.8Hz),2.56-2.63(2H,m),3.08(2H,d,J=12.4Hz),4. 93-5.00(1H,m),5.05(2H,s),5.99(1H,d,J=5.6Hz),7.08(1H,t,J=8.4Hz),7.20(1H ,d,J=5.6Hz),7.25(4H,d,J=6.4Hz),7.79-7.83(2H,m),8.67(1H,s),10.89(1H,s). * No NH2 peak was observed.

[0545] Example 28 This example describes the synthesis of N-(4-(2-amino-3-(3-(1-(2-methoxyethyl)piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 28.

[0546] [ka]

[0547] A mixture of N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 27, 60 mg, 0.01 mmol), 1-bromo-2-methoxyethane (11.0 μL, 0.12 mmol), potassium iodide (13.0 mg, 0.01 mmol), and KCO (16.0 mg, 0.01 mmol) in CHCN (2.0 mL) was heated at 80° C. overnight in a sealed vessel. After cooling at room temperature, DCM and water were poured into the reaction mixture, and the separated aqueous layer was extracted with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=98 / 2) to give N-(4-(2-amino-3-(3-(1-(2-methoxyethyl)piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (24 mg, 37%) as an ivory solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.49(6H,d,J=6.8Hz),1.53-1.61(1H,m),1.86(2H,d,J=16.0Hz), 2.01(2H,t,J=14.0Hz),2.42(2H,d,J=6.8Hz),2.54(2H,t,J=6.0Hz),2.95(2H,d,J=11.6Hz),3.34( 3H,s),3.49(2H,t,J=5.6Hz),4.93-4.98(1H,m),5.01(2H,s),5.98(1H,d,J=5.6Hz),7.08(1H,t,J= 8.4Hz), 7.20(1H,d,J=7.6Hz),7.25(4H,d,J=6.8Hz),7.79-7.83(2H,m),8.67(1H,s),10.89(1H,s). * No NH2 peak was observed.

[0548] Example 29 This example describes the synthesis of N-(4-(2-amino-3-(3-(1-isopropylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxmide in one embodiment of the present invention. See Figure 29.

[0549] [ka]

[0550] A mixture of N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Example 27, 50.0 mg, 0.08 mmol), 2-iodopropane (16.0 μL, 0.16 mmol), and KCO (22.0 mg, 0.16 mmol) was stirred at 50° C. for 3 hours. After cooling at room temperature, the reaction mixture was washed with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (DCM / MeOH=97 / 3) to give N-(4-(2-amino-3-(3-(1-isopropylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxmide (17.0 mg, 32%) as a white solid. 1H-NMR (MeOD, Varian, 400MHz): δ0.91(6H,d,J=6.8Hz),1.17(2H,d,J=8.4Hz),1.41(6H,d,J=6.4 Hz),1.67(2H,d,J=12.4Hz),2.02(2H,t,J=11.2Hz),2.38(2H,d,J=6.0Hz),2.50-2.61(1H,m),2 .71(2H,d,J=10.0Hz),4.75-4.77(1H,m),5.93(1H,d,J=5.6Hz),6.14(1H,s),7.19(1H,t,J=8.4 Hz),7.33-7.41(5H,m),7.76(1H,d,J=6.0Hz),7.93(1H,d,J=12.8Hz),8.66(1H,s),10.9(1H,s). * No NH peak was observed.

[0551] Example 30 This example illustrates an enzyme assay for determining the inhibitory activity of exemplary compounds of formula (I) in one aspect of the present invention.

[0552] All kinase reactions were performed in 5 μL using tyrosine kinase buffer with 0.2 μg / μL poly(Glu4, Tyr1) substrate, 10 μM ATP, serial dilutions of inhibitors, and incubated for 60 min at room temperature. After the indicated incubation times, 5 μL ADP-GLO was added. TM Reagent (Promega, Madison, WI) was added to the reaction and the plate was incubated for 40 minutes at room temperature. 10 μL of kinase detection reagent was then added and after a 40 minute incubation period, luminescence was recorded to determine IC 50 All 384-well assay plates were prepared using GLOMAX™ from Promega (Madison, WI). TM Reads were taken using a Discover Microplate Luminometer. Both Microsoft Excel and Prism from GraphPad 7 Software (La Jolla, CA) were used to plot, analyze, and calculate biochemical values ​​for all kinase reactions.

[0553] [Table 1-1]

[0554] [Table 1-2]

[0555] Example 31 This example describes the preparation of epidermal growth factor receptor (EGFR) TKI-resistant cell lines in one embodiment of the present invention.

[0556] EGFR tyrosine kinase inhibitors (TKIs) inhibit EGFR and are used to treat non-small cell lung cancer (NSCLC) that has activating mutations in the EGFR gene. While most EGFR-mutant NSCLC respond to EGFR TKIs, the majority of these tumors eventually become resistant to drug treatment. In approximately 50% of these cases, resistance is due to the EGFR TKIs. T790M Approximately 5% are due to the occurrence of secondary mutations in c-MET, approximately 5% are due to amplification of c-MET, and approximately 20% are due to overexpression of AXL.

[0557] c-MET amplification contributes to the acquisition of resistance to EGFR TKIs because it is a redundant pathway for the activation of PI3K / AKT signaling, which promotes cancer cell survival, thus circumventing the inhibition of upstream EGFR signaling in the presence of EGFR TKIs.

[0558] AXL is a member of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, and when activated, it can increase tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interaction. Overexpression or abnormal activation of AXL has been described in many malignant tumors of epithelial and hematologic origin and is often associated with poor prognosis, increased recurrence rate, decreased disease-free survival, and poor overall survival. Furthermore, AXL expression is associated with epithelial-mesenchymal transition (EMT), a common feature of metastatic tumors that often correlates with EGFR TKI resistance. Therefore, AXL is an attractive molecular target for many solid tumors, including NSCLC.

[0559] To investigate the c-MET and AXL mechanisms of EGFR TKI resistance, resistant cells of EGFR TKI-hypersensitive EGFR exon 19 mutant NSCLC cell lines, HCC827 and PC9, were generated by exposing these cells to increasing concentrations of EGFR TKI for more than 3 months.

[0560] The human cell line HCC827 was purchased from the American Type Culture Collection (Manassas, VA), and the PC9 cell line was obtained from the RIKEN Cell Bank (Ibaraki, Japan). HCC827 / ER, HCC827 / GR, HCC827 / OR, and PC9 / ER cells, which contain a deletion in EGFR exon 19 and overexpression of c-MET and AXL, were generated from HCC827 or PC9 cells by stepwise exposure to gefitinib, erlotinib, and osimertinib. Gefitinib-resistant cells were designated HCC827 / GR. Erlotinib-resistant cells were designated PC9 / ER and HCC827 / ER. Osimertinib-resistant cells were designated HCC827 / OR.

[0561] All of these cell lines were maintained in Roswell Park Memorial Institute (RPMI) 1640 medium (GIBCO, Carlsbad, CA) containing 1 μM gefitinib, erlotinib, and osimertinib with 10% fetal bovine serum (FBS), penicillin (100 U / mL), and streptomycin (50 μg / mL) in a humidified CO2 incubator at 37°C. All cell lines were authenticated by Sanger sequencing, human phospho-RTK array kit (R&D systems), and Western blot analysis.

[0562] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0563] Example 32 This example illustrates a cell viability assay of exemplary compounds of formula (I) in one aspect of the present invention.

[0564] Cell viability assays were performed by plating 1,000 cells per well of HCC827 or PC9 resistant cells, respectively, in white, clear-bottom 384-well plates. Cells were treated with each TKI over a 10-dose range from 1 nM to 10,000 nM. Seventy-two hours after drug treatment, cell viability was measured using the CellTiter-Glo 2.0 assay (Promega, Madison, WI). EGFR TKI (gefitinib, erlotinib, and osimertinib)-resistant cell lines derived from the parental EGFR TKI-sensitive HCC827 or PC9 cell lines were established by continuous exposure of the cells to EGFR TKIs for a period of more than three months. The resistant cell lines were designated HCC827 / ER and PC9 / ER and showed 1,000-fold higher resistance to erlotinib than the parental cells (erlotinib IC ). 50, <0.01 μM in HCC827 or PC9 cells and >10 μM in HCC827 / ER or PC9 / ER cells). HCC827 / GR showed 4,000-fold higher resistance to gefitinib than parental cells (gefitinib IC 50 , <0.002 μM in HCC827 cells and 8.9 μM in HCC827 / GR cells). HCC827 / OR cells were 3,000-fold more resistant to osimertinib than parental cells (osimertinib IC 50 , <0.0003 μM in HCC827 cells and >1 μM in HCC827 / OR cells). The combination of an EGFR TKI and an inhibitor of formula (I) overcame acquired resistance to the EGFR TKI. Table 2 shows the resistance overcoming of EGFR TKI-resistant cells by representative compounds.

[0565] [Table 2-1]

[0566] [Table 2-2]

[0567] Example 33 This example describes the synthesis of N-(4-((2-amino-3-(3-methyl-3-morpholinobut-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 30.

[0568] [ka]

[0569] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 16, 50.0 mg, 0.08 mmol), 4-(2-methylbut-3-yn-2-yl)morpholine (17.0 mg, 0.11 mmol), copper(I) iodide (2.8 mg, 0.02 mmol), and TEA (41.0 μL, 0.30 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.7 mg, 7.55 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (EtOAc / MeOH=9 / 1) to give N-(4-((2-amino-3-(3-methyl-3-morpholinobuta-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (8.0 mg, 15%) as an ivory solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.46(6H,s),2.69(4H,m),3.02(3H,s),3.10(3H,s),3.74(4H,m),4.74(2H,s)5.14(2 H,brs),6.05(1H,d,J=5.6Hz),7.07(1H,t,J=8.4Hz),7.26-7.18(5H,m),7.78-7.82(2H,m),8.52(1H,s),10.79(1H,s).

[0570] Example 34 This example describes the synthesis of N-(4-((2-amino-3-(3-morpholinoprop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 31.

[0571] [ka]

[0572] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 16, 50.0 mg, 0.08 mmol), 4-(prop-2-yn-1-yl)morpholine (14.0 mg, 0.11 mmol), copper(I) iodide (2.8 mg, 0.02 mmol), and TEA (41.0 μL, 0.30 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.7 mg, 7.55 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. To the reaction mixture, 4-(prop-2-yn-1-yl)morpholine (14.0 mg, 0.11 mmol), copper(I) iodide (2.8 mg, 0.02 mmol), TEA (41.0 μL, 0.30 mmol), and Pd(PPh3)4 (8.7 mg, 7.55 μmol) were added again. After degassing with N2, the mixture was stirred at 90 °C for 3 h. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (EtOAc / MeOH=9 / 1) to give N-(4-((2-amino-3-(3-morpholinoprop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (6.0 mg, 11%) as an ivory solid. 1 H-NMR(CDCl3,Varian,400MHz):δ2.63-2.64(4H,m),3.02(3H,s),3.10(3H,s),3.60(2H,s),3.73-3.75(4H,m),4.73(2H, s),5.18(2H,brs)5.99(1H,brs),7.08(1H,t,J=8.8Hz),7.19-7.26(5H,m),7.79-7.82(2H,m),8.52(1H,s),10.8(1H,s).

[0573] Example 35 This example describes the synthesis of N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 32.

[0574] [ka]

[0575] Step A: tert-butyl 4-(4-(2-amino-4-(4-(1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate

[0576] [ka]

[0577] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 16, 100 mg, 0.15 mmol), tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (76.0 mg, 0.30 mmol), copper(I) iodide (5.75 mg, 0.03 mmol), and TEA (82.0 μL, 0.60 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (17.45 mg, 0.02 mmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (EtOAc / MeOH = 95 / 5 to EtOAc / MeOH = 9 / 1) to give tert-butyl 4-(4-(2-amino-4-(4-(1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (34 mg, 29%) as an orange solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.42(9H,s),1.46(6H,s),2.62(4H,m),3.02(3H,s),3.10(3H,s),3.44(4H,m),4.73(2H,s) ,5.03(2H,s),6.06(1H,d,J=5.6Hz),7.03(1H,t,J=8.8Hz),7.17-7.26(5H,m),7.79-7.81(2H,m),8.51(1H,s),10.79(1H,s).

[0578] Step B: N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0579] [ka]

[0580] To a solution of tert-butyl 4-(4-(2-amino-4-(4-(1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (34.0 mg, 0.04 mmol) in DCM (1 mL) was added TFA (33.0 μL, 0.43 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=9 / 1) to give N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (32.0 mg, 98%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.44(6H,s),2.62(4H,brs),2.91(4H,t,J=4.8Hz),3.02(3H,s),3.10(3H,s),4.74(2H,s),5.02(2H,s) ),6.06(1H,d,J=5.6Hz),7.04(1H,t,J=8.8Hz),7.17-7.26(5H,m),7.76-7.80(1H,m),7.83(1H,d,J=6.0Hz),8.53(1H,s),10.78(1H,s). * No NH peak was observed.

[0581] Example 36 This example describes the synthesis of N-(4-((2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 33.

[0582] [ka]

[0583] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 16, 50.0 mg, 0.07 mmol), 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (25.0 mg, 0.15 mmol), copper(I) iodide (2.88 mg, 0.02 mmol), and TEA (41.0 μL, 0.30 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.7 mg, 7.55 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (from pure EtOAc to EtOAc / MeOH=97 / 3) to give N-(4-((2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (9.7 mg, 15%) as an orange solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.45(6H,s),2.26(3H,s),2.49(4H,brs),2.73(4H,brs),3.02(3H,s),3.10(3H,s),4.73(2H, s),5.02(2H,s),6.01(1H,d,J=6.0Hz),7.06(1H,t,J=8.8Hz),7.17-7.26(5H,m),7.77-7.81(2H,m),8.51(1H,s).10.78(1H,s).

[0584] Example 37 This example describes the synthesis of N-(4-((2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 34.

[0585] [ka]

[0586] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 16, 30.0 mg, 0.04 mmol), 1-methyl-4-(prop-2-yn-1-yl)piperidine hydrochloride (15.7 mg, 0.09 mmol), copper(I) iodide (1.7 mg, 9.06 μmol), and TEA (25.0 μL, 0.18 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (5.23 mg, 4.53 μmol) was added to the reaction mixture, which was stirred at 90 °C overnight in a sealed tube. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (from pure EtOAc to EtOAc / MeOH=95 / 5) to give N-(4-((2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.5 mg, 4.5%) as an orange solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.40-1.45(2H,m),1.56(1H,m),1.84(2H,d,J=12 .8Hz),1.93-2.00(2H,m),2.27(3H,s),2.42(2H,d,J=6.4Hz),2.89(2H,d,J=11Hz) ,3.02(3H,s),3.10(3H,s),4.73(2H,s),5.06(2H,brs),5.97(1H,d,J=6Hz),7.08( 1H,t,J=8.4Hz),7.17-7.26(5H,m),7.77-7.82(2H,m),8.52(1H,s),10.80(1H,s).

[0587] Example 38 This example describes the synthesis of N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 35.

[0588] [ka]

[0589] Step A: tert-butyl 4-(3-(2-amino-4-(4-(1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-yl)piperidine-1-carboxylate

[0590] [ka]

[0591] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 16, 75.0 mg, 0.11 mmol), tert-butyl 4-(prop-2-yn-1-yl))piperidine-1-carboxylate (50.0 mg, 0.22 mmol), copper(I) iodide (4.26 mg, 0.02 mmol), and TEA (61.0 μL, 0.45 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (12.94 mg, 0.01 mmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (neat EtOAc to 97 / 3 EtOAc / MeOH) to give tert-butyl 4-(3-(2-amino-4-(4-(1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-yl)piperidine-1-carboxylate (31.0 mg, 36%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.44(9H,s),1.71(3H,m),1.81(2H,d,J=8Hz),2.45(2H,d,J=6.8Hz),2.69(2H,brs),3.02(3H,s),3.10(3H,s),4.12 (2H,brs),4.73(2H,s),5.07(2H,brs),5.98(1H,d,J=5.6Hz),7.08(1H,t,J =8.4Hz),7.18-7.26(5H,m),7.77-7.79(2H,m),8.51(1H,s),10.80(1H,s).

[0592] Step B: N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0593] [ka]

[0594] To a solution of tert-butyl 4-(3-(2-amino-4-(4-(1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-yl)piperidine-1-carboxylate (31.0 mg, 0.04 mmol)) in DCM (1 mL) was added TFA (32.0 μL, 0.41 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added TFA (32.0 μL, 0.41 mmol) again at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=9 / 1) to give N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (14.0 mg, 44%) as a white solid. 1H-NMR(CD3OD,Varian,400MHz):δ1.34-1.42(3H,m),1.75(1H,m),1.88-1.94(2H ,m),2.49(2H,d,J=6.4Hz),2.68-2.75(2H,m),2.99(3H,s),3.11(3H,s),3.11-3 .16(2H,m),4.96(2H,s),6.00(1H,d,J=6Hz),7.12-7.16(1H,m),7.23-7.30(3H, m),7.33-7.37(2H,m),7.71(1H,d,J=6.4Hz),7.89(1H,d,J=12.8Hz),8.67(1H,s) * No amide NH or NH2 peaks were observed.

[0595] Example 39 This example describes the synthesis of N-(4-((2-amino-3-(3-methyl-3-morpholinobut-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 36.

[0596] [ka]

[0597] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 18, 50.0 mg, 0.07 mmol), 4-(2-methylbut-3-yn-2-yl)morpholine (17.0 mg, 0.11 mmol), copper(I) iodide (2.8 mg, 0.01 mmol), and TEA (40.0 μL, 0.29 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.4 mg, 7.26 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / hexane=4 / 1) to give N-(4-((2-amino-3-(3-methyl-3-morpholinobuta-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10 mg, 18%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.45(6H,s),2.67(4H,m),2.71(3H,s),3.73(4H,t,J=4.8Hz),5.03(2H,brs),5.12( 2H,s),6.02(1H,d,J=6.0Hz),7.06(1H,t,J=8.4Hz),7.15-7.26(6H,m),7.79-7.83(2H,m),8.87(1H,s),10.82(1H,s).

[0598] Example 40 This example describes the synthesis of N-(4-((2-amino-3-(3-morpholinoprop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 37.

[0599] [ka]

[0600] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 18, 50.0 mg, 0.07 mmol), 4-(prop-2-yn-1-yl)morpholine (18.0 mg, 0.14 mmol), copper(I) iodide (2.8 mg, 0.02 mmol), and TEA (40.0 μL, 0.29 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.4 mg, 7.26 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (with EtOAc) to give N-(4-((2-amino-3-(3-morpholinoprop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (7.4 mg, 13%) as an ivory solid. 1H-NMR(CDCl3,Varian,400MHz):δ2.61-2.63(4H,m),2.71(3H,s),3.59(2H,s),3.73-3.75(4H,m),5.09(2H,brs),5.13 (2H,s),5.97(1H,d,J=6.0Hz),7.08(1H,t,J=8.8Hz),7.17-7.26(6H,m),7.82-7.80(2H,m),8.87(1H,s),10.84(1H,s).

[0601] Example 41 This example describes the synthesis of N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 38.

[0602] [ka]

[0603] Step A: tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate

[0604] [ka]

[0605] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 18, 70.0 mg, 0.10 mmol), tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (51.0 mg, 0.20 mmol), copper(I) iodide (3.87 mg, 0.02 mmol), and TEA (55.0 μL, 0.41 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (11.7 mg, 10.17 μmol) was added to the reaction mixture and stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=97 / 3) to give tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (36.0 mg, 44%) as a brown solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.42(6H,s),1.44-1.46(9H,m),2.62(4H,brs),2.71(3H,s),3.44-3.45(4H,m),5.0 0(2H,s),5.13(2H,brs),5.99(1H,m),7.06(1H,m),6.99-7.25(6H,m),7.79-7.82(2H,m),8.87(1H,s),10.83(1H,s).

[0606] Step B: N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0607] [ka]

[0608] To a solution of tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (36.0 mg, 0.04 mmol) in DCM (1 mL) was added TFA (35.0 μL, 0.45 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=95 / 5) to give N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (5.4 mg, 10%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.44(6H,s),2.62(4H,brs),2.70(3H,s),2.90(4H,brs),5.01(2H,brs),5.12(2 H,s),6.03(1H,d,J=6Hz),7.05(1H,t,J=8.4Hz),7.15-7.26(6H,m),7.79-7.83(2H,m),8.87(1H,s),10.83(1H,s). * No NH peak was observed.

[0609] Example 42 This example describes the synthesis of N-(4-((2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 39.

[0610] [ka]

[0611] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 18, 50.0 mg, 0.07 mmol), 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (24.0 mg, 0.14 mmol), copper(I) iodide (2.8 mg, 0.02 mmol), and TEA (40.0 μL, 0.29 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.4 mg, 7.26 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=97 / 3) to give N-(4-((2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (6.3 mg, 10%) as an ivory solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.45(6H,s),2.26(3H,s),2.50(4H,brs),2.71(4H,brs),2.71(3H,s),5.04(2H,brs),5. 12(2H,s),6.00(1H,d,J=6.4Hz),7.06(1H,t,J=8.4Hz),7.19-7.26(6H,m),7.78-7.81(2H,m),8.87(1H,s),10.82(1H,s).

[0612] Example 43 This example describes the synthesis of N-(4-((2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 40.

[0613] [ka]

[0614] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 18, 50.0 mg, 0.07 mmol), 1-methyl-4-(prop-2-yn-1-yl)piperidine hydrochloride (25.0 mg, 0.14 mmol), copper(I) iodide (2.8 mg, 0.02 mmol), and TEA (40.0 μL, 0.29 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.4 mg, 7.26 μmol) was added to the reaction mixture, which was stirred at 90 °C overnight in a sealed tube. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=97 / 3) to give N-(4-((2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (3.5 mg, 5.8%) as a yellow solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.33-1.43(2H,m),1.55(1H,m),1.84(2H,d,J=12H z),2.00(2H,t,J=17.4Hz),2.25(3H,s),2.43(2H,d,J=6.8Hz),2.71(3H,s),2.85(2H ,d,J=12Hz),5.02(2H,brs),5.12(2H,s),5.96(1H,d,J=6Hz),7.08(1H,t,J=8.8Hz), 7.17-7.20(1H,m),7.22-7.25(5H,m),7.77-7.82(2H,m),8.87(1H,s),10.84(1H,s).

[0615] Example 44 This example describes the synthesis of N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 41.

[0616] [ka]

[0617] Step A: tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-yn-1-yl)piperidine-1-carboxylate

[0618] [ka]

[0619] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 18, 77.0 mg, 0.11 mmol), tert-butyl 4-(prop-2-yn-1-yl)piperidine-1-carboxylate (50.0 mg, 0.22 mmol), copper(I) iodide (4.26 mg, 0.02 mmol), and TEA (61.0 μL, 0.45 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (12.9 mg, 0.01 mmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (none EtOAc) to give tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-yn-1-yl)piperidine-1-carboxylate (27.0 mg, 30%) as an orange solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.44(9H,s),1.74-1.83(3H,m),2.45(2H,d,J=6.8Hz),2.69(2H,brs),2.71(3H,s),4.10(2H,brs),5.13(2H,s), 5.19(2H,brs),5.96(1H,d,J=6.4Hz),7.08(1H,t,J=8.4Hz),7.14-7.25( 6H,m),7.77(1H,d,J=6Hz),7.83-7.80(1H,m),8.87(1H,s),10.85(1H,s). * No NH2 peak was observed.

[0620] Step B: N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0621] [ka]

[0622] To a solution of tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-yn-1-yl)piperidine-1-carboxylate (27.0 mg, 0.03 mmol) in DCM (1 ml) was added TFA (26.0 μL, 0.34 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=95 / 5) to give N-(4-((2-amino-3-(3-(piperidin-4-yl))prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-((2-methylthiazol-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (7.1 mg, 27%) as a yellow solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.30-1.40(3H,m),1.61(1H,m),1.88(2H,d,J =12Hz),2.45(2H,d,J=6.8Hz),2.61-2.70(2H,m),2.71(3H,s),3.19(2H,d,J=1 2Hz),5.02(2H,brs),5.13(2H,s),5.99(1H,d,J=4Hz),7.03-7.08(1H,m),7.17 -7.19(1H,m),7.22-7.24(5H,m),7.79-7.81(2H,m),8.87(1H,s),10.84(1H,s).

[0623] Example 45 This example describes the synthesis of N-(4-((2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. See Figure 42.

[0624] [ka]

[0625] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (Intermediate 20, 70.0 mg, 0.12 mmol), 1-methyl-4-(prop-2-yn-1-yl)piperidine hydrochloride (41.0 mg, 0.24 mmol), copper(I) iodide (4.5 mg, 0.02 mmol), and TEA (64.0 μL, 0.47 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (14.0 mg, 0.01 mmol) was added to the reaction mixture, which was stirred at 90 °C in a sealed tube overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=97 / 3) to give N-(4-((2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (2.4 mg, 3%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.34-1.44(3H,m),1.81(2H,m),1.88-1.97(2H,m),2.26(3H,s),2.43(2H,d,J=6.4Hz),2.83-2 .89(2H,brs),3.93(3H,s),5.01(2H,brs),5.99(1H,m),7.14-7.10(1H,m),7.25-7.28(5H,m),7.82-7.85(2H,m),10.81(1H,s).

[0626] Example 46 This example describes the synthesis of N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. See Figure 43.

[0627] [ka]

[0628] Step A: tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamido)phenoxy)pyridin-3-yl)prop-2-yn-1-yl)piperidine-1-carboxylate

[0629] [ka]

[0630] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (Intermediate 20, 75.0 mg, 0.13 mmol), tert-butyl 4-(prop-2-yn-1-yl)piperidine-1-carboxylate (56.0 mg, 0.25 mmol), copper(I) iodide (4.82 mg, 0.02 mmol), and TEA (69.0 μL, 0.51 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (15.0 mg, 0.01 mmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (none EtOAc) to give tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamido)phenoxy)pyridin-3-yl)prop-2-yn-1-yl)piperidine-1-carboxylate (17.0 mg, 19%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.43(9H,s),1.62(3H,m),1.78(2H,d,J=12Hz),2.43(2H,d,J=6Hz),2.69(2H,brs),3.92(3H,s),4.09(2H,brs),5.10(2 H,brs),6.01(1H,d,J=5.6Hz),7.08-7.12(1H,m),7.24-7.26(1H,m),7.26-7 .28(4H,m),7.80(1H,d,J=5.6Hz),7.86(1H,dd,J=12,2.8Hz),10.83(1H,s).

[0631] Step B: N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0632] [ka]

[0633] To a solution of tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamido)phenoxy)pyridin-3-yl)prop-2-yn-1-yl)piperidine-1-carboxylate (17.0 mg, 0.02 mmol) in DCM (1 mL) was added TFA (20.0 μL, 0.25 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=9 / 1) to give N-(4-((2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (5.9 mg, 38%) as a yellow solid. 1H-NMR(CD3OD,Varian,400MHz):δ1.29-1.38(3H,m),1.72(1H,m),1.84-1.91(2H,m),2.47(2H,d,J=6.8Hz),2.62-2.69(2H,m),3.10(2H,d,J=12Hz ),3.79(3H,s),6.02(1H,d,J=5.6Hz),7.16-7.20(1H,m),7.26-7.30(2H, m),7.35-7.41(3H,m),7.72(1H,d,J=6Hz),7.90(1H,dd,J=12.4,2.4Hz). * No amide NH or NH2 peaks were observed.

[0634] Example 47 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. See Figure 44.

[0635] [ka]

[0636] Step A: tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamido)pyridin-3-yl)-2-methylbut-3-yn-2yl)piperazine-1-carboxylate

[0637] [ka]

[0638] To a solution of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (Intermediate 20, 100 mg, 0.17 mmol) in DMF (3.4 mL) was added tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (43.0 mg, 0.17 mmol), copper(I) iodide (6.43 mg, 0.03 mmol), and TEA (92.0 μL, 0.68 mmol) at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (20.0 mg, 0.02 mmol), the reaction mixture was heated at 90 °C for 18 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH-SiO2 (sole EtOAc) to give tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamido)pyridin-3-yl)-2-methylbut-3-yn-2yl)piperazine-1-carboxylate (30.0 mg, 25%) as a yellow solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.31(9H,s),1.36(6H,s),2.44-2.50(4H,m),3.27(4H,s),3.67(3H,s),5.95(1H,d,J=5.6Hz),6.1 3(2H,s),7.22(1H,t,J=9.0Hz),7.35-7.39(4H,s),7.46(1H,d,J=8.8Hz),7.79(1H,d,J=6.0Hz),7.85(1H,d,J=12.4Hz),10.8(1H,s).

[0639] Step B: N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0640] [ka]

[0641] To a solution of tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamido)pyridin-3-yl)-2-methylbut-3-yn-2yl)piperazine-1-carboxylate (30.0 mg, 0.04 mmol) in DCM (1 mL) was added TFA (32.0 μL, 0.42 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After cooling to 0° C., the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was triturated with DCM and hexanes. The resulting solid was collected by filtration and dried under vacuum to give N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (19.3 mg, 75%) as a yellow solid. 1H-NMR(DMSO-d6,Varian,400MHz):δ1.32(6H,s),2.42-2.48(4H,m),2.69(4H,s),3.67(3H,s),5.99(1H,d,J=5.6Hz),6.11(2H, s),7.22(1H,t,J=8.8Hz),7.39-7.34(4H,m),7.47(1H,d,J=9.2Hz),7.80(1H,d,J=5.6Hz),7.86(1H,d,J=12.8Hz),10.8(1H,s). * No NH peak was observed.

[0642] Example 48 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. See Figure 45.

[0643] [ka]

[0644] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (Intermediate 20, 50.0 mg, 0.08 mmol), 4-(2-methylbut-3-yn-2-yl)morpholine (19.43 mg, 0.13 mmol), copper(I) iodide (3.22 mg, 0.02 mmol), and TEA (46.0 μL, 0.34 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (9.77 mg, 8.46 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (8.0 mg, 15%) as a brown solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.45(6H,s),2.66(4H,m),3.71-3.74(4H,m),3.93(3H,s),5.05(2H, s),6.05(1H,d,J=6.0Hz),7.10(1H,t,J=8.4Hz),7.25-7.29(5H,m),7.83-7.85(2H,m),10.80(1H,s).

[0645] Example 49 This example describes the synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide in one embodiment of the present invention. See Figure 46.

[0646] [ka]

[0647] A mixture of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (Intermediate 20, 50.0 mg, 0.08 mmol), 4-(prop-2-yn-1-yl)morpholine (15.88 mg, 0.13 mmol), copper(I) iodide (3.22 mg, 0.02 mmol), and TEA (46.0 μL, 0.34 mmol) in DMF (1 mL) was degassed with N. To the reaction mixture was added Pd(PPh) (9.77 mg, 8.46 μmol), and the mixture was stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EA pure to EA / MeOH=97 / 3) to give N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (4.9 mg, 10%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ2.62(4H,m),3.60(2H,s),3.75(4H,m),3.93(3H,s),5.07(2H,s) ,5.98(1H,d,J=6.4Hz),7.13(1H,t,J=8.6Hz),7.25-7.28(5H,m),7.83-7.86(2H,m),10.82(1H,s).

[0648] Example 50 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 47.

[0649] [ka]

[0650] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 22, 100 mg, 0.17 mmol), 4-(2-methylbut-3-yn-2-yl)morpholine (39.8 mg, 0.26 mmol), copper(I) iodide (6.6 mg, 0.04 mmol), and TEA (94.0 μL, 0.69 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (20.0 mg, 0.02 mmol) was added to the reaction mixture, which was stirred at 130 °C in a sealed tube for 2 h. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=9 / 1). The product was purified by preparative TLC on NH—SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (8.0 mg, 7.7%) as a yellow solid. 1H-NMR(CD3OD,Varian,400MHz):δ1.47(6H,s),2.72(4H,m),3.70(4H,m),6.03(1H,d,J=6.4Hz), 7.12(1H,t,J=8.8Hz),7.20-7.29(5H,m),7.75(1H,d,J=6.0Hz),7.85-7.88(1H,m),8.67(1H,s). * Amine and amide protons were not observed.

[0651] Example 51 This example describes the synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 48.

[0652] [ka]

[0653] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 22, 100 mg, 0.17 mmol), 4-(prop-2-yn-1-yl)morpholine (32.5 mg, 0.26 mmol), copper(I) iodide (6.6 mg, 0.04 mmol), and TEA (94.0 μL, 0.69 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (20.0 mg, 0.02 mmol) was added to the reaction mixture, which was stirred at 130° C. for 2 h in a sealed tube. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=85 / 15). The product was purified by preparative TLC on NH—SiO (EtOAc / MeOH=85 / 15) to give N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (5.4 mg, 5.4%) as a yellow solid. 1 H-NMR (CD3OD, Varian, 400MHz): δ2.65(4H,m),3.59(2H,s),3.71(4H,m),5.97(1H,d,J=6.0Hz), 7.14(1H,t,J=8.4Hz),7.20-7.29(5H,m),7.74(1H,d,J=6.4Hz),7.85-7.89(1H,m),8.67(1H,s). * Amine and amide protons were not observed.

[0654] Example 52 This example describes the synthesis of N-(4-((2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 49.

[0655] [ka]

[0656] Step A: tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate

[0657] [ka]

[0658] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 22, 200 mg, 0.35 mmol), tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (131 mg, 0.52 mmol), copper(I) iodide (13.2 mg, 0.07 mmol), and TEA (189 μL, 1.39 mmol) in DMF (1.5 mL) was degassed with N. Pd(PPh) (40.0 mg, 0.04 mmol) was added to the reaction mixture, which was stirred at 130 °C in a sealed tube for 2 h. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / MeOH=97 / 3) to give tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (25.5 mg, 10%) as a yellow solid. 1 H-NMR(CD3OD,Varian,400MHz):δ1.40(9H,s),1.48(6H,s),2.67(4H,m),3.42(4H,m),6.03(1H,d,J=6.0Hz),7.1 3(1H,t,J=8.4Hz),7.23-7.25(3H,m),7.32-7.35(2H,m),7.75(1H,d,J=6.4Hz),7.87-7.90(1H,m),8.53(1H,s). * Amine and amide protons were not observed.

[0659] Step B: N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0660] [ka]

[0661] To a solution of tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (25.5 mg, 0.04 mmol) in DCM (1 mL) was added TFA (56.0 μL, 0.73 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by preparative TLC on NH—SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (7.8 mg, 35%) as a yellow solid. 1 H-NMR(CD3OD,Varian,400MHz):δ1.49(6H,s),2.88(4H,m),3.13(4H,m),6.04(1H,d,J=6.0Hz), 7.11(1H,t,J=8.8Hz),7.23-7.30(5H,m),7.76(1H,d,J=5.6Hz),7.88-7.89(1H,m),8.63(1H,s). * Amine and amide protons were not observed.

[0662] Example 53 This example describes the synthesis of N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 50.

[0663] [ka]

[0664] Step A: tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate

[0665] [ka]

[0666] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 22, 200 mg, 0.35 mmol), tert-butyl 4-(prop-2-yn-1-yl)piperidine-1-carboxylate (116 mg, 0.52 mmol), copper(I) iodide (13.2 mg, 0.07 mmol), and TEA (0.19 mL, 1.39 mmol) in DMF (2 mL) was degassed with N. Pd(PPh) (40.0 mg, 0.04 mmol) was added to the reaction mixture, which was stirred at 130 °C in a sealed tube for 2 h. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (neat EtOAc to EtOAc / MeOH 97 / 3) to afford tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (77.9 mg, 33%) as a yellow solid. 1H-NMR(CD3OD,Varian,400MHz):δ1.16-1.26(2H,m),1.42(9H,s),1.72(1H,brs),1.80(2H,d,J=13.2Hz),2.46(2H,d,J=6.4Hz),2.72(2H,brs) ,4.03-4.10(2H,m),6.01(1H,d,J=6.0Hz),7.125(1H,t,J=8.6Hz),7.2 3-7.33(5H,m),7.72(1H,m),7.86-7.90(1H,d,J=12.4Hz),8.54(1H,s). * Amine and amide protons were not observed.

[0667] Step B: N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0668] [ka]

[0669] To a solution of tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (77.9 mg, 0.12 mmol) in DCM (1 mL) was added TFA (0.18 mL, 2.32 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by preparative TLC on SiO (EtOAc / MeOH=4 / 1). The product was washed with water and extracted with EtOAc. The organic layer was concentrated in vacuo. The residue was dissolved in MeOH. The solids were removed and the filtrate was concentrated in vacuo and dried under vacuum to give N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (2.5 mg, 4%) as a yellow solid. 1 H-NMR (CD3OD, Varian, 400 MHz): δ 1.51-1.58 (2H, m), 1.93 (1H, m), 2.06-2.10 (2H, m), 2.58 (2H, d, J = 6.4 Hz), 2.96-3.03 (2H, m), 3.37-3.40 (2H, m), 6.07 (1H, d, J = 6.0 Hz), 7.18 (1H, t, J = 8.8 Hz), 7.24-7.37 (5H, m), 7.73-7.75 (1H, m), 7.88-7.92 (1H, m), 8.52 (1H, s). *Amine and amide protons were not observed.

[0670] Example 54 This example describes the synthesis of N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 51.

[0671] [ka]

[0672] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 22, 100 mg, 0.17 mmol), 1-methyl-4-(prop-2-yn-1-yl)piperidine hydrochloride (45.0 mg, 0.26 mmol), copper(I) iodide (6.6 mg, 0.04 mmol), and TEA (94.0 μL, 0.70 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (20.0 mg, 0.02 mmol) was added to the reaction mixture, which was stirred at 130 °C in a sealed tube for 2 h. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC on NH-SiO (EtOAc / MeOH=4 / 1). The product was purified by preparative TLC on SiO (MeOH only) to give N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.8 mg, 1.7%) as a white solid. 1 H-NMR (CD3OD, Varian, 400MHz): δ1.44-1.54(2H,m),1.61-1.68(1H,m),1.92-1.96(2H,m),2.43-2.51(7H,m),3.12-3.15( 2H,m),6.02(1H,d,J=5.6Hz),7.08-7.12(1H,m),7.21-7.30(5H,m),7.72(1H,d,J=5.6Hz),7.84-7.88(1H,m),8.66(1H,s). * Amine and amide protons were not observed.

[0673] Example 55 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 52.

[0674] [ka]

[0675] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 24, 50.0 mg, 0.08 mmol), 4-(2-methylbut-3-yn-2-yl)morpholine (17.0 mg, 0.11 mmol), copper(I) iodide (2.8 mg, 0.02 mmol), and TEA (41.0 μL, 0.30 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.7 mg, 7.56 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (DCM / MeOH=95 / 5) to give N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (16.0 mg, 31%) as a yellow solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.45(6H,s),1.95-2.05(4H,m),2.65-2.6 8(4H,m),3.52-3.57(2H,m),3.71-3.74(4H,m),4.14-4.18(2H,m),4.77-4.8 4(1H,m),5.04(2H,s),6.04(1H,d,J=6.0Hz),7.06(1H,t,J=8.8Hz),7.19-7. 20(1H,m),7.24-7.25(4H,m),7.78-7.83(2H,m),8.68(1H,s),10.83(1H,s).

[0676] Example 56 This example describes the synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 53.

[0677] [ka]

[0678] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 24, 50.0 mg, 0.08 mmol), 4-(prop-2-yn-1-yl)morpholine (14.0 mg, 0.12 mmol), copper(I) iodide (2.8 mg, 0.02 mmol), and TEA (41.0 μL, 0.30 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.7 mg, 7.56 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. To the mixture were added copper(I) iodide (2.8 mg, 0.02 mmol), TEA (41.0 μL, 0.30 mmol), and Pd(PPh3)4 (8.7 mg, 7.56 μmol), and the mixture was stirred at 90 °C for 7 h. After cooling at room temperature, the reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (DCM / MeOH = 95 / 5). The product was purified by column chromatography on NH—SiO (sole EtOAc) to afford N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (18.0 mg, 37%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.95-2.07(4H,m),2.61-2.64(4H,m),3.5 1-3.57(2H,m),3.60(2H,s),3.73-3.75(4H,m),4.14-4.19(2H,m),4.78-4.8 4(1H,m),5.07(2H,s),5.98(1H,d,J=5.6Hz),7.09(1H,t,J=8.4Hz),7.19-7. 22(1H,m),7.24-7.25(4H,m),7.78-7.83(2H,m),8.68(1H,s),10.85(1H,s).

[0679] Example 57 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 54.

[0680] [ka]

[0681] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 24, 50.0 mg, 0.08 mmol), 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (19.0 mg, 0.11 mmol), copper(I) iodide (2.88 mg, 0.02 mmol), and TEA (41.0 μL, 0.30 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.7 mg, 7.56 μmol) was added to the reaction mixture, which was then stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was diluted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (sole EtOAc) to give N-(4-(2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (16.9 mg, 32%) as a yellow solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.45(6H,s),1.98-2.05(4H,m),2.26(3H,s) ,2.48(4H,brs),2.73(4H,brs),3.52-3.57(2H,m),4.14-4.17(2H,m),4.78-4 .84(1H,m),5.04(2H,s),6.01(1H,d,J=5.6Hz),7.07(1H,t,J=8.8Hz),7.18-7 .20(1H,m),7.24-7.25(4H,m),7.77-7.81(2H,m),8.68(1H,s),10.83(1H,s).

[0682] Example 58 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 55.

[0683] [ka]

[0684] Step A: tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate

[0685] [ka]

[0686] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 24, 100 mg, 0.15 mmol), tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (57.0 mg, 0.23 mmol), copper(I) iodide (5.76 mg, 0.03 mmol), and TEA (82.0 μL, 0.61 mmol) in DMF (2 mL) was degassed with N. Pd(PPh) (17.47 mg, 0.02 mmol) was added to the reaction mixture and stirred at 90 °C overnight. To the mixture was added tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (57.0 mg, 0.23 mmol), copper(I) iodide (5.76 mg, 0.03 mmol), TEA (82.0 μL, 0.61 mmol), and Pd(PPh3)4 (17.47 mg, 0.02 mmol), and the mixture was stirred overnight at 90° C. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / MeOH=97 / 3) to give tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (52.6 mg, 44%) as a beige solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.43(9H,s),1.50(6H,s),1.95-2.05(4H,m),2.62(4H,m),3.44(4H,m),3.54(2H,t,J=11Hz),4.14-4.17(2H,m),4.78 -4.84(1H,s),5.06(2H,s),6.03(1H,brs),7.06(1H,t,J=8.0Hz),7.18-7.2 0(1H,m),7.24-7.26(4H,m),7.81-7.78(2H,m),8.64(1H,s),10.84(1H,s).

[0687] Step B: N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0688] [ka]

[0689] To a solution of tert-butyl 4-(4-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (52.6 mg, 0.07 mmol) in DCM (1 mL) was added TFA (0.10 mL, 1.34 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=95 / 5) to give N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (24.0 mg, 52%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.45(6H,s),1.98-2.04(4H,m),2.63(4H,brs ),2.92(4H,m),3.51-3.57(2H,m),4.15-4.17(2H,m),4.78-4.84(1H,m),5.02( 2H,s),6.05(1H,d,J=6Hz),7.05(1H,t,J=8.8Hz),7.18-7.20(1H,m),7.24-7.2 6(4H,m),7.77-7.81(1H,m),7.83(1H,d,J=6.0Hz),8.68(1H,s),10.83(1H,s). * No NH peak was observed.

[0690] Example 59 This example describes the synthesis of N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 56.

[0691] [ka]

[0692] Step A: tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate

[0693] [ka]

[0694] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 24, 100 mg, 0.15 mmol), tert-butyl 4-(prop-2-yn-1-yl)piperidine-1-carboxylate (51.0 mg, 0.23 mmol), copper(I) iodide (5.76 mg, 0.03 mmol), and TEA (82.0 μL, 0.61 mmol) in DMF (2 mL) was degassed with N. Pd(PPh) (17.47 mg, 0.02 mmol) was added to the reaction mixture and stirred at 90 °C overnight. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (sole EtOAc) to give tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (60.9 mg, 53%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.21-1.27(2H,m),1.44(9H,s),1.72(1H,brs),1.81(2H ,d,J=14Hz),1.98-2.05(4H,m),2.45(2H,d,J=6.4Hz),2.69(2H,brs),3.52-3.57(2H,m),4 .09-4.18(4H,m),4.78-4.84(1H,m),4.99(2H,s),5.98(1H,d,J=6.0Hz),7.08(1H,t,J=8. 8Hz),7.19-7.21(1H,m),7.24-7.26(4H,m),7.79-7.81(2H,m),8.68(1H,s),10.84(1H,s).

[0695] Step B: N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0696] [ka]

[0697] To a solution of tert-butyl 4-(3-(2-amino-4-(2-fluoro-4-(3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (49.3 mg, 0.07 mmol) in DCM (1 mL) was added TFA (0.10 mL, 1.30 mmol) at room temperature. The residue was diluted with DCM and then neutralized with TEA. The mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=9 / 1) to give N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (27.0 mg, 64%) as a yellow solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.20-1.23(2H,m),1.82(2H,d,J=12.4Hz),1.98-2.07( 5H,m),2.43(2H,d,J=6.8Hz),2.57-2.62(2H,m),3.06-3.10(2H,m),3.52-3.57(2H,m),4. 14-4.18(2H,m),4.78-4.84(1H,m),5.02(2H,s),5.99(1H,d,J=6.0Hz),7.08(1H,t,J=8.6 Hz),7.18-7.20(1H,m),7.24-7.26(4H,m),7.78-7.81(2H,m),8.68(1H,s),10.84(1H,s). * No NH peak was observed.

[0698] Example 60 This example describes the synthesis of N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 57.

[0699] [ka]

[0700] A mixture of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 24, 50.0 mg, 0.08 mmol), 1-methyl-4-(prop-2-yn-1-yl)piperidine hydrochloride (19.7 mg, 0.11 mmol), copper(I) iodide (2.88 mg, 0.02 mmol), and TEA (41.0 μL, 0.30 mmol) in DMF (1 mL) was degassed with N. Pd(PPh) (8.74 mg, 7.56 μmol) was added to the reaction mixture, which was stirred at 90 °C overnight in a sealed tube. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=97 / 3) to give N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15.8 mg, 31%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.33-1.43(2H,m),1.55(1H,m),1.82-2.05(8H,m),2 .25(3H,s),2.43(2H,d,J=6.4Hz),2.83-2.86(2H,m),3.52-3.57(2H,m),4.15-4.18(2 H,m),4.80-4.84(1H,m),5.01(2H,s),5.97(1H,d,J=5.6Hz),7.09(1H,t,J=8.8Hz),7. 20(1H,d,J=8.0Hz),7.24-7.26(4H,m),7.78-7.81(2H,m),8.68(1H,s),10.84(1H,s).

[0701] Example 61 This example describes the synthesis of N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 58.

[0702] [ka]

[0703] To a solution of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 26, 50.0 mg, 0.08 mmol) in DMF (1.7 mL), 4-(prop-2-ynyl)morpholine (10.6 mg, 0.08 mmol), copper(I) iodide (3.21 mg, 0.02 mmol), and TEA (46.0 μL, 0.34 mmol) were added at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (9.74 mg, 8.43 μmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (sole EtOAc) to give N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (26.8 mg, 54%) as an ivory solid. 1H-NMR(DMSO-d6,Varian,400MHz):δ0.79-0.84(1H,m),1.11-1.30(6H,m),1.55-1.66(3H,m ),1.79(2H,d,J=11.2Hz),2.32(2H,q,J=12.0Hz),2.42-2.48(5H,m),3.54(4H,s),3.92(2H, q,J=6.9Hz),4.70-4.80(1H,m),5.89(1H,d,J=5.6Hz),6.26(2H,s),7.22-7.26(1H,m),7.4 4(1H,d,J=9.2Hz),7.78(1H,d,J=6.0Hz),7.92(1H,d,J=12.4Hz),8.71(1H,s),11.1(1H,s).

[0704] Example 62 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 59.

[0705] [ka]

[0706] To a solution of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 26, 50.0 mg, 0.08 mmol) in DMF (1.7 mL), 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (14.0 mg, 0.08 mmol), copper(I) iodide (3.21 mg, 0.02 mmol), and TEA (46.0 μL, 0.34 mmol) were added at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (9.74 mg, 8.43 μmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=50 / 1) to give N-(4-(2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (6.4 mg, 12%) as an ivory solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ1.10-1.18(2H,m),1.22(3H,t,J=6.8Hz),1.24-1.27(1H,m),1. 33(6H,s),1.58-1.66(3H,m),1.75-1.84(2H,m),2.08(3H,s),2.22-2.38(6H,m),3.28-3.36(4H,m) ,3.92(2H,q,J=7.2Hz),4.70-4.80(1H,m),5.98(1H,d,J=6.0Hz),6.09(2H,s),7.18(1H,t,J=9.6Hz ),7.41(1H,d,J=10.8Hz),7.80(1H,d,J=6.4Hz),7.91(1H,d,J=13.2Hz),8.70(1H,s),11.1(1H,s).

[0707] Example 63 This example describes the synthesis of N-(4-(2-amino-3-(3-(methyl-3-morpholinebut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 60.

[0708] [ka]

[0709] To a solution of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 26, 50.0 mg, 0.08 mmol) in DMF (1.7 mL), 1-methyl-4-(prop-2-ynyl)piperidine (12.0 mg, 0.08 mmol), copper(I) iodide (3.21 mg, 0.02 mmol), and TEA (46.0 μL, 0.34 mmol) were added at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (9.74 mg, 8.43 μmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=50 / 1) to give N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.0 mg, 2%) as a white solid. 1H-NMR(DMSO-d6,Varian,400MHz):δ1.10-1.18(2H,m),1.22(3H,t,J=7.2Hz),1.27-1.30(2H,m),1.36-1.48(1H,m ),1.55-1.69(4H,m),1.75-1.82(3H,m),2.10(2H,s),2.27-2.34(2H,m),2.39(2H,d,J=7.2Hz),2.63-2.76(2H,m), 3.30-3.33(3H,m),3.92(2H,q,J=6.8Hz),4.70-4.80(1H,m),5.74(1H,s),5.90(1H,d,J=6.0Hz),6.17(2H,s),7.22 (1H,t,J=9.0Hz),7.42(1H,d,J=10.4Hz),7.75(1H,d,J=6.0Hz),7.91(1H,d,J=12.4Hz),8.71(1H,s),11.1(1H,s).

[0710] Example 64 This example describes the synthesis of N-(4-((2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-(dimethylamino)-2-oxoethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 61.

[0711] [ka]

[0712] To a solution of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 26, 50.0 mg, 0.08 mmol) in DMF (1.7 mL), 4-(2-methylbut-3-yn-2-yl)morpholine (13.0 mg, 0.08 mmol), copper(I) iodide (3.21 mg, 0.02 mmol), and TEA (0.05 mL, 0.34 mmol) were added at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (9.74 mg, 8.43 μmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (neat EtOAc to EtOAc / MeOH=100 / 1) to give N-(4-(2-amino-3-(3-(methyl-3-morpholinebut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (6.2 mg, 12%) as a white solid. 1 H-NMR(DMSO-d6,Varian,400MHz):δ1.10-1.19(1H,m),1.22(3H,t,J=7.0Hz),1.23-1.27(1H,m),1.3 4(6H,s),1.54-1.66(3H,m),1.77-1.88(2H,m),2.28-2.40(4H,m),3.30-3.32(4H,m),3.51-3.55(3H ,m),3.92(2H,q,J=6.4Hz),4.70-4.80(1H,m),5.99(1H,d,J=5.6Hz),6.12(2H,s),7.18(1H,t,J=9.0 Hz),7.42(1H,d,J=9.2Hz),7.81(1H,d,J=5.6Hz),7.91(1H,d,J=12.4Hz),8.70(1H,s),11.1(1H,s).

[0713] Example 65 This example describes the synthesis of N-(4-(2-amino-3-(3-piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 62.

[0714] [ka]

[0715] Step A: tert-butyl 4-(3-(2-amino-4-(4-(3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate

[0716] [ka]

[0717] To a solution of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 26, 110 mg, 0.18 mmol) in DMF (3.7 mL), tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (41.0 mg, 0.18 mmol), copper(I) iodide (7.06 mg, 0.04 mmol), and TEA (0.10 mL, 0.74 mmol) were added at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (21.0 mg, 0.02 mmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc / hexane = 3 / 1 to EtOAc / hexane = 5 / 1) to afford tert-butyl 4-(3-(2-amino-4-(4-(3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (31.0 mg, 24%) as a yellow solid. 1 H-NMR(DMSO-d6,Varian,400MHz):δ1.01-1.18(2H,m),1.22(3H,t,J=7.0Hz),1.27-1.31(2H,m),1.34( 9H,s),1.56-1.69(6H,m),1.79(2H,d,J=13.2Hz),2.27-2.38(2H,m),2.41(2H,d,J=6.0Hz),3.30-3.32 (3H,m),3.84-3.96(4H,m),4.70-4.80(1H,m),5.90(1H,d,J=6.0Hz),6.19(2H,s),7.20(1H,t,J=8.8Hz ),7.42(1H,d,J=7.6Hz),7.75(1H,d,J=5.6Hz),7.92(1H,dd,J=14.0,2.0Hz),8.71(1H,s),11.1(1H,s).

[0718] Step B: N-(4-(2-amino-3-(3-piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0719] [ka]

[0720] To a solution of tert-butyl 4-(3-(2-amino-4-(4-(3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (31.0 mg, 0.04 mmol) in DCM (1 mL) was added TFA (35.0 μL, 0.45 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After cooling to 0° C., the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with DCM and hexane. The resulting solid was collected by filtration and dried under vacuum to give N-(4-(2-amino-3-(3-piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (11.9 mg, 45%) as a beige solid. 1H-NMR (DMSO-d6, Varian, 400MHz): δ1.05-1.34(8H,m),1.53-1.71(6H,m),1.79(2 H,d,J=12.4Hz),2.28-2.50(6H,m),2.93(2H,s),3.92(2H,q,J=7.2Hz),4.70-4.80 (1H,m),5.88(1H,d,J=6.0Hz),6.17(2H,s),7.22(1H,t,J=8.8Hz),7.43(1H,d,J= 9.2Hz),7.75,(1H,d,J=6.0Hz),7.92(1H,d,J=14.8Hz),8.70(1H,s),11.1(1H,s). * No protons from NH were observed.

[0721] Example 66 This example describes the synthesis of N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 63.

[0722] [ka]

[0723] Step A: tert-butyl 4-(4-(2-amino-4-(4-(3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl))piperazine-1-carboxylate.

[0724] [ka]

[0725] To a solution of N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 26, 120 mg, 0.20 mmol) in DMF (3.7 mL), tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (51.0 mg, 0.20 mmol), copper(I) iodide (7.70 mg, 0.04 mmol), and TEA (0.11 mL, 0.81 mmol) were added at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (23.0 mg, 0.02 mmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (neat EtOAc to EtOAc / MeOH = 50 / 1) to afford tert-butyl 4-(4-(2-amino-4-(4-(3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl))piperazine-1-carboxylate (30.0 mg, 21%) as an ivory solid. 1 H-NMR(DMSO-d6,Varian,400MHz):δ1.11-1.19(1H,m),1.22(3H,t,J=7.0Hz),1.22-1.27(2H,m),1.31(9H ,s),1.36(6H,s),1.55-1.63(3H,m),1.79(2H,d,J=11.6Hz),2.32(2H,q,J=9.6Hz),2.48-2.44(4H,m),3.2 6(4H,s),3.92(2H,q,J=7.2Hz),4.70-4.80(1H,m),5.96(1H,d,J=6.0Hz),6.13(2H,s),7.17(1H,t,J=9.0 Hz),7.39(1H,d,J=9.6Hz),7.80(1H,d,J=6.0Hz),7.91(1H,dd,J=14.8,2.4Hz),8.70(1H,s),11.1(1H,s).

[0726] Step B: N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0727] [ka]

[0728] To a solution of tert-butyl 4-(4-(2-amino-4-(4-(3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl))piperazine-1-carboxylate (30.0 mg, 0.04 mmol) in DCM (1 mL) was added TFA (32.0 μL, 0.42 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After cooling to 0° C., the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with DCM and hexane. The resulting solid was collected by filtration and dried under vacuum to give N-(4-(2-amino-3-(3-methyl-3-(piperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-cyclohexyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10.3 mg, 40%) as a yellow solid. 1H-NMR(DMSO-d6,Varian,400MHz):δ1.10-1.16(1H,m),1.22(3H,t,J=7.0Hz),1.33(6H,s),1.52-1 .67(3H,m),1.74-1.81(2H,m),2.27-2.39(3H,m),2.48-2.53(3H,m),2.77(2H,s),3.30-3.32(4H,m ),3.92(2H,q,J=7.6Hz),4.70-4.80(1H,m),5.98(1H,d,J=5.2Hz),6.12(2H,s),7.19(1H,t,J=9.0H z),7.42(1H,d,J=9.2Hz),7.81(1H,d,J=6.0Hz),7.92(1H,d,J=13.2Hz),8.70(1H,s),11.1(1H,s). * No protons from NH were observed.

[0729] Example 67 This example describes the synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 64.

[0730] [ka]

[0731] A mixture of 1,3-diallyl-N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 28, 60.0 mg, 0.11 mmol), 4-(prop-2-ynyl)morpholine (20.0 mg, 0.16 mmol), copper(I) iodide (4.1 mg, 0.02 mmol), and TEA (58.0 μL, 0.43 mmol) in DMF (1 mL) was degassed with N. To the reaction mixture was added Pd(PPh) (12.0 mg, 10.6 μmol) and stirred at 90 °C for 4 h. After cooling at room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=10 / 1) to give 1,3-diallyl-N-(4-(2-amino-3-(3-morpholinoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10.0 mg, 16%) as a yellow solid. 1 H-NMR (DMSO-d6, Varian, 400MHz): δ2.44(4H,m),3.53(6H,m),4.46-4.50(2H,m),4.57(2H,d,J=5.6Hz),5.12-5.14(2H,m),5.22-5.27(2H,m),5.80- 5.96(3H,m),6.24(2H,brs),7.24(1H,t,J=9.2Hz),7.43(1H,d,J=8.8Hz), 7.79(1H,d,J=5.6Hz),7.92(1H,d,J=13.2Hz),8.68(1H,m),11.04(1H,s).

[0732] Example 68 This example describes the synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 65.

[0733] [ka]

[0734] To a solution of 1,3-diallyl-N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 28, 50.0 mg, 0.09 mmol) in DMF (1.8 mL) was added 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (22.0 mg, 0.13 mmol), copper(I) iodide (3.38 mg, 0.02 mmol), and TEA (0.05 mL, 0.36 mmol) at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (10.3 mg, 8.88 μmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (sole EtOAc) to give 1,3-diallyl-N-(4-(2-amino-3-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (8.0 mg, 15%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.47(6H,s),2.27(3H,s),2.50(4H,s),2.74(4H ,s),4.52(2H,d,J=5.6Hz),4.64(2H,d,J=5.6Hz),5.01(2H,s),5.27(2H,d,J=11.2 Hz),5.34(1H,d,J=5.6Hz),5.41(1H,d,J=10.4Hz),5.96-5.88(2H,m),6.02(1H,d, J=5.6Hz), 7.10(2H,t,J=8.4Hz),7.82(2H,d,J=6.8Hz),8.48(1H,s),11.0(1H,s).

[0735] Example 69 This example describes the synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 66.

[0736] [ka]

[0737] To a solution of 1,3-diallyl-N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 28, 100 mg, 0.18 mmol) in DMF (1.8 mL) was added 1-methyl-4-(prop-2-ynyl)piperidine (37.0 mg, 0.27 mmol), copper(I) iodide (6.76 mg, 0.02 mmol), and TEA (0.10 mL, 0.71 mmol) at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (21.0 mg, 0.02 mmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=50 / 1) to give 1,3-diallyl-N-(4-(2-amino-3-(3-(1-methylpiperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.0 mg, 1%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ0.79-0.89(1H,m),1.35-1.44(2H,m),1.85(2H,d,J=12.0Hz),1. 93(2H,t,J=11.4Hz),2.26(3H,s),2.45(2H,d,J=6.4Hz),2.86(2H,d,J=10.8Hz),4.53(2H,d,J=5.6 Hz),4.64(2H,d,J=5.2Hz),5.01(2H,s),5.27(2H,d,J=10.8Hz),5.34(1H,d,J=6.0Hz),5.40(2H,d, J=10.8Hz), 5.99-5.88(3H,m),7.12(1H,t,J=8.4Hz),7.84-7.78(2H,m),8.48(1H,s),11.0(1H,s).

[0738] Example 70 This example describes the synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 67.

[0739] [ka]

[0740] To a solution of 1,3-diallyl-N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 28, 100 mg, 0.18 mmol) in DMF (1.8 mL) was added 4-(2-methylbut-3-yn-2-yl)morpholine (41.0 mg, 0.27 mmol), copper(I) iodide (6.76 mg, 0.02 mmol), and TEA (97.0 μL, 0.71 mmol) at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (21.0 mg, 0.02 mmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=30 / 1) to give 1,3-diallyl-N-(4-(2-amino-3-(3-methyl-3-morpholinobut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.2 mg, 1%) as a white solid. 1 H-NMR(CDCl3,Varian,400MHz):δ1.47(6H,s),2.64-2.71(4H,m),3.71-3.79(4H ,m),4.52(2H,d,J=6.4Hz),4.64(2H,d,J=5.6Hz),5.02(2H,s),5.27(2H,d,J=10. 4Hz),5.34(1H,d,J=5.6Hz),5.41(2H,d,J=11.2Hz),5.88-6.00(1H,m),6.04(1H ,d,J=6.0Hz),7.10(2H,t,J=8.6Hz),7.85-7.81(2H,m),8.48(1H,s),11.0(1H,s)

[0741] Example 71 This example describes the synthesis of 1,3-diallyl-N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide in one embodiment of the present invention. See Figure 68.

[0742] [ka]

[0743] Step A: tert-butyl 4-(3-(2-amino-4-(4-(1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate

[0744] [ka]

[0745] To a solution of 1,3-diallyl-N-(4-(2-amino-3-iodopyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Intermediate 28, 150 mg, 0.27 mmol) in DMF (5.3 mL), tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (89.0 mg, 0.40 mmol), copper(I) iodide (10.1 mg, 0.05 mmol), and TEA (0.15 mL, 1.07 mmol) were added at room temperature. The mixture was degassed by purging and backfilling with Ar in several portions. After the addition of Pd(PPh3)4 (31.0 mg, 0.03 mmol), the reaction mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO (EtOAc / MeOH=50 / 1) to afford tert-butyl 4-(3-(2-amino-4-(4-(1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (43.0 mg, 25%) as a yellow solid. 1 H-NMR(CDCl3,Varian,400MHz):δ0.78-0.88(1H,m),1.21-1.29(4H,m),1.44(9H,s) ,1.65(4H,s),2.46(2H,d,J=6.4Hz),4.52(2H,d,J=6.0Hz),4.64(2H,d,J=5.2Hz),5. 02(2H,s),5.27(2H,d,J=10.8Hz),5.34(1H,d,J=5.6Hz),5.41(2H,d,J=10.4Hz),5. 88-5.98(3H,m),7.12(1H,t,J=8.8Hz),7.48-7.55(2H,m),8.48(1H,s),11.0(1H,s).

[0746] Step B: 1,3-diallyl-N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0747] [ka]

[0748] To a solution of tert-butyl 4-(3-(2-amino-4-(4-(1,3-diallyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)piperidine-1-carboxylate (43.0 mg, 0.06 mmol) in DCM (1.3 mL) was added TFA (50.0 μL, 0.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After cooling to 0° C., the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO (EtOAc / MeOH=10 / 1) to give 1,3-diallyl-N-(4-(2-amino-3-(3-(piperidin-4-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (3.3 mg, 9%) as a white solid. 1H-NMR(CDCl3,Varian,400MHz):δ1.24-1.30(3H,m),1.83(2H,d,J=14.4Hz),2.44(2H,d,J=6.4H z),2.61(2H,t,J=12.2Hz),3.09(2H,d,J=11.6Hz),4.53(2H,d,J=6.4Hz),4.64(2H,d,J=6.0Hz), 5.02(2H,s),5.27(2H,d,J=10.8Hz),5.34(1H,d,J=6.0Hz),5.41(2H,d,J=10.4Hz),5.88-5.99(2 H,m),6.00(1H,d,J=6.0Hz),7.11(1H,t,J=9.0Hz),7.80-7.83(2H,m),8.49(1H,s),11.0(1H,s). * No protons from NH were observed.

[0749] Example 72 This example illustrates an enzyme assay for determining the inhibitory activity of exemplary compounds of formula (I) in accordance with an embodiment of the present invention.

[0750] All kinase reactions were performed in 5 μL using tyrosine kinase buffer with 0.2 μg / μL poly(Glu4, Tyr1) substrate, 10 μM ATP, serial dilutions of inhibitors, and incubated for 60 min at room temperature. After the indicated incubation times, 5 μL ADP-GLO was added. TM Reagent (Promega, Madison, WI) was added to the reaction and the plate was incubated for 40 minutes at room temperature. 10 μL of kinase detection reagent was then added and after a 40 minute incubation period, luminescence was recorded to determine IC 50 All 384-well assay plates were prepared using GLOMAX™ from Promega (Madison, WI). TM Reads were taken using a Discover Microplate Luminometer. Both Microsoft Excel and Prism from GraphPad 7 Software (La Jolla, CA) were used to plot, analyze, and calculate biochemical values ​​for all kinase reactions.

[0751] [Table 3-1]

[0752] [Table 3-2]

[0753] Example 73 This example illustrates a cell viability assay of exemplary compounds of formula (I) in one aspect of the present invention.

[0754] Cell viability assays were performed by plating 1,000 HCC827 or PC9 resistant cells per well in white, clear-bottom 384-well plates. Cells were treated with each TKI over a 10-dose range from 1 nM to 10,000 nM. Seventy-two hours after drug treatment, cell viability was measured using the CellTiter-Glo 2.0 assay (Promega, Madison, WI). EGFR TKI (gefitinib, erlotinib, and osimertinib)-resistant cell lines derived from the parental EGFR TKI-sensitive HCC827 or PC9 cell lines were established by continuous exposure of the cells to EGFR TKIs for a period of more than three months. The resistant cell lines were designated PC9 / ER, HCC827 / ER, HCC827 / GR, and HCC827 / OR. All of these resistant cells showed 1,000-fold greater resistance to EGFR TKIs than the parental cells.

[0755] The efficacy of the combination of an EGFR TKI and an inhibitor of formula (I) in EGFR TKI-resistant cells is shown in Table 4.

[0756] [Table 4-1]

[0757] [Table 4-2]

[0758] Use of the terms "a," "an," "the," "at least one," and similar referents in the context of describing the invention (particularly in the context of the claims below) should be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. Use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") should be construed to mean one item (A or B) selected from the listed items or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" should be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary terminology (e.g., "such as") provided herein is intended merely to better clarify the invention and does not impose limitations on the scope of the invention unless otherwise stated in the claims. No terminology herein should be construed as indicating any element not recited in the claims as essential to the practice of the invention.

[0759] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of these preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors expect that skilled artisans will employ such variations as appropriate, and the inventors intend to practice the invention otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

Claims

1. Compounds of formula (I) or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, R １ is H, alkyl, haloalkyl, halo, or CN; R ２ is H, alkyl, haloalkyl, halo, or CN; R ３ is H or halo; Q is H, CN, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl, where said alkenyl or alkynyl is -CH=CR ４ (CX') ｍ (CH ２ ) ｎ NR ５ R ６ , -C≡C(CX') ｍ (CH ２ ) ｎ NR ５ R ６ , -CH=CR ４ (CX') ｍ (CH ２ ) ｎ CHR ５ R ６ , -C≡C(CX') ｍ (CH ２ ) ｎ CHR ５ R ６ , -CH=CR ４ (CX') ｍ (CH ２ ) ｎ NR ７ OR ８ , and -C≡C(CX') ｍ (CH ２ ) ｎ NR ７ OR ８ is selected from the group consisting of: Here, R ４ is hydrogen or halo; X' is H ２ , (C １－６ Alkyl) ２ , or = O; m is either 0 or 1; n is 0 or 1 to 3; -NR ５ R ６ It either forms a heterocyclic ring with 4 to 7 members or does not form a ring structure, and the heterocyclic ring is either a heteroaryl ring or a heterocyclyl ring. -NR ５ R ６ When a 4- to 7-membered heterocycle is formed, the 4- to 7-membered heterocycle is -NR ５ R ６ In addition to the nitrogen, it contains an arbitrary second heteroatom and a linear C １ ~C ６ Alkyl, branched C ３ ~C ６ Alkyl, hydroxy, C １ ~C ６ Alkoxyalkyls, carboxylic acids, linear C １ ~C ４ Alkylcarboxylic acids, and branched C ３ ~C ４ It is optionally substituted with one or more substituents independently selected from the group consisting of alkylcarboxylic acids; -NR ５ R ６ When R does not form a ring structure, ５ is hydrogen, linear C １ ~C ６ Alkyl and branched C ３ ~C ６ Selected from the group consisting of alkyl, and R ６ This is a linear C molecule optionally substituted with hydrogen, at least one fluoro or at least one hydroxyl. １ ~C ６ Branched C molecules optionally substituted with alkyl, at least one fluoro, or at least one hydroxyl group. ３ ~C ６ Selected from the group consisting of alkyl and cycloalkyl groups optionally substituted with at least one fluoro or at least one hydroxyl; - CHR ５ R ６ It either forms a heterocyclic ring with 4 to 7 members or does not form a ring structure, and the heterocyclic ring is either a heteroaryl ring or a heterocyclyl ring. - CHR ５ R ６ When a 4- to 7-membered heterocycle is formed, the 4- to 7-membered heterocycle contains one or two heteroatoms and linear C １ ~C ６ Alkyl, branched C ３ ~C ６ Alkyl, hydroxy, C １ ~C ６ Alkoxyalkyls, carboxylic acids, linear C １ ~C ４ Alkylcarboxylic acids, and branched C ３ ~C ４ It is optionally substituted with one or more substituents independently selected from the group consisting of alkylcarboxylic acids; -CHR ５ R ６ When R does not form a ring structure, ５ R is selected from the group consisting of hydrogen, linear C １ -C ６ alkyl, and branched C ３ -C ６ alkyl, and R ６ is selected from the group consisting of hydrogen, linear C １ -C ６ alkyl optionally substituted with at least one fluoro or at least one hydroxy, branched C ３ -C ６ alkyl optionally substituted with at least one fluoro or at least one hydroxy, and cycloalkyl optionally substituted with at least one fluoro or at least one hydroxy; -NR ７ OR ８ does not form a ring structure, and R ７ is selected from the group consisting of hydrogen, linear C １ to C ６ alkyl, and branched C ３ to C ６ alkyl, and R ８ is selected from the group consisting of hydrogen, linear C １ to C ６ alkyl optionally substituted with at least one fluoro, hydroxy, or alkoxy group, branched C ３ to C ６ alkyl optionally substituted with at least one fluoro, hydroxy, or alkoxy group, and cycloalkyl optionally substituted with at least one fluoro, hydroxy, or alkoxy group; G is, 【Chemistry 2】 (In the formula, R ９ is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or heteroarylalkyl, where the heteroaryl group of the heteroarylalkyl may be substituted or unsubstituted; R １０ is H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl, alkenyl or alkynyl, where alkyl, alkenyl or cycloalkyl may be substituted with one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino (where the alkyl group of dialkylamino may be the same or different), heteroaryl, substituted heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl (where the alkyl group of dialkylcarbamoyl may be the same or different), and heterocyclylcarbonyl; and Y is N, C-H, or C-alkyl.

2. R １ and R ２ The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein both atoms are hydrogen.

3. R ３ A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a halo.

4. Q is CN, halo, optionally substituted phenyl, optionally substituted heterocyclyl, or -CH=CR ４ (CX') ｍ (CH ２ ) ｎ NR ５ R ６ -C≡C(CX') ｍ (CH ２ ) ｎ NR ５ R ６ -CH=CR ４ (CX') ｍ (CH ２ ) ｎ CHR ５ R ６ -C≡C(CX') ｍ (CH ２ ) ｎ CHR ５ R ６ -CH=CR ４ (CX') ｍ (CH ２ ) ｎ NR ７ OR ８ , and -C≡C(CX') ｍ (CH ２ ) ｎ NR ７ OR ８ An alkenyl or alkynyl moiety selected from the group consisting of, Here, R ４ is hydrogen or halo; X' is H ２ , (C １－６ Alkyl) ２ , or = O; m is either 0 or 1; n is either 0 or 1; -NR ５ R ６ Each of these is a morpholinyl, piperadinyl, or piperidinyl molecule, each optionally substituted with one or more substituents independently selected from the group consisting of nitrogen protecting groups, alkyl, hydroxy, alkoxy, and alkoxyalkyl groups. - CHR ５ R ６ Each of these is a tetrahydropyranyl, morpholinyl, piperadinyl, or piperidinyl, each optionally substituted with one or more substituents independently selected from the group consisting of nitrogen protecting groups, alkyl, hydroxy, alkoxy, and alkoxyalkyl groups. R ７ is hydrogen, linear C １ ~C ６ Alkyl and branched C ３ ~C ６ Selected from the group consisting of alkyl, and R ８ This is a linear C, optionally substituted with at least one alkoxy group. １ ~C ６ Branched C molecules optionally substituted with alkyl and at least one alkoxy group ３ ~C ６ Selected from the group consisting of alkyl groups, The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. R ９ is a phenyl substituted with alkyl, haloalkyl, halo, and / or CN; and (i) Y is C-H or (ii) Y is N, the compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. The compound of formula (I) is formula (Ib): 【Transformation 3】 (In the formula, 【Chemistry 4】 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of -C≡C- or -CH=CH-.

7. R １ and R ２ The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein both atoms are hydrogen.

8. R ３ A compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound is a halo.

9. X' is H ２ (C1-6 alkyl) ２ , or = O; and -NR ５ R ６ The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein each of the compounds is optionally substituted with one or more substituents independently selected from the group consisting of nitrogen protecting groups, alkyl, hydroxy, alkoxy, and alkoxyalkyl groups, and is a morpholinyl, piperazinyl, or piperidinyl.

10. R ９ is a phenyl substituted with alkyl, haloalkyl, halo, and / or CN; and (i) Y is C-H or (ii) Y is N, the compound of claim 6 or a pharmaceutically acceptable salt thereof.

11. The compound of formula (I) is formula (Ic): 【Transformation 5】 (In the formula, 【Transformation 6】 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of -C≡C- or -CH=CH-.

12. R １ and R ２ The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein both atoms are hydrogen.

13. R ３ A compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the compound is a halo.

14. X' is H ２ (C1-6 alkyl) ２ , or = O; R ７ is linear C １ ~C ６ Alkyl and branched C ３ ~C ６ Selected from the group consisting of alkyl, and R ８ is linear C １ ~C ６ Alkyl and branched C ３ ~C ６ A compound according to claim 11, selected from the group consisting of alkyl groups, or a pharmaceutically acceptable salt thereof.

15. R ９ is a phenyl substituted with alkyl, haloalkyl, halo, and / or CN; and (i) Y is C-H or (ii) Y is N, the compound of claim 11 or a pharmaceutically acceptable salt thereof. 【Request Item 16】 【Chemistry 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 A compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

17. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

18. The use of a pharmaceutically effective amount of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the preparation of an agent for the prevention or treatment of an AXL, Mer and / or c-Met-mediated disease in a subject, wherein the disease is selected from the group consisting of papillary thyroid carcinoma, pancreatic cancer, lung cancer, colon cancer, breast cancer, neuroblastoma, pain, cachexia, dermatitis, and asthma.

19. The use of claim 18, wherein the lung cancer is non-small cell lung cancer.

20. Use of a pharmaceutically effective amount of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the preparation of agents for such inhibition in cells requiring inhibition of AXL, Mer, and / or c-Met enzymes.

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