Compounds useful for modulating AhR signaling

Abstract

JPEG2024533046000233.jpg51159Compounds of general chemical formula (I) as described and defined herein, processes for preparing said compounds, pharmaceutical compositions and combinations containing said compounds, and the use of said compounds and pharmaceutical compositions as single agents or in combination with other active ingredients in the treatment or prevention of disease, in particular cancer or conditions involving immune dysfunction or other conditions associated with abnormal AhR signaling.

Description

[Technical Field]

[0001] The present invention relates to compounds of general chemical formula (I), as described and defined herein, methods for preparing the compounds, pharmaceutical compositions and combinations containing the compounds, and the use of the compounds and pharmaceutical compositions as sole agents or in combination with other active ingredients in the treatment or prevention of diseases, particularly cancer or conditions involving immune dysfunction or other conditions associated with abnormal AhR signaling. Such compounds are also useful in the expansion of hematopoietic stem cells (HSCs) and the utilization of HSCs in autologous or allogeneic transplantation for the treatment of patients with genetic and autoimmune diseases and various hematopoietic disorders. [Background technology]

[0002] The aryl hydrocarbon receptor (AhR) is a ligand-activated receptor belonging to the basic helix-loop-helix-Per / ARNT / Sim family. After ligand binding in the cytoplasm, AhR dissociates from a complex with Hsp90 and the AhR-interacting protein XAP2, allowing nuclear translocation of the ligand-bound AhR. Within the nucleus, AhR dimerizes with the AhR nuclear translocator (ARNT) and then binds to xenobiotic response elements (XREs), promoting the up- or down-regulation of multiple target genes in many different tissues. AhR is best known for its induction of various members of the cytochrome P450 family, including CYP1A1, CYP1A2, and CYP1B1, which are required for the binding and clearance of environmental toxins. Regarding the activation of AhR by xenobiotics, this receptor has been shown to play a role in various physiological processes, including embryonic development, tumorigenesis, and inflammation (Esser and Rannug, Pharmacol Rev, 2015, 67:259; Roman et al., Pharmacol Ther, 2018, 185:50).

[0003] AhR is expressed on a variety of immune cells, including dendritic cells, macrophages, T cells, NK cells, and B cells, and plays an important role in immune regulation (Quintana and Sherr, Pharmacol Rev, 2013, 65:1148; Nguyen et al., Front Immunol, 2014, 5:551). The toxic / harmful effects of classical exogenous AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are well known, including potent immunosuppression and the initiation of malignant transformation (Esser et al., Trends Immunol, 2009, 30:447; Feng et al., Biochimica et Biophysica Acta, 2013, 1836:197). Physiological effects of AhR agonists on immune cells include promoting regulatory T cell (Treg) generation (Pot, Swiss Med Wkly, 2012, 142:w13592), modulating Th17 cell differentiation and activation (Baricza et al., Cell Mol Life Sci, 2016, 73:95), and stimulating interleukin-22 (IL-22) expression and / or release in human activated peripheral blood mononuclear cells and T cells (Ramirez et al., Eur J Immunol, 2010, 40:2450; Effner et al., Sci Rep, 2017, 7:44005). AhR also regulates the function of antigen-presenting cells such as dendritic cells and macrophages. AhR activation reduces the expression of class II major histocompatibility complex and costimulatory molecules and reduces the production of Th1- and Th17-polarizing cytokines by dendritic cells (Mezrich et al., J Immunol, 2010, 185:3190; Nguyen et al., Proc Natl Acad Sci USA, 2010, 107:19961; Quintana et al., 2010, Proc Natl Acad Sci USA, 107:20768). Indeed, AhR activation enhances the ability of DCs to promote regulatory T cell differentiation (Jurado-Manzano et al., 2017, Immunol Lett, 190:84).

[0004] In addition to xenobiotics, AhR can also bind metabolites of tryptophan degradation, including kynurenine (KYN) and kynurenic acid (KYNA). Indoleamine 2,3-dioxygenase 1 and 2 (IDO1 / IDO2) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyze the commitment step of the KYN metabolic pathway and are expressed in immune cells (IDO1) and various cancer cells (IDO1 and TDO2) (Pilotte et al., Proc Nat Acad Sci, 2012, 109:2497). Inhibitors of IDO1 have attracted considerable attention as potential novel therapeutics to stimulate the immune system to recognize and eliminate cancer cells (Cheong and Sun, Trends Pharmacol Sci, 2018, 39:307). Traditionally, the immunosuppressive effects of IDO1 have been attributed primarily to a reduction in tryptophan levels, which activates GCN2 (general control non-derepressible 2) kinase and inhibits T-cell proliferation / activation in both the draining lymph nodes and the tumor microenvironment. More recently, it has emerged that the efficacy of IDO inhibitors may be partly a result of reduced production of AhR agonists. These endogenously formed AhR agonists have been shown to exert diverse effects on immune cells, including upregulation of IDO1 in dendritic cells (Julliard et al., Front Immunol, 2014;5:458), inhibition of human T cell proliferation (Frumento et al., J Exp Med, 2002;196:459; Terness et al., J Exp Med, 2002;196:447; Opitz et al., Nature, 2011;478:197), and upregulation of PD-1 expression in cytotoxic T lymphocytes (Liu et al., Cancer Cell, 2018;33:480). As emphasized above, IDO1 is not the only source of endogenous AhR agonists.TDO2 is primarily expressed in the liver but is also constitutively expressed in some cancers, particularly malignant gliomas, hepatocellular carcinomas, melanomas, bladder cancers, breast cancers, lung cancers, and colorectal cancers (Opitz et al., Nature, 2011, 478:197; Pilotte et al., Proc Nat Acad Sci, 2012, 109:2497; D'Amato et al., Cancer Res, 2015, 75(21):4651; Hsu et al., Oncotarget, 2016, 7(19):27584; Chen et al., Dis Markers, 2016, 2016:8169724). Such data suggest that AhR antagonists may have broader efficacy than selective IDO-1 inhibitors, because they would attenuate endogenous AhR agonist signaling regardless of its source. This assertion has gained weight with the recent discovery of another enzyme, interleukin-4 inducible 1 (IL4I1), that enables the production of endogenous AhR agonists (Sadik et al., Cell, 2020, 182:10).

[0005] In addition to their effects on immune cells, such endogenous agonists have also been implicated in cancer progression through direct effects on tumors. For example, KYN enhances human glioblastoma cell survival and migration (Opitz et al., Nature, 2011, 478:197). Other studies have also suggested that AhR is involved in cancer progression in the absence of environmental ligands. The AhR repressor (AHRR) protein acts as a tumor suppressor gene in several human cancers (Zudaire et al., J Clin Invest, 2008, 118:640). The expression and "constitutive" (endogenous ligand-agonist) activity of AhR in breast cancer cells correlates with tumor aggressiveness (Schlezinger et al., Biol Chem, 2006, 387:1175; Yang et al., J Cell Biochem, 2008, 104:402) and regulates the expression of genes associated with tumor invasion (Yang et al., Oncogene, 2005, 24:7869). Ectopic AhR expression in nonmalignant human breast epithelial cells induces epithelial-mesenchymal transition and increases cell proliferation rate by more than 50% (Brooks and Eltom, Curr Cancer Drug Targets, 2011, 11:654). Furthermore, AhR knockdown-induced genetic changes in human breast cancer cell lines are consistent with reversion of mesenchymal cells to a less aggressive epithelial phenotype (Narasimhan et al., Int J Mol Sci, 2018, 19:1388). AhR antagonists or AhR knockdown have been shown to reduce proliferation, survival, invasiveness, and migration of human breast cancer cells in culture (Parks et al., Mol Pharmacol, 2014, 86:593; D'Amato et al., Cancer Res, 2015, 75(21):4651; Narasimhan et al., Int J Mol Sci, 2018, 19:1388) and glioblastoma cell survival (Gramatzki et al., Oncogene, 2009, 28:2593; Opitz et al., Nature, 2011, 478:197; Guastella et al., J Neuro-oncol, 2018, in press).Finally, AhR antagonists inhibit the formation of tumor-like masses formed by cancer stem cells (CSCs), a subset of tumor cells responsible for tumor initiation, progression, and metastasis (Stanford et al., Mol Cancer Res, 2016, 14:696).

[0006] Thus, AhR agonists released from immune cells and tumor cells act in an autocrine and paracrine manner to promote tumor growth. Therefore, agents that reduce or inhibit these effects may be useful in treating cancer and / or conditions associated with immune dysfunction. Therefore, such agents may also be useful in a variety of other diseases / conditions, including, but not limited to, obesity (Rojas et al., Int J Obesity, 2020, 44:948) and various viral infections (Giovannoni et al., Nat Neurosci. 2020, 23:939; Giovannoni et al., ResSq. 2020, rs.3.rs-25639).

[0007] WO2017 / 202816 relates to compounds and compositions for treating or preventing cancer or conditions with abnormal immune responses, or other disorders associated with abnormal AhR signaling. In particular, WO2017 / 202816, WO2018 / 146010, and WO2019 / 101642 relate to heterocyclic compounds capable of inhibiting AhR function, among other things. WO2020 / 081840 relates to aryl hydrocarbon receptor antagonists, such as substituted imidazopyridines and imidazopyrazines, and methods for expanding hematopoietic stem cells by culturing hematopoietic stem or progenitor cells in the presence of these chemicals. WO2020 / 039093 relates to compositions and methods using tetrahydropyridopyrimidine derivatives as AhR modulators.

[0008] WO 2018 / 153893 relates to 6-amido-1H-indol-2-yl compounds capable of acting as aryl hydrocarbon receptor (AhR) modulators, in particular as AhR antagonists. The present invention further relates to the use of the compounds in the treatment and / or prevention of diseases and / or conditions via binding to the aryl hydrocarbon receptor. WO 2020 / 021024 relates to bicyclic compounds capable of acting as aryl hydrocarbon receptor (AhR) modulators, in particular as AhR antagonists. The present invention further relates to the use of the compounds in the treatment and / or prevention of diseases and / or conditions via binding to the aryl hydrocarbon receptor. WO 2020 / 043880 relates to heterocyclic compounds as ARH inhibitors, used as single agents or in combination with other active ingredients, for the prevention of diseases, in particular cancer or conditions involving immune dysfunction, or other conditions associated with abnormal AhR signaling. WO2020 / 018848 relates to methods for expanding stem cells and / or lineage-specific progenitor cells (such as hematopoietic stem cells and / or lineage-specific progenitor cells) at least in part by using compounds that antagonize the AhR. WO2020 / 050409 relates to novel heterocyclic compounds that have aryl hydrocarbon receptor antagonist activity and are useful for promoting platelet production. WO2019 / 236766 relates to methods for expanding stem cells and / or lineage-specific progenitor cells at least in part by using lactam compounds that antagonize the AhR. WO2019 / 018562 relates to compositions and methods using heteroaryl amides as AhR-modulating compounds for treating diseases modulated at least in part by the AhR. WO2018 / 195397 relates to compositions and methods relating to indole AhR inhibitors. WO2018 / 146010 relates to the preparation of 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for use as single agents or in combination with other active ingredients for the treatment or prevention of diseases, in particular cancer or conditions associated with an abnormal immune response.WO2010 / 059401 relates to compounds and compositions that expand the number of CD34+ cells for transplantation purposes. In particular, WO2010 / 059401 relates to heterocyclic compounds that are capable of downregulating, inter alia, the activity and / or expression of AhR.

[0009] WO 2012 / 015914 relates to compositions and methods for modulating AhR activity. In particular, WO 2012 / 015914 relates to heterocyclic compounds that modulate AhR activity, for use in therapeutic compositions that inhibit cancer cell proliferation and tumor cell invasion and metastasis, among other things. WO 2020 / 051207 relates to AhR antagonists and methods for modulating AhR activity, as well as methods for expanding hematopoietic stem cells by culturing hematopoietic stem or progenitor cells in the presence of these chemicals. Furthermore, the present disclosure provides methods for treating various conditions, such as cancer, by administering these AhR antagonists. US 2018 / 327411 A1 relates to compounds and compositions useful as AhR inhibitors for treating various diseases, disorders, and conditions associated with AhR. US 2019 / 389857 A1 relates to AhR modulators, particularly compounds that can act as AhR antagonists. WO2020 / 039093 discloses AhR modulators.

[0010] The compounds of the present disclosure have one or more beneficial properties that make them particularly suitable for pharmaceutical use: for example, high potency (e.g., in U937 and / or IL-22 assays), adequate bioavailability, low cardiotoxicity (e.g., in hERG assays), adequate cell permeability (e.g., in Caco-2 assays), good solubility (e.g., kinetic solubility), a chromLogD value of less than 5, and / or improved metabolic stability (such as improved CYP3A4 metabolism). Efficacy assays include, for example, those described below. While the inventors have obtained many different templates and structure-activity relationship data, it is not easy to design compounds with the levels of activity and properties described herein. Summary of the Invention

[0011] [1] A compound of formula (I): [ka] and; where Y is a phenyl or a 3- to 6-membered ring (such as a 5- or 6-membered ring), optionally containing 1, 2, or 3 heteroatoms selected from N, O, and S, and the phenyl or ring is R 5 and R 6 may be substituted with; R 1 But H, C 1~3 Alkyl, (-CH2)pCN, -COC 1~3 Alkyl, -CO(CH2)qNR 7 R 8 , -SO2C 1~3 Alkyl, -SO2NR 7 R 8 , -(CH2)qPh, C 3~5 Cycloalkyl, C with 1 to 6 halogen groups 1~3 Alkyl, OR Y and -NR 7 R 8 C having one or more independently selected from 1~3 Alkyl (one OR Y and optionally 1-NR 7 R 8 etc.), -(CH2)p'OC substituted with 1 to 6 halogen groups 1-3 Alkyl (such as -(CH2)p'OCF3), -C 0~3 Alkylene C(O)C 0~3 alkyl, wherein the alkyl is OR Y and -NR 7 R 8 at least one group selected from (one OR Y and optionally 1-NR 7 R 8 (including oxetane, Z, -C(O)(CH2)qZ, -C(O)O(CH2)qZ, -C(O)O(CH2)pPh, -C(O)(CH2)qZ′, -C(O)O(CH2)qZ′; R 2 But H or C 1~3 Alkyl, C 3~5 cycloalkyl, halogen and optionally OR Y , halogen-NR 7 R 8 C having one or more groups independently selected from 1~3 Alkyl (OR Y and halogen (e.g., F), especially as a single group); R 2 ', H, C 1~3 is alkyl or halogen; R 3 But H or C 1~3 is alkyl; R 4 is a heterocyclic 9- to 13-membered ring (e.g., aromatic or partially saturated) having at least one heteroatom selected from N, O, and S, and the substituent R 9 , R 9 ′ and R 10 having; R 5 H, oxo, hydroxy, halogen (F, Cl, etc.), CN, C 1~3 Alkyl, C 3~5 Cycloalkyl, -OC 1~3 Alkyl (e.g., -OCH3), -(O) with 1 to 6 halogen groups 0~1 C 1~3 Alkyl (e.g., CF3 or OCHF2), C with one or more ORY groups 1~3 Alkyl, -C(O)C 1~3 Alkyl NR 7 R 8 , -SO2C 1~3 Alkyl, -SO2NR 7 R 8 , or NR 7 R 8 (e.g., NH2); R 6 H, oxo, hydroxy, halogen (F, Cl, etc.), CN, C 1~3 Alkyl, -C(O)C 1~3 Alkyl NR 7 R 8 , -SO2C 1~3Alkyl, or -SO2NR 7 R 8 and; R 7 But H or C 1~3 Alkyl, or -C(O)OR Y , e.g., H or C 1~3 is alkyl (such as -CH3); R 8 But H or C 1~3 is alkyl (such as -CH3); R 9 H, hydroxy, halogen (F, Cl, etc.), CN, C 1~3 Alkyl, C 1~3 Alkoxy (e.g., OMe), C with 1 to 6 halogen groups 1~3 Alkyl (e.g., CF3), C with one or more ORY groups 1~3 Alkyl, -C 3~5 Cycloalkyl, -(CH2)qOC substituted with 1 to 6 halogen groups 1~3 Alkyl (-C 1~3 Alkyl OCF3, etc.), -COC 1~3 Alkyl NR 7 R 8 , -SO2C 1~3 Alkyl, or -SO2NR 7 R 8 and; R 9 ' is H, OH, halogen (F, Cl, etc.), CN, C 1~3 Alkyl, C 1~3 Alkoxy (e.g., OMe), C with 1 to 6 halo groups 1~3 Alkyl (e.g., CF3), C with one or more OH groups 1~3 Alkyl, -CO(CH2)qNR 7 R 8 , -SO2C 1~3 Alkyl, or -SO2NR 7 R 8 and; R 10 H, hydroxy, halogen (F, Cl, etc.), CN, C 1~3 Alkyl, -C(O)C 1~3 Alkyl NR 7 R 8 , -SO2C1~3 Alkyl, or -SO2NR 7 R 8 and; R 11 But H, C 1~3 Alkyl (such as -CH3) or C 2~6 is a hydroxyalkyl (such as -CH2CH2OH); R Y But H or C 1~4 Alkyl, e.g., H or C 1~3 alkyl (such as H, -CH3 or -CH2CH3); X is CH2, S, -SO2, NR 11 or O; Z' is a 5- or 6-membered heteroaryl having at least one heteroatom (e.g., 1 or 2 nitrogens) selected from N, O, and S, wherein the heteroaryl optionally contains hydroxy, halogen (F, Cl, etc.), CN, C 1~3 It may contain 1, 2 or 3 substituents selected from alkyl; Z is a 3- to 6-membered ring optionally containing 1, 2, or 3 heteroatoms (e.g., 1 or 2 nitrogens) selected from N, O, and S; R 5 and R 6 (e.g., a 5- or 6-membered cycloalkyl or heterocyclic ring containing at least a heteroatom selected from N, O, and S, and optionally hydroxy, halogen (F, Cl, etc.), CN, C 1~3 alkyl (including no substituents); n is 0 or 1 (e.g., 0); n′ is 0 or 1; m is 0, 1, 2 or 3; p is an integer 1, 2 or 3 (e.g., 1); p′ is an integer 2 or 3 (e.g., 2); q is 0, 1, 2 or 3 (e.g., 0 or 1); A compound of formula (I) or a pharmaceutically acceptable salt thereof: [2] Compounds of formula (I) according to item [1], wherein Y is a 3-6 membered ring containing 1, 2, or 3 heteroatoms, optionally selected from N, O, and S, each of which is R 5 and R 6 a 3- to 6-membered ring substituted with, for example, a 5- to 6-membered ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, each of which is R 5 and R 6 A compound of formula (I) wherein the ring is a 5- to 6-membered ring substituted with [3] A compound of formula (I) according to item [1] or [2], wherein Y is a nitrogen-containing 5- or 6-membered ring; A compound of formula (I). [4] A compound of formula (I) according to item [3], wherein the ring is aromatic; A compound of formula (I): [5] Compounds of formula (I) according to item [3] or [4], wherein the rings are independently selected from pyrimidine, pyridine, triazole and thiazole, in particular pyrimidine and / or pyridine; A compound of formula (I). [6] Compounds of formula (I) according to item [5], wherein R 5 is located at the 5-position of the Y group, A compound of formula (I). [7] A compound according to any one of items [1] to [6], wherein n is 0; A compound of formula (I). [8] A compound of formula (II) according to item [1], comprising: [ka] Here, X and R 1 , R 2 , R 3 , R 4 and m is defined above for compounds of formula (I), A compound of formula (II) or a pharmaceutically acceptable salt thereof: [9] A compound according to any one of items [1] to [8], wherein R 1 But hydrogen, -C 1~3 (R 1 is, for example, hydrogen or -C 1~3 alkyl, especially H), A compound of formula (I).

[10] A compound according to item [9], wherein R 1 is selected from methyl, ethyl, propyl and isopropyl, in particular isopropyl; compound.

[11] A compound according to any one of items [1] to

[10] , wherein R 2 are independently selected from H, methyl, -CH2OCH3, -CH2OH, CF3, and -CH2N(CH3)2 (R 2 is H or methyl, etc.), compound.

[12] A compound according to any one of items [1] to

[11] , wherein R 2 ′ is methyl or H (R 2 ′ is H, etc.), compound.

[13] A compound according to any one of items [1] to

[12] , wherein R 3 is H, compound.

[14] A compound according to any one of items [1] to

[13] , wherein R 4 is, for example, a partially saturated 9- or 13-membered ring or aromatic heterocycle selected from indole, tetrahydrobenzoindole, tetrahydrocarbazole, and tetrahydropyridoindole (e.g., R 4 is a 9- to 13-membered heteroaryl; compound.

[15] A compound according to item

[14] , wherein R 4 is a 9-membered heterocyclic ring, e.g., a heteroaromatic ring (R 4 tryptophan, etc.) compound.

[16] A compound according to item

[15] , wherein R 4 is a 13-membered heterocyclic ring, for example a partially saturated heterocyclic ring (such as tetrahydrocarbazole); compound.

[17] A compound according to any one of items [1] to

[16] , wherein R 5 are independently selected from oxo, methyl, ethyl, —CF3, —OCF3, —OCH3 and halogen-containing groups (such as halogen, e.g., fluoro); compound.

[18] A compound according to any one of items [1] to

[17] , wherein R 6 are independently selected from methyl, ethyl, -OCH3, and H (R 6 is H, etc.), compound.

[19] A compound according to any one of items [1] to

[18] , wherein R 7 is H, compound.

[20] A compound according to any one of items [1] to

[19] , wherein R 8 is H, compound.

[21] A compound according to any one of items [1] to

[20] , wherein R 9 H, methyl, OCF3 and -C 3~5 cycloalkyl (R 9 is H, methyl, or -C 3~5 cycloalkyl, or H, methyl, or OCF3, etc.), compound.

[22] A compound according to any one of items [1] to

[21] , wherein R 9 ' are independently selected from H, F and methyl (R 9 ′ is H or F), compound.

[23] A compound according to any one of items [1] to

[22] , wherein R 10 are independently selected from H, F and methyl (R10 is H or F, especially H), compound.

[24] A compound according to any one of items [1] to

[23] , wherein X is NR 11 That is, compound.

[25] A compound according to any one of items [1] to

[24] , wherein R 11 is H, compound.

[26] A compound according to any one of items [1] to

[25] , wherein m is 2; compound.

[27] A compound according to any one of items [1] to

[25] , wherein m is 1; compound.

[28] A compound according to any one of items [1] to

[27] , wherein n is 1; compound.

[29] A compound according to any one of items [1] to

[28] , 2-(5-Fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(4-Fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(3,5-Difluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine Amine;2-(5-Fluoro-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(5-Fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(5-Fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-8-isopropyl-6 ,7-Dihydropyrimido[5,4-b][1,4]oxazin-4-amine;N-[2-(1H-indol-3-yl)ethyl]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;(7S)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;(7R)-2-(5-fluoro-3-pyridyl)-N-[2-( N-[2-(1H-indol-3-yl)ethyl]-2-(4-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-[2-(1H-indol-3-yl)ethyl-[2-(2-methylthiazol-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl]amino]ethanol;2-(2-Ethyl-4-methyl-thiazol-5-yl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-2-thiazol-2-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(2-methylthiazol-5-yl-N-(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)-7 ,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;N-[2-(1H-indol-3-yl)ethyl]-2-(6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(5-fluoro-6-methyl-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;3-[4-[2-(1H-indol-3-yl)ethylamino] -7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one;3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol;5-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one;5-(4-((2-(1H-indol- 3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1-methyl-pyridin-2-one; N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-2-(6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;3-[4-[2-(6-Fluoro-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one; 3-(4-((2-(6-Fluoro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 2-[2-(Difluoromethoxy)-3-pyridyl]-N-[2-(1H-indol-3-yl)ethoxy]- N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-5-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 4-[2-(6-fluoro-1H-indol-3-yl)ethoxy]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine; 3-(4-(2-( 1H-indol-3-yl)ethoxy)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one;3-(4-(2-(1H-indol-3-yl)ethoxy)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol;(R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4 ]oxazin-2-yl)pyridin-2(1H)-one;(R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol;(R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(hydroxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one;(R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(hydroxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; (7S)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (6S)-2-(5-fluoro-3-pyridyl)-N-[ 2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;(6R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,7-dimethyl-6,8-dihydropyrimido[ 5,4-b][1,4]oxazin-4-amine;(7R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;N-[2-(1H-indol-3-yl)ethyl]-2-(2-methylthiazol-5-yl-8-(oxetan-3-yl)-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine;2-(2-methylthiazol-5-yl)-8-(oxetan-3-yl)-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (7R)-8-[2-(dimethylamino)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine; (7R)-8-[2-(dimethylamino)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine;[(7R)-8-[2-(dimethylamino)ethyl]-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-7-yl]methanol; 2-[2-(2-methylthiazol-5-yl)-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-8-yl]e 7-[(dimethylamino)methyl]-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 8-Methylsulfonyl-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine; 3-(4-((2 -(2-Chloro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one;3-(4-((2-(2-chloro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol;3-[4-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido [5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one; 3-(4-((2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-[4-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one;3-(4-((2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-(4-((2-(6-(trifluoromethoxy)-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; 3-(4-((2-(6-(trifluoromethoxy)-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-(1H)-one; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-8-methyl-7,8-dihydro-6H-pyrimido; (S)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; (S)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridine -2-ol;(7R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;(R)-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one;(R)-3-(4-((2-(6- Fluoro-1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-[(7R)-4-[2-(1H-indol-3-yl)ethoxy]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one; (R)-3-(4-(2-(1H-indol-3-yl)ethoxy)-7-(methoxymethyl) )-7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol;(7R)-2-(3,5-difluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(3-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(2-Methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(2,4-dimethylthiazol-5-yl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (7R)-7-(Methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro- 1H-Carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;[(7R)-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl]methanol;N-[2-(1H-indol-3-yl)ethyl]-2-(1-methyltriazol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl]methyl Xazin-4-amine;(7R)-2-(4-Fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;(7R)-2-(3-Fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;5-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro- 6H-Pyrimido[5,4-b][1,4]oxazin-2-yl]-1-methyl-pyridin-2-one;(7R)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;[(7R)-4-[2-(1H-indol-3-yl)ethylamino]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl]methanol;2-(2-Methylthiazol-5-yl-N-[(4R)-1,3,4,5-tetrahydrobenzo[cd]indol-4-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(2-Methylthiazol-5-yl-N-[(4S)-1,3,4,5-tetrahydrobenzo[cd]indol-4-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 3-[4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazole- 3-yl]amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one;(R)-3-(4-((2,3,4,9-tetrahydro-1H-carbazol-3-yl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol;N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4 -amine;2-(5-fluoro-2-methoxy-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-fluoropyridin-2(1H)-one;3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7, 8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-fluoropyridin-2-ol; 2-(5-fluoro-2-methoxy-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-methylpyridin-2(1H)-one;3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-methylpyridin-2-ol; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-(trifluoromethyl)pyridin-2(1H)-one; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5 ,4-b][1,4]oxazin-2-yl)-5-(trifluoromethyl)pyridin-2-ol;5-Fluoro-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one;5-Fluoro-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol (R)-5-Fluoro-3-(4-((2,3,4,9-tetrahydro-1H-carbazol-3-yl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; (R)-5-Fluoro-3-(4-((2,3,4,9-tetrahydro-1H-carbazol-3-yl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-(4-((2-(1H-indol-3-yl)ethyl)amino ... 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-chloropyridin-2-ol; 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-6-methyl-1H-pyridin-2-one;3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-6-methylpyridin-2-ol; and 2-(2-amino-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; or a pharmaceutically acceptable salt thereof.

[28] The compound according to any one of items [1] to

[27] , wherein the compound is 3-(4-(2-(1H-indol-3-yl)ethoxy)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one or a pharmaceutically acceptable salt thereof.

[29] A compound according to any one of items [1] to

[26] , wherein the compound is selected from the novel structures disclosed herein or pharmaceutically acceptable salts thereof.

[30] A compound according to any one of items [1] to

[29] , wherein the compound is: [ka] or a pharmaceutically acceptable salt thereof; compound.

[31] A compound according to any one of items [1] to

[29] , wherein the compound is: [ka] or a pharmaceutically acceptable salt thereof.

[32] A compound according to any one of items [1] to

[29] , wherein the compound is: [ka] or a pharmaceutically acceptable salt thereof.

[33] A compound according to any one of items [1] to

[26] , wherein m is 1; compound.

[34] A compound according to any one of items [1] to

[26] , wherein n is 1; compound.

[35] A compound according to item

[34] , wherein the compound is: [ka] or a pharmaceutically acceptable salt thereof. compound.

[36] A pharmaceutical composition comprising a compound according to any one of items [1] to

[35] and a pharmaceutically acceptable excipient, diluent or carrier.

[37] A compound according to any one of items [1] to

[35] or a composition according to item

[36] for use in treatment, particularly in cancer treatment.

[38] Use of a compound according to any one of items [1] to

[35] or a composition according to item

[36] in the manufacture of a therapeutic agent for cancer treatment.

[39] A therapeutic method comprising administering a therapeutically effective amount of a compound according to any one of items [1] to

[35] or a composition according to item

[36] to a patient in need thereof, for example, for the treatment of cancer.

[40] A compound or composition for use according to item

[37] or for use according to item

[38] , comprising one or more checkpoint inhibitors, such as: further comprising one or more checkpoint inhibitors selected from the group including PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, checkpoint kinase inhibitor 1 (CHEK1 / CHK1), checkpoint kinase inhibitor 2 (CHEK2 / CHK2), ATM and Rad3 related gene product (ATR) inhibitors, ataxia telangiectasia mutated gene product (ATM) inhibitors, Wee1 dual specificity protein kinase (Wee1) inhibitors, poly ADP-ribose polymerase (PARP) inhibitors, and Myt1 inhibitors; Compound or composition.

[41] The method according to item

[39] , wherein one or more checkpoint inhibitors, such as: further comprising administering one or more checkpoint inhibitors selected from the group including a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a checkpoint kinase inhibitor 1 (CHEK1 / CHK1), a checkpoint kinase inhibitor 2 (CHEK2 / CHK2), an ATM and Rad3 related gene product (ATR) inhibitor, an ATM and Rad3 related gene product (ATR) inhibitor, a Wee1 dual specificity protein kinase (Wee1) inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, and a Myt1 inhibitor; method.

[42] Combination therapy, A compound according to any one of items [1] to

[35] or a composition according to item

[36] , and one or more checkpoint inhibitors, for example: one or more checkpoint inhibitors selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, checkpoint kinase inhibitor 1 (CHEK1 / CHK1), checkpoint kinase inhibitor 2 (CHEK2 / CHK2), ATM and Rad3 related gene product (ATR) inhibitors, ataxia telangiectasia mutated gene product (ATM) inhibitors, Wee1 dual specificity protein kinase (Wee1) inhibitors, poly ADP-ribose polymerase (PARP) inhibitors, and Myt1 inhibitors; Combination therapy.

[43] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R2, R4, and Y are as defined in item [1], and B is boron; method.

[44] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R4, R1 and Y are as defined in item [1], and B is boron; method.

[45] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R2, R4, R7 and Y are as defined in item [1], and B is boron; method.

[46] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R1, R2, R3, R4, R5, R7 and Y are as defined in item [1], and B is boron; method.

[47] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R1, R2, R3, R4, R5, R7 and Y are as defined in item [1], and B is boron; method.

[48] ​​A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R1, R2, R3, R4, R5, R6 and Y are as defined in item [1], and B is boron; method.

[49] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R2, R4 and Y are as defined in item [1], and B is boron; method.

[50] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R1, R4, and Y are as defined in item [1], and B is boron; method.

[51] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R2, R4, and Y are as defined in item [1], and B is boron; method.

[52] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R4 and Y are as defined in item [1], and B is boron; method.

[53] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R2, R4, R7 and Y are as defined in item [1], and B is boron; method.

[54] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R1, R2, R3, R4, R5, R7 and Y are as defined in item [1], and B is boron; method.

[55] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R1, R2, R3, R4, R5, R7 and Y are as defined in item [1], and B is boron; method.

[56] A method for preparing a compound according to any one of items [1] to

[35] , comprising the steps: [ka] Includes; wherein R1, R2, R3, R4, R5, R6 and Y are as defined in item [1], and B is boron; method.

[0012] In one embodiment, R 1 is C(O)OR Y In one embodiment, R Y is H.

[0013] In one embodiment, R Y is C 1~3 alkyl (such as CH). In one embodiment, R 2 is not H. In one embodiment, R 2 In one embodiment, R′ is not H. 3 is not H. In one embodiment, R 2 and R 2 In one embodiment, R′ is not H. 2 and R 3 is not H. In one embodiment, R 2 ′ and R 3is not H. In one embodiment, R 2 , R 2 ′ and R 3 is not H. In one embodiment, when m is 1, n is 1 or 2, and Y is pyridine, R 5 and R 6 and one or both of R are not H. In one embodiment, when Y is pyridine, R 5 and R 6 is not H. In one embodiment, one or both of R 4 is a 9-membered heterocyclic ring, for example, a 9-membered heterocyclic ring having N. In one embodiment, R 4 is indole. In one embodiment, R 5 is not H. In one embodiment, R 5 is hydroxy. In one embodiment, R 5 is oxo. In one embodiment, R 5 is OCHF2. In one embodiment, R 5 Ha-OC 1~3 alkyl (such as -OCH). In one embodiment, R 6 is not H. In one embodiment, R 9 is H. In one embodiment, R 9 is not H. In one embodiment, R 9 ' is not H.

[0014] In one embodiment, R 10 is not H. In one embodiment, R 11 is C 2~6 In one embodiment, X is O. In one embodiment, n is 0. In one embodiment, m is 1.

[0015] In one embodiment, compounds of the disclosure have an activity of 10 nM or less (eg, 5 nM or less) in the U937 assay (such as 9, 8, 7, 6, 5, 4, 3, 2 or 1 nM, especially 1 nM).

[0016] In one embodiment, compounds of the disclosure have an activity in the IL-22 assay of 20 nM or less (eg, 10 nM or less) (such as 9, 8, 7, 6, 5, 4, 3, 2 nM, especially 2 nM).

[0017] In one embodiment, compounds of the present disclosure have a ratio of greater than 6.6 / 1.7 in a Caco-2 / efflux assay. Advantageously, this high potency, most importantly, allows the molecule to be optimized for other properties that meet the candidate drug target profile, thereby balancing all properties to make the molecule "drug-like."

[0018] The compound of the present invention effectively inhibits AhR.The compound is useful for treating or preventing the pathological condition that exogenous and endogenous AhR ligand induces abnormal immune response (for example, uncontrolled cell growth, proliferation and / or survival of tumor cells, immunosuppression).This abnormality may be observed in association with cancer, inappropriate cellular immune response and inappropriate cellular inflammatory response.

[0019] In one embodiment, the compounds of the present disclosure are useful for treating cancer, such as liquid and / or solid tumors and / or their metastases. Examples of cancers include head and neck cancer (including brain tumors and brain metastases), breast cancer, including non-small cell lung cancer and small cell lung cancer, and cancers of the gastrointestinal tract (including stomach, esophagus, colon, and colorectum), biliary tract cancer, pancreatic cancer, liver cancer, endocrine cancer, breast cancer, ovarian cancer, bladder cancer, kidney cancer, prostate cancer, bone cancer, and skin cancer.

[0020] In one embodiment, the cancer is an epithelial cancer. In one embodiment, the cancer is a sarcoma. In one embodiment, the cancer is metastatic. DETAILED DESCRIPTION OF THE INVENTION

[0021] In one embodiment, Y is independently selected from pyridine, pyrimidine, thiazole, triazole, and pyridone.

[0022] In one embodiment, R 5 are independently oxo.

[0023] In general, the substituents used in the molecules of the present disclosure are those suitable for use as therapeutic molecules. Reactive molecules (such as epoxides) are typically used as intermediates.

[0024] C of this specification 1~3 Alkyl refers to straight or branched chain alkyl, for example, methyl, ethyl, propyl, or isopropyl. When the alkyl is optionally substituted as defined herein, it will generally be a straight or branched chain alkylene.

[0025] C of this specification 1~x Alkylene refers to a straight or branched alkyl chain of 1 to X carbons in length with a terminal substituent (such as an alcohol), e.g., a -CHCHCH- substituent is a C3 straight chain alkylene. When the alkylene is branched, the branch terminates in an alkyl group to satisfy the valence, e.g., a -CHCH(CH3)- substituent is a C3 branched chain alkylene.

[0026] C of this specification 1~3 Alkoxy refers to a branched or straight alkyl chain that includes an oxygen atom positioned in the chain, for example, where the oxygen connects the alkoxy group to the rest of the molecule (such as -OCH3), or where a carbon connects the alkoxy group to the rest of the molecule and the oxygen is positioned within the alkoxy chain (such as -CH2OCH3).

[0027] Halogen herein includes fluoro, chloro, bromo or iodo.

[0028] Examples of alkyls having up to six halogen groups include -CH2F, -CH2CL, -CHF2, -CHCL2, -CF3, -CCL2, -CH2CF3, -CF2CF3, -CH2CHCL2, -CHCCL3.

[0029] C(O) represents carbonyl.

[0030] C 3~5 Cycloalkyl includes cyclopropyl, cyclobutyl and cyclopentyl.

[0031] A 3- to 6-membered ring, optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, refers to a ring containing 3 or 6 atoms, which is saturated, partially saturated, or aromatic (e.g., as defined below).

[0032] In one embodiment, the 3- to 6-membered ring contains no heteroatoms, hi one embodiment, the 3- to 6-membered ring contains 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur.

[0033] In one embodiment, the ring is saturated. Examples of saturated rings include cyclopropane, cyclobutene, cyclopentane, cyclohexane, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, oxathiolane, 1,3-dioxolane, pyrazolidine, pyrrolidine, thiolane, imidazoline, piperidine, tetrahydropyran, dioxane, morpholine, thiane, dithiane, piperazine, and thiomorpholine.

[0034] In one embodiment, a 5- or 6-membered ring is provided that optionally contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, which refers to a saturated, partially saturated, or aromatic ring containing 5 or 6 atoms, including when all atoms are carbon or when 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur are present, such as, for example: cyclopentadiene, phenyl, thiophene, furan, pyrroline, pyrrole, pyrazoline, pyrazole, imidazoline, imidazole, oxazole, isopropyl alcohol, methyl ... Examples of the thiazole include isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, triazine, thiazine, oxazine, thiopyran, 2H-pyran, 4H-pyran, dioxin, 2H-thiopyran, 4H-thiopyran, 4H-1,2-oxazine, 2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,3-oxazine, 6H-1,3-oxazine, 4H-1,4-oxazine, 4H-1,4-thiazine, 2H-1,2-thiazine, and 6H-1,2-thiazine.

[0035] In one embodiment, a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur is provided, which refers to a saturated, partially saturated, or aromatic ring containing 5 or 6 atoms, wherein 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur are present; as defined above, for example, thiophene, furan, pyrroline, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyridine, pyrimidine, pyrazine, triazine, thiazine, oxazine, pyrroline, 4-H-pyran, thiopyran, etc.

[0036] In one embodiment, the ring is saturated.

[0037] In one embodiment, the ring is a saturated carbocyclic ring. In one embodiment, the ring is a saturated heterocyclic ring. In one embodiment, the ring is a partially saturated ring or an aromatic ring. In one embodiment, the ring is a partially saturated ring or an aromatic carbocyclic ring. In one embodiment, the ring is a partially saturated ring or an aromatic heterocyclic ring. In one embodiment, the ring is a 5-membered ring. In one embodiment, the ring is a 6-membered ring. In one embodiment, the 5- or 6-membered ring is unsaturated or aromatic. In one embodiment, the 5- or 6-membered ring is selected from cyclopentadiene, phenyl, pyridine and pyrazine (such as phenyl and pyridine). In one embodiment, Z' is a 5- or 6-membered heteroaryl having at least one heteroatom (e.g., 1 or 2 nitrogens) selected from N, O and S, wherein the heteroaryl is optionally selected from hydroxy, halogen (e.g., F, Cl), CN, C 1~3 It may contain 1, 2 or 3 substituents selected from alkyl.

[0038] A 5- or 6-membered ring heteroaryl herein is a ring containing 5 or 6 atoms, wherein at least one atom is a heteroatom (e.g., selected from nitrogen, oxygen, or sulfur); said 5- or 6-membered ring heteroaryl includes pyrrole, pyrazole, imidazole, thiophene, oxazole, isothiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiopyran, oxazine, and thiazine (including pyrrole, pyrazole, and pyridine and pyrimidine).

[0039] Unless the context indicates otherwise, a heterocyclic 5- to 6-membered ring herein generally refers to a non-aromatic ring containing 5 or 6 atoms, wherein at least one atom is a heteroatom (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S), such as pyrrolidine, imidazolidine, pyrazolidine, oxathiolane, tetrahydrofuran, morpholine, piperidine, piperazine, tetrahydropyran, thiane, dithiane, thiomorpholine, and the like.

[0040] A heterocyclic 9-13 membered ring herein refers to a bicyclic or tricyclic system containing 9-13 atoms, including, for example, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is saturated, partially unsaturated, or aromatic.

[0041] As used herein, 9-13 membered heteroaryl refers to a bicyclic or tricyclic system containing 9-13 atoms, wherein at least one ring is aromatic and at least one ring contains a heteroatom, e.g., 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; such 9-13 membered heteroaryls include indoline, indole, isoindole, indolizine, indazole, benzimidazole, azaindole, pyrazolopyrimidine, purine, benzofuran, isobenzofuran, benzothiophene, benzo[a]indole, benzo[b ... Examples of such an alkyl acrylate include isoxazole, benzisothiazole, benzoxazole, benzothiadiazole, adenine, guanine, tetrahydroquinoline, dihydroisoquinoline, quinoline, isoquinoline, quinolizine, quinoxaline, phthalazine, cinnoline, naphthyridine, pyridopyrimidine, pyridopyrazine, pteridine, chromene, isochromene, chromenone, benzoxazine, quinolinone, isoquinolinone, dibenzofuran, carbazole, acridine, phenothiazine, and 2,3,4,9-tetrahydro-1H-carbazole.

[0042] In one embodiment, R 4 is a 9- or 10-membered heteroaryl.

[0043] As used herein, 9-10 membered heteroaryl refers to a bicyclic ring system containing 9 or 10 atoms, wherein at least one ring is aromatic and at least one ring contains heteroatoms, e.g., 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; such 9-10 membered heteroaryls include indoline, indole, isoindole, indolizine, indazole, benzimidazole, azaindole, pyrazolopyrimidine, purine, benzofuranoside, benzophenone, benzophenone-1, benzophenone-2, benzophenone-3, benzophenone-4, benzophenone-5, benzophenone-6, benzophenone-7, benzophenone-8, benzophenone-9, benzophenone-11, benzophenone-12, benzophenone-13, benzophenone-14, benzophenone-15, benzophenone-16, benzophenone-17, benzophenone-18, benzophenone-19, benzophenone-20, benzophenone-21, benzophenone-22, benzophenone-23, benzophenone-24, benzophenone-25, benzophenone-26, benzophenone-27, benzophenone-28, benzophenone-29, benzophenone-30, benzophenone-31, benzophenone-32, benzophenone-33, benzophenone-34, benzophenone-35, benzophenone-36, benzophenone-37, benzophenone-38, benzophenone-39, benzophenone-40, benzophenone-41, benzophenone-42, benzophenone-43, benzophenone-44, benzophenone-45, benzophenone-46, benzophenone-47, benzophenone-4 Examples of suitable benzophenones include benzophenone, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, benzothiadiazole, adenine, guanine, tetrahydroquinoline, dihydroisoquinoline, quinoline, isoquinoline, quinolizine, quinoxaline, phthalazine, cinnoline, naphthyridine, pyridopyrimidine, pyridopyrazine, pyridopyrazine, pteridine, chromene, isochromene, chromenone, benzoxazine, quinolinone, and isoquinolinone.

[0044] In one embodiment, the 9 or 10 membered heteroaryl is selected from indolyl and benzimidazolyl (such as indol-3-yl or benzimidazol-2-yl).

[0045] As used herein, Ph refers to phenyl.

[0046] In one embodiment, R 1 is oxetanyl. In one embodiment, n' is 0. In one embodiment, n' is 1.

[0047] The compounds of the present disclosure can be prepared by the methods described herein.

[0048] In one embodiment, the compound of formula (III): [ka] The compound and Y′-R x wherein the process for preparing a compound of formula (I) is provided by reacting where R 1 , R 2 , R 2 ′, R 3 , R 4 , X, m, and n are as defined for compounds of formula (I), Y′ is an activated derivative of Y (Y is also defined in formula (I)), and R X is an activating group. In one embodiment, the reaction is a condensation reaction. General routes 1-8 can be used to prepare compounds of the present disclosure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0049] In one embodiment, any one of general routes 1 to 8 is used.

[0050] In one embodiment, any one of general routes 1 to 4 is used. In one embodiment, any one of general routes 5 to 8 is used. In one embodiment, any one of general routes 1, 2 or 5 to 8 is used. In one embodiment, general route 1 is used. In one embodiment, general route 2 is used. In one embodiment, general route 3 is used. In one embodiment, general route 4 is used. In one embodiment, general route 5 is used. In one embodiment, general route 6 is used. In one embodiment, general route 7 is used. In one embodiment, general route 8 is used.

[0051] Protecting groups may be necessary to protect chemically sensitive groups during one or more of the reactions described above in order to efficiently carry out the manufacturing steps. Thus, conventional protecting groups may be utilized to protect intermediate compounds, if desired or necessary. Protecting groups and methods for their removal are described in "Protective Groups in Organic Synthesis" (Theodora W. Greene and Peter GM Wuts, John Wiley & Sons, Revised 4th Edition, 2006, ISBN-10:0471697540).

[0052] Examples of salts of the compounds of the present disclosure include all pharmaceutically acceptable salts, including, but not limited to, acid addition salts of strong mineral acids (such as HCl and HBr salts) and strong organic acid addition salts (such as methanesulfonate salts).

[0053] The present disclosure also includes solvates of the compounds disclosed herein. Examples of solvates include hydrates.

[0054] Novel intermediates are an aspect of the present invention.

[0055] A further aspect of the present disclosure is a method of making the compounds disclosed herein.

[0056] Also provided herein are pharmaceutical compositions comprising a compound according to the present disclosure and an excipient, diluent, or carrier. Remington's Pharmaceutical Sciences (Mack Publishing Company, NJ, 1991) contains a thorough discussion of pharmaceutically acceptable carriers.

[0057] The pharmaceutical compositions of the present disclosure can be administered by a variety of routes, including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, transdermal (see, e.g., WO 98 / 20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal, or rectal. Hypodermic sprays can also be used to administer the pharmaceutical compositions of the present invention.

[0058] In one embodiment, the therapeutic composition may be prepared as an injectable solution or suspension.Suitable solid forms can also be prepared that are in solid form before injection and are mixed with a liquid vehicle to form a solution or suspension.Suitable liquids for reconstituting such solid forms (including lyophilized solids) may be selected from aqueous solutions, such as saline, dextrose, or water for injection.In one embodiment, the reconstituted liquid formulation is isotonic.

[0059] In one embodiment, a pharmaceutical composition according to the present disclosure is provided as a tablet or capsule for oral administration.

[0060] treatment The present disclosure also includes methods of treating a patient (e.g., for the treatment of cancer) comprising administering a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutical composition comprising same).

[0061] Also provided are compounds of the present disclosure (or pharmaceutical compositions comprising same) for use in therapy (eg, for use in treating cancer).

[0062] In a further aspect, there is provided a compound of the present disclosure (or a pharmaceutical composition comprising same) for use in the manufacture of a therapeutic medicament for the treatment of cancer.

[0063] In one embodiment, the cancer is an epithelial cancer, for example, selected from liver cancer (such as hepatocellular carcinoma), biliary tract cancer, breast cancer (such as estrogen receptor non-positive breast cancer), prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, lung cancer, gastric cancer, pancreatic cancer, bone cancer, bladder cancer, head and neck cancer, thyroid cancer, skin cancer, renal cancer, and esophageal cancer, for example, gastric cancer.

[0064] In one embodiment, the cancer is selected from the group comprising hepatocellular carcinoma, cholangiocarcinoma, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic and esophageal cancer.

[0065] In one embodiment, the cholangiocarcinoma is cancer at a site selected from the intrahepatic bile duct, left hepatic duct, right hepatic duct, common hepatic duct, cystic duct, common bile duct, ampulla of Vater, and combinations thereof.

[0066] In one embodiment, the cholangiocarcinoma is cancer of the intrahepatic bile duct. In one embodiment, the cholangiocarcinoma is cancer of the left hepatic duct. In one embodiment, the cholangiocarcinoma is cancer of the right hepatic duct. In one embodiment, the cholangiocarcinoma is cancer of the common hepatic duct. In one embodiment, the cholangiocarcinoma is cancer of the cystic duct. In one embodiment, the cholangiocarcinoma is cancer of the common bile duct. In one embodiment, the cholangiocarcinoma is cancer of the ampulla of Vater. In one embodiment, the epithelial cancer is carcinoma.

[0067] In one embodiment, the treatment according to the present disclosure is adjuvant therapy, for example, adjuvant therapy after surgery.

[0068] In one embodiment, the therapy according to the present disclosure is neoadjuvant therapy, for example, neoadjuvant therapy to shrink a tumor prior to surgery.

[0069] In one embodiment, the tumor is a solid tumor. In one embodiment, the cancer is a primary cancer, a secondary cancer, a metastatic cancer, or a combination thereof. In one embodiment, the treatment according to the present disclosure is suitable for treating a secondary tumor. In one embodiment, the cancer is a metastatic cancer. In one embodiment, the treatment according to the present disclosure is suitable for treating a primary cancer and a metastatic cancer. In one embodiment, the treatment according to the present disclosure is suitable for treating a secondary cancer and a metastatic cancer. In one embodiment, the treatment according to the present disclosure is suitable for treating a primary cancer, a secondary cancer, and a metastatic cancer.

[0070] In one embodiment, treatment according to the present disclosure is suitable for treating cancerous cells in lymph nodes.

[0071] In one embodiment, said liver cancer is primary liver cancer.In one embodiment, said liver cancer is secondary liver cancer.In one embodiment, said liver cancer is stage 1, 2, 3A, 3B, 3C, 4A or 4B.

[0072] In one embodiment, the gastric cancer is at stage 0, I, II, III or IV.

[0073] The precise therapeutically effective amount for a human subject will depend on the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, number and frequency of administration, drug combination, and responsiveness and tolerance to therapy. This amount can be determined by routine testing and is within the discretion of the clinician. Generally, a therapeutically effective amount will be 0.01 mg / kg to 1000 mg / kg, e.g., 0.1 mg / kg to 500 mg / kg. Pharmaceutical compositions may conveniently be provided in unit dose form, containing a predetermined amount of the active agent of the invention per dose.

[0074] Combination therapy In one embodiment, the compounds of the present disclosure are used in combination therapy, for example, where the additional therapy is an anti-cancer therapy.

[0075] In one embodiment, the anti-cancer therapy is chemotherapy.

[0076] As used herein, chemotherapeutic agent and chemotherapy or cytotoxic agent are used synonymously unless the context indicates otherwise.

[0077] Chemotherapy, as used herein, is intended to refer to certain antitumor chemical agents or drugs (e.g., alkylating agents, antimetabolites including thymidylate synthase inhibitors, anthracyclines, microtubule inhibitors including plant alkaloids, topoisomerase inhibitors, PARP inhibitors, and other antitumor agents) that "selectively" destroy malignant cells and tissues. Of course, many of these agents have serious side effects, so "selectively" is used loosely in the above context.

[0078] The preferred dose may be selected by the physician based on the nature of the cancer being treated.

[0079] Examples of alkylating agents that may be used in the methods of the present disclosure include alkylating agents selected from nitrogen mustards, nitrosoureas, tetrazines, aziridines, platins and derivatives, and non-classical alkylating agents.

[0080] Platinum-containing chemotherapeutic agents (also called platins) include, for example, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, and poplatin (liposomal cisplatin), particularly cisplatin, carboplatin, and oxaliplatin.

[0081] The dose of cisplatin ranges from about 20 to about 270 mg / m depending on the actual cancer. 2 The dose ranges from about 70 to about 100 mg / m 2 It is often in the range of

[0082] Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, and busulfan.

[0083] Nitrosoureas include N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, and streptozotocin. Tetrazines include dacarbazine, mitozolomide, and temozolomide.

[0084] Aziridines include thiotepa and diaziquone (AZQ).

[0085] Examples of antimetabolites that may be used in the methods of the present disclosure include antifolates (e.g., methotrexate and pemetrexed), purine analogs (e.g., thiopurines (such as azathioprine, mercaptopurine, thiopurine), fludarabine (including the phosphate form), pentostatin and cladribine), pyrimidine analogs (e.g., fluoropyrimidines (such as 5-fluorouracil and its prodrugs, such as capecitabine [Xeloda®])), floxuridine, gemcitabine, cytarabine, decitabine, raltitrexed (tomudex) hydrochloride, cladribine, and 6-azauracil.

[0086] Examples of anthracyclines that may be used in the methods of the present disclosure include daunorubicin (daunomycin), daunorubicin (liposomal), doxorubicin (adriamycin), doxorubicin (liposomal), epirubicin, idarubicin, valrubicin (currently used only to treat bladder cancer), and mitoxantrone (an anthracycline analog), particularly doxorubicin.

[0087] Examples of microtubule inhibitors that may be used in the methods of the present disclosure include vinca alkaloids and taxanes.

[0088] Vinca alkaloids include entirely natural chemicals such as vincristine and vinblastine, and also semisynthetic vinca alkaloids such as vinorelbine, vindesine, and vinflunine.

[0089] Taxanes include paclitaxel, docetaxel, abraxane, cabazitaxel, and derivatives thereof. Derivatives of taxanes herein include modified versions of taxanes, such as taxol, for example, in micelle formulations. Derivatives also include chemical derivatives that are modified using synthetic chemistry with taxanes as starting materials.

[0090] Topoisomerase inhibitors that may be used in the methods of the present disclosure include type I topoisomerase inhibitors, type II topoisomerase inhibitors, and type II topoisomerase poisons. Type I inhibitors include topotecan, irinotecan, indotecan, and indimitecan. Type II inhibitors include genistein and ICRF193, which has the following structure: [ka]

[0091] Type II poisons include amsacrine, etoposide, etoposide phosphate, teniposide, and doxorubicin and fluoroquinolones.

[0092] In one embodiment, the chemotherapeutic combination used is, for example, a platin and 5-FU or a prodrug thereof, such as cisplatin or oxaplatin and capecitabine or gemcitabine (such as FOLFOX).

[0093] In one embodiment, the chemotherapy comprises a combination of chemotherapeutic agents, particularly cytotoxic chemotherapeutic agents.

[0094] In one embodiment, the chemotherapy combination comprises a platin (such as cisplatin) and fluorouracil or capecitabine.

[0095] In one embodiment, the chemotherapy combination is capecitabine and oxaliplatin (Xelox).

[0096] In one embodiment, the chemotherapy is a combination of folinic acid and 5-FU, optionally in combination with oxaliplatin.

[0097] In one embodiment, the chemotherapy is a combination of folinic acid, 5-FU, and irinotecan (FOLFIRI), optionally in combination with oxaliplatin (FOLFIRINOX). The regimen consists of: irinotecan (180 mg / m 2 administered intravenously for 90 minutes) and folinic acid (400 mg / m 2 [or 2x 250mg / m 2 ] administered as an intravenous infusion over 120 minutes, followed by fluorouracil (400–500 mg / m 2 bolus intravenous administration), followed by fluorouracil (2400–3000 mg / m 2 (46-hour intravenous infusion). This cycle is typically repeated every two weeks. The doses listed above may vary from cycle to cycle.

[0098] In one embodiment, the chemotherapy combination uses a microtubule inhibitor, such as vincristine sulfate, epothilone A, N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide (ABT-751), a taxol-derived chemotherapy agent, such as paclitaxel, abraxane, or docetaxel, or a combination thereof.

[0099] In one embodiment, the chemotherapy combination comprises an antimetabolite such as capecitabine (xeloda), fludarabine phosphate, fludarabine (Fludara), decitabine, raltitrexed (Tomudex), gemcitabine hydrochloride and cladribine.

[0100] In one embodiment, the anticancer therapy combination uses an mTor inhibitor. Examples of mTor inhibitors include everolimus (RAD001), WYE-354, KU-0063794, papamycin (sirolimus), temsirolimus, deforolimus (MK-8669), AZD8055, and BEZ235 (NVP-BEZ235).

[0101] In one embodiment, the anticancer therapy combination uses a MEK inhibitor. Examples of MEK inhibitors include AS703026, CI-1040 (PD184352), AZD6244 (selumetinib), PD318088, PD0325901, AZD8330, PD98059, U0126-EtOH, BIX02189, or BIX02188.

[0102] In one embodiment, the chemotherapy combination uses an AKT inhibitor. Examples of AKT inhibitors include MK-2206 and AT7867.

[0103] In one embodiment, the anticancer therapy uses an Aurora kinase inhibitor, examples of which include Aurora A inhibitor I, VX-680, AZD1152-HQPA (balasertib), SNS-314 mesylate, PHA-680632, ZM-447439, CCT129202, and hesperadin.

[0104] In one embodiment, the chemotherapy combination uses a p38 inhibitor, such as N-[4-({4-[3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido]naphthalen-1-yloxy}methyl)pyridin-2-yl]-2-methoxyacetamide, as disclosed in WO2010 / 038086.

[0105] In one embodiment, the combination utilizes a Bcl-2 inhibitor. Examples of Bcl-2 inhibitors include obatoclax mesylate, ABT-737, ABT-263 (navitoclax), and TW-37.

[0106] In one embodiment, the chemotherapy combination includes ganciclovir, which may assist in controlling the immune response and / or tumor angiogenesis.

[0107] In one embodiment, the anti-cancer therapy includes a PARP inhibitor.

[0108] In one embodiment, the anti-cancer therapy includes an inhibitor of cancer metabolism that specifically inhibits the activity of the DHODH enzyme.

[0109] In one embodiment, a compound of the present disclosure is used in combination with a checkpoint inhibitor (e.g., in a combination therapy). Accordingly, the present disclosure provides a combination therapy comprising a compound or pharmaceutical composition of the present disclosure and a checkpoint inhibitor or a combination of checkpoint inhibitors.

[0110] In one embodiment, the checkpoint inhibitor is selected from the group comprising PD-1 inhibitors, PD-L1 / L2 inhibitors, CTLA-4 inhibitors, checkpoint kinase inhibitor 1 (CHEK1 / CHK1), checkpoint kinase inhibitor 2 (CHEK2 / CHK2), ATM and Rad3 related gene product (ATR) inhibitors, ataxia telangiectasia mutated gene product (ATM) inhibitors, Wee1 dual specificity protein kinase (Wee1) inhibitors, poly ADP-ribose polymerase (PARP) inhibitors and Myt1 inhibitors.

[0111] In one embodiment, the checkpoint inhibitor is selected from the group comprising a PD-1 inhibitor, a PD-L1 / L2 inhibitor, a CTLA-4 inhibitor, and combinations thereof. In one embodiment, a combination of a PD-1 inhibitor and a PD-L1 inhibitor is used. In one embodiment, a combination of a PD-1 and a CTA-4 inhibitor is used. In one embodiment, a combination of a PD-L1 and a CTA-4 inhibitor is used. In one embodiment, a combination of a PD-1, PD-L1 and a CTA-4 inhibitor is used.

[0112] In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as KEYTRUDA®, lambrolizumab, and MK-3475), PDR001 (Novartis; also known as spartalizumab), MEDI-0680 (AstraZeneca; also known as AMP-514), cemiplimab (Regeneron; also known as REGN-2810), JS001 or "toripalimab" (TAIZHOU JUNSHI PHARMA), BGB-A317 ("tislelizumab"; Beigene), INCSHR1210 (Jiangsu Hengrui "camrelizumab" (Medicine; also known as SHR-1210), TSR-042 or "dostallimab" (Tesaro Biopharmaceutical; also known as ANB011), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals; also known as WBP3055), STI-1110 (Sorrento Therapeutics), AGEN2034 or "balstilimab" (Agenus), MGA012 or "retifanlimab" (Macrogenics), IBI308 or "sintilimab" (Innovent), BCD-100 or "bevacizumab" (Biocad), and JTX-4014 (Jounce Therapeutics).

[0113] In one embodiment, the checkpoint inhibitor is pembrolizumab. In one embodiment, the checkpoint inhibitor is nivolumab. In one embodiment, the checkpoint inhibitor is cemiplimab. In one embodiment, the checkpoint inhibitor is dostarlimab.

[0114] In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor, hi one embodiment, the PD-L1 inhibitor is selected from the group including atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), KN035, CK-301 (Checkpoint Therapeutics), AUNP12 (Aurigene), CA-170 (Aurigen / Curis), and BMS-986189 (BMS).

[0115] In one embodiment, the checkpoint inhibitor is atezolizumab. In one embodiment, the checkpoint inhibitor is avelumab. In one embodiment, the checkpoint inhibitor is durvalumab.

[0116] In one embodiment, the checkpoint inhibitor is a CTLA-4 inhibitor, hi one embodiment, the CTLA-4 inhibitor is selected from the group comprising ipilimumab (Yervoy), tremelimumab.

[0117] In one embodiment, the checkpoint inhibitor is an antibody or binding fragment specific for a checkpoint protein, particularly those disclosed herein (such as PD-1, PD-L1, or CTLA-4).

[0118] In one embodiment, the checkpoint kinase inhibitor is independently selected from the following: 3-[(Aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide hydrochloride;(3R,4S)-4-[[2-(5-fluoro-2-hydroxyphenyl)-6,7-dimethoxy-4-quinazolinyl]amino]-α,α-dimethyl-3-pyrrolidinemethanol dihydrochloride;4,4'-Diacetyldiphenylurea bis(guanylhydrazone) ditosylate;9-Hydroxy-4-phenyl-pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione;(R)-α-Amino-N-[5,6-di Hydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide; 9,10,11,12-tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1,3(2H)-dione; 4'-[5-[[3-[(cyclopropylamino)methyl]phenyl]amino]-1H-pyrazol-3-yl]-[1,1'-biphenyl]-2,4-diol; and (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).

[0119] In one embodiment, the one or more therapies used in the methods herein are regular, meaning continuous or frequent treatment with low doses of anti-cancer drugs, often administered in combination with other treatments.

[0120] In one embodiment, multiple cycles of treatment (such as chemotherapy) are used, for example, 2, 3, 4, 5, 6, 7 or 8 cycles of treatment.

[0121] In the context of this specification, "comprising" is intended to mean "including." Where technically appropriate, embodiments of the invention may be combined.

[0122] In this specification, embodiments are described as including a particular feature / element, and the disclosure also includes other embodiments that consist of, or consist essentially of, that feature / element.

[0123] Technical references, such as patents and patent applications, are incorporated herein by reference.

[0124] Any embodiment specifically and explicitly recited herein may be the basis for a waiver, either alone or in combination with one or more additional embodiments.

[0125] The present invention will now be described with reference to the following examples, which are merely illustrative and should not be construed as limiting the scope of the invention.

[0126] Example The compounds of the invention can be made by methods similar to those described in WO2020 / 039093 and PCT / SG2021 / 050095, both of which are incorporated herein by reference.

[0127] General method 1 To a flask containing 1,4-dioxane (6 mL) was added 2,4,6-trichloropyrimidin-5-ol (1.0 equiv.), tert-butyl N-(2-hydroxyethyl)carbamate (1.10 equiv.), triphenylphosphine (1.20 equiv.), and diisopropyl azodicarboxylate (1.20 equiv.) and the resulting mixture was stirred at room temperature for 1 hour. The reaction was concentrated to dryness in vacuo to give a residue which was then purified by automated flash column chromatography on silica (40 g cartridge) eluting with 15% EtOAc in isohexane to give the desired product as a solid.

[0128] General method 2a Aryl halide (1 equiv.), amine (1.1 equiv.), methanol or ethanol (10 mL / mmol), and triethylamine (2 equiv.) were placed in a suitable round-bottom flask or reaction vial and stirred at ambient temperature for 3–16 h (reaction monitored by UPLC analysis). The reaction mixture was evaporated to dryness, and the resulting residue was partitioned with ethyl acetate and water. The organic phase was separated and washed successively with saturated bicarbonate solution, water, and brine, then dried over sodium sulfate; filtered, and evaporated. Purification by chromatography or trituration was performed, if necessary.

[0129] General method 2b A 60% solution of sodium hydride (1.00 equiv.) in mineral oil and indole-3-ethanol (1.10 equiv.) in THF were stirred for 30 minutes and added to a solution of the appropriate chloropyrimidine (1.00 equiv.) in THF at -78 °C. The mixture was stirred overnight, allowing the cooling bath to dry (i.e., slowly warm) over time. After diluting the reaction with DCM, the mixture was washed with 2.5 M citric acid solution and water. The organic phase was concentrated to dryness to give the product. Purification by chromatography or trituration was performed, if necessary.

[0130] General method 3 A solution of the Boc-protected amine (1.0 equiv.) in dichloromethane (10 mL / mmol) was treated with 4N hydrogen chloride in 1,4-dioxane (25.0 equiv.), and the resulting mixture was stirred at ambient temperature for 1 h. The reaction was concentrated, and the resulting residue was triturated with diethyl ether (50 mL / mmol); it was filtered and dried under vacuum to give the desired product.

[0131] General method 4 A solution of the appropriate intermediate (1.0 equiv.) in iso-propan-2-ol was treated with triethylamine (14 equiv.), and the resulting mixture was stirred in a microwave oven (CEM, 200 watts) at 110-160°C for 2-6 hours. The reaction was concentrated to dryness to give a solid residue; it was suspended in water with stirring. The mixture was filtered, and the solid was dried under vacuum to give the desired product as a solid. Purification by chromatography or trituration was carried out, if necessary.

[0132] General method 5a An aryl halide (1 equiv.), an arylboronic acid (1.5–2.0 equiv.), potassium carbonate (1.5–2.0 equiv.), and dioxane / water (5:1, ca. 60 vol.) were added to a suitable round-bottom flask or reaction vial. After flushing the headspace with nitrogen, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloride (0.2–0.3 equiv.) was added. The reaction mixture was heated at 100°C under a nitrogen atmosphere for 2–24 h until the reaction was complete as determined by UPLC analysis. The reaction mixture was evaporated to dryness. Purification by chromatography or trituration was performed, if necessary.

[0133] General method 5b Aryl halide (1 equiv.), arylboronic acid (1.5–2.0 equiv.), tripotassium phosphate (0.5 M aqueous solution, 1.5–2.0 equiv.), and dioxane were added to a suitable round-bottom flask or reaction vial. After flushing the headspace with nitrogen, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.2–0.3 equiv.) was added. The reaction mixture was heated at 100°C under a nitrogen atmosphere for 2–24 h until the reaction was judged complete by UPLC analysis. Purification by chromatography or trituration was performed, if necessary.

[0134] General method 5c To the (tri-n-butylstannyl)aryl (1.10 equiv.) was added the chloro-aryl (1.00 equiv.) in toluene (4 mL), followed by tetrakis(triphenylphosphine)palladium(0) (0.2 equiv.). The solution was heated at 110° C. for 1 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated to dryness. Purification by chromatography or trituration was carried out if necessary.

[0135] Intermediate of Example 1 1.1:2,4,6-trichloropyrimidin-5-ol [ka] A stirred solution of 2,4,6-trichloro-5-methoxy-pyrimidine (1.05 g, 4.92 mmol, 1.0 equiv.) in dichloromethane (35 mL) was cooled to 0° C. and treated with 1 M boron tribromide in dichloromethane (17 mL, 17.2 mmol, 3.5 equiv.); the resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was cooled to 0° C. and diluted by the sequential addition of methanol (10 mL) and water (50 mL); the resulting mixture was extracted with dichloromethane (2×30 mL). The combined organic extracts were dried (NaSO), filtered, and concentrated in vacuo to give 2,4,6-trichloropyrimidin-5-ol as an off-white solid (1.01 g, 4.81 mmol, 98% yield). This material was used directly in the next step without further purification. UPLC-MS analysis (2 minutes, acidic): rt=0.79 minutes, m / z=196.9 / 198.9 / 200.9 [MH]-, purity 93%. 13 C NMR (101MHz, DMSO) δ 149.73, 145.68, 145.64.

[0136] 1.2: tert-Butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate [ka] Prepared using 2,4,6-trichloropyrimidin-5-ol (0.35 g, 1.63 mmol, 1.0 equiv) and tert-butyl N-(2-hydroxyethyl)carbamate (0.28 mL, 1.80 mmol, 1.10 equiv) according to general procedure 1. The crude product was purified by column chromatography (40 g cartridge) eluting with 15% EtOAc in isohexane to give tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate as a white solid (0.42 g, 1.21 mmol, 74.21% yield). UPLC-MS analysis (2 min, basic): rt=1.18 min, no ionization), purity 100%. 1 H NMR (400MHz, DMSO-D6) δ 7.03(t, J=5.6Hz, 1H), 4.13(t, J=5.7Hz, 2H), 3.37 - 3.33(m, 2H), 1.39(s, 9H).

[0137] 1.3: tert-Butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (0.36 g, 1.05 mmol, 1.0 equiv.) and tryptamine (0.18 g, 1.10 mmol, 1.05 equiv.). The reaction was concentrated to dryness, and the residue was dispersed in water (25 mL). The resulting suspension was filtered to give tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate as an off-white solid (500 mg, 1.05 mmol, 99.99% yield). This product was used in the next step without further purification. UPLC-MS analysis (2 minutes, basic): rt=1.25 minutes (M+H+=466.2 / 468.3 / 470.3), purity 98% 1 H NMR (400MHz, DMSO-D6) δ 10.83(s, 1H), 8.03(d, J=6.2Hz, 1H), 7.64(d, J=7.9Hz, 1H), 7.35(dt, J=8.1, 1.0Hz, 1H), 7.19(d, J=2.3Hz, 1H), 7.13 - 7.00(m, 2H), 7.03 - 6.93(m, 1H), 3.92(t, J=5.4Hz, 2H), 3.62(q, J=6.9Hz, 2H), 3.30 - 3.22(m, 2H), 2.99(t, J=7.6Hz, 2H), 1.39(s, 9H).

[0138] 1.4:5-(2-aminoethoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate (1.00 equiv, 0.50 g, 1.05 mmol) was used to give 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride as an off-white solid (0.47 g, 1.05 mmol, 99.97% yield). This product was used in the next step without further purification. UPLC-MS analysis (2 min, basic): rt=1.09 min (M+H+=366.2 / 368.2 / 370.2), purity 92%. 1H NMR (400MHz, DMSO-D6) δ 10.86(d, J=2.4Hz, 1H), 8.38(t, J=6.0Hz, 1H), 8.30(s, 3H), 7.67(d, J=7.8Hz, 1H), 7.35(d, J=8.1Hz, 1H), 7.20(d, J=2.3Hz, 1H), 7.14 - 7.04(m, 1H), 7.04 - 6.94(m, 1H), 4.14(t, J=5.0Hz, 2H), 3.70 - 3.58(m, 2H), 3.23(h, J=5.5Hz, 2H), 3.06 - 2.91(m, 2H).

[0139] 1.5:2-Chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (1.00 equiv, 0.25 g, 0.571 mmol) was used to give 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (0.18 g, 0.488 mmol, 85.52% yield), which was used in the next step without further purification. UPLC-MS analysis (2 minutes, basic): rt=1.03 minutes (M+H+=330.2 / 332.2), purity 91% 1 H NMR (400MHz, DMSO-D6) δ 10.79(s, 1H), 7.67(d, J=7.9Hz, 1H), 7.33(d, J=7.9Hz, 1H), 7.22 - 6.91(m, 4H), 6.61(s, 1H), 4.07(s, 2H), 3.60 - 3.48(m, 2H), 3.39(s, 2H), 2.90(t, J=7.9Hz, 2H).

[0140] Example 1: 2-(5-Fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.0 equiv., 150 mg, 0.414 mmol) and 5-fluoropyridine-3-boronic acid (2.0 equiv., 117 mg, 0.828 mmol). The crude product was purified by column chromatography (40 g column) eluting with a 90–100% (v / v) EtOAc gradient in isohexane to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (50 mg, 0.128 mmol, 30.94% yield). UPLC-MS analysis (4 min, basic): rt=1.79 min (M+H+=391.3), 100% purity. 1 H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 9.23(t, J=1.8Hz, 1H), 8.59(d, J=2.9Hz, 1H), 8.28 - 8.15(m, 1H), 7.63(dd, J=7.9, 1.1Hz, 1H), 7.34(dt, J=7.9, 0.9Hz, 1H), 7.20(d, J=2.2Hz, 1H), 7.14 - 7.03(m, 1H), 7.03 - 6.95(m, 1H), 6.92(d, J=2.6Hz, 1H), 6.45(t, J=5.9Hz, 1H), 4.25 - 4.08(m, 2H), 3.80 - 3.62(m, 2H), 3.45(q, J=3.8Hz, 2H), 3.07 - 2.91(m, 2H). 19 F NMR (376MHz, DMSO-D6) δ -128.14.

[0141] Example 2: 2-(4-Fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] General procedure 5b was followed using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (65 mg, 0.18 mmol, 1.0 equiv.) and 4-fluorobenzeneboronic acid (50 mg, 0.359 mmol, 2.0 equiv.). The crude product was purified by column chromatography (20 g column) eluting with a 30–80% (v / v) EtOAc gradient in isohexane to give 2-(4-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a pale yellow solid (33 mg, 0.0839 mmol, 46.77% yield). UPLC-MS analysis (4 min, basic): rt=2.00 min (M+H+=390.3, MH-=388.2), purity 99%. 1 H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 8.38 - 8.11(m, 2H), 7.63(dt, J=7.8, 1.0Hz, 1H), 7.35(dt, J=8.1, 0.9Hz, 1H), 7.33 - 7.12(m, 3H), 7.14 - 7.03 (m, 1H), 7.03 - 6.94 (m, 1H), 6.84 - 6.67 (m, 1H), 6.27 (t, J=5.9Hz, 1H), 4.24 - 4.06 (m, 2H), 3.83 - 3.63(m, 2H), 3.43(q, J=3.7Hz, 2H), 3.11 - 2.89 (m, 2H). 19 F NMR (376MHz, DMSO-D6) δ -113.65.

[0142] Example 3: 2-(3,5-difluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (65 mg, 0.18 mmol, 1.0 equiv) and 3,5-difluorobenzene-boronic acid (57 mg, 0.36 mmol, 2.0 equiv). The crude product was purified by column chromatography (20 g cartridge) eluting with a 30–80% (v / v) EtOAc gradient in isohexane to give 2-(3,5-difluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (9.0 mg, 0.0221 mmol, 12.32% yield). UPLC-MS analysis (4 min, basic): rt=2.14 min, m / z=408.2 [M+H]+, 100% purity. 1 H NMR (400MHz, DMSO-D6) δ 10.82(s, 1H), 7.95 - 7.76(m, 2H), 7.65(dd, J=7.7, 1.1Hz, 1H), 7.41 - 7.31(m, 1H), 7.31 - 7.22 (m, 1H), 7.19 (d, J=2.3Hz, 1H), 7.12 - 7.04 (m, 1H), 7.02 - 6.93 (m, 1H), 6.93 - 6.84 (m, 1H), 6.42 (t, J=5.9Hz, 1H), 4.20 - 4.06(m, 2H), 3.79 - 3.61(m, 2H), 3.44(q, J=3.7Hz, 2H), 3.03 - 2.88(m, 2H). 19 F NMR (376MHz, DMSO-D6) δ -110.27.

[0143] Intermediate of Example 4 4.1: tert-Butyl N-[2-[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxyethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (0.34 g, 0.99 mmol, 1.0 equiv) and (R)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (203 mg, 1.09 mmol, 1.10 equiv) in ethanol (3 mL) at 50° C. The reaction was concentrated to dryness in vacuo to give an oily residue, which was dispersed in water (25 mL). The resulting suspension was filtered and the solid dried under vacuum to give tert-butyl N-[2-[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxyethyl]carbamate as an off-white solid (0.33 g, 0.693 mmol, 70.33% yield), which was further purified and used directly in the next step. UPLC-MS analysis (2 min, basic): rt=1.30 min, m / z=492.1 / 494.1 / 496.1 [M+H]+, purity 97%. 1 H NMR (400MHz, DMSO-D6) δ 10.75(s, 1H), 7.90(d, J=8.4Hz, 1H), 7.34(d, J=7.8Hz, 1H), 7.26(d, J=7.9Hz, 1H), 7.17(d, J=6. 8Hz, 1H), 7.01(t, J=7.6Hz, 1H), 6.93(t, J=7.4Hz, 1H), 4.33(s, 1H), 4.00(d, J=5.9Hz, 2H), 3.19 - 2.96(m, 2H), 2.88(s, 2H), 2.78 - 2.63(m, 1H), 2.13(s, 1H), 2.08 - 1.96 (m, 1H), 1.39 (s, 9H), 1.18 (t, J=7.4Hz, 1H).

[0144] 4.2: (3R)-N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride [ka] Prepared according to general procedure 3 using tert-butyl N-[2-[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxyethyl]carbamate (500 mg, 0.99 mmol, 1.0 equiv.). The crude product was dissolved in methanol (3 mL) and stirred, and the resulting solution was treated with diethyl ether (50 mL). The resulting suspension was filtered, and the solid was washed with diethyl ether to give (3R)-N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride as an off-white solid (0.33 g, 0.693 mmol, 70.33% yield). This material was used directly in the next step without further purification. UPLC-MS analysis (2 min, basic): rt=1.17 min, m / z=392.1 / 394.1 / 396.1 [M+H]+, purity 90%. 1 H NMR (400MHz, DMSO-D6) δ 10.77(s, 1H), 8.26(s, 3H), 8.07(d, J=8.4Hz, 1H), 7.33(d, J=7.7Hz, 1H), 7.27(d, J=8.0Hz, 1H), 7.01(t, J=7.5Hz, 1H), 6.94(t, J=7.4Hz, 1H), 4.37(d, J=10.6Hz, 1H), 4.19(t, J=5.3Hz, 2H), 3.31 - 3.22 (m, 2H), 3.02 (dd, J=14.8, 5.5Hz, 1H), 2.98 - 2.70 (m, 3H), 2.22 - 2.00 (m, 2H).

[0145] 4.3: 2-Chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, (3R)-N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride (130 mg, 0.27 mmol, 1.0 equiv) was used to give 2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (98 mg, 0.273 mmol, 99.92% yield). This material was used directly in the next step without further purification. UPLC-MS analysis (2 min, basic): rt=1.08 min, m / z=356.2 / 358.2 [M+H]+, purity 99%. 1 H NMR (400MHz, DMSO-D6) δ 10.70(s,1H), 7.53 - 7.06(m,3H), 7.10 - 6.80(m,2H), 6.42(d, J=8.6Hz, 1H), 4.27(s,1H), 4.09(s,2H), 3.40(s,2H), 3.02 - 2.78(m,3H), 2.67 - 2.59(m,1H), 2.00(s,2H).

[0146] Example 4: 2-(5-Fluoro-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (95 mg, 0.26 mmol, 1.0 equiv) and 5-fluoropyridine-3-boronic acid (74 mg, 0.53 mmol, 2.0 equiv). The crude product was purified by column chromatography (40 g cartridge) eluting with a 90–100% (v / v) EtOAc gradient in isohexane to give 2-(5-fluoro-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (48 mg, 0.115 mmol, 43.61% yield). UPLC-MS analysis (4 min, basic): rt=1.95 min, m / z=417.2 [M+H]+, 100% purity. 1 H NMR (400MHz, DMSO-D6) δ 10.73(s, 1H), 9.18(t, J=1.7Hz, 1H), 8.56(d, J=2.9Hz, 1H), 8.27 - 8.11(m, 1H), 7.33(d, J=7.7Hz, 1H), 7.26(dt, J=8.0, 1.0Hz, 1H), 7.08 - 6.85(m, 3H), 6.17(d, J=8.3Hz, 1H), 4.65 - 4.43(m, 1H), 4.27 - 4.07(m, 2H), 3.52 - 3.41(m, 2H), 3.06(dd, J=14.9, 5.3Hz, 1H), 3.01 - 2.88 (m, 1H), 2.88 - 2.78(m, 1H), 2.74 - 2.63(m, 1H), 2.20 - 2.10(m, 1H), 2.07 - 1.92(m, 1H). 19 F NMR (376MHz, DMSO-D6) δ -128.07.

[0147] Intermediate of Example 5 5.1: tert-Butyl N-[1-methyl-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate [ka] Prepared using 2,4,6-trichloropyrimidin-5-ol (0.30 g, 1.43 mmol, 1.0 equiv) and N-Boc-2-amino-1-propanol (0.24 mL, 1.57 mmol, 1.10 equiv) according to general procedure 1. The reaction was concentrated to dryness and the residue was purified by automated flash column chromatography on silica (40 g cartridge) eluting with 18–20% EtOAc in isohexane to give tert-butyl N-[1-methyl-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate as a white solid (208 mg, 0.583 mmol, 40.81% yield). UPLC-MS analysis (2 min, basic): rt=1.26 min, no ionization, 100% purity. 1 H NMR (400MHz, DMSO) δ 6.92 (d, J=7.9Hz, 1H), 4.01 (q, J=5.0Hz, 2H), 3.86 (dd, J=13.8, 7.2Hz, 1H), 1.38 (s, 9H), 1.18 (dd, J=9.2, 6.8Hz, 3H)

[0148] 5.2: tert-Butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxy-1-methylethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[1-methyl-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate (0.21 g, 0.58 mmol, 1.0 equiv.) and tryptamine (0.098 g, 0.61 mmol, 1.05 equiv.). The reaction was concentrated to dryness to give an oily residue, which was suspended in water (25 mL) with stirring. The resulting suspension was filtered to give tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxy-1-methylethyl]carbamate as an off-white solid (267 mg, 0.478 mmol, 81.95% yield). This material was used directly in the next step without further purification. UPLC-MS analysis (2 min, basic): rt=1.30 min, m / z=480.2 [M+H]+, purity 86%. 1 H NMR (400MHz, DMSO-D6) δ 10.87 - 10.82(m, 1H), 8.01(s, 1H), 7.63(d, J=7.8Hz, 1H), 7.35(dt, J=8.1, 1.0Hz, 1H), 7.19(d, J=2.4Hz, 1H), 7.12 - 6.94(m, 3H), 3.87(d, J=7.9Hz, 1H), 3.72(dt, J=9.5, 4.8Hz, 1H), 3.68 - 3.58(m, 2H), 3.00(t, J=7.7Hz, 2H), 1.40(s, 8H), 1.17(t, J=7.2Hz, 2H), 1.07(d, J=6.0Hz, 3H).

[0149] 5.3: 5-(2-aminopropoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxy-1-methylethyl]carbamate (0.27 g, 0.56 mmol, 1.0 equiv.) was used to give 5-(2-aminopropoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride as an off-white solid (0.26 g, 0.530 mmol, 95.42% yield). This material was used directly in the next step without further purification. UPLC-MS analysis (2 min, basic): rt=1.09 min, m / z=380.2 / 382.2 / 384.1 [M+H]+, purity 85%. 1 H NMR (400MHz, DMSO-D6) δ 10.86(s, 1H), 8.32(t, J=5.7Hz, 3H), 7.67(d, J=7.8Hz, 1H), 7.39 - 7.28(m, 1H), 7.21(d, J=2.3Hz, 1H), 7.12 - 7.05(m, 1H), 7.04 - 6.94(m, 1H), 4.07 - 3.95(m, 2H), 3.64(q, J=6.7Hz, 3H), 3.03 - 2.95(m, 2H), 1.26(d, J=6.8Hz, 3H).

[0150] 5.4: 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general procedure 4, 5-(2-aminopropoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (0.20 g, 0.48 mmol, 1.0 equiv) was used to give 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (0.17 g, 0.500 mmol, 83.4% yield). This material was used directly in the next step without further purification. UPLC-MS analysis (2 min, basic): rt=1.09 min, m / z=344.2 / 346.1 [M+H]+, purity 100%. 1 H NMR (400MHz, DMSO-D6) δ 10.79(s, 1H), 7.67(d, J=7.9Hz, 1H), 7.33(d, J=8.0Hz, 1H), 7.26 - 7.14(m, 2H), 7.07(t, J=7.5Hz, 1H), 6.98(t, J=7.4Hz, 1H), 6.64(t, J=5.9Hz, 1H), 4.19 - 4.03(m, 1H), 3.74 - 3.41 (m, 4H), 2.90 (t, J=7.7Hz, 2H), 1.11 (d, J=6.3Hz, 3H).

[0151] Example 5: 2-(5-Fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (80 mg, 0.23 mmol, 1.0 equiv) and 5-fluoropyridine-3-boronic acid (66 mg, 0.47 mmol, 2.0 equiv). The crude product was purified by column chromatography (20 g cartridge) eluting with a 30–70% (v / v) EtOAc gradient in isohexane to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (55 mg, 0.136 mmol, 58.44% yield). UPLC-MS analysis (4 min, basic): rt=1.91 min, m / z=405.2 [M+H]+, 100% purity. 1 H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 9.23(t, J=1.7Hz, 1H), 8.59(d, J=2.9Hz, 1H), 8.31 - 8.14(m, 1H), 7.72 - 7.59(m, 1H), 7.39 - 7.29(m, 1H), 7.20(d, J=2.3Hz, 1H), 7.11 - 7.04(m, 1H), 7.04 - 6.93(m, 2H), 6.48(t, J=6.0Hz, 1H), 4.26 - 4.11(m, 1H), 3.81 - 3.65(m, 3H), 3.61(tt, J=6.9, 5.5, 3.9Hz, 1H), 2.99(dd, J=8.8, 6.4Hz, 2H), 1.17(d, J=6.4Hz, 3H). 19 F NMR (376MHz, DMSO-D6) δ -128.12.

[0152] The substance of Example 5 (51 mg, 0.125 mmol) was subjected to chiral separation to give two optical isomers (Example 8 and Example 9).

[0153] Intermediate of Example 6 6.1: N-(2-(1H-indol-3-yl)ethyl)-2,6-dichloro5-(2-(isopropylamino)ethoxy)pyrimidin-4-amine [ka] A stirred solution of 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (134 mg, 0.33 mmol, 1.0 equiv.), triethylamine (0.046 mL, 0.33 mmol, 1.0 equiv.), acetic acid (0.038 mL, 0.67 mmol, 2.0 equiv.), and acetone (0.074 mL, 0.99 mmol, 3.0 equiv.) in 1,2,dichloroethane (10 mL) was treated with sodium triacetoxyborohydride (106 mg, 0.49 mmol, 1.5 equiv.), and the resulting mixture was stirred for 4 h. The reaction was quenched by the addition of methanol (1 mL), and the resulting mixture was evaporated to dryness in vacuo. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was removed and washed three times with water (10 mL) before drying (NaSO); it was filtered and evaporated to dryness to give 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[2-(isopropylamino)ethoxy]pyrimidin-4-amine as a beige oil (160 mg, 0.314 mmol, 94.45% yield). This material was further purified and used directly in the next step. UPLC-MS analysis (2 min, basic): rt=1.28 min, m / z=408.2 / 410.2 / 412.2 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.85(s, 1H), 9.18(s, 1H), 7.61(d, J=7.8Hz, 1H), 7.35(dt, J=8.2, 0.9Hz, 1H), 7.18(d, J=2.3Hz, 1H), 7.08(ddd, J=8.1, 7.0, 1.2Hz, 1H), 6.99( ddd.

[0154] 6.2: 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-8-isopropyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 4 using 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[2-(isopropylamino)ethoxy]pyrimidin-4-amine (160 mg, 0.31 mmol, 1.0 equiv). The reaction was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous phase was extracted twice with EtOAc (10 mL), and the combined organics were dried (NaSO); it was filtered and evaporated to dryness to give 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-8-isopropyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as a brown oil (136 mg, 0.344 mmol, 109.47% yield). This material was further purified and used directly in the next step. UPLC-MS analysis (basic, 2 min): rt=1.25 min, m / z=372.2 / 374.2 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 10.79(s, 1H), 7.67(dt, J=7.8, 1.0Hz, 1H), 7.33(dt, J=8.1, 1.0Hz, 1H), 7.16(d, J=2.2Hz, 1H), 7.07(ddd, J=8.1, 7.0, 1.2Hz , 1H), 6.98(ddd, J=8.0, 7.0, 1.1Hz, 1H), 6.56(t, J=5.9Hz, 1H), 4.73(hept, J=6.8Hz, 1H), 4.09(dd, J=5.0, 3.7Hz, 2H), 3.57 - 3.49(m, 2H), 3.36(t, J=4.4Hz, 2H), 2.90(dd, J=8.8, 6.5Hz, 2H), 1.10(d, J=6.8Hz, 6H).

[0155] Example 6: 2-(5-Fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-8-isopropyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-8-isopropyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (145 mg, 0.37 mmol, 1.0 equiv) and 5-fluoropyridine-3-boronic acid (103 mg, 0.73 mmol, 2.0 equiv). The crude product was purified by column chromatography (40 g cartridge) eluting with a 20–40% (v / v) EtOAc gradient in isohexane to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-8-isopropyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (85 mg, 0.190 mmol, 51.93% yield). UPLC-MS analysis (basic, 4 min): rt=2.29 min, m / z=433.3 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 9.28(s, 1H), 8.60(d, J=3.0Hz, 1H), 8.27(d, J=10.1Hz, 1H), 7.63(d, J =7.9Hz, 1H), 7.34(d, J=8.1Hz, 1H), 7.20(s, 1H), 7.07(t, J=7.5Hz, 1H), 6.97(t, J=7. 4Hz, 1H), 6.39(t, J=6.0Hz, 1H), 5.07(p, J=6.7Hz, 1H), 4.18(t, J=4.3Hz, 2H), 3.72( q, J=7.1Hz, 2H), 3.42(t, J=4.3Hz, 2H), 2.98(t, J=7.6Hz, 2H), 1.17(d, J=6.7Hz, 6H). 19 F NMR (376MHz, DMSO-D6) δ -128.13.

[0156] Example 7: N-[2-(1H-indol-3-yl)ethyl]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 200 mg, 0.606 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 205 mg, 0.910 mmol). The crude product was purified by column chromatography (40 g cartridge) eluting with a gradient of 70% to 90% EtOAc / DCM to give N-[2-(1H-indol-3-yl)ethyl]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine) as a brown solid (98 mg, 0.239 mmol, 39.39% yield). UPLC-MS analysis (basic, 4 min): rt=1.70 min, m / z=393.0 [M+H]+, purity 96%. 1H NMR (400MHz, DMSO-D6) δ 10.81 (s, 1H), 8.02 (s, 1H), 7.66 (d, J=8.0Hz, 1H), 7.35 (dt, J=8.1, 1.0Hz, 1H), 7.19 (d, J=2.3Hz, 1H), 7.08 (m, 1H), 7.00 (m, 1H), 6.87 (s, 1H), 6.36 (t, J=5.9Hz, 1H), 4.12 - 4.08(m, 2H), 3.63(q, J=6.8Hz, 2H), 3.41(t, J=3.8Hz, 2H), 2.99 - 2.92(m, 2H), 2.64(s, 3H).

[0157] Example 8: (7S)-2-(5-フルオロ-3-ピリジル)-N-[2-(1H-インド-ル-3-イル)エチル]-7-メチル-7,8-ジヒドロ-6H-ピリミド[5,4-b][1,4]オキサジン-4-アミン

change

[0158] Example 9: (7R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Title compound (17 mg, 0.0420 mmol, yield 33.66%) Chemical purity: 99.93%, m / z=405.3 Enantiomeric excess: 95.8 19F NMR (376MHz, DMSO-D6) δ -128.12. UPLC-MS analysis (6 min, basic, EtOH, 30% NH3): rt=3.36 min, m / z=405.3 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 9.23(t, J=1.7Hz, 1H), 8.59(d, J=2.9Hz, 1H), 8.22(m, 1H), 7.63(d, J =7.8Hz, 1H), 7.34(dt, J=8.2, 0.9Hz, 1H), 7.20(d, J=2.3Hz, 1H), 7.07(m, 1H), 7.02 - 6.93(m, 2H), 6.48(t, J=5.9Hz, 1H), 4.23 - 4.15(m, 1H), 3.70(dd, J=10.4, 6.9Hz, 3H), 3.61(d, J=7.0Hz, 1H), 3.03 - 2.95(m, 2H), 1.16(d, J=6.4Hz, 3H).

[0159] Example 10: N-[2-(1H-indol-3-yl)ethyl]-2-(4-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 95 mg, 0.289 mmol) and 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 98 mg, 0.434 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%) in isohexane to give N-[2-(1H-indol-3-yl)ethyl]-2-(4-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine) as a beige solid (70 mg, 0.177 mmol, 61.06% yield). UPLC-MS analysis (4 min, basic): rt=1.71 min, m / z=393.3 [M+H]+, purity 99%. 1H NMR (400MHz, DMSO-D6) δ 10.80(s, 1H), 8.85(s, 1H), 7.58(d, J=8.0Hz, 1H), 7.34(dt, J=8.0, 0.9Hz, 1H), 7.16(d, J=2.3Hz , 1H), 7.07(m, 1H), 6.98(m, 1H), 6.82(s, 1H), 6.35(t, J=5.9Hz, 1H), 4.11(t, J=4.3Hz, 2H), 3.70 - 3.60 (m, 2H), 3.41 (d, J=4.0Hz, 2H), 3.02 - 2.93 (m, 2H), 2.79 (s, 3H).

[0160] Intermediate of Example 11 11.1: tert-Butyl N-[2-[2,4-dichloro-6-[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]pyrimidin-5-yl]oxyethyl]carbamate [ka] Following general procedure 2a, tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (1.00 equiv., 0.40 g, 1.17 mmol) and 2-{[2-(1H-indol-3-yl)ethyl]amino}ethanol (1.29 equiv., 0.31 g, 1.50 mmol) was used to give tert-butyl N-[2-[2,4-dichloro-6-[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]pyrimidin-5-yl]oxyethyl]carbamate as a white solid (707 mg, 1.09 mmol, 93.70% yield). UPLC-MS analysis (basic, 2 min): rt=1.16 min, m / z=510.2 / 512.2 / 514.2 [M+H]+, purity 79%. 1H NMR (400MHz, DMSO-D6) δ 10.88 - 10.78(m, 1H), 7.67(d, J=7.8Hz, 1H), 7.40 - 7.27(m, 1H), 7.17(d, J=2.3Hz, 1H), 7.13 - 7.05(m, 1H), 7.05 - 6.93(m, 2H), 4.81(t, J=5.4Hz, 1H), 3.87(t, J=7.8Hz, 2H), 3.81(t, J=5.7Hz, 2H), 3.70(d, J=5.6Hz, 2H), 3. 58(q, J=5.6Hz, 2H), 3.24(q, J=5.7Hz, 2H), 3.07(t, J=7.1Hz, 1H), 2.99(dd, J=9.0, 6.6Hz, 2H), 1.38(s, 9H).

[0161] 11.2: 2-[[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-[2-(1H-indol-3-yl)ethyl]amino]ethanol hydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]pyrimidin-5-yl]oxyethyl]carbamate (1.00 equiv, 707 mg, 1.09 mmol) was used to give 2-[[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-[2-(1H-indol-3-yl)ethyl]amino]ethanol hydrochloride as a yellow solid (568 mg, 1.27 mmol, 116.26% crude yield). UPLC-MS analysis (basic, 2 min): rt=0.80 min, m / z=410.3 / 412.3 / 414.3 [M+H]+, purity 100%. 1H NMR (400MHz, DMSO-D6) δ 10.87(d, J=2.3Hz, 1H), 8.20(s, 3H), 7.68(d, J=7.7Hz, 1H), 7.34(dt, J=8.1, 1.0Hz, 1H), 7.18(d, J=2.4Hz , 1H), 7.07(m, 1H), 6.99(m, 1H), 4.03(t, J=5.4Hz, 2H), 3.85(t, J=7.9Hz, 4H), 3.60(t, J=5.7Hz, 4H), 3.18 - 3.13(m, 2H), 3.04 - 2.93(m, 2H), 1.19(t, J=7.3Hz, 1H).

[0162] 11.3: 2-[(2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-[2-(1H-indol-3-yl)ethyl]amino]ethanol [ka] Following general method 4, 2-[[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-[2-(1H-indol-3-yl)ethyl]amino]ethanol hydrochloride (1.00 equiv, 150 mg, 0.336 mmol) was used to give 2-[(2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-[2-(1H-indol-3-yl)ethyl]amino]ethanol as a beige solid (110 mg, 0.246 mmol, 73.35% yield). UPLC-MS analysis (basic, 2 min): rt=0.97 min, m / z=374.3 / 376.3[M+H]+, purity 84%. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 7.68(d, J=7.8Hz, 1H), 7.39 - 7.28(m, 2H), 7.12(d, J=2.3Hz, 1H), 7.06(ddd, J=8.1, 7.0, 1.2Hz, 1H), 6.98(ddd, J=8.0, 6.9, 1.1Hz, 1H), 4.71 - 4.64(m, 1H), 4.01(t, J=4.4Hz, 2H), 3.81 - 3.66(m, 2H), 3.56(q, J=4.6Hz, 4H), 3.39(q, J=4.0Hz, 2H), 3.00 - 2.85(m, 2H).

[0163] Example 11: 2-[2-(1H-indol-3-yl)ethyl-[2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl]amino]ethanol [ka] Prepared according to general procedure 5b using 2-[(2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-[2-(1H-indol-3-yl)ethyl]amino]ethanol (1 equiv., 110 mg, 0.246 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 76 mg, 0.339 mmol). The crude product was purified by column chromatography (24 g cartridge) eluting with a MeOH / EtOAc gradient from 0% to 10% to give 2-[2-(1H-indol-3-yl)ethyl-[2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl]amino]ethanol as an orange solid (38 mg, 0.0876 mmol, 38.72% yield). UPLC-MS analysis (basic, 4 min): rt=1.63 min, m / z=437.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.84(d, J=2.3Hz, 1H), 7.99(s, 1H), 7.59(d, J=7.8Hz, 1H), 7.34(dt, J=8.2, 1.0Hz, 1H), 7.16(d, J=2.3Hz, 1H), 7.13 - 7.04 (m, 2H), 6.99 (m, 1H), 4.74 - 4.68 (m, 1H), 4.05 (t, J=4.3Hz, 2H), 3.84 - 3.76(m, 2H), 3.62(q, J=5.0, 4.1Hz, 4H), 3.42(d, J=4.1Hz, 2H), 2.99(dd, J=9.7, 6.0Hz, 2H), 2.64(s, 3H).

[0164] Example 12: 2-(2-ethyl-4-methyl-thiazol-5-yl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (73 mg, 0.220 mmol, 1 equiv.) and 2-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (1.50 equiv., 84 mg, 0.331 mmol). The crude product was purified by column chromatography (24 g cartridge) eluting with a gradient of 70% to 90% EtOAc / Hex to give 2-(2-ethyl-4-methyl-thiazol-5-yl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (68 mg, 0.163 mmol, 73.79% yield). UPLC-MS analysis (basic, 4 min): rt=1.96 min, m / z=421.1 [M+H]+, purity 100%. 1H NMR (400MHz, DMSO-D6) δ 10.82(s, 1H), 7.59(d, J=7.8Hz, 1H), 7.33(dt, J=8.1, 0.9Hz, 1H), 7.15(d, J= 2.2Hz, 1H), 7.07(m, 1H), 6.97(m, 1H), 6.78(d, J=2.6Hz, 1H), 6.34(t, J=5.9Hz) , 1H), 4.09(t, J=4.2Hz, 2H), 3.62(q, J=6.7Hz, 2H), 3.39(d, J=4.7Hz, 2H), 2.9 5(t, J=7.7Hz, 2H), 2.88(q, J=7.5Hz, 2H), 2.71(s, 3H), 1.28(t, J=7.5Hz, 3H).

[0165] Example 13: N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-2-thiazol-2-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5c using 2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 107 mg, 0.301 mmol) and 2-(tri-n-butylstannyl)thiazole (1.10 equiv., 0.10 mL, 0.331 mmol). The crude product was purified by column chromatography (12 g cartridge) eluting with a gradient of EtOAc (60% to 100%) in hexane to give N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-2-thiazol-2-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (23 mg, 0.0579 mmol, 19.25% yield). UPLC-MS analysis (4 min, basic): rt=1.84 min, m / z=405.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO) δ 10.71(s, 1H), 7.83(d, J=3.2Hz, 1H), 7.67(d, J=3.2Hz, 1H), 7.33(d, J=7.7Hz, 1H), 7.26(dt, J=8.1, 0.9Hz, 1H), 7.06(d, J=2.6Hz, 1H), 7.00(m, 1H), 6.92(m, 1H), 6.21(d, J=8.3Hz, 1H), 4.46(s, 1H), 4.17(t, J=4.4Hz, 2H), 3.45(d, J=4.1Hz, 2H), 3.05(m, 1H), 2.92 - 2.82(m, 2H), 2.71 - 2.65(m, 1H), 2.20 - 1.88(m, 2H).

[0166] Example 14 14.1: tert-Butyl N-[2-[2,4-dichloro-6-(1,3,4,5-tetrahydrobenzo[cd]indol-4-ylamino)pyrimidin-5-yl]oxyethyl]carbamate [ka] According to general procedure 2a, tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (1.00 equiv., 163 mg, 0.477 mmol), 1,3,4,5-tetrahydrobenzo[cd]indol-4-amine (1.29 equiv., 106 mg, 0.614 mmol) in ethanol (2.1679 mL) was used to give tert-butyl N-[2-[2,4-dichloro-6-(1,3,4,5-tetrahydrobenzo[cd]indol-4-ylamino)pyrimidin-5-yl]oxyethyl]carbamate as a beige solid (239 mg, 0.470 mmol, 98.55% yield). UPLC-MS analysis (2 min, basic): rt=1.26 min, m / z=478.3 / 480.3 / 482.3 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 10.71(d, J=2.2Hz, 1H), 7.92(d, J=8.6Hz, 1H), 7.21 - 7.08(m, 2H), 7.07 - 6.95(m, 3H), 6.74(d, J=7.2Hz, 1H), 4.42(dd, J=9.8, 5.1Hz, 1H), 4.01(t, J=5.3Hz, 2H), 3.18 - 3.01(m, 4H), 2.98 - 2.88(m, 1H), 1.39(s, 9H).

[0167] 14.2: N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-1,3,4,5-tetrahydrobenzo[cd]indol-4-amine hydrochloride [ka] Following general method 3, N-[2-[2,4-dichloro-6-(1,3,4,5-tetrahydrobenzo[cd]indol-4-ylamino)pyrimidin-5-yl]oxyethyl]carbamate (1.00 equiv., 239 mg, 0.470 mmol) was used to give N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-1,3,4,5-tetrahydrobenzo[cd]indol-4-amine hydrochloride as a gray solid (204 mg, 0.493 mmol, 83.85% yield). UPLC-MS analysis (2 min, basic): rt=1.11 min, m / z=378.1, 381.1, 383.1 [M+H]+, purity 75%. 1H NMR (400MHz, DMSO-D6) δ 10.72(d, J=2.1Hz, 1H), 8.35(s, 3H), 8.24(t, J=9.4Hz, 1H), 7.16(d, J=8.3Hz, 1H), 7.04 - 6.95(m, 2H), 6.74(d, J=6.9Hz, 1H), 4.45(m, 1H), 4.24 - 4.17(m, 2H), 3.27(m, 3H), 3.11 - 2.99(m, 3H).

[0168] 14.3:2-Chloro-N-(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-1,3,4,5-tetrahydrobenzo[cd]indol-4-amine hydrochloride (1.00 equiv, 558 mg, 1.13 mmol) was used to give 2-chloro-N-(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a gray solid (409 mg, 0.958 mmol, 84.69% yield). UPLC-MS analysis (2 min, basic): rt=1.04 min, m / z=342.2 / 344.2 [M+H]+, purity 98%. 1H NMR (400MHz, DMSO-D6) δ 10.65(s, 1H), 7.17(d, J=3.0Hz, 1H), 7.13(d, J=8.0Hz, 1H), 7.04 - 6.96(m, 2H), 6.71(d, J=7.0Hz, 1H), 6.34(d, J=8.8Hz, 1H), 4.52 - 4.36(m, 1H), 4.08(t, J=4.3Hz, 2H), 3.39(q, J=3.8Hz, 2H), 3.01(q, J=5.9Hz, 3H), 2.86(m, 1H).

[0169] Example 14: 2-(2-methylthiazol-5-yl-N-(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 60 mg, 0.176 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 75 mg, 0.331 mmol). The crude product was purified by column chromatography (12 g cartridge) eluting with a gradient of EtOAc (80% to 100%; v / v) in heptane to give 2-(2-methylthiazol-5-yl-N-(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine) as a beige solid (27 mg, 0.0646 mmol, 36.77% yield). UPLC-MS analysis (2 min, basic): rt=1.80 min; m / z=405.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.64(d, J=2.1Hz, 1H), 7.90(s, 1H), 7.14(d, J=8.1Hz, 1H), 7.02 - 6.97(m, 2H), 6.92(d, J=2.6Hz, 1H), 6.71(d, J=6.9Hz, 1H), 6.00(d, J=8.6Hz, 1H), 4.57(tt, J=9.2, 4.6Hz, 1H), 4.09(t, J=4.3Hz, 2H), 3.42 - 3.36 (m, 2H), 3.15 - 2.99 (m, 3H), 2.95 - 2.83 (m, 1H), 2.57 (s, 3H).

[0170] The title compound of Example 14 (125 mg, 0.309 mmol) was subjected to chiral separation to give two optical isomers (Example 61 and Example 62).

[0171] Example 15: N-[2-(1H-indol-3-yl)ethyl]-2-(6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5a using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 90 mg, 0.273 mmol) and 2-methylpyridine-5-boronic acid (1.50 equiv., 56 mg, 0.409 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%) in isohexane followed by preparative HPLC to give N-[2-(1H-indol-3-yl)ethyl]-2-(6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (8.0 mg, 0.0205 mmol, 7.51% yield). UPLC-MS analysis (6 min, basic): rt=2.94 min, m / z=387.1 [M+H]+, purity 99%. 1H NMR (400MHz, DMSO-D6) δ 10.76(s, 1H), 9.19(dd, J=2.3, 0.8Hz, 1H), 8.31(dd, J=8.1, 2.2Hz, 1H), 7.58(d, J=7.8Hz, 1H), 7.30(dd, J=8.1, 1.0Hz , 1H), 7.24(d, J=8.1Hz, 1H), 7.15(d, J=2.2Hz, 1H), 7.03(m, 1H), 6.94(m, 1H), 6.78(s, 1H), 6.27(t, J=5.9Hz, 1H), 4.11 - 4.05 (m, 2H), 3.66 (dt, J = 8.3, 6.2 Hz, 2H), 3.38 (q, J = 3.7 Hz, 2H), 2.99 - 2.90 (m, 2H). 3H not observed (Me).

[0172] Example 16: 2-(5-Fluoro-6-methyl-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 90 mg, 0.273 mmol) and 3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%) in isohexane to give 2-(5-fluoro-6-methyl-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (8.0 mg, 0.0192 mmol, 7.03% yield). UPLC-MS analysis (4 min, basic): rt=1.85 min, m / z=405.1 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.76(s, 1H), 9.04(t, J=1.6Hz, 1H), 8.09(dd, J=10.9, 1.7Hz, 1H), 7.58(dd, J=7.8, 1.0Hz, 1H), 7.30(dt, J=8.1, 0.9Hz , 1H), 7.15(d, J=2.4Hz, 1H), 7.03(m, 1H), 6.93(m, 1H), 6.85(s, 1H), 6.36(t, J=5.9Hz, 1H), 4.09(t, J=4.3Hz, 2H), 3.71 - 3.61(m, 2H), 3.39(d, J=3.9Hz, 2H), 2.98 - 2.90 (m, 2H). 3H not observed. 19F NMR (376MHz, DMSO-D6) δ 126.00

[0173] Example 17: 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 150 mg, 0.455 mmol) and (2-oxo-1H-pyridin-3-yl)boronic acid (1.50 equiv., 95 mg, 0.682 mmol). The crude product was purified by column chromatography (40 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane to give 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one as a beige solid (83 mg, 0.214 mmol, 46.98% yield).

[0174] Example 17 is a keto / enol tautomer. It can also exist in the form: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (2 min, basic): rt=1.64 min, m / z=389.1 [M+H]+, 100% purity. 1H NMR (400 MHz, DMSO-D6) δ 10.78 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.30 (dt, J = 8.0, 0.9 Hz, 2H), 7.17 (d, J = 2.4 Hz, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.88 (s, 1H), 6.73 (s, 1H), 4.11 (t, J = 4.3 Hz, 2H), 3.63 (q, J = 6.8 Hz, 2H), 3.43 (d, J = 3.7 Hz, 2H), 3.02 - 2.92 (m, 2H). 1H not observed.

[0175] Example 18: 5-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (150 mg, 0.455 mmol) and 6-hydroxypyridine-3-boronic acid pinacol ester (151 mg, 0.682 mmol). The crude product was purified by column chromatography (40 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane to give 5-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one as a yellow solid (77 mg, 0.195 mmol, 42.81% yield).

[0176] Example 18 is a keto / enol tautomer. It can also exist in the form: 5-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (2 min, basic): rt=1.46 min, m / z=389.1 [M+H]+, 100% purity. 1H NMR Analysis. 1H NMR (400 MHz, DMSO-D6) δ 10.78 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.30 (dt, J = 8.0, 0.9 Hz, 2H), 7.17 (d, J = 2.4 Hz, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.88 (s, 1H), 6.73 (s, 1H), 4.11 (t, J = 4.3 Hz, 2H), 3.63 (q, J = 6.8 Hz, 2H), 3.43 (d, J = 3.7 Hz, 2H), 3.02 - 2.92 (m, 2H). 1H not observed.

[0177] Example 19: 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1-methyl-pyridin-2-one [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (150 mg, 0.455 mmol) and 1-methyl-2-oxopyridine-3-boronic acid (104 mg, 0.682 mmol). The crude product was purified by column chromatography (12 g cartridge) eluting with a gradient of EtOAc (0% to 100% v / v) in hexane to give 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1-methyl-pyridin-2-one as a yellow solid (13 mg, 0.0304 mmol, 6.68% yield). UPLC-MS analysis (4 min, basic): rt=1.38 min, m / z=403.1 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 10.70(s, 1H), 7.70(d, J=6.7Hz, 1H), 7.60(d, J=7.9Hz, 1H), 7.54(s, 1H), 7.27(dd, J=8.2, 1.1Hz, 1H), 7.10(d, J=2.3Hz, 1H), 6.99(m, 1H), 6.88 - 6.79(m, 1H), 6.65(s, 1H), 6.19(t, J=6.8Hz, 2H), 4.05(dt, J=13.1, 4.8Hz, 2H), 3.51(q, J=7.0Hz, 2H), 3.42(s, 3H), 3.37(s, 2H), 2.93 - 2.85(m, 2H).

[0178] Example 20: N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-2-(6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (140 mg, 0.403 mmol) and 2-methylpyridine-5-boronic acid (83 mg, 0.604 mmol). The crude product was purified by column chromatography (24 g cartridge) eluting with an EtOAc (0% to 100%; v / v) gradient in isohexane followed by preparative HPLC to give N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-2-(6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (37 mg, 0.0887 mmol, 22.04% yield). UPLC-MS analysis (6 min, basic): rt=2.98 min, m / z=405.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.84(s, 1H), 9.17(dd, J=2.3, 0.8Hz, 1H), 8.29(dd, J=8.0, 2.2Hz, 1H), 7.54(dd, J=8.7, 5.5H z, 1H), 7.24 (dt, J=8.1, 0.7Hz, 1H), 7.15 (d, J=2.1Hz, 1H), 7.06 (dd, J=10.2, 2.3Hz, 1H), 6.84 - 6.74(m, 2H), 6.28(t, J =5.9Hz, 1H), 4.11 - 4.00 (m, 2H), 3.65 (q, J = 6.9 Hz, 2H), 3.39 (t, J = 3.9 Hz, 2H), 2.97 - 2.88 (m, 2H). 3H not observed. 19F NMR (376MHz, DMSO-D6) δ -122.37 - -122.40(m).

[0179] Example 21: 3-[4-[2-(6-fluoro-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one [ka] Prepared according to general method 5b using 2-chloro-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (160 mg, 0.461 mmol) and (2-oxo-1H-pyridin-3-yl)boronic acid (96 mg, 0.691 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane to give 3-[4-[2-(6-fluoro-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one as a beige solid (5.0 mg, 0.0122 mmol, 2.64% yield).

[0180] Example 21 is a keto / enol tautomer. It can also exist in the following form: 3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (6 min, basic): rt=2.73 min, m / z=407.1 [M+H]+, purity 99%. H NMR (400 MHz, DMSO-D6) δ 10.86 (s, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 7.52 (dd, J = 8.6, 5.6 Hz, 1H), 7.30 (s, 1H), 7.16 (s, 1H), 7.06 (dd, J = 10.2, 2.4 Hz, 1H), 6.90 (s, 1H), 6.80 (t, J = 9.0 Hz, 1H), 6.70 (s, 1H), 4.11 (t, J = 4.3 Hz, 2H), 3.61 (d, J = 7.5 Hz, 2H), 3.42 (s, 2H), 2.94 (t, J = 7.6 Hz, 2H). No H is observed. 19F NMR (376MHz, DMSO-D6) δ -122.36.

[0181] Example 22: 2-[2-(difluoromethoxy)-3-pyridyl]-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.0 equiv., 150 mg, 0.414 mmol) and 5-fluoropyridine-3-boronic acid (2.0 equiv., 117 mg, 0.828 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane to give 2-[2-(difluoromethoxy)-3-pyridyl]-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (79 mg, 0.175 mmol, 57.64% yield). UPLC-MS analysis (4 min, basic): rt=1.79 min, m / z=439.1 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.70(s, 1H), 8.23(dd, J=4.9, 2.0Hz, 1H), 8.03(dd, J=7.5, 2.0Hz, 1H), 7.68(s, 1H), 7.56 - 7.48(m, 1H), 7.34 - 7.23(m, 2H), 7.08(d, J=2.3Hz, 1H), 6.99(m, 1H), 6.85 - 6.76(m, 2H), 6.30(t, J=5.9Hz, 1H), 4.13 - 4.06(m, 2H), 3.55(q, J=7.0Hz, 2H), 3.38(q, J=3.7Hz, 2H), 2.94 - 2.86 (m, 2H). 19F NMR (376MHz, DMSO-D6) δ -86.79, -86.82

[0182] Example 23: N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-5-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (180 mg, 0.546 mmol) and (2-methoxy-5-methyl-3-pyridyl)boronic acid (137 mg, 0.819 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane to give N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-5-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (175 mg, 0.408 mmol, 74.67% yield). UPLC-MS analysis (2 min, basic): rt=1.07 min, m / z=417.2, [M+H]+, purity 98%. 1H NMR (400MHz, DMSO-D6) δ 10.72(s, 1H), 7.95(dd, J=2.5, 0.9Hz, 1H), 7.62(dd, J=2.5, 0.7Hz, 1H), 7. 57(d, J=7.9Hz, 1H), 7.26(m, 1H), 7.09(d, J=2.3Hz, 1H), 6.99(m, 1H), 6.82 - 6.71(m, 2H), 6.25(t, J=5.9Hz, 1H), 4.0(q, J=3.7Hz, 2H), 3.73(s, 3H), 3.56 - 3.46(m, 2H), 3.40 - 3.34(m, 2H), 2.94 - 2.86(m, 2H), 2.20(s, 3H).

[0183] Intermediate of Example 24 24.1: tert-Butyl N-[2-[2,4-dichloro-6-[2-(6-fluoro-1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethyl]carbamate [ka] According to general method 2b, 2-(6-fluoro-1H-indol-3-yl)ethanol (1.10 equiv., 261 mg, 1.46 mmol) and tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (1.00 equiv., 454 mg, 1.33 mmol) was used to obtain tert-butyl N-[2-[2,4-dichloro-6-[2-(6-fluoro-1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethyl]carbamate as a yellow solid (654 mg, 1.09 mmol, 82.25% yield). UPLC-MS analysis (acidic, 2 min): rt=1.31 min, no ionization, purity 81%. 1H NMR (400MHz, DMSO-D6) δ 10.96(s, 1H), 7.63(dd, J=8.7, 5.4Hz, 1H), 7.26(d, J=2.3Hz, 1H), 7.12(dd, J=10.2, 2.3Hz, 1H), 6.92 - 6.77(m, 2H), 4.62(t, J=7.0Hz, 2H), 4.00(d, J=5.7Hz, 2H), 3.26 - 3.12(m, 4H), 1.37(d, J=2.6Hz, 9H). 19F NMR (376MHz, DMSO-D6) δ -122.28

[0184] 24.2: 2-[2,4-dichloro-6-[2-(6-fluoro-1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethanamine hydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-[2-(6-fluoro-1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethyl]carbamate (1.00 equiv, 854 mg, 1.42 mmol) was used to give 2-[2,4-dichloro-6-[2-(6-fluoro-1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethanamine hydrochloride as a pink solid (484 mg, 1.02 mmol, 71.65% yield). UPLC-MS analysis (2 min, basic): rt=1.10 min, m / z=385.2, 387.2, 389.2 [M+H]+, purity 89%. 1H NMR (400MHz, DMSO-D6) δ 11.03 - 10.93(m, 1H), 8.11(s, 3H), 7.64(dd, J=8.7, 5.5Hz, 1H), 7.28(d, J=2.3Hz, 1H), 7.14(dd, J=10.2, 2.4Hz, 1H ), 6.88(m, 1H), 4.65(t, J=7.1Hz, 2H), 4.18(t, J=5.3Hz, 2H), 3.22(t, J=7.1Hz, 2H), 3.14(q, J=5.4Hz, 2H). 19F NMR (376MHz, DMSO-D6) δ- 122.19.

[0185] 24.3: 2-chloro-4-[2-(6-fluoro-1H-indol-3-yl)ethoxy]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ka] Following general method 4, 2-[2,4-dichloro-6-[2-(6-fluoro-1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethanamine hydrochloride (1.00 equiv, 400 mg, 0.949 mmol) was used to give 2-chloro-4-[2-(6-fluoro-1H-indol-3-yl)ethoxy]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine as a beige solid (285 mg, 0.449 mmol, 47.38% yield). UPLC-MS analysis (2 min, basic): rt=1.07 min, m / z=349.2, 351.2 [M+H]+, purity 55%. 1H NMR (400MHz, DMSO-D6) δ 10.90(s, 1H), 7.79(s, 1H), 7.59(dd, J=8.7, 5.4Hz, 1H), 7.16(d, J=2.3Hz, 1H), 7.11 - 7.06(m, 1H), 6.83 - 6.75(m, 1H), 4.39(t, J=7.1Hz, 2H), 4.03(t, J=4.3Hz, 2H), 3.38(q, J=3.8Hz, 2H), 3.04(t, J=7.1Hz, 2H). 19F NMR (376MHz, DMSO-D6) δ - 122.40.

[0186] Example 24: 4-[2-(6-fluoro-1H-indol-3-yl)ethoxy]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ka] Prepared according to general procedure 5b using 2-chloro-4-[2-(6-fluoro-1H-indol-3-yl)ethoxy]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (1.00 equiv., 140 mg, 0.221 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 75 mg, 0.331 mmol). The crude product was purified by column chromatography (12 g cartridge) eluting with a gradient of 100% EtOAc (v / v) in isohexane followed by preparative HPLC to give 4-[2-(6-fluoro-1H-indol-3-yl)ethoxy]-2-(2-methylthiazol-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine as a white solid (5.5 mg, 0.0130 mmol, 5.87% yield). UPLC-MS analysis (4 min, basic): rt=1.78 min, m / z=412.1 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.93(s, 1H), 7.99(s, 1H), 7.58(dd, J=8.7, 5.5Hz, 1H), 7.51(d, J=2.8Hz, 1H), 7.20(d, J=2.3Hz, 1H), 7.12 - 7.02(m, 1H), 6.81(m, 1H), 4.49(t, J=7.3Hz, 2H), 4.05(t, J=4.2Hz, 2H), 3.42 - 3.35(m, 2H), 3.09(t, J=7.2Hz, 2H), 2.60(s, 3H).

[0187] Intermediate of Example 25 25.1: tert-Butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethyl]carbamate [ka] Prepared according to general procedure 2b using tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (1.00 equiv., 0.36 g, 1.05 mmol) and tryptophor (1.10 equiv., 190 mg, 1.16 mmol). The crude product was purified by column chromatography (20 g column) eluting with 20–30% EtOAc in isohexane to give tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethyl]carbamate as a white solid (0.31 g, 0.650 mmol, 61.86% yield). UPLC-MS analysis (acidic, 2 min): rt=1.30 min, no ionization, purity 98%. 1H NMR (400MHz, DMSO-D6) δ 10.86(s, 1H), 7.60(d, J=7.8Hz, 1H), 7.31(dt, J=8.1, 1.0Hz, 1H), 7.22(d, J=2.4Hz, 1H), 7.04(ddd, J=8.1, 6.9, 1.2Hz, 1H), 6.96(ddd, J=7.9, 6.9, 1.1Hz, 1H), 6.82(t, J=5.7Hz, 1H), 4.57(t, J=7.1Hz, 2H), 3.97(t, J=5.7Hz, 2H), 3.16(dt, J=7.9, 6.4Hz, 4H), 1.33(s, 9H).

[0188] 25.2: 2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethanamine hydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethyl]carbamate (1.00 equiv, 1.13 g, 2.42 mmol) was used to give 2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethanamine hydrochloride as a grey solid (0.23 g, 0.568 mmol, 85.46% yield). UPLC-MS analysis: (2 min, acidic): rt=0.89 min, m / z=367.2 / 369.2 / 371.2 [M+H]+, purity 97%. 1H NMR analysis: 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 8.31(d, J=5.7Hz, 1H), 8.21(s, 3H), 7.62(t, J=6.4Hz, 1H), 7.30(t, J=6.6Hz, 1H), 7.18 - 7.12(m, 1H), 7.02(t, J=6.7Hz, 1H), 6.94(q, J=6.7Hz, 1H), 4.08(d, J=5.2Hz, 2H), 3.58(s, 2H), 3.18(s, 2H), 2.93(s, 2H). 19F NMR (376MHz, DMSO) δ- 122.19.

[0189] 25.3: 2-Chloro-4-[2-(1H-indol-3-yl)ethoxy]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ka] Following general method 4, 2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxyethanamine hydrochloride (1.00 equiv, 140 mg, 0.346 mmol) was used to give 2-chloro-4-[2-(1H-indol-3-yl)ethoxy]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine as an off-white solid (128 mg, 0.348 mmol, 100.43% yield). UPLC-MS analysis: (2 min, basic): rt=1.10 min, m / z=331.1 / 333.1 [M+H]+, purity 90%. 1H NMR analysis: 1H NMR (400MHz, DMSO-D6) δ 10.83(s, 1H), 7.80(s, 1H), 7.59(d, J=7.9Hz, 1H), 7.30(d, J=8.1Hz, 1H), 7.16(d, J=2.4Hz, 1H), 7.03(t, J= 7.5Hz, 1H), 6.94(t, J=7.5Hz, 1H), 4.40(t, J=7.4Hz, 2H), 4.03(s, 2H), 3.38(s, 2H), 3.06(t, J=7.4Hz, 2H).

[0190] Example 25: 3-(4-(2-(1H-indol-3-yl)ethoxy)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] Prepared according to general method 5b using 2-chloro-4-[2-(1H-indol-3-yl)ethoxy]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (1.0 equiv., 50 mg, 0.151 mmol) and (2-hydroxy-3-pyridyl)boronic acid (1.5 equiv., 31.49 mg, 0.226 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a MeOH (10–15%; v / v) gradient in DCM to give 3-[4-[2-(1H-indol-3-yl)ethoxy]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as a beige solid (13 mg, 0.0308 mmol, 20.39% yield).

[0191] Example 25 is a keto / enol tautomer. It can also exist in the following form: 3-(4-(2-(1H-indol-3-yl)ethoxy)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.33 min, m / z=390.3 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 13.93(s, 1H), 10.89(s, 1H), 8.51(s, 1H), 8.17(s, 1H), 8.07(s, 1H), 7.62(d, J=7.9Hz, 1H), 7.35(d, J=8.1Hz, 1H), 7.25(s, 1H), 7.07(t, J=7.5Hz, 1H), 6.98(s, 2H), 4.62(s, 2H), 4.13(d, J=13.8Hz, 2H), 3.49(s, 2H), 3.22 - 3.11(m, 2H).

[0192] [Table 1]

[0193] Intermediate of Example 26 26.1: 2,6-Dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-methoxy-pyrimidin-4-amine [ka] Prepared according to general procedure 2a using 2,4,6-trichloro-5-methoxypyrimidine (1 equiv., 1.50 g, 7.03 mmol) and tryptamine (1.15 equiv., 1.29 g, 8.08 mmol) in ethanol (15 mL). Removal of volatiles and trituration with water / MeOH gave 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-methoxy-pyrimidin-4-amine (2.30 g, 6.82 mmol, 97.06% yield). UPLC-MS analysis (4 min, basic): rt=1.93 min, m / z=336.9 / 338.8 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.82(s, 1H), 8.19(t, J=5.9Hz, 1H), 7.63(d, J=7.9, 1.4, 0.7Hz, 1H), 7.34(dt, J=8.1, 1.0Hz, 1H), 7.18(d, J=2.4H) z, 1H), 7.07(td, J=8.1, 7.0, 1.2Hz, 1H), 6.98(td, J=8.0, 7.0, 1.1Hz, 1H), 3.70(s, 3H), 3.60(q, 2H), 2.97(t, 2H).

[0194] 26.2: 2,4-Dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-ol [ka] To a solution of 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-methoxy-pyrimidin-4-amine (1 equiv., 2.30 g, 6.82 mmol) in DCM (120 mL) was added boron tribromide (1.2 equiv., 8.2 mL, 8.19 mmol) in DCM (1 M) under a nitrogen atmosphere, and the mixture was stirred for 18 h. Further addition of boron tribromide solution and stirring was required for reaction completion as determined by UPLC analysis. The reaction mixture was quenched with MeOH (30 mL) and water (300 mL). The layers were separated and the aqueous layer was extracted twice with DCM. The organics were concentrated and absorbed onto silica. This was loaded onto a silica-packed column and the product was eluted with an EtOAc:hexane mixture to give 2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-ol as a brown solid (1.50 g, 4.64 mmol, 68.05% yield). Note: 20% transhalogenation occurred to produce 2-bromo-4-chloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-ol. This by-product was always present in the synthetic route, which reacted identically with its chloro counterpart. UPLC-MS analysis (4 min, acidic): rt = 1.09 min, m / z = 322.9 / 324.9 / 326.9 [MH]-, 99% purity. 20% brominated regioisomer. 1 H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 10.16(s, 1H), 7.78(t, J=5.9Hz, 1H), 7.66(d, 1H), 7.33(dt, J=8.1, 1.0Hz, 1H), 7.17(d, J=2.3 , 1.2Hz, 1H), 7.07(ddd, J=8.1, 7.0, 1.2Hz, 1H), 6.98(ddd, J=8.0, 7.0, 1.2Hz, 1H), 3.60(q, 2H), 2.95(t, 2H).

[0195] 26.3: tert-Butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate [ka] Prepared using 2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-ol (1 equiv., 360 mg, 1.11 mmol) and N-Boc-(s)-2-amino-3-methoxy-1-propanol (1.4 equiv., 0.32 g, 1.56 mmol) according to general procedure 1. The crude product was purified by column chromatography eluting with hexanes, followed by 10:1 and 4:1 hexanes:EtOAc to give tert-butyl N-[(1R)-1-[[2-bromo-4-chloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate as a brown oil (100 mg, 0.177 mmol, 15.86% yield). UPLC-MS analysis (4 min, basic): rt=2.31 min, m / z=510.0 / 512.1 / 514.2 [M+H]+, purity 98%. 1H NMR (400MHz, DMSO-D6) δ 10.84(s, 1H), 8.87(s, 1H), 7.91(m, 1H), 7.63(d, J=8.1Hz, 1H), 7.34(d, J=8.1, Hz, 1H), 7.18(s, 1H), 7.11 - 7.02 (m, 1H), 6.98 (t, J=8.5, 6.0Hz, 1H), 4.81 - 4.72 (m, 1H), 4.00 - 3.83(m, 2H), 3.62(q, J=7.6Hz, 2H), 3.36(s, 2H), 3.23(s, 3H), 2.98(t, J=7.7Hz, 2H), 1.39(s, 9H).

[0196] 26.4:5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate (1 equivalent, 400 mg, 0.635 mmol) was used to give 5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (330 mg, 0.739 mmol, 90.63% yield). UPLC-MS analysis (4 min, basic): rt=1.91 min, m / z=410.0 / 412.0 / 414.0 [M+H]+, purity 80%. 1H NMR (400MHz, DMSO-D6) δ 10.85(s, 1H), 8.87(s, 1H), 8.47(brs, 3H), 7.66(d, J=8.1Hz, 1H), 7.34(d, J =7.9Hz, 1H), 7.20(s, 1H), 7.06(t, J=7.8Hz, 1H), 6.99(t, J=7.5Hz, 1H), 4.81 - 4.72 (m, 1H), 4.20 - 4.11 (m, 1H), 4.04 (dd, J=10.2, 6.0Hz, 1H), 3.72 (brs, 1H), 3.67 - 3.58 (m, 3H), 3.32 (s, 3H), 2.98 (t, J=7.9Hz, 2H).

[0197] 26.5: (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general procedure 4, 5-[(2R)-2-amino-3-methoxypropoxy]-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (1 equivalent, 330 mg, 0.739 mmol) was used to give (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (160 mg, 0.428 mmol, 57.43% yield). UPLC-MS analysis (4 min, basic): rt=1.74 min, m / z=374 / 376 [M+H]+, purity 81%. 1H NMR (400MHz, DMSO-D6) δ 10.80(s, 1H), 7.65(d, J=8.0Hz, 1H), 7.36 - 7.25(m, 2H), 7.16(s, 1H), 7.06(t, J=7.5Hz, 1H), 6.97(t, J=7.4Hz, 1H), 6.75(t, 1H), 4.81 - 4.72(m, 1H), 4.04(d, J=11.0Hz, 1H), 3.95(d, J=10.5Hz, 1H), 3.64(brs, 1H), 3.50(q, J=7.7Hz, 2H), 3.28(s, 3H), 2.89(t, J=7.8Hz, 2H). 1H is not observed.

[0198] Example 26: (R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] Prepared according to general method 5b using (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (0.82 equiv., 160 mg, 0.428 mmol) and (2-oxo-1,2-dihydropyridin-3-yl)boronic acid (1.6 equiv., 116 mg, 0.838 mmol). The crude product was purified by reverse-phase chromatography (12 g cartridge) eluting with a MeCN (0% to 100%; v / v) gradient in water (acidic buffer) to give 3-[(7R)-4-[2-(1H-indol-3-yl)ethylamino]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as a yellow solid (45 mg, 0.0978 mmol, 18.68% yield), 157374-4.

[0199] Example 26 is a keto / enol tautomer. It can also exist in the following form: (R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, acidic): rt=1.50 min, m / z=433.1 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 10.87 - 10.81(m, 1H), 8.53(d, J=7.5Hz, 1H), 8.14(brs, 1H), 7.58(d, J=7.9Hz, 1H), 7.54(brs , 1H), 7.34(d, J=8.0Hz, 1H), 7.21(d, J=2.3Hz, 1H), 7.07(t, J=8.1, 6.9, Hz, 1H), 7.02 - 6.94(m, 2H), 6.86(brs, 1H), 4.08(m, J=10.7, 5.9Hz, 2H), 3.73(brs, 1H), 3.66(q, J=7.0Hz, 2H), 3.46 - 3.36(m, 2H), 3.31(m, 4H), 2.99(t, J=7.6Hz, 2H).

[0200] Example 27: (R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(hydroxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] To a solution of 3-[(7R)-4-[2-(1H-indol-3-yl)ethylamino]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol (1 equiv., 30 mg, 0.0694 mmol) in DCM (2 mL) was added a solution of boron tribromide in DCM (1 M, 3 equiv., 0.21 mL, 0.208 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was carefully quenched with MeOH (0.5 mL), followed by the addition of 1 M NaOH (vigorously stirring) to pH = 7. The organic layer was reduced to dryness and loaded onto a silica-packed column. The product was eluted with MeCN, followed by MeCN containing 1%, 5%, and 10% water. The crude material was triturated with diethyl ether (0.5 mL), filtered, and dried under air and then under vacuum at 45 °C for 2 hours to give 3-[(7R)-7-(hydroxymethyl)-4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as a yellow solid (4.0 mg, 0.00908 mmol, 13.09% yield). Example 27 is a keto / enol tautomer. It may also exist in the form: (R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(hydroxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, acidic): rt=1.53 min, m / z=419.1 [M+H]+, purity 95%. 1H NMR (400MHz, DMSO-D6) δ 10.84(s, 1H), 8.53(d, J=7.6Hz, 1H), 8.12(brs, 1H), 7.58(d, J=7.8Hz, 1H) , 7.46(brs, 1H), 7.34(dt, J=8.1, 0.9Hz, 1H), 7.21(d, J=2.3Hz, 1H), 7.07(d dd, J=8.1, 6.9, 1.2Hz, 1H), 6.97(m, 2H), 6.83(brs, 1H), 5.02(t, J=5.1Hz, 1H), 4.10(qd, J=10.6, 3.2Hz, 2H), 3.66(q, J=7.1Hz, 2H), 3.51(m, 2H), 3.45 - 3.36 (m, 1H), 2.99 (t, J=7.6Hz, 2H).

[0201] Intermediate of Example 28 28.1: tert-Butyl N-[(1S)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate [ka] Prepared according to general procedure 1 using 2,4,6-trichloropyrimidin-5-ol (1.00 equiv., 0.30 g, 1.43 mmol) and N-Boc-(R)-2-amino-3-methoxy-1-propanol (1.10 equiv., 0.24 mL, 1.57 mmol) and N-Boc-(R)-2-amino-3-methoxy-1-propanol (1.10 equiv., 0.24 mL, 1.57 mmol). The crude product was purified by column chromatography (40 g column, packed in DCM) eluting with 18-20% EtOAc in isohexane to give tert-butyl N-[(1S)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate as a white solid (256 mg, 0.636 mmol, 44.47% yield). UPLC-MS analysis (2 min, basic): rt=1.24 min, no ionization, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 6.97 (d, J=8.2Hz, 1H), 4.19 (dd, J=9.7, 4.8Hz, 1H), 4.08 (dd, J=9.7, 6.4Hz, 1H), 4.01 - 3.88(m, 1H), 3.43(d, J=6.1Hz, 2H), 3.28(s, 3H), 1.39(s, 9H).

[0202] 28.2: tert-Butyl N-[(1S)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate [ka] Prepared according to general method 2a using tert-butyl N-[(1S)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate (1.00 equiv., 0.25 g, 0.647 mmol) and tryptamine (1.05 equiv., 0.11 g, 0.679 mmol). The reaction was concentrated to dryness to give an oily residue, which was suspended in water (25 mL) with stirring. The resulting suspension was filtered, and the solid was dried under vacuum to give tert-butyl N-[(1S)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate as an off-white solid (297 mg, 0.378 mmol, 58.50% yield). UPLC-MS analysis (2 min, basic): rt = 1.31 min, m / z = 510.2 / 512.2 / 514.2 [M+H]+, 65% purity. 1H NMR (400MHz, DMSO-D6) δ 10.84(s, 1H), 7.91(s, 1H), 7.64(d, J=7.8Hz, 1H), 7.35(dt, J=8.0, 0.9Hz, 1H), 7.19(d, J=2.4Hz, 1H), 7.12 - 7.03(m, 2H), 6.99(ddd, J=8.0, 7.0, 1.1Hz, 1H), 3.96(d, J=6.4Hz, 2H), 3.88(t, J=6.4Hz, 1H), 3.63(q, J=7.0Hz, 2H), 3.38(d, J=4.3Hz, 2H), 3.24(s, 3H), 2.99(t, J=7.7Hz, 2H), 1.40(s, 9H).

[0203] 28.3: 2,6-Dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(2S)-2-amino-3-methoxy-propoxy]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[(1S)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate (1.00 equiv., 0.30 g, 0.582 mmol) was used to give 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(2S)-2-amino-3-methoxy-propoxy]pyrimidin-4-amine hydrochloride as a beige solid (260 mg, 0.559 mmol, 96.01% yield). UPLC-MS analysis: (2 min, basic): rt=1.13 min, m / z=410.3 / 412.3 / 414.3 [M+H]+, purity 96%. 1H NMR (400MHz, DMSO-D6) δ 10.85(d, J=2.1Hz, 1H), 8.43(s, 3H), 8.27(t, J=6.0Hz, 1H), 7.67(d, J=7.7Hz, 1H), 7.35(dt, J=8.1, 1.0Hz, 1H), 7.21(d, J=2.4Hz, 1H), 7.08( ddd, J=8.2, 7.0, 1.2Hz, 1H), 7.00(ddd, J=8.0, 7.0, 1.1Hz, 1H), 4.15(dd, J=10.2, 4.1Hz, 1H), 4.05(dd, J=10.1, 6.1Hz, 1H), 3.74(s, 1H), 3.68 - 3.59 (m, 4H), 3.04 - 2.95 (m, 2H). 3H is not observed; it is below the water signal.

[0204] 28.4: (7S)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(2S)-2-amino-3-methoxy-propoxy]pyrimidin-4-amine hydrochloride (1.00 equiv, 0.25 g, 0.560 mmol) was used to give (7S)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (371 mg, 0.556 mmol, 99.31% yield). UPLCMS (basic, 2 min): rt = 1.08 min, m / z = 374.2 / 376.2 [M+H] + , purity 96%. 1H NMR (400MHz, DMSO-D6) δ 10.80(s, 1H), 7.66(d, J=7.8Hz, 1H), 7.33(dt, J=8.0, 0.9Hz, 1H), 7.27(d, J=3.2Hz, 1H), 7.16(d, J=2.4Hz, 1H), 7.07(ddd, J=8.2, 7.0, 1.2Hz, 1H), 6.98(ddd, J=7.9, 7.0, 1.1Hz, 1H), 6.72(t, J=5.9Hz, 1H), 4.05(dd, J=10.7, 3.9Hz, 1H), 3.96(dd, J=10.7, 2.9Hz, 1H), 3.69 - 3.61(m, 1H), 3.57 - 3.47(m, 2H), 3.07(q, J=7.3Hz, 2H), 2.95 - 2.86(m, 2H), 1.19(d, J=7.3Hz, 3H).

[0205] Example 28: (7S)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using (7S)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 330 mg, 0.883 mmol) and 5-fluoropyridine-3-boronic acid (2.00 equiv., 249 mg, 1.77 mmol). The crude product was purified by column chromatography (20 g column) eluting with a 30–70% (v / v) EtOAc gradient in isohexane to give (7S)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a brown solid (60 mg, 0.138 mmol, 15.64% yield). UPLC-MS analysis: (4 min, basic): rt=1.87 min, m / z=435.3 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.89 - 10.72 (m, 1H), 9.23 (t, J=1.8Hz, 1H), 8.60 (d, J=2.9Hz, 1H), 8.29 - 8.15(m, 1H), 7.63(d, J=7.8Hz, 1H), 7.35(d, J=8.1Hz, 1H), 7.20(d, J=2.3Hz, 1H), 7.11 - 7.01(m, 2H), 7.02 - 6.92 (m, 1H), 6.56 (t, J=5.9Hz, 1H), 4.18 - 3.99 (m, 2H), 3.79 - 3.63 (m, 3H), 3.48 - 3.35(m, 2H), 3.32(s, 3H), 3.00(t, J=7.6Hz, 2H). 19F NMR (376MHz, DMSO-D6) δ -128.09.

[0206] Intermediate of Example 29 29.1: tert-Butyl N-[(1S)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate [ka] Prepared according to general method 1 using 2,4,6-trichloropyrimidin-5-ol (1.00 equiv., 150 mg, 0.715 mmol) and (R)-1-(Boc-amino)-2-propanol (1.10 equiv., 138 mg, 0.786 mmol). Further addition of DIAD, amino-alcohol, and triphenylphosphine was repeated, and the mixture was stirred for an additional 24 h to drive the reaction to completion. The crude product was purified by column chromatography eluting with 9:1 and 4:1 hexanes:EtOAc to give tert-butyl N-[(2S)-2-(2,4,6-trichloropyrimidin-5-yl)oxypropyl]carbamate as a white solid (150 mg, 0.421 mmol, 58.86% yield). UPLC-MS analysis: (4 min, basic): rt=2.05 min, no ionization, 93% purity. 1H NMR (400MHz, DMSO-D6) δ 7.02 (t, J=5.9Hz, 1H), 4.62 (q, J=6.1Hz, 1H), 3.29 - 3.12 (m, 2H), 1.36 (s, 9H), 1.26 (d, J=6.3Hz, 3H).

[0207] 29.2: tert-Butyl N-[(2S)-2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxypropyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[(2S)-2-(2,4,6-trichloropyrimidin-5-yl)oxypropyl]carbamate (1.00 equiv., 150 mg, 0.421 mmol) and tryptamine (1.05 equiv., 71 mg, 0.442 mmol). The reaction was concentrated to dryness to give an oily residue, which was suspended in water (15 mL) with stirring. The resulting suspension was filtered, and the solid was dried under vacuum to give tert-butyl N-[(2S)-2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxypropyl]carbamate as a brown solid (165 mg, 0.343 mmol, 81.66% yield). UPLC-MS (4 min, basic): rt=2.21 min, m / z=480.3 / 482.3 / 484.3 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.82 (d, J=2.4Hz, 1H), 7.96 (d, J=6.3Hz, 1H), 7.69 - 7.64(m, 1H), 7.34(dt, J=8.1, 1.0Hz, 1H), 7.17(d, J=2.3Hz, 1H), 7.11 - 6.92(m, 3H), 4.37(q, J=5.9Hz, 1H), 3.68 - 3.54(m, J=6.5Hz, 2H), 3.17(t, J=5.6Hz, 2H), 2.96(t, J=7.7Hz, 2H), 1.37(d, J=2.5Hz, 9H), 1.16(d, J=6.2Hz, 3H).

[0208] 29.3: 2,6-Dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(1S)-2-amino-1-methyl-ethoxy]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[(2S)-2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxypropyl]carbamate (1.00 equiv, 200 mg, 0.416 mmol) gave 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(1S)-2-amino-1-methyl-ethoxy]pyrimidin-4-amine hydrochloride as a brown solid (173 mg, 0.415 mmol, 99.71% yield). UPLC-MS analysis (2 min, basic): rt=1.13 min, m / z=380.3 / 382.3 / 384.3 [M+H]+, purity 88%.

[0209] 29.4: (6S)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared using 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(1S)-2-amino-1-methyl-ethoxy]pyrimidin-4-amine hydrochloride (1.00 equiv., 173 mg, 0.415 mmol) according to general procedure 4. The reaction mixture was reduced to dryness and the crude product was purified by column chromatography to give (6S)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a white solid (70 mg, 0.204 mmol, 49.04% yield). UPLC-MS analysis (4 min, basic): rt=1.74 min, m / z=344.2 / 346.2 [M+H]+, purity 100%. 1H NMR (400MHz, DMSO-D6) δ 10.79(s, 1H), 7.67(d, J=7.8Hz, 1H), 7.33(dt, J=8.1, 1.0Hz, 1H), 7.15(d, J=2.3Hz, 1H), 7.12 - 7.02(m, 2H), 6.97(ddd, J=8.0, 7.0, 1.1Hz, 1H), 6.48(t, J=5.9Hz, 1H), 4.08 - 3.96(m, 1H), 3.52(dt, J=8.3, 6.4Hz, 2H), 3.41(ddd, J=12.7, 4.2, 2.6Hz, 1H), 3.03 (ddd, J=12.6, 7.9, 1.3Hz, 1H), 2.90 (dd, J=8.9, 6.4Hz, 2H), 1.29 (d, J=6.2Hz, 3H).

[0210] Example 29: (6S)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using (6S)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 70 mg, 0.204 mmol) and 5-fluoropyridine-3-boronic acid (2.00 equiv., 57 mg, 0.407 mmol). The crude product was purified by column chromatography eluting with 1:1 and 2:1 EtOAc:hexanes to give (6S)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (18 mg, 0.0441 mmol, 21.64% yield). UPLC-MS analysis: (4 min, basic): rt=1.89 min, m / z=405.3 [M+H]+, purity 99%. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 9.22(t, J=1.7Hz, 1H), 8.58(d, J=2.9Hz, 1H), 8.21(ddd, J=10.3, 2.9, 1.6Hz, 1H), 7.67 - 7.62(m, 1H), 7.34(dt, J=8.1, 0.9Hz, 1H), 7.19(d, J=2.3Hz, 1H), 7.07(ddd, J=8.2, 6.9, 1.2H z, 1H), 6.97 (ddd, J=7.9, 7.0, 1.0Hz, 1H), 6.91 (d, J=3.6Hz, 1H), 6.32 (t, J=6.0Hz, 1H), 4.15 - 4.05(m, 1H), 3.71(q, J=6.9Hz, 2H), 3.46(ddd, J=12.4, 4.0, 2.6Hz, 1H), 3.10(ddd, J=12.5, 7.8, 1.4Hz, 1H), 3.03 - 2.95(m, 2H), 1.33(d, J=6.2Hz, 3H). 19F NMR (376MHz, DMSO-D6) δ -128.14 (dd, J=10.4, 1.9Hz).

[0211] Intermediate of Example 30 30.1: tert-Butyl N-[(2R)-2-(2,4,6-trichloropyrimidin-5-yl)oxypropyl]carbamate [ka] Prepared using 2,4,6-trichloropyrimidin-5-ol (1.00 equiv., 200 mg, 0.9528 mmol) and (S)-1-(Boc-amino)-2-propanol (1.10 equiv., 184 mg, 1.047 mmol) according to general procedure 1. The crude product was purified by column chromatography (40 g column) eluting with 18–20% EtOAc in isohexane to give tert-butyl N-[(2R)-2-(2,4,6-trichloropyrimidin-5-yl)oxypropyl]carbamate as a white solid (335 mg, 0.705 mmol, 73.94% yield). UPLC-MS analysis: (2 min, basic): rt=1.24 min, no ionization, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 7.01(t, J=5.8Hz, 1H), 4.63(dt, J=12.1, 6.3Hz, 1H), 3.29 - 3.21(m, 1H), 3.21 - 3.14 (m, 1H), 1.38 (s, 9H), 1.26 (d, J=6.3Hz, 3H).

[0212] 30.2: tert-Butyl N-[(2R)-2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxypropyl]carbamate [ka] According to general method 2a, tert-butyl N-[(2R)-2-(2,4,6-trichloropyrimidin-5-yl)oxypropyl]carbamate (1.00 equiv., 335 mg, 0.9393 mmol) and tryptamine (1.05 equiv., 158 mg, 0.9863 mmol) was used to give tert-butyl N-[(2R)-2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxypropyl]carbamate as an off-white solid (383 mg, 0.551 mmol, 58.61% yield). UPLC-MS (2 min, acidic): rt=1.28 min, m / z=480.3 / 482.3 / 484.3 [M+H]+, purity 69%. 1H NMR (400MHz, DMSO-D6) δ 10.82(s, 1H), 7.95(s, 1H), 7.67(s, 1H), 7.37 - 7.31(m, 1H), 7.17(d, J=2.4Hz, 1H), 7.10 - 7.04(m, 1H), 7.04 - 6.94(m, 2H), 4.37(d, J=6.0Hz, 1H), 3.68 - 3.57(m, 2H), 3.17(t, J=5.8Hz, 2H), 2.96(t, J=7.7Hz, 2H), 1.37(s, 9H), 1.19 - 1.18(m, 3H).

[0213] 30.3: 5-[(1R)-2-amino-1-methyl-ethoxy]-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[(2R)-2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxypropyl]carbamate (1.00 equiv, 383 mg, 0.5505 mmol) was used to give 5-[(1R)-2-amino-1-methyl-ethoxy]-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride as a yellow solid (227 mg, 0.387 mmol, 70.25% yield). UPLC-MS analysis (2 min, acidic): rt=0.96 min, m / z=380.1 / 382.1 / 384.1[M+H]+, purity 71%. 1H NMR (400MHz, DMSO-D6) δ 10.85(s, 1H), 8.21(s, 4H), 7.68(d, J=7.8Hz, 1H), 7.35(dt, J=8.0, 0.9Hz, 1H), 7.19(d, J=2.4Hz, 1H), 7.08(ddd, J=8.2, 5.9, 1.3Hz, 1H), 7.00(ddd, J=8.0, 7.0, 1.1Hz, 1H), 4.83 - 4.68(m, 1H), 4.70 - 4.57(m, 1H), 3.63(d, J=6.7Hz, 1H), 3.20 - 3.13(m, 2H), 2.97(t, J=7.7Hz, 2H), 1.17(d, J=6.6Hz, 3H).

[0214] 30.4: (6R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared using 5-[(1R)-2-amino-1-methyl-ethoxy]-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (1.00 equiv., 227 mg, 0.3541 mmol) according to general procedure 4. The reaction mixture was reduced to dryness, and the crude product was purified by column chromatography (40 g cartridge) eluting with 0% to 20% EtOAc / DCM to give (6R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (71 mg, 0.2065 mmol, 58.3% yield). UPLC-MS analysis (2 min, basic): rt=1.09 min, m / z=344.2 / 346.2 [M+H]+, purity 100%. 1H NMR (400MHz, DMSO-D6) δ 10.80(s, 1H), 7.71 - 7.60(m, 1H), 7.38 - 7.28(m, 1H), 7.16(d, J=2.3Hz, 1H), 7.13 - 7.05(m, 2H), 6.98(ddd, J=7.9, 6.9, 1.1Hz, 1H), 6.49(t, J=5.9Hz, 1H), 4.07 - 3.93(m, 1H), 3.52(q, J=7.0Hz, 2H), 3.42(ddd, J=12.5, 4.0, 2.5Hz, 1H), 3.04(dd, J=12.5, 8.0Hz, 1H), 2.95 - 2.87(m, 2H), 1.29(d, J=6.3Hz, 3H).

[0215] Example 30: (6R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using (6R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 71 mg, 0.2065 mmol) and 5-fluoropyridine-3-boronic acid (1.50 equiv., 44 mg, 0.3098 mmol). The crude product was purified by column chromatography (12 g cartridge) eluting with DCM / EtOAc 60%-80% followed by preparative HPLC to give (6R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a white solid (24 mg, 0.0592 mmol, 28.69% yield). UPLC-MS analysis: (4 min, basic): rt=1.90 min, m / z=405.0 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.82(s, 1H), 9.23(t, J=1.7Hz, 1H), 8.59(d, J=2.9Hz, 1H), 8.22(ddd, J=10.3, 2.9, 1.6 Hz, 1H), 7.64 (d, J=7.9Hz, 1H), 7.35 (dt, J=8.2, 1.0Hz, 1H), 7.20 (d, J=2.3Hz, 1H), 7.15 - 7.06(m, 1H), 6.98(ddd, J=8.0, 7.0, 1.1Hz, 1H), 6.92(d, J=3.6Hz, 1H), 6.33(t, J=6.0Hz, 1H), 4. 10(ddd, J=7.8, 6.3, 2.5Hz, 1H), 3.72(q, J=6.8Hz, 2H), 3.47(ddd, J=12.4, 4.0, 2.5Hz, 1H), 3.16 - 3.06(m, 1H), 3.00(dd, J=8.8, 6.4Hz, 2H), 1.33(d, J=6.2Hz, 3H) 19F NMR (376MHz, DMSO-D6) δ -128.14

[0216] Intermediate of Example 31 31.1: tert-Butyl N-[1,1-dimethyl-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate [ka] Prepared using 2,4,6-trichloropyrimidin-5-ol (1.00 equiv., 250 mg, 1.25 mmol) and tert-butyl N-(2-hydroxy-1,1-dimethylethyl)carbamate (1.10 equiv., 261 mg, 1.38 mmol) according to general procedure 1. The crude product was purified by column chromatography eluting with hexanes and 20:1 and 9:1 hexanes:EtOAc to give tert-butyl N-[1,1-dimethyl-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate as a colorless oil (40 mg, 0.108 mmol, 8.61% yield). UPLC-MS analysis: (4 min, basic): rt=2.15 min, no ionization, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 7.02 (s, 1H), 3.36 (d, J=6.6Hz, 2H), 1.38 (s, 15H).

[0217] 31.2: tert-Butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxy-1,1-dimethylethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[1,1-dimethyl-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate (1.00 equiv., 40 mg, 0.108 mmol) and tryptamine (1.00 equiv., 17 mg, 0.108 mmol) in ethanol (2 mL). The reaction was concentrated to dryness to give an oily residue, which was suspended in water (10 mL). The resulting suspension was filtered and the solid was dried under vacuum to give tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxy-1,1-dimethylethyl]carbamate as an off-white solid (64 mg, 0.104 mmol, 95.96% yield). UPLC-MS (4 min, basic): rt=2.31 min, m / z=494.0 / 496.0 / 468.0, [M+H]+, purity 93% 1H NMR (400 MHz, DMSO-D6) δ 10.83 (s, 1H), 8.19 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.18 (s, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 3.65 (s, 2H), 3.15 (s, 1H), 3.00 (t, J = 7.8 Hz, 2H), 1.42 (s, 9H), 1.39 (s, 6H). 1H not observed; due to water peak below.

[0218] 31.3: 5-(2-amino-2-methyl-propoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine [ka] Prepared using tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxy-1,1-dimethylethyl]carbamate (1.00 equiv., 64 mg, 0.104 mmol) according to general method 3. The crude product was purified by column chromatography eluting with EtOAc containing MeOH (5% ammonia) to give 5-(2-amino-2-methyl-propoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine as a white solid (14 mg, 0.0320 mmol, 30.86% yield). UPLC-MS analysis (4 minutes, basic): rt=2.00 minutes, m / z=394.3 / 396.3 / 398.3 [M+H]+, purity 90%

[0219] 31.4: 2-Chloro-N-[2-(1H-indol-3-yl)ethyl]-7,7-dimethyl-6,8-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, 5-(2-amino-2-methyl-propoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine (1.00 equiv., 14 mg, 0.0355 mmol) was used to give 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,7-dimethyl-6,8-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (12 mg, 0.0335 mmol, 103.18% yield). UPLC-MS analysis (2 min, basic): rt=1.11 min, m / z=358.3 / 360.3 [M+H]+, purity 96%.

[0220] Example 31: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,7-dimethyl-6,8-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,7-dimethyl-6,8-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 12 mg, 0.0335 mmol) and 5-fluoropyridine-3-boronic acid (2.00 equiv., 9.5 mg, 0.0671 mmol). The crude product was purified by column chromatography eluting with 2:1 and 1:1 hexanes:EtOAc to give 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,7-dimethyl-6,8-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as a white solid (5.0 mg, 0.0114 mmol, 33.85% yield). UPLC-MS analysis: (4 min, basic): rt=1.17 min, m / z=419.3 [M+H]+, purity 95%. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 9.23(t, J=1.7Hz, 1H), 8.58(d, J=2.9Hz, 1H), 8.24 - 8.18(m, 1H), 7.63(d, J=7.9Hz, 1H), 7.34(d, J=8.1Hz, 1H), 7.17(d, J=2.2Hz, 1H), 7.07(t, J=7.6Hz, 1H), 7.02 - 6.92(m, 2H), 6.22(t, J=6.0Hz, 1H), 3.70(q, J=7.1Hz, 2H), 3.16(d, J=2.6Hz, 2H), 2.99(t, J=7.6Hz, 2H), 1.28(s, 6H). 19F NMR (376MHz, DMSO-D6) δ -128.17 (dd, J=10.2, 2.0Hz).

[0221] Intermediate of Example 32 32.1: tert-Butyl N-[(1R)-2,2,2-trifluoro-1-[(2,4,6-trichloropyrimidin-5-yl)oxymethyl]ethyl]carbamate [ka] Prepared according to general method 1 using 2,4,6-trichloropyrimidin-5-ol (1.00 equiv., 210 mg, 1.05 mmol) and tert-butyl N-[(1R)-2,2,2-trifluoro-1-(hydroxymethyl)ethyl]carbamate (1.10 equiv., 265 mg, 1.16 mmol). The crude product was purified by column chromatography eluting with hexane, followed by 20:1 and 10:1 hexane:EtOAc to give tert-butyl N-[(1R)-2,2,2-trifluoro-1-[(2,4,6-trichloropyrimidin-5-yl)oxymethyl]ethyl]carbamate as a white solid (290 mg, 0.706 mmol, 67.07% yield). UPLC-MS analysis: (4 min, basic): rt = 2.16 min, no ionization, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 7.84(d, J=9.1Hz, 1H), 4.66(dt, J=13.1, 8.3Hz, 1H), 4.45(dd, J=10.6, 4.4Hz, 1H), 4.26(dd, J=10.7, 8.1Hz, 1H), 1.41(s, 9H). 19F NMR (376MHz, DMSO-D6) δ -72.99 (d, J=8.1Hz).

[0222] 32.2: tert-Butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2,2,2-trifluoroethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[(1R)-2,2,2-trifluoro-1-[(2,4,6-trichloropyrimidin-5-yl)oxymethyl]ethyl]carbamate (1.00 equiv., 290 mg, 0.706 mmol) and tryptamine (1.00 equiv., 113 mg, 0.706 mmol) in ethanol (5 mL). The reaction was concentrated to dryness to give an oily residue, which was suspended in water (10 mL). The resulting suspension was filtered and the solid dried under vacuum to give tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2,2,2-trifluoro-ethyl]carbamate as an off-white solid (500 mg, 0.702 mmol, 99.36% yield). UPLC-MS (4 min, basic): rt=2.28 min, m / z=534.0 / 535.9 / 537.9, [M+H]+, purity 100%

[0223] 32.3: 2,6-Dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(2R)-2-amino-3,3,3-trifluoropropoxy]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2,2,2-trifluoro-ethyl]carbamate was used to give 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(2R)-2-amino-3,3,3-trifluoropropoxy]pyrimidin-4-amine hydrochloride as a purple solid (260 mg, 0.536 mmol, 57.26% yield). UPLC-MS analysis (4 minutes, basic): rt=2.02 minutes, m / z=433.9 / 435.8 / 437.9 [M+H]+, purity 97% 1H NMR (400MHz, DMSO-D6) δ 10.85(s, 1H), 9.77 - 9.71(m, 3H), 8.61(t, J=6.0Hz, 1H), 7.70(d, J=7.8Hz, 1H), 7.34(d, J=8.1Hz, 1H), 7.21(d, J=2.3Hz, 1H), 7.07(t, J=7.5Hz, 1H), 6.99(t, J=7.4Hz, 1H), 4.88 - 4.74(m, 1H), 4.44(dd, J=11.0, 4.0Hz, 1H), 3.65(dt, J=13.1, 7.0Hz, 2H), 3.00(t, J=7.8Hz, 2H). 1H not observed due to water peak below. 19F NMR (376 MHz, DMSO-D6) δ -70.26 (d, J = 8.1 Hz).

[0224] 32.4: (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 4 using 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(2R)-2-amino-3,3,3-trifluoropropoxy]pyrimidin-4-amine hydrochloride (1.00 equiv., 252 mg, 0.536 mmol) at 165° C. The crude product was purified by column chromatography eluting with hexane:acetone to give (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a yellow solid (23 mg, 0.0578 mmol, 10.79% yield). UPLC-MS analysis (2 min, basic): rt=1.80 min, m / z=398.3 / 400.3, [M+H]+, purity 99%. 1H NMR (400MHz, DMSO-D6) δ 10.79(s, 1H), 8.02(d, J=5.5Hz, 1H), 7.65(d, J=7.9Hz, 1H), 7.32(d, J=8.1Hz, 1H), 7.16(s, 1H), 7.06(t, J=7.6Hz, 1H) , 6.97(t, J=7.4Hz, 2H), 4.48(d, J=12.2Hz, 2H), 3.90(d, J=12.1Hz, 1H), 3.52(q, J=7.2Hz, 2H), 2.90(t, J=7.9Hz, 2H).

[0225] Example 32: (7R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 23 mg, 0.0578 mmol) and 5-fluoropyridine-3-boronic acid (2.00 equiv., 16 mg, 0.116 mmol). The crude product was purified by column chromatography eluting with 3:1 to 3:2 hexanes:EtOAc to give (7R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a white solid (14 mg, 0.0305 mmol, 52.82% yield). UPLC-MS analysis: (4 min, basic): rt=1.94 min, m / z=459.3[M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 9.23(t, J=1.7Hz, 1H), 8.61(d, J=2.9Hz, 1H), 8.22(ddd, J=10. 2, 2.9, 1.6Hz, 1H), 7.83(d, J=5.7Hz, 1H), 7.62(d, J=7.8Hz, 1H), 7.34(d, J=1 .0Hz, 1H), 7.19(d, J=2.3Hz, 1H), 7.06(ddd, J=8.1, 7.0, 1.2Hz, 1H), 6.97(dd d, J=8.0, 7.0, 1.1Hz, 1H), 6.77(t, J=5.9Hz, 1H), 4.54(d, J=12.1Hz, 1H), 4.52 - 4.41(m, 1H), 4.01 - 3.93(m, 1H), 3.71(dt, J=10.7, 7.2Hz, 2H), 2.99(t, J=7.7Hz, 2H). 19F NMR (376MHz, DMSO-D6) δ -73.59 - -73.74(m), -127.99(d, J=10.5Hz).

[0226] Intermediate of Example 33 33.1: 2,6-Dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[2-(oxetan-3-ylamino)ethoxy]pyrimidin-4-amine [ka] A stirred solution of 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (1.00 equiv., 150 mg, 0.372 mmol) and 3-oxetanone (1.30 equiv., 0.031 mL, 0.484 mmol) in methanol (3.7 mL) was treated with sodium cyanoborohydride (3.00 equiv., 70 mg, 1.12 mmol), and the resulting mixture was stirred for 18 h. After adding additional 3-oxetanone (0.01 mL), the reaction was stirred at room temperature for 2 h. The reaction was quenched by adding water (25 mL) and extracted with dichloromethane (30 mL, twice). The resulting solution was washed successively with saturated brine solution (25 mL). The organic phase was then separated and dried (Na2SO4) before being concentrated to dryness. The crude product was purified by flash column chromatography on silica (40 g column) eluting with 0–100% isohexane / EtOAc over 5 column volumes, followed by an EtOAc / MeOH gradient (product eluted at 10% MeOH) to give 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[2-(oxetan-3-ylamino)ethoxy]pyrimidin-4-amine as an off-white solid (115 mg, 0.251 mmol, 67.26% yield). UPLC-MS analysis: (2 min, basic): rt=1.12 min, m / z=422.1 / 424.1 / 426.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.86(s, 1H), 8.74(t, J=5.8Hz, 1H), 7.69 - 7.53(m, 1H), 7.36(dt, J=8.1, 1.0Hz, 1H), 7.19(d, J=2.4Hz, 1H), 7.08(s, 1H), 7.04 - 6.93(m, 1H), 4.57(t, J=6.6Hz, 2H), 4.27(t, J=6.1Hz, 2H), 3.94 - 3.83(m, 2H), 3.80(p, J=6.5Hz, 1H), 3.60(td, J=8.1, 7.6, 6.0Hz, 2H), 2.97(t, J=7.5Hz, 2H), 2.88(s, 1H), 2.70(t, J=5.1Hz, 2H).

[0227] 33.2: 2-Chloro-N-[2-(1H-indol-3-yl)ethyl]-8-(oxetan-3-yl)-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] To a solution of 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[2-(oxetan-3-ylamino)ethoxy]pyrimidin-4-amine (1.00 equiv., 95 mg, 0.207 mmol) in 1,4-dioxane (4.1 mL) was added potassium tert-butoxide (1.25 equiv., 29 mg, 0.259 mmol) at room temperature. Tri-o-tolylphosphine (0.0800 equiv., 5.0 mg, 0.0166 mmol) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (0.0400 equiv., 7.6 mg, 0.00828 mmol) were added sequentially while the solution was degassed by bubbling N2 through it. The mixture was stirred for 24 hours on a preheated plate at 100 °C. The reaction was diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with water, and the organics were then dried over NaSO and concentrated to dryness. The crude product was purified by flash column chromatography on silica (20 g cartridge, packed in DCM) eluting with an EtOAc gradient in iso-hexane (0% to 100% v / v; product eluted at 80% EtOAc) to give 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-8-(oxetan-3-yl)-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as a yellowish solid (15 mg, 0.0389 mmol, 18.78% yield). UPLC-MS analysis: (2 min, acidic): rt=1.11 min, m / z=386.0 / 387.9 [M+H]+, purity 100%. 1H NMR (400MHz, DMSO-D6) δ 10.80(s, 1H), 7.66(d, J=7.8Hz, 1H), 7.34(dt, J=8.1, 1.0Hz, 1H), 7.16(d, J=2.3Hz, 1H), 7.13 - 7.0(m, 1H), 7.04 - 6.93(m, 1H), 6.78(t, J=5.9Hz, 1H), 5.39(p, J=7.1Hz, 1H), 4.84 - 4.58(m, 4H), 4.34 - 4.14(m, 2H), 3.63(t, J=4.3Hz, 2H), 3.58 - 3.41(m, 2H), 3.02 - 2.82(m, 2H).

[0228] Example 33: N-[2-(1H-indol-3-yl)ethyl]-2-(2-methylthiazol-5-yl-8-(oxetan-3-yl)-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-8-(oxetan-3-yl)-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 12 mg, 0.0311 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 11 mg, 0.0467 mmol). The crude product was purified by column chromatography (20 g column) eluting with a 0–100% (v / v) EtOAc gradient in isohexane to give N-[2-(1H-indol-3-yl)ethyl]-2-(2-methylthiazol-5-yl-8-(oxetan-3-yl)-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine) as a gray solid (4.5 mg, 0.0100 mmol, 32.26% yield). UPLC-MS analysis: (4 min, basic): rt=1.83 min, m / z=449.3 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.80(s, 1H), 8.06(s, 1H), 7.70 - 7.60(m, 1H), 7.35(dt, J=8.1, 1.0Hz, 1H), 7.18(d, J=2.3Hz, 1H), 7.12 - 7.03 (m, 1H), 7.02 - 6.93 (m, 1H), 6.51 (t, J=5.9Hz, 1H), 5.25 (p, J=7.3Hz, 1H), 4.88 - 4.67 (m, 4H), 4.33 - 4.20 (m, 2H), 3.73 - 3.59(m, 2H), 3.51(t, J=4.3Hz, 2H), 3.01 - 2.87(m, 2H), 2.65(s, 3H).

[0229] Intermediate of Example 34 34.1: tert-Butyl N-[2-[2,4-dichloro-6-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-ylamino)pyrimidin-5-yl]oxyethyl]carbamate [ka] According to general procedure 2a, tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (1.00 equiv., 0.30 g, 0.876 mmol) and 6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-amine (1.10 equiv., 0.26 g, 0.963 mmol) ( WO2020816 36) in ethanol (4.4 mL) was reacted at 50°C for 4 hours to give tert-butyl N-[2-[2,4-dichloro-6-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-ylamino)pyrimidin-5-yl]oxyethyl]carbamate as a brown solid (0.52 g, 0.843 mmol, 96.29% yield). UPLC-MS analysis: (2 min, basic): rt=1.11 min, m / z=493.3 / 495.3 / 497.3 [M+H]+, purity 89%. 1H NMR (400MHz, DMSO-D6) δ 11.04(s, 1H), 8.20(dd, J=4.6, 1.5Hz, 1H), 7.93(d, J=8.2Hz, 1H), 7.65 - 7.50 (m, 1H), 7.20 (t, J=5.9Hz, 1H), 7.00 (dd, J=8.1, 4.6Hz, 1H), 4.44 - 4.21 (m, 1H), 4.09 - 3.94 (m, 2H), 3.15 (dd, J=15.1, 5.4Hz, 1H), 3.10 - 2.78(m, 3H), 2.76 - 2.65(m, 1H), 2.22 - 1.93(m, 3H), 1.38(s, 9H).

[0230] 34.2: N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-amine dihydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-ylamino)pyrimidin-5-yl]oxyethyl]carbamate (1.00 equiv, 0.30 g, 0.486 mmol) was used to give N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-amine dihydrochloride as a brown solid (0.27 g, 0.486 mmol, 100.01% yield). UPLC-MS analysis: (2 min, basic): rt=0.94 min, m / z=393.3 / 395.3 / 397.3 [M+H]+, purity 90%. 1H NMR (400MHz, DMSO-D6) δ 15.97(s, 1H), 12.74(s, 1H), 8.74 - 8.19(m, 6H), 7.61 - 7.50(m, 1H), 4.47(t, J=7.1Hz, 1H), 4.33 - 4.15(m, 2H), 3.34 - 3.18 (m, 3H), 3.15 - 2.94 (m, 3H), 2.35 - 2.24 (m, 1H), 2.18 - 2.06 (m, 1H).

[0231] 34.3: 2-Chloro-N-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, N-[5-(2-aminoethoxy-2,6-dichloro-pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-amine dihydrochloride (1.0 equiv, 0.25 g, 0.450 mmol) was used to give 2-chloro-N-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a brown solid (0.17 g, 0.412 mmol, 91.37% yield). UPLC-MS analysis: (2 min, basic): rt=0.86 min, m / z=357.2 / 359.2 [M+H]+, purity 89%. 1H NMR (400MHz, DMSO-D6) δ 10.95(s, 1H), 8.19(dd, J=4.8, 1.4Hz, 1H), 7.59(dd, J=8.0, 1.4Hz, 1H), 7.16(s, 1H), 6.99(dd, J=8.1, 4.6Hz, 1H), 6.45(d, J=8.3Hz, 1H), 4.34 - 4.16 (m, 1H), 4.10 (t, J=4.3Hz, 2H), 3.45 - 3.36 (m, 2H), 3.04 (dd, J=15.1, 5.3Hz, 1H), 2.98 - 2.77 (m, 2H), 2.74 - 2.61 (m, 1H), 2.14 - 1.90(m, 2H).

[0232] Example 34: 2-(2-methylthiazol-5-yl-N-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 90 mg, 0.224 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 76 mg, 0.337 mmol). The crude product was purified by column chromatography (20 g column) eluting with a 0–100% (v / v) EtOAc gradient in isohexane followed by EtOAc / MeOH (0–15% MeOH) to give 2-(2-methylthiazol-5-yl-N-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (34 mg, 0.0786 mmol, 35.02% yield). UPLC-MS analysis: (4 min, basic): rt=1.42 min, m / z=420.1 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.98(s, 1H), 8.20(dd, J=4.6, 1.5Hz, 1H), 7.97(s, 1H), 7.61(dd, J=8.1, 1.4Hz, 1H), 6.99(dd, J=8.1, 4.6Hz, 1H), 6.95 - 6.83(m, 1H), 6.14(d, J=8.1Hz, 1H), 4.45 - 4.33(m, 1H), 4.13(t, J=4.3Hz, 2H), 3.48 - 3.38(m, 2H), 3.09(dd, J=15.2, 5.3Hz, 1H), 3.01 - 2.81 (m, 2H), 2.78 - 2.68(m, 1H), 2.60(s, 3H), 2.22 - 2.10(m, 1H), 2.02 - 1.90(m, 1H).

[0233] Intermediate of Example 35 35.1: (3R)-N-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine [ka] Following general procedure 2a, 2,4,6-trichloro-5-methoxypyrimidine (1.00 equiv., 0.32 mL, 2.34 mmol) and (R)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (1.05 equiv., 0.46 g, 2.46 mmol) in ethanol (5 mL) was used to give (3R)-N-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-amine as an off-white solid (0.84 g, 2.31 mmol, 98.72% yield). UPLC-MS (4 min, basic): rt=2.06 min, m / z=363.2 / 365.2 / 367.2 [M+H]+, purity 96%. 1H NMR (400MHz, DMSO-D6) δ 10.75(s, 1H), 8.15(d, J=8.3Hz, 1H), 7.33(d, J=7.8Hz, 1H), 7.25(d, J=7.9Hz, 1H), 7.09 - 6.86(m, 2H), 4.33(s, 1H), 3.76(s, 3H), 3.07(s, 1H), 2.99(dd, J=14.9, 5.3Hz, 1H), 2.85(s, 2H), 2.09 - 1.98(m, 2H).

[0234] 35.2: 2,4-Dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-ol [ka] To a solution of (3R)-N-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (1.00 equiv., 600 mg, 1.65 mmol) in DCM (10 mL) was added boron tribromide (3.00 equiv., 5.0 mL, 4.96 mmol) in DCM (1 M) under a nitrogen atmosphere, and the mixture was stirred for 18 h. Further addition of boron tribromide solution and stirring was required for reaction completion as determined by UPLC analysis. The reaction mixture was quenched with MeOH (10 mL) and water (20 mL). The DCM layer was separated, the aqueous layer was extracted twice with DCM, and the organics were washed with brine. The organic layer was dried over sodium sulfate, filtered, and reduced to dryness on a rotary evaporator under vacuum at 40 °C to give 2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-ol (530 mg, 1.52 mmol, 91.88% yield) as a red solid. UPLC-MS (4 min, acidic): rt=0.80 / 0.82 min, m / z=349.2 / 351.2 / 353.2 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.75(s, 1H), 10.21(s, 1H), 7.64(d, J=8.3Hz, 1H), 7.33(d, J=7.7Hz, 1H), 7.28 - 7.20(m, 1H), 7.00(ddd, J=8.1, 7.0, 1.3Hz, 1H), 6.92(td, J=7.4, 7.0, 1.1Hz, 1H), 4. 34(h, J=7.3Hz, 1H), 2.98(dd, J=14.9, 5.3Hz, 1H), 2.83(tt, J=11.7, 6.3Hz, 2H), 2.74 - 2.63(m, 1H), 2.04(h, J=5.1Hz, 2H).

[0235] 35.3: tert-Butyl N-[(1R)-1-[[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate [ka] Prepared according to general method 1 using 2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-ol (1.00 equiv., 0.75 g, 2.10 mmol) and tert-butyl N-[(1S)-1-(hydroxymethyl)-2-methoxy-ethyl]carbamate (1.05 equiv., 454 mg, 2.21 mmol). The crude product was purified by column chromatography eluting with hexanes only, followed by 5:1 and 4:1 hexanes:EtOAc to give tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate as a white solid (1.10 g, 1.93 mmol, 91.58% yield). UPLC-MS (4 min, basic): rt=2.33 min, m / z=536.2 / 538.2 / 540.2 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 10.76(s, 1H), 7.72(d, J=8.2Hz, 1H), 7.34(d, J=7.7Hz, 1H), 7.26(d, J=8.0Hz, 1H), 7.13(d, J=7.8Hz, 1H), 7.01(t, J=7.5Hz, 1H), 6.93(t, J=7 .4Hz, 1H), 4.34(s, 1H), 3.96(d, J=8.8Hz, 3H), 3.41(d, J=5.7Hz, 2H), 3.26(s, 3H), 3.07(dd, J=14.8, 5.3Hz, 1H), 2.91(d, J=15.0Hz, 2H), 2.78 - 2.59(m, 1H), 2.16(d, J=12.0Hz, 1H), 2.05(d, J=11.8Hz, 1H), 1.39(s, 9H).

[0236] 35.4: (3R)-N-[5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride [ka] Following general method 3, tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate (1.00 equiv, 1.10 g, 2.04 mmol) was used to give (3R)-N-[5-[(2R)-2-amino-3-methoxypropoxy]-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride as a white solid (600 mg, 1.27 mmol, 62.12% yield). UPLC-MS (2 min, basic): rt=1.02 min, m / z=436.1 / 438.1 / 440.1 [M+H]+. 1H NMR (400MHz, DMSO-D6) δ 10.76(s, 1H), 8.51(s, 3H), 8.04(d, J=8.4Hz, 1H), 7.33(d, J=7.8Hz, 1H), 7.2 6(d, J=8.0Hz, 1H), 7.01(t, J=7.5Hz, 1H), 6.93(t, J=7.4Hz, 1H), 4.38(s, 1H) , 4.27(dd, J=10.1, 3.9Hz, 1H), 4.10(dd, J=10.1, 5.7Hz, 1H), 3.76(s, 1H), 3. 66(d, J=6.0Hz, 2H), 3.34(d, J=1.6Hz, 3H), 3.02(dd, J=14.9, 5.4Hz, 1H), 2.94 - 2.75(m, 3H), 2.10(s, 2H).

[0237] 35.5: N-[(1R)-1-[[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]-N',N'-dimethylethane-1,2-diamine [ka] A stirred solution of (3R)-N-[5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride (1.00 equiv., 350 mg, 0.740 mmol), (dimethylamino)acetaldehyde sulfite (1:1) (1.10 equiv., 138 mg, 0.814 mmol) and triethylamine (1.00 equiv., 0.10 mL, 0.740 mmol) in methanol (5 mL) was treated with sodium cyanoborohydride (3.00 equiv., 140 mg, 2.22 mmol) and the mixture was stirred at room temperature for 3 days. The reaction was quenched by adding water (25 mL) and extracted with dichloromethane (30 mL, twice). The resulting solution was washed successively with saturated brine solution (25 mL). The organic phase was then separated and dried (NaSO) before being concentrated to dryness. The crude product was purified by column chromatography eluting with EtOAc, followed by 5% and 10% MeOH in EtOAc (ammonia buffer) to give N-[(1R)-1-[[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]-N′,N′-dimethylethane-1,2-diamine as a pink solid (200 mg, 0.370 mmol, 50.05% yield). UPLC-MS analysis: (4 min, basic): rt=2.09 min, m / z=507.3 / 509.3 / 511.3 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 10.75(s, 1H), 8.64(s, 1H), 7.34(d, J=7.8Hz, 1H), 7.26(d, J=8.0Hz, 1H), 7.01(t, J=7.6Hz, 1H), 6.93(t, J=7.5Hz, 1H), 4.33(s, 1H), 4.03(q, J=7.4Hz, 2H), 3.75(t, J=8.5Hz, 1H), 3.45 - 3.32(m, 6H), 3.11(dd, J=14.9, 5.3Hz, 1H), 2.99(s, 1H), 2.86(d, J=13.9Hz, 2H), 2.68(s, 3H), 2.21(s, 6H), 2.03(s, 1H), 1.26 - 1.13(m, 2H).

[0238] 35.6: (7R)-2-chloro-8-[2-(dimethylamino)ethyl]-7-(methoxymethyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general procedure 4, N-[(1R)-1-[[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]-N′,N′-dimethylethane-1,2-diamine (1.00 equiv., 200 mg, 0.394 mmol) was used to give (7R)-2-chloro-8-[2-(dimethylamino)ethyl]-7-(methoxymethyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as a white solid (140 mg, 0.282 mmol, 71.65% yield). UPLC-MS analysis (4 min, basic): rt=2.04 min, m / z=471.4 / 473.4, [M+H]+, purity 87%. 1H NMR (400MHz, DMSO) δ 10.69(s, 1H), 7.32(d, J=7.7Hz, 1H), 7.24(d, J=7.9Hz, 1H), 6.99(t, J=7.5Hz, 1H), 6.91(t, J=7.4Hz, 1H), 6.53(d, J=8.4Hz, 1H), 4.31(d, J=10 .7Hz, 1H), 4.25(s, 1H), 3.84(dq, J=13.4, 6.7Hz, 2H), 3.74(d, J=10.6Hz, 1H), 3.45(dd, J=9.5, 5.9Hz, 1H), 3.35(dd, J=17.3, 9.0Hz, 6H), 3.02 - 2.74(m, 4H), 2.72 - 2.56(m, 1H), 2.25(s, 6H), 2.09 - 1.88(m, 2H).

[0239] Example 35: (7R)-8-[2-(dimethylamino)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] According to general procedure 5b, (7R)-2-chloro-8-[2-(dimethylamino)ethyl]-7-(methoxymethyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 70 mg, 0.149 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazolinone were prepared. Azole (2.00 equiv., 67 mg, 0.297 mmol) was used to afford (7R)-8-[2-(dimethylamino)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as a white solid (40 mg, 0.0712 mmol, 47.91% yield). UPLC-MS analysis: (4 min, basic): rt=2.09 min, m / z=534.4 [M+H]+, purity 95%. 1H NMR (400MHz, DMSO-D6) δ 10.70(s, 1H), 7.99(s, 1H), 7.32(d, J=7.7Hz, 1H), 7.25(d, J=7.9Hz, 1H), 6.99(ddd, J=8.1, 7.0, 1.3Hz, 1H), 6.97 - 6.86(m, 1H), 6.18(d, J=8.2Hz, 1H), 4.47 - 4.34(m, 1H), 4.31(dd, J=10.7, 1.4Hz, 1H), 3.98(dt, J=13.9, 6.9Hz, 1H), 3.78(ddd, J=13.2, 9.3, 4.2Hz, 2H), 3.46(dd, J=9.4 , 5.5Hz, 1H), 3.38(dt, J=9.3, 6.9Hz, 2H), 3.31(s, 3H), 3.02(dd, J=14.9, 5.3Hz, 1H), 2.84(td, J=16.2, 15.5, 9.9Hz, 2H), 2.72 - 2.63(m, 1H), 2.60(s, 3H), 2.22(s, 6H), 2.14 - 2.05 (m, 1H), 2.02 - 1.88 (m, 1H). 2H is below the DMSO signal.

[0240] Example 36: [(7R)-8-[2-(dimethylamino)ethyl]-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-7-yl]methanol [ka] To a solution of (7R)-8-[2-(dimethylamino)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 18 mg, 0.0320 mmol) in DCM (3 mL) was added a solution of boron tribromide in DCM (1 M, 2.00 equiv., 0.064 mL, 0.0641 mmol), and the mixture was stirred at ambient temperature for 18 hours. Further addition of boron tribromide solution and stirring was required for reaction completion, as determined by UPLC analysis. The reaction mixture was carefully quenched by adding MeOH (1 mL) followed by water. The layers were separated, and the aqueous layer was extracted twice with DCM. The organics were dried over NaSO, filtered, and concentrated to dryness. The crude product was purified by column chromatography eluting with 1%–5% MeOH in DCM (ammonia buffer) to give [(7R)-8-[2-(dimethylamino)ethyl]-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-7-yl]methanol as a white solid (7.0 mg, 0.0129 mmol, 40.36% yield). UPLC-MS (4 min, acidic): rt=1.84 min, m / z=520.4 [M+H]+, purity 96% 1H NMR (400MHz, DMSO-D6) δ 10.70(s, 1H), 7.99(s, 1H), 7.32(d, J=7.7Hz, 1H), 7.25(d, J=8.1Hz, 1H), 6.99(ddd, J=8.1, 7.0, 1.3Hz, 1H), 6.96 - 6.87(m, 1H), 6.11(d, J=8.2Hz, 1H), 5.17(s, 1H), 4.38(d, J=10.3Hz, 2H), 3.94(dt, J=13.7, 6.7Hz, 1H), 3.76(d, J=10.4Hz, 1H), 3.61 - 3.50(m, 2H), 3.50 - 3.34 (m, 2H), 3.02 (dd, J = 14.8, 5.3 Hz, 1H), 2.84 (q, J = 15.5, 12.4 Hz, 2H), 2.60 (s, 3H), 2.24 (s, 6H), 2.11 (d, J = 12.1 Hz, 1H), 1.95 (ddt, J = 14.2, 8.9, 4.8 Hz, 1H). 3H was below the solvent signal.

[0241] Intermediate of Example 37 37.1: (3R)-N-[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethoxy]-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine [ka] A stirred solution of (3R)-N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride (1.00 equiv., 300 mg, 0.700 mmol) and (tert-butyldimethylsilyloxy)acetaldehyde (1.30 equiv., 0.19 mL, 0.910 mmol) in methanol (5 mL) was treated with sodium cyanoborohydride (3.00 equiv., 132 mg, 2.10 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction was quenched by the addition of water (25 mL) and extracted twice with dichloromethane (60 mL). The resulting solution was washed successively with saturated brine solution (25 mL). The organic phase was then separated and dried (Na2SO4) before being concentrated to dryness. The crude product was purified by column chromatography eluting with isohexane containing EtOAc (0% to 100%; v / v) to give (3R)-N-[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethoxy]-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine as a waxy white solid (180 mg, 0.180 mmol, 25.70% yield). UPLC-MS analysis: (2 min, basic): rt=1.51 min, m / z=550.3 / 552.3 / 554.3 [M+H]+, purity 55%. 1H NMR (400MHz, DMSO-D6) δ 10.76(d, J=4.5Hz, 1H), 8.87(s, 1H), 7.34(d, J=7.6Hz, 1H), 7.27(dt, J=8.0, 1.0Hz, 1H), 7.06 - 6.98(m, 1H), 6.98 - 6.89 (m, 1H), 4.31 (s, 1H), 4.05 - 3.94 (m, 2H), 3.72 - 3.58 (m, 2H), 3.58 - 3.43 (m, 1H), 3.14 - 3.04 (m, 1H), 2.99 - 2.83 (m, 4H), 2.75 - 2.63 (m, 3H), 2.21 - 2.11(m, 1H), 2.06 - 1.95(m, 1H), 0.93 - 0.76(m, 9H), 0.12 - -0.10(m, 6H).

[0242] 37.2:8-[2-[tert-Butyl(dimethyl)silyl]oxyethyl]-2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, (3R)-N-[5-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethoxy]-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine (1.00 equiv., 180 mg, 0.180 mmol) was used to give 8-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (130 mg, 0.177 mmol, 98.44% yield). UPLC-MS analysis (2 min, basic): rt=1.49 min, m / z=514.3 / 516.3 [M+H]+, purity 70%. 1H NMR (400MHz, DMSO-D6) δ 10.65(s, 1H), 7.27(d, J=7.8Hz, 1H), 7.21(dd, J=8.1, 4.9Hz, 1H), 6.95(t, J=7.4Hz, 1H), 6.88(t, J=7.4 Hz, 1H), 6.32(d, J=8.6Hz, 1H), 4.09(t, J=4.4Hz, 2H), 3.71(t, J=5.8Hz, 2H), 3.51(t, J=4.3Hz, 3H), 2.97 - 2.75(m, 4H), 2.67 - 2.53(m, 2H), 2.03 - 1.88(m, 2H), 0.80(s, 9H), -0.06(s, 6H).

[0243] 37.3:8-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 8-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 120 mg, 0.163 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 55 mg, 0.245 mmol). The crude product was purified by column chromatography (20 g column) eluting with a 0–60% (v / v) EtOAc gradient in isohexane to give 8-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as a pale yellow oil (75 mg, 0.124 mmol, 75.60% yield). UPLC-MS analysis: (2 min, basic): rt=1.53 min, m / z=577.4 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.70(s, 1H), 7.98(s, 1H), 7.31(d, J=7.7Hz, 1H), 7.25(dt, J=7.9, 0.9Hz, 1H), 7.06 - 6.95(m, 1H), 6.94 - 6.85(m, 1H), 6.03(d, J=8.3Hz, 1H), 4.40(s, 1H), 4.16(s, 2H), 3.81(t, J=6.0Hz, 2H ), 3.64(t, J=6.0Hz, 2H), 3.57(t, J=4.4Hz, 2H), 3.01(dd, J=14.8, 5.3Hz, 1H), 2.94 - 2.74 (m, 2H), 2.59 (s, 3H), 2.57 - 2.52 (m, 1H), 2.16 - 2.05 (m, 1H), 2.01 - 1.91 (m, 1H), 0.85 (s, 9H), 0.04 (s, 6H).

[0244] Example 37: 2-[2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-8-yl]ethanol [ka] To a solution of 8-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 75 mg, 0.124 mmol) in MeCN (2.4704 mL) was added 4 M hydrogen chloride in dioxane (30.0 equiv., 0.93 mL, 3.71 mmol), and the reaction mixture was stirred at room temperature for 15 min. The reaction was concentrated to dryness to give a residue, which was then diluted with MTBE (10 mL) and EtO (5 mL). x3) ​​to give 2-[2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-8-yl]ethanol as a yellow solid (36 mg, 0.0778 mmol, 63.01% yield). UPLC-MS analysis: (4 min, basic): rt=1.93 min, m / z=463.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.76(s, 1H), 8.12(s, 1H), 7.36(d, J=7.7Hz, 1H), 7.33 - 7.26(m, 1H), 7.08 - 6.99(m, 1H), 6.99 - 6.91 (m, 1H), 6.14 (bs, 1H), 4.48 - 4.40 (m, 1H), 4.21 (t, J=4.5Hz, 2H), 3.78 - 3.50 (m, 6H), 3.05 (dd, J=14.9, 5.2Hz, 1H), 2.98 - 2.82 (m, 2H), 2.75 - 2.68 (m, 1H), 2.67 (s, 3H), 2.20 - 2.08 (m, 1H), 2.08 - 1.95 (m, 1H). 1H not observed.

[0245] Intermediate of Example 38 38.1: tert-Butyl 2-chloro-7-[(dimethylamino)methyl]-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazine-8-carboxylate [ka] A mixture of 2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-ol (1.00 equiv., 0.35 g, 1.00 mmol), [(2R)-2-(tert-butoxycarbonylamino)-3-(dimethylamino)propyl]methanesulfonate (1.44 equiv., 0.45 g, 1.44 mmol) (mesylate synthesized from the corresponding N-Boc amino alcohol and used without purification), and cesium carbonate (2.00 equiv., 0.65 g, 2.00 mmol) in DMF (6.6817 mL) was stirred at 110° C. for 24 h. The mixture was cooled and then poured into water (100 mL) containing crushed ice. The resulting precipitate was filtered, dissolved in a mixture of DCM / MeOH (9:1), and dried over NaSO. It was then filtered and concentrated. The crude material was purified by column chromatography eluting with a gradient of 0% to 100% EtOAc in isohexane, followed by MeOH (0% to 20% v / v) in EtOAc to give tert-butyl 2-chloro-7-[(dimethylamino)methyl]-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazine-8-carboxylate as a brown solid (155 mg, 0.266 mmol, 26.53% yield). Note: Product isolated as a mixture of diastereoisomers due to racemization of one of the two stereocenters. UPLC-MS analysis: (2 min, basic): rt=1.29 min, m / z=513.3 / 515.3 [M+H]+, purity 88%. 1H NMR (400MHz, DMSO-D6) δ 10.71(s, 1H), 7.36 - 7.27(m, 2H), 7.27 - 7.23(m, 1H), 7.02 - 6.97(m, 1H), 6.95 - 6.91(m, 1H), 4.53 - 4.47 (m, 1H), 4.39 - 4.26 (m, 1H), 4.06 - 3.98 (m, 1H), 3.03 - 2.94 (m, 2H), 2.87 - 2.78 (m, 2H), 2.41 - 2.31 (m, 1H), 2.27 - 2.17 (m, 7H), 2.11 - 1.93(m, 3H), 1.49(s, 9H).

[0246] 38.2: tert-Butyl 7-[(dimethylamino)methyl]-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazine-8-carboxylate [ka] Prepared according to general procedure 5b using tert-butyl 2-chloro-7-[(dimethylamino)methyl]-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazine-8-carboxylate (1.00 equiv., 165 mg, 0.212 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 72 mg, 0.318 mmol). The crude product was purified by column chromatography (20 g column) eluting with a 0–100% (v / v) EtOAc gradient in isohexane followed by 0–20% (v / v) MeOH in EtOAc to give tert-butyl 7-[(dimethylamino)methyl]-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazine-8-carboxylate as a yellow oil (90 mg, 0.127 mmol, 59.65% yield). Note: Product isolated in a previous step as a mixture of diastereoisomers due to racemization of one of the two stereocenters. UPLC-MS analysis: (2 min, basic): rt=1.29 / 1.30 min, m / z=576.3 [M+H]+, purity 81%.

[0247] Example 38: 7-[(Dimethylamino)methyl]-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] To a solution of tert-butyl 7-[(dimethylamino)methyl]-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazine-8-carboxylate (1.00 equiv., 150 mg, 0.229 mmol) in DCM (1.1959 mL) was added 4 M hydrogen chloride in dioxane (25.0 equiv., 1.4 mL, 5.73 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated to dryness to give a residue that was triturated with EtO (10 mL) and filtered. The crude product was purified by preparative HPLC (basic method) to give 7-[(dimethylamino)methyl]-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine) as an off-white solid (12 mg, 0.0241 mmol, 10.50% yield). Note: Product isolated in a previous step as a mixture of diastereoisomers due to racemization of one of the two stereocenters. UPLC-MS analysis: 4 min, basic): rt=1.96 / 1.97 min, m / z=476.3 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.71(s, 1H), 7.97(s, 1H), 7.33(d, J=7.7Hz, 1H), 7.29 - 7.20(m, 1H), 7.06 - 6.97(m, 1H), 6.97 - 6.88(m, 1H), 6.80 - 6.70 (m, 1H), 6.21 (d, J=8.2Hz, 1H), 4.48 - 4.34 (m, 1H), 4.12 - 3.96 (m, 2H), 3.68 - 3.56 (m, 1H), 3.07 - 2.97 (m, 1H), 2.97 - 2.78(m, 2H), 2.72 - 2.63(m, 1H), 2.60(s, 3H), 2.42 - 2.26(m, 2H), 2.20(s, 6H), 2.15 - 2.06(m, 1H), 2.04 - 1.91(m, 1H).

[0248] Intermediate of Example 39 39.1: N-[2-[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxyethyl]methanesulfonamide [ka] To a solution of (3R)-N-[5-(2-aminoethoxy)-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride (1.00 equiv., 0.30 g, 0.616 mmol) and triethylamine (2.00 equiv., 0.17 mL, 1.23 mmol) in DCM (6.1576 mL) was added methanesulfonyl chloride (1.10 equiv., 0.052 mL, 0.677 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature for 3 hours. The reaction mixture was diluted with DCM (30 mL). After dilution with HCl, the organic phase was washed three times with 1 N HCl (15 mL), dried over NaSO, filtered, and concentrated to dryness. The crude product was purified by column chromatography eluting with an EtOAc (0% to 100%; v / v) gradient in isohexane to give N-[2-[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxyethyl]methanesulfonamide as a viscous pale yellow oil (290 mg, 0.536 mmol, 87.11% yield). UPLC-MS analysis: (2 min, basic): rt=1.12 min, m / z=470.2 / 472.2 / 474.2 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.74(s, 1H), 7.69(s, 1H), 7.41(s, 1H), 7.33(d, J=7.7Hz, 1H), 7.25(dt, J=8.0, 1.0Hz, 1H), 7.07 - 6.97(m, 1H), 6.95 - 6.85 (m, 1H), 4.40 - 4.25 (m, 1H), 4.09 - 4.02 (m, 2H), 3.38 (t, J=5.5Hz, 2H), 3.04 (dd, J=14.8, 5.4Hz, 1H), 2.96 (s, 3H), 2.92 - 2.79(m, 2H), 2.76 - 2.64(m, 1H), 2.17 - 2.07(m, 1H), 2.08 - 1.99(m, 1H).

[0249] 39.2: 2-Chloro-8-methylsulfonyl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] To a mixture of N-[2-[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxyethyl]methanesulfonamide (220 mg, 0.407 mmol) and potassium phosphate tripotassium (121 mg, 0.570 mmol) in 1,4-dioxane (4.0691 mL) was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (7.5 mg, 0.00814 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14 mg, 0.0244 mmol). The mixture was stirred at 100 °C for 24 h. The reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was evaporated to dryness. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0% to 80%; v / v) in isohexane to give 2-chloro-8-methylsulfonyl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (130 mg, 0.291 mmol, 71.42% yield). UPLC-MS analysis: (2 min, basic): rt=1.14 min, m / z=434.3 / 436.3 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.72(s, 1H), 7.42(d, J=8.4Hz, 1H), 7.36 - 7.29(m, 1H), 7.31 - 7.21(m, 1H), 7.03 - 6.97(m, 1H), 6.96 - 6.87 (m, 1H), 4.43 - 4.24 (m, 3H), 3.97 - 3.88 (m, 2H), 3.49 (s, 3H), 3.01 - 2.93 (m, 1H), 2.93 - 2.78 (m, 2H), 2.73 - 2.62 (m, 1H), 2.09 - 2.00(m, 2H).

[0250] Example 39: 8-Methylsulfonyl-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] According to general procedure 5b, 2-chloro-8-methylsulfonyl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (115 mg, 0.257 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1 0.50 equiv., 87 mg, 0.386 mmol) to afford 8-methylsulfonyl-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (107 mg, 0.215 mmol, 83.81% yield). UPLC-MS analysis: (4 min, basic): rt=1.93 min, m / z=497.2 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.74(s, 1H), 8.08(s, 1H), 7.41 - 7.29(m, 1H), 7.29 - 7.20(m, 1H), 7.11 - 6.95(m, 2H), 6.95 - 6.87(m, 1H), 4.50(s, 1H), 4.39 - 4.27(m, 2H), 3.95(t, J=4.3Hz, 2H), 3.59(s, 3H), 3.03(dd, J=14.9, 5.3Hz, 1H), 2.98 - 2.80(m, 2H), 2.78 - 2.68 (m, 1H), 2.64 (s, 3H), 2.17 - 2.08(m, 1H), 2.08 - 1.96(m, 1H).

[0251] Intermediate of Example 40 40.1: tert-Butyl N-[2-[2,4-dichloro-6-[2-(2-chloro-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (857 mg, 2.50 mmol) and 2-(2-chloro-1H-indol-3-yl)ethanamine hydrochloride (578 mg, 2.50 mmol) (synthesized by chlorination of tryptamine hydrochloride and used without purification). The reaction was concentrated to dryness, and the resulting crude product was purified by column chromatography eluting with a gradient of hexane to 4:1 hexane:EtOAc to give tert-butyl N-[2-[2,4-dichloro-6-[2-(2-chloro-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate as a brown solid (570 mg, 1.14 mmol, 45.53% yield). UPLC-MS analysis: (4 min, basic): rt=2.31 min, m / z=500.0 / 502.0 / 504.0 [M+H]+, purity 100%. 1H NMR (400MHz, DMSO-D6) δ 11.67(s, 1H), 8.09(t, J=6.0Hz, 1H), 7.63 - 7.56(m, 1H), 7.27(dt, J=8.1, 1.0Hz, 1H), 7.15 - 6.99(m, 3H), 3.87(t, J=5.4Hz, 2H), 3.53(q, J=6.9Hz, 2H), 3.23(q, J=5.6Hz, 2H), 2.99 - 2.91(m, 2H), 1.37(s, 9H).

[0252] 40.2: 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(2-chloro-1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-[2-(2-chloro-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate (570 mg, 1.14 mmol) was used to give 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(2-chloro-1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride as a yellow solid (330 mg, 0.755 mmol, 66.33% yield). UPLC-MS analysis (4 minutes, basic): rt=1.90 minutes, m / z=400.0 / 402.0 / 404.0 [M+H]+, purity 99%. 1H NMR (400MHz, DMSO-D6) δ 11.70(s, 1H), 8.36(t, J=6.0Hz, 1H), 8.22(s, 3H), 7.64(d, J=7.8Hz, 1H), 7.28(dt, J=8.1, 0.9Hz, 1H), 7.14 - 7.10 (m, 1H), 7.10 - 7.00 (m, 1H), 4.09 (t, J=5.0Hz, 2H), 3.56 - 3.49 (m, 2H), 3.25 - 3.18 (m, 2H), 3.00 - 2.92 (m, 2H).

[0253] 40.3: 2-Chloro-N-[2-(2-chloro-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared using 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(2-chloro-1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (370 mg, 0.846 mmol) according to general method 4. The reaction mixture was reduced to dryness and the crude product was purified by column chromatography eluting with 3:1 and 1:1 hexanes:EtOAc to give 2-chloro-N-[2-(2-chloro-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a brown solid (120 mg, 0.329 mmol, 38.93% yield). UPLC-MS analysis (4 min, basic): rt=1.87 min, m / z=364.0 / 366.0 [M+H]+, purity 75%. 1H NMR (400MHz, DMSO-D6) δ 11.62(s, 1H), 7.69 - 7.62(m, 1H), 7.26(dt, J=8.1, 1.0Hz, 1H), 7.14(t, J=2.6Hz, 1H), 7.10(ddd, J=8. 2, 7.1, 1.2Hz, 1H), 7.02(ddd, J=8.1, 7.1, 1.1Hz, 1H), 6.69(t, J=6.0Hz, 1H), 4.07 - 3.98(m, 2H), 3.47 - 3.35(m, 4H), 2.91 - 2.83(m, 2H).

[0254] Example 40: 3-(4-((2-(2-chloro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] Prepared according to general procedure 5b using 2-chloro-N-[2-(2-chloro-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (120 mg, 0.329 mmol) and (2-hydroxy-3-pyridyl)boronic acid (46 mg, 0.329 mmol). The crude product was purified by preparative HPLC to give 3-[4-[2-(2-chloro-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as a yellow solid (3.0 mg, 0.00709 mmol, 2.15% yield).

[0255] Example 40 is a keto / enol tautomer. It can also exist in the following forms: 3-(4-((2-(2-chloro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.71 min, m / z=423.1 / 425.1 [M+H]+, purity 100%. 1H NMR (400MHz, DMSO-D6) δ 11.64(s, 1H), 8.51(m, 1H), 8.22(s, 1H), 8.12(m, 1H), 7.56(d, J=7.9Hz, 1H), 7.35(m, 1H), 7.26(dt, J = 8.1, 1.0Hz, 1H), 7.10(ddd, J=8.1, 7.1, 1.3Hz, 1H), 7.08 - 6.98(m, 1H), 6.91(m, 1H), 6.78(m, 1H), 4.13(t, J=4.2Hz, 2H), 3.59(q, J=6.9Hz, 2H), 3.46(m, J=4.7Hz, 2H), 3.01 - 2.92 (m, 2H).

[0256] Intermediate of Example 41 41.1: tert-Butyl N-[2-[2,4-dichloro-6-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (400 mg, 1.17 mmol) and 2-(7-fluoro-2-methyl-1H-indol-3-yl)ethanamine oxalate (330 mg, 1.17 mmol). The reaction was concentrated to dryness and the residue was triturated with 20:1 MeCN:MeOH. It was filtered and washed with diethyl ether to give tert-butyl N-[2-[2,4-dichloro-6-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate as a brown solid (500 mg, 1.00 mmol, 85.93% yield). UPLC-MS analysis: (2 min, basic): rt=1.30 min, m / z=498.2 / 500.2 / 502.2 [M+H]+. 1H NMR (400MHz, DMSO-D6) δ 11.20(s, 1H), 8.06(d, J=6.4Hz, 1H), 7.33(d, J=7.8Hz, 1H), 7.08(s, 1H), 6.90(td, J=7.8, 4.8Hz, 1H), 6.84 - 6.75(m, 1H), 3.87(h, J=6.2 Hz, 2H), 3.47(q, J=6.8Hz, 2H), 3.2(q, J=5.3Hz, 2H), 2.94 - 2.86(m, 2H), 2.34(s, 3H), 1.38(d, J=2.0Hz, 9H). 19F NMR (376MHz, DMSO-D6) δ -134.21.

[0257] 41.2: 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]pyrimidin-4-amine [ka] Prepared using tert-butyl N-[2-[2,4-dichloro-6-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate (500 mg, 1.00 mmol) according to general method 3. The crude product was purified by column chromatography using EtOAc / MeOH (basic buffer, TEA) to give 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]pyrimidin-4-amine as an off-white solid (210 mg, 0.527 mmol, 52.56% yield). UPLC-MS analysis (4 min, basic): rt=1.96 min, m / z=398.0 / 400.0 / 402.0 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 11.21(s, 1H), 7.34(d, J=7.8Hz, 1H), 6.90(td, J=7.8, 4.8Hz, 1H), 6.80(dd, J=11.4, 7.8Hz, 1H), 3.79(t, J=5.0Hz, 2H), 3.51 - 3.41(m, 2H), 2.96 - 2.86(m, 2H), 2.80(t, J=5.1Hz, 2H), 2.34(s, 3H). 3H is not observed. 19F NMR (376MHz, DMSO-D6) δ -134.18 (dd, J=11.7, 4.8Hz).

[0258] 41.3: 2-Chloro-N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]pyrimidin-4-amine (192 mg, 0.483 mmol) was used to give 2-chloro-N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (170 mg, 0.470 mmol, 97.27% yield). UPLC-MS analysis (4 min, basic): rt=1.75 min, m / z=362.0 / 364.0 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 11.14(s, 1H), 7.39 - 7.33(m, 1H), 7.11(s, 1H), 6.88(td, J=7.8, 4.9Hz, 1H), 6.79(ddd, J=11.5, 7.8, 0 .9Hz, 1H), 6.61(t, J=6.0Hz, 1H), 4.05(dd, J=4.9, 3.7Hz, 2H), 3.38(s, 4H), 2.87 - 2.77(m, 2H), 2.33(s, 3H).

[0259] Example 41: 3-[4-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one [ka] Prepared according to general method 5b using 2-chloro-N-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (85 mg, 0.235 mmol) and (2-oxo-1,2-dihydropyridin-3-yl)boronic acid (1.50 equiv., 49 mg, 0.352 mmol). The crude product was purified by column chromatography eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane followed by MeOH (0% to 20%; v / v) in EtOAc to give 3-[4-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one as a pale yellow solid (40 mg, 0.0932 mmol, 39.69% yield).

[0260] Example 41 is a keto / enol tautomer. It can also exist in the following form: 3-(4-((2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.86 min, m / z=421.4 [M+H]+, purity 98%. 1H NMR (400MHz, DMSO-D6) δ 11.15(s, 1H), 8.46(dd, J=7.6, 2.1Hz, 1H), 8.14(dd, J=4.8, 2.1Hz,1H), 7.43 - 7.28(m, 2H), 7.01 - 6.86(m, 2H), 6.85 - 6.69(m, 2H), 4.14 (t, J=4.3Hz, 2H), 3.54(q, J=7.0Hz, 2H), 3.47(d, J=4.9Hz, 2H), 2.91(t, J=7.6Hz, 2H), 2.34(s, 3H). 1H is not observed. 19F NMR (376MHz, DMSO-D6) δ -134.27.

[0261] Intermediate of Example 42 42.1: tert-Butyl N-[2-[2,4-dichloro-6-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (350 mg, 1.02 mmol) and 2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethanamine hydrochloride (413 mg, 1.02 mmol). After evaporation of the reaction mixture, the residue was suspended in water and the precipitate was collected by filtration. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0% to 80%; v / v) in isohexane to give tert-butyl N-[2-[2,4-dichloro-6-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate as an off-white solid (230 mg, 0.343 mmol, 33.57% yield). UPLC-MS analysis (2 min, basic): rt=1.29 min, m / z=516.2 / 518.1 / 520.1 [M+H]+, purity 77%. 1H NMR (400MHz, DMSO-D6) δ 11.28(s, 1H), 8.01(t, J=5.9Hz, 1H), 7.12(dd, J=9.6, 2.2Hz, 1H), 7.09 - 6.99(m, 1H), 6.85 - 6.73(m, 1H), 3.84(t, J=5.5Hz, 2H), 3.42(q, J=6.8Hz, 2H), 3.22(q, J=5.5Hz, 2H), 2.82(t, J=7.6Hz, 2H), 2.29(s, 3H), 1.34(s, 9H). 19F NMR (376MHz, DMSO-D6) δ -123.23, -130.75.

[0262] 42.2: 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate (225 mg, 0.336 mmol) was used to give 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride as an off-white solid (210 mg, 0.325 mmol, 96.78% yield). UPLC-MS analysis (2 min, basic): rt=1.20 min, m / z=416.3 / 418.2 / 420.2 [M+H]+, purity 81%. 1H NMR (400MHz, DMSO-D6) δ 11.29(s, 1H), 8.42(t, J=6.0Hz, 1H), 8.29(s, 3H), 7.17(dd, J=9.5, 2.2Hz, 1H), 6.86 - 6.72(m, 1H), 4.08(t, J=5.0Hz, 2H), 3.43(q, J=6.6Hz, 2H), 3.25 - 3.15(m, 2H), 2.88 - 2.80(m, 2H), 2.31(d, J=6.4Hz, 3H). 19F NMR (376MHz, DMSO-D6) δ -123.16 (t, J=9.5Hz), -130.72 (d, J=11.2Hz).

[0263] 42.3: 2-Chloro-N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, 5-(2-aminoethoxy)-2,6-dichloro-N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (190 mg, 0.340 mmol) was used to give 2-chloro-N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (150 mg, 0.336 mmol, 98.75% yield). UPLC-MS analysis (2 min, basic): rt=1.21 min, m / z=380.3 / 382.2 [M+H]+, purity 67%. 1H NMR (400MHz, DMSO-D6) δ 11.22(s, 1H), 7.16(dt, J=9.6, 2.5Hz, 1H), 7.08(d, J=2.5Hz, 1H), 6.84 - 6.70(m, 1H), 6.58(t, J=5.7Hz, 1H), 4.09 - 3.91(m, 2H), 3.33(q, J=3.3Hz, 2H), 3.30(d, J=5.6Hz, 2H), 2.81 - 2.67(m, 2H), 2.34 - 2.20(m, 3H). 19F NMR (376MHz, DMSO-D6) δ -123.40, -130.96.

[0264] Example 42: 3-[4-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one [ka] Prepared according to general method 5b using 2-chloro-N-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (90 mg, 0.201 mmol) and (2-oxo-1,2-dihydropyridin-3-yl)boronic acid (1.50 equiv., 42 mg, 0.302 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane followed by MeOH (0% to 20%; v / v) in EtOAc to give 3-[4-[2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one as a yellow solid (40 mg, 0.0912 mmol, 45.29% yield).

[0265] Example 42 is a keto / enol tautomer. It can also exist in the following form: 3-(4-((2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.90 min, m / z=439.3 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 11.22(s, 1H), 8.41(dd, J=7.6, 2.1Hz, 1H), 8.10(dd, J=4.8, 2.1Hz, 1H), 7.31(s, 1H), 7.08(dd, J=9.7, 2.2Hz, 1H), 6.87(dd, J=7.5, 4.8Hz, 1H), 6.82 - 6.72(m, 1H), 6.69(t, J=6.2Hz, 1H), 4.09(t, J=4.2Hz, 2H), 3.49(q, J=7.0Hz, 2H), 3.42(s, 2H), 2.83(t, J=7.4Hz, 2H), 2.29(s, 3H). 1H is not observed. 19F NMR (376MHz, DMSO-D6) δ -123.40, -130.90.

[0266] Intermediate of Example 43 43.1: tert-Butyl N-[2-[2,4-dichloro-6-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethylamino]pyrimidin-5-yl]oxyethyl]carbamate [ka] This was prepared according to general procedure 2a using tert-butyl N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (0.50 g, 1.46 mmol) and 2-[6-(trifluoromethoxy)-1H-indol-3-yl]ethanamine (356 mg, 1.46 mmol). The solvent was evaporated to dryness under reduced pressure, and the resulting crude product was purified by column chromatography eluting with a gradient of MeOH (0% to 5% v / v) in DCM to give tert-butyl N-[2-[2,4-dichloro-6-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethylamino]pyrimidin-5-yl]oxyethyl]carbamate as a beige solid (676 mg, 1.07 mmol, 73.22% yield). UPLC-MS analysis (2 min, acidic): rt=1.33 min, m / z=550.2 / 552.2 / 554.2 [M+H]+, purity 87%. 1H NMR (400MHz, DMSO-D6) δ 11.09(s, 1H), 8.05(s, 1H), 7.72(d, J=8.6Hz, 1H), 7.31(t, J=2.6Hz, 2H), 7.09(s, 1H), 7.01 - 6.94(m, 1H), 3.90(t, J=5.5Hz, 2H), 3.61(q, J=7.0Hz, 2H), 3.31 - 3.23(m, 2H), 2.98(t, J=7.5Hz, 2H), 1.38(d, J=1.8Hz, 9H). 19F NMR (376MHz, DMSO-d6) δ -56.71.

[0267] 43.2: 5-(2-aminoethoxy)-2,6-dichloro-N-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethyl]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethylamino]pyrimidin-5-yl]oxyethyl]carbamate (676 mg, 1.23 mmol) was used to give 5-(2-aminoethoxy)-2,6-dichloro-N-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethyl]pyrimidin-4-amine hydrochloride as a brown solid (645 mg, 1.22 mmol, 99.26% yield). UPLC-MS analysis (2 min, acidic): rt=0.98 min, m / z=450.2 / 452.2 / 454.2 [M+H]+, purity 92%. 1H NMR (400MHz, DMSO-D6) δ 11.13(s, 1H), 8.43(d, J=35.9Hz, 4H), 7.76(d, J=8.9Hz, 1H), 7.35 - 7.29(m, 2H), 6.97(d, J=8.6Hz, 1H), 4.1(d, J=5.4Hz, 2H), 3.61(d, J=6.1Hz, 2H), 3.22(s, 2H), 2.98(t, J=7.5Hz, 2H). 19F NMR (376MHz, DMSO-d6) δ -56.70.

[0268] 43.3: 2-Chloro-N-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared using 5-(2-aminoethoxy)-2,6-dichloro-N-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethyl]pyrimidin-4-amine hydrochloride (676 mg, 1.39 mmol) according to general method 4. The solvent was evaporated to dryness under reduced pressure, and the resulting crude product was purified by column chromatography eluting with a MeOH (0% to 10%; v / v) gradient in DCM to give 2-chloro-N-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a brown solid (320 mg, 0.565 mmol, 56.00% yield). UPLC-MS analysis (2 min, acidic): rt=1.15 min, m / z=414.2 / 416.2 [M+H]+, purity 73%. 1H NMR (400MHz, DMSO-D6) δ 11.05(s, 1H), 7.75(d, J=8.6Hz, 1H), 7.29(dd, J=5.8, 2.2Hz, 2H), 7.12(s, 1H), 6.95(ddd, J=8.7, 2.2, 1. 1Hz, 1H), 6.67(t, J=5.9Hz, 1H), 4.06(t, J=4.4Hz, 2H), 3.50(q, J=7.0Hz, 2H), 3.38(p, J=3.7Hz, 2H), 2.93 - 2.85(m, 2H). 19F NMR (376MHz, DMSO-d6) δ -56.70.

[0269] Example 43: 3-(4-((2-(6-(trifluoromethoxy)-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] Prepared according to general procedure 5b using 2-chloro-N-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 320 mg, 0.773 mmol) and (2-hydroxy-3-pyridyl)boronic acid (1.50 equiv., 161 mg, 1.16 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a MeOH (0% to 10%; v / v) gradient in DCM and then by preparative HPLC (basic method) to give 3-[4-[2-[6-(trifluoromethoxy)-1H-indol-3-yl)]ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as a yellowish solid (19 mg, 0.0404 mmol, 5.23% yield).

[0270] Example 43 is a keto / enol tautomer. It can also exist in the form: 3-(4-((2-(6-(trifluoromethoxy)-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=2.01 min, m / z=473.3 [M+H]+, purity 99%. 1H NMR (400 MHz, DMSO-D6) δ 11.09 (s, 1H), 8.50 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.42 - 7.25 (m, 3H), 6.96 (d, J = 10.6 Hz, 2H), 6.78 (s, 1H), 4.14 (s, 2H), 3.66 (s, 2H), 3.46 (s, 2H), 3.00 (s, 2H). 1H signals are not observed. 19F NMR (376MHz, DMSO-d6) δ -56.69.

[0271] Intermediate of Example 44 44.1: tert-Butyl N-methyl-N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate [ka] Prepared using 2,4,6-trichloropyrimidin-5-ol (0.30 g, 1.43 mmol) and tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (0.29 mL, 1.71 mmol) according to general method 1. The crude product was purified by column chromatography (40 g cartridge) eluting with a gradient of EtOAc (0% to 45% v / v) in heptane to give tert-butyl N-methyl-N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate as a colorless oil (130 mg, 0.365 mmol, 25.51% yield). UPLC-MS analysis (2 min, basic): rt=1.27 min, no ionization, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 4.16 (s, 2H), 3.53 (t, J=5.4Hz, 2H), 2.85 (s, 3H), 1.35 (s, 9H).

[0272] 44.2: tert-Butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]-N-methylcarbamate [ka] General procedure 2a was followed, using tert-butyl N-methyl-N-[2-(2,4,6-trichloropyrimidin-5-yl)oxyethyl]carbamate (1.00 equiv., 120 mg, 0.336 mmol) and tryptamine (1.11 equiv., 60 mg, 0.374 mmol) in ethanol (1.8 mL). The reaction was concentrated to dryness to give an oily residue, which was suspended in water (25 mL) with stirring. The resulting suspension was filtered, and the solid was dried under vacuum to give tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]-N-methylcarbamate as a white solid (145 mg, 0.284 mmol, 84.32% yield). UPLC-MS analysis (2 min, basic): rt=1.30 min, m / z=480.2 / 482.2 / 484.1 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 8.05(d, J=41.3Hz, 1H), 7.59(d, J=7.8Hz, 1H), 7.30(d, J=8.1Hz, 1H), 7.15(d, J=2.3Hz, 1H), 7.02(t, J=7.4Hz, 1H), 6 .94(t, J=7.4Hz, 1H), 3.91(d, J=18.9Hz, 2H), 3.57(q, J=7.0Hz, 2H), 3.46(s, 2H), 2.94(d, J=7.7Hz, 2H), 2.83(s, 3H), 1.36(s, 9H).

[0273] 44.3: 2,6-Dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[2-(methylamino)ethoxy]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[2-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]-N-methylcarbamate (140 mg, 0.274 mmol) was used to give 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[2-(methylamino)ethoxy]pyrimidin-4-amine hydrochloride as a beige solid (125 mg, 0.258 mmol, 94.17% yield). UPLC-MS analysis (2 min, basic): rt=1.20 min, m / z=380.3 / 382.2 / 384.2 [M+H]+, purity 86%. 1H NMR (400MHz, DMSO-D6) δ 10.86(s, 1H), 9.29(s, 2H), 8.50(t, J=6.0Hz, 1H), 7.68(d, J=7.8Hz, 1H), 7.34(d, J=8.2Hz, 1H), 7.30 - 7.17(m, 1H), 7.07(t, J=7.7Hz, 1H), 6.99(q, J=8.1Hz, 1H), 4.18(t, J=4.9Hz, 2H), 3.63(q, J=7.1Hz, 2H), 3.12 - 2.95 (m, 4H), 2.60 (t, J=5.3Hz, 3H).

[0274] 44.4: 2-Chloro-N-[2-(1H-indol-3-yl)ethyl]-8-methyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, 2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[2-(methylamino)ethoxy]pyrimidin-4-amine hydrochloride (1.00 equiv, 120 mg, 0.2476 mmol) was used to give 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-8-methyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (90 mg, 0.246 mmol, 99.36% yield). UPLC-MS analysis (2 min, basic): rt=1.13 min, m / z=344.1 / 346.1 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 10.75(s, 1H), 7.62(d, J=7.8Hz, 1H), 7.29(d, J=8.1Hz, 1H), 7.11(d, J=2.3Hz, 1H), 7.07 - 6.96(m, 1H), 6.96 - 6.89(m, 1H), 6.55(t, J=6.0Hz, 1H), 4.11(t, J=4.4Hz, 2H), 3.47(q, J=7.0Hz, 2H), 3.38(t, J=4.4Hz, 2H), 2.92(s, 3H), 2.85(t, J=7.7Hz, 2H).

[0275] Example 44: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-8-methyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine (85 mg, 0.232 mmol) and (2-oxo-1,2-dihydropyridin-3-yl)boronic acid (48 mg, 0.349 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0–100%; v / v) in isohexane followed by MeOH (0–10%; v / v) in EtOAc to give 3-[4-[2-(1H-indol-3-yl)ethylamino]-8-methyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as an off-white solid (24 mg, 0.0567 mmol, 24.38% yield).

[0276] Example 44 is a keto / enol tautomer. It can also exist in the following form: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.82 min, m / z=403.4 [M+H]+, purity 95%. 1H NMR (400 MHz, DMSO-D6) δ 10.84 (s, 1H), 8.58 (s, 1H), 8.15 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.12 - 7.03 (m, 1H), 7.04 - 6.91 (m, 2H), 6.78 (s, 1H), 4.24 (t, J = 4.4 Hz, 2H), 3.64 (q, J = 7.0 Hz, 2H), 3.51 (s, 2H), 3.11 (s, 3H), 2.99 (t, J = 7.6 Hz, 2H). 1H not observed.

[0277] Example 45: (S)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] Prepared according to general method 5b using (7S)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (150 mg, 0.401 mmol) and (2-hydroxy-3-pyridyl)boronic acid (84 mg, 0.602 mmol). The crude product was purified by reverse-phase column chromatography (23 g cartridge) eluting with a water gradient (5% to 95% acidic buffer) containing MeCN to give 3-[(7S)-4-[2-(1H-indol-3-yl)ethylamino]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as a yellow solid (41 mg, 0.0920 mmol, 22.92% yield).

[0278] Example 45 is a keto / enol tautomer. It can also exist in the following form: (S)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, acidic): rt=1.32 min, m / z=433.4 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.84(s, 1H), 8.53(s, 1H), 8.19 - 8.06(m, 1H), 7.58(d, J=7.8Hz, 1H), 7.53(s, 1H), 7.34(dd, J=8.1, 1.0Hz, 1H), 7.21(d, J=2.2Hz, 1H), 7.10 - 7.03(m, 1H), 7.03 - 6.90(m, 2H), 6.85(s, 1H), 4.18 - 3.99(m, 2H), 3.73(s, 1H), 3.66(q, J=6.9Hz, 2H), 3.48 - 3.40 (m, 2H), 2.99 (t, J = 7.6 Hz, 2H). 4H not observed. 1H NMR (400 MHz, methanol-D4) δ 8.54 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.29 (dq, J = 8.1, 1.1 Hz, 1H), 7.11 (s, 1H), 7.09 - 7.03 (m, 1H), 7.03 - 6.94 (m, 1H), 6.81 (dd, J = 7.5, 5.5 Hz, 1H), 4.19 - 4.07 (m, 2H), 3.78 (t, J = 7.1 Hz, 3H), 3.52 - 3.43(m, 2H), 3.40(s, J=1.0Hz, 3H), 3.08(t, J=7.2Hz, 2H).

[0279] Intermediate of Example 46 46.1: tert-Butyl N-[(1R)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate [ka] Prepared using 2,4,6-trichloropyrimidin-5-ol (1.00 equiv., 0.30 g, 1.43 mmol) and tert-butyl N-[(1S)-1-(hydroxymethyl)-2-methoxy-ethyl]carbamate (1.10 equiv., 0.32 g, 1.57 mmol) according to general procedure 1. The crude product was purified by column chromatography (40 g column) eluting with 18–20% EtOAc in isohexane to give tert-butyl N-[(1R)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate as a white solid (380 mg, 0.983 mmol, 68.77% yield). UPLC-MS analysis: (2 min, basic): rt=1.22 min, no ionization, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 6.97(d, J=8.2Hz, 1H), 4.19(dd, J=9.8, 4.8Hz, 1H), 4.07(dd, J=9.7, 6.4Hz, 1H), 3.98 - 3.91(m, 1H), 3.43(d, J=6.1Hz, 2H), 3.28(s, 3H), 1.39(s, 9H).

[0280] 46.2: tert-Butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[(1R)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate (1.00 equiv., 0.38 g, 0.983 mmol) and tryptamine (1.05 equiv., 0.17 g, 1.03 mmol) in ethanol (4.2 mL). The reaction was concentrated to dryness to give an oily residue, which was suspended in water (10 mL) and stirred. The resulting suspension was filtered and the solid dried under vacuum to give tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate as an off-white solid (534 mg, 0.942 mmol, 95.81% yield). UPLC-MS analysis (2 min, basic): rt=1.29 min, m / z=510.3 / 512.3 / 514.3 [M+H]+, purity 95%. 1H NMR (400MHz, DMSO-D6) δ 10.84(s, 1H), 7.91(s, 1H), 7.67 - 7.59(m, 1H), 7.35(dt, J=8.2, 1.0Hz, 1H), 7.19(d, J=2.4Hz, 1H), 7.12 - 7.06(m, 1H), 7.05(d, J=7.7Hz, 1H), 6.99(ddd, J=8.0, 7.0, 1.1Hz, 1H), 3.96(d, J=6.3Hz, 1H), 3.88(t, J=6.5Hz, 1H), 3.63(q, J=6.9Hz, 2H), 3.38(s, 2H), 3.24(s, 3H), 3.09(q, J=7.1Hz, 1H), 2.99(t, J=7.6Hz, 2H), 1.40(s, 9H).

[0281] 46.3: 2,6-Dichloro-N-[2-(1H-indol-3-yl)ethyl]-5-[(2R)-2-amino-3-methoxy-propoxy]pyrimidin-4-amine hydrochloride [ka] Following general method 3, tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate (1.00 equiv, 0.53 g, 1.05 mmol) was used to give 5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride as a beige solid (465 mg, 0.937 mmol, 89.54% yield). UPLC-MS analysis (2 min, basic): rt=1.13 min, m / z=410.3 / 412.3 / 414.2 [M+H]+, purity 92%. 1H NMR (400MHz, DMSO-D6) δ 10.85(s, 1H), 8.59(s, 3H), 8.48(t, J=6.0Hz, 1H), 7.68(d, J=7.8Hz, 1H), 7.37 - 7.30(m, 1H), 7.20(d, J=2.3Hz, 1H), 7.10 - 7.03(m, 1H), 7.02 - 6.95(m, 1H), 4.21(d, J=6.2Hz, 1H), 4.06(dd, J=10.1, 5.6Hz, 1H), 3.75 - 3.68 (m, 1H), 3.69 - 3.58 (m, 4H), 3.32 (s, 3H), 3.04 - 2.93 (m, 2H).

[0282] 46.4: (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general procedure 4, 5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-N-[2-(1H-indol-3-yl)ethyl]pyrimidin-4-amine hydrochloride (1.00 equiv, 0.47 g, 0.937 mmol) was used to give (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (0.34 g, 0.833 mmol, 88.97% yield). UPLC-MS analysis (2 min, basic): rt=1.06 min, m / z=374.2 / 376.1 [M+H]+, purity 93%. 1H NMR (400MHz, DMSO-D6) δ 10.79(s, 1H), 7.66(d, J=7.8Hz, 1H), 7.33(d, J=8.1Hz, 1H), 7.27(d, J=3.2Hz, 1H), 7.16(d, J=2.3Hz, 1H), 7.12 - 7.03(m, 1H), 7.03 - 6.94(m, 1H), 6.72(t, J=5.9Hz, 1H), 4.04(dd, J=10.7, 4.0Hz, 1H), 3.96(dd, J=10.7, 2.9Hz, 1H), 3.70 - 3.59 (m, 1H), 3.52 (q, J=6.9Hz, 2H), 3.38 - 3.33(m, 2H), 3.29(s, 3H), 2.90(t, J=7.7Hz, 2H).

[0283] Example 46: (7R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 100 mg, 0.249 mmol) and 5-fluoropyridine-3-boronic acid (2.00 equiv., 70 mg, 0.498 mmol). The crude product was purified by column chromatography (20 g column) eluting with a 0–100% (v / v) EtOAc gradient in isohexane to give (7R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (62 mg, 0.143 mmol, 57.36% yield). UPLC-MS analysis (4 min, basic): rt=1.86 min, m / z=435.4 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 9.23(t, J=1.8Hz, 1H), 8.60(d, J=2.9Hz, 1H), 8.30 - 8.16(m, 1H), 7.63(d, J=7.8Hz, 1H), 7.34(dt, J=8.1, 1.0Hz, 1H), 7.20(d, J=2.3Hz, 1H), 7.15 - 7.03(m, 2H), 7.03 - 6.93 (m, 1H), 6.56 (t, J=5.9Hz, 1H), 4.13 - 4.01 (m, 2H), 3.78 - 3.65 (m, 3H), 3.45 - 3.35(m, 2H), 3.32(s, 3H), 2.99(dd, J=8.9, 6.4Hz, 2H). 19F NMR (376MHz, DMSO-D6) δ -128.10.

[0284] Intermediate of Example 47 47.1: tert-Butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(6-fluoro-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[(1R)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate (1.00 equiv., 250 mg, 0.647 mmol) and 2-(6-fluoro-1H-indol-3-yl)ethanamine (1.10 equiv., 127 mg, 0.714 mmol) in ethanol (4.3 mL). The reaction was concentrated to dryness to give an oily residue, which was suspended in water (50 mL) and stirred. The resulting suspension was filtered and the solid was dried under vacuum to give tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(6-fluoro-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate as a white solid (290 mg, 0.472 mmol, 73.00% yield). UPLC-MS analysis (2 min, basic): rt=1.29 min, m / z=529.3 / 531.3 / 533.3 [M+H]+, purity 86%. 1H NMR (400MHz, DMSO-D6) δ 10.88(s, 1H), 7.87(s, 1H), 7.58(dd, J=8.6, 5.5Hz, 1H), 7.14(d, J=2.3Hz, 1H), 7.07(dd, J=10.2, 2.3Hz, 1H), 7.02 - 6.91 (m, 1H), 6.80 (ddd, J=9.8, 8.6, 2.4Hz, 1H), 3.94 - 3.78 (m, 3H), 3.70 - 3.39 (m, 2H), 3.38 - 3.30(m, 2H), 3.21(d, J=15.4Hz, 3H), 2.92(t, J=7.6Hz, 2H), 1.34(d, J=0.8Hz, 9H).

[0285] 47.2: 2,6-Dichloro-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-5-[(2R)-2-amino-3-methoxy-propoxy]pyrimidin-4-amine [ka] Prepared using tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(6-fluoro-1H-indol-3-yl)ethylamino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate (220 mg, 0.416 mmol) according to general procedure 3. The reaction was concentrated and the crude product purified by column chromatography using EtOAc / MeOH (1% TEA) to give 2,6-dichloro-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-5-[(2R)-2-amino-3-methoxy-propoxy]pyrimidin-4-amine as an off-white material (70 mg, 0.159 mmol, 38.08% yield). UPLC-MS analysis (2 min, basic): rt=1.18 min, m / z=428.0 / 430.0 / 432.0 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.87(s, 1H), 7.56(dd, J=8.7, 5.5Hz, 1H), 7.15(d, J=2.3Hz, 1H), 7.07(ddd, J=10.2, 2.4, 0.5Hz , 1H), 6.80(ddd, J=9.8, 8.6, 2.4Hz, 1H), 4.05(q, J=5.3Hz, 2H), 3.88(dd, J=9.9, 3.7Hz, 1H), 3.61 - 3.49 (m, 3H), 3.22 (s, 1H), 3.20 (s, 4H), 3.01 (dd, J = 13.5, 7.1 Hz, 1H), 2.92 (t, J = 7.4 Hz, 2H). No 1H peak was observed.

[0286] 47.3: (7R)-2-chloro-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, 5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]pyrimidin-4-amine (70 mg, 0.163 mmol) was used to give (7R)-2-chloro-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (50 mg, 0.115 mmol, 70.27% yield). Note: The reaction required multiple microwave irradiation cycles (total of 13 hours at 140° C.). UPLC-MS analysis (2 min, basic): rt=1.07 min, m / z=392.3 / 394.3 [M+H]+, purity 90%. 1H NMR (400MHz, DMSO-D6) δ 10.83(s, 1H), 7.61(dd, J=8.6, 5.6Hz, 1H), 7.24(d, J=3.2Hz, 1H), 7.12(d, J=2.2Hz, 1H), 7.05(dd, J=10.2, 2.4Hz, 1H), 6.82 - 6.75(m, 1H), 6.71(t, J=5.9Hz, 1H), 4.03 - 3.85(m, 3H), 3.60(s, 2H), 3.44(dd, J=8.5, 6.3Hz, 2H), 3.25(s, 3H), 2.87 - 2.79(m, 2H).

[0287] Example 47: (R)-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] Prepared according to general method 5b using (7R)-2-chloro-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (50 mg, 0.128 mmol) and (2-hydroxy-3-pyridyl)boronic acid (27 mg, 0.191 mmol). The crude product was purified by reverse-phase column chromatography (23 g cartridge) eluting with a water gradient (5% to 95% acidic buffer) containing MeCN to give 3-[(7R)-4-[2-(6-fluoro-1H-indol-3-yl)ethylamino]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as a yellow solid (11 mg, 0.0232 mmol, 18.18% yield).

[0288] Example 47 is a keto / enol tautomer. It can also exist in the following forms: (R)-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, acidic): rt=1.34 min, m / z=451.3 [M+H]+, purity 95%. 1H NMR (400MHz, DMSO-D6) δ 10.91(s, 1H), 8.47(brs, 1H), 8.16(s, 1H), 8.11(brs, 1H), 7.55(dd, J=8.7, 5.5Hz, 1H), 7.51(brs, 1H), 7.21(d, J=2.2Hz, 1H), 7.10(dd, J=10.2, 2.4Hz, 1H), 6.92(brs, 1H), 6.89 - 6.78(m, 2H), 4.15 - 4.01(m, 2H), 3.73(m, 1H), 3.65(q, J=7.0Hz, 2H), 3.45 - 3.35(m, 2H), 3.31(s, 3H), 3.02 - 2.93(t, 2H). 19F NMR (376MHz, DMSO-D6) δ -122.36 (td, J=10.0, 5.5Hz).

[0289] Intermediate of Example 48 48.1: tert-Butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate [ka] Prepared according to general procedure 2b using tert-butyl N-[(1R)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate (590 mg, 1.53 mmol) and tryptophor (246 mg, 1.53 mmol) at −40° C. The crude product was purified by column chromatography eluting with 8:1 to 3:1 hexanes:EtOAc to give tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate as a white solid (350 mg, 0.684 mmol, 44.85% yield). UPLC-MS analysis (4 min, basic): rt=2.28 min, no ionization, 98% purity. 1H NMR (400MHz, DMSO-D6) δ 10.89(s, 1H), 7.63(d, J=7.9Hz, 1H), 7.35(dq, J=8.1, 0.9Hz, 1H), 7.25(d, J=2.4Hz, 1H), 7.08(ddd, J=8.2, 6.6, 1.2Hz, 1H), 7.00(ddt, J=7.8, 6.9, 0.8Hz, 1H), 6.79(d, J=8.2Hz, 1H), 4.62(t, J=7.1Hz, 2H), 4.08(dd, J=10.2, 5.2Hz, 1H), 4.03 - 3.91(m, 1H), 3.90 - 3.81(m, 1H), 3.33(d, J=6.1Hz, 2H), 3.22(d, J=7.4Hz, 5H), 1.37(s, 9H).

[0290] 48.2: (2R)-1-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxy-3-methoxy-propan-2-amine hydrochloride [ka] Following general method 3, tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate (1.00 equiv, 350 mg, 0.657 mmol) was used to give (2R)-1-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxy-3-methoxy-propan-2-amine hydrochloride as a purple solid (210 mg, 0.422 mmol, 64.25% yield). UPLC-MS analysis (2 min, basic): rt=1.13 min, m / z=411.2 / 413.1 / 415.2 [M+H]+, purity 90%. 1H NMR (400 MHz, DMSO-D6) δ 10.95 (s, 1H), 8.39 (s, 3H), 7.63 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 4.66 (t, J = 7.1 Hz, 2H), 4.16 (q, J = 2.4 Hz, 2H), 3.57 (s, 2H), 3.29 (s, 3H), 3.23 (t, J = 7.1 Hz, 2H). 1H is not observed, likely due to overlap with the water peak.

[0291] 48.3: (7R)-2-chloro-4-[2-(1H-indol-3-yl)ethoxy]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ka] Following general method 4, (2R)-1-[2,4-dichloro-6-[2-(1H-indol-3-yl)ethoxy]pyrimidin-5-yl]oxy-3-methoxy-propan-2-amine hydrochloride (180 mg, 0.402 mmol) was used to give (7R)-2-chloro-4-[2-(1H-indol-3-yl)ethoxy]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine as an off-white solid (150 mg, 0.344 mmol, 85.61% yield). UPLC-MS analysis (2 min, basic): rt=1.09 min, m / z=375.2 / 377.1 [M+H]+, purity 86%. H NMR (400 MHz, DMSO-D6) δ 10.83 (s, 1H), 7.97 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.94 (t, J = 7.4 Hz, 1H), 4.40 (t, J = 7.3 Hz, 2H), 4.06 - 3.86 (m, 2H), 3.65 (s, 1H), 3.25 (s, 3H), 3.07 (t, J = 7.3 Hz, 2H). 2H is not observed; water signal is below.

[0292] Example 48: 3-[(7R)-4-[2-(1H-indol-3-yl)ethoxy]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one [ka] Prepared according to general method 5b using (7R)-2-chloro-4-[2-(1H-indol-3-yl)ethoxy]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (100 mg, 0.229 mmol) and (2-oxo-1,2-dihydropyridin-3-yl)boronic acid (48 mg, 0.344 mmol). The crude material was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0–100%; v / v) in isohexane, followed by MeOH (0–10%; v / v) in EtOAc, followed by reverse-phase column chromatography (12 g cartridge) eluting with a gradient of MeCN (0.1% NH) (0%–95%; v / v) in water (0.1% NH) to give 3-[(7R)-4-[2-(1H-indol-3-yl)ethoxy]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one as an off-white solid (47 mg, 0.105 mmol, 45.84% yield).

[0293] Example 48 is a keto / enol tautomer. It can also exist in the following form: (R)-3-(4-(2-(1H-indol-3-yl)ethoxy)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.64 min, m / z=343.3 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 13.86(s, 1H), 10.89(s, 1H), 8.51(s, 1H), 8.28(s, 1H), 8.17(s, 1H), 7.61(d, J=7.9Hz, 1H), 7.35(d, J=8.1Hz, 1H), 7.25(s, 1H) , 7.07(t, J=7.5Hz, 1H), 6.98(s, 2H), 4.63(s, 2H), 4.08(s, 2H), 3.79(s, 1H), 3.42(d, J=6.3Hz, 2H), 3.18(s, 2H), 2.54(s, 3H).

[0294] Example 49: (7R)-2-(3,5-difluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 150 mg, 0.373 mmol) and 3,5-difluorobenzeneboronic acid (1.00 equiv., 59 mg, 0.373 mmol). The crude product was purified by column chromatography (40 g column) eluting with a 0–100% (v / v) EtOAc gradient in isohexane to give (7R)-2-(3,5-difluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a yellow solid (58 mg, 0.128 mmol, 34.43% yield). UPLC-MS analysis (4 min, basic): rt=2.18 min, m / z=452.4 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.82(s, 1H), 7.90 - 7.77(m, 2H), 7.72 - 7.58 (m, 1H), 7.35 (dt, J=8.1, 1.0Hz, 1H), 7.26 (tt, J=9.0, 2.5Hz, 1H), 7.20 (d, J=2.3Hz, 1H), 7.14 - 7.03 (m, 1H), 7.03 - 6.91 (m, 2H), 6.53 (t, J=5.9Hz, 1H), 4.18 - 3.99 (m, 2H), 3.82 - 3.59 (m, 3H), 3.47 - 3.35(m, 2H), 3.31(s, 3H), 3.04 - 2.94(m, 2H). 19F NMR (376MHz, DMSO-D6) δ -110.24.

[0295] Example 50: 2-(3-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5a using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 75 mg, 0.227 mmol) and 3-fluorobenzeneboronic acid (1.50 equiv., 48 mg, 0.341 mmol). The reaction mixture was reduced to dryness under vacuum and the resulting crude product was purified by reverse-phase column chromatography eluting with MeCN+0.1% NH3 / water+0.1% NH3 to give 2-(3-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (17 mg, 0.0423 mmol, 18.62% yield). UPLC-MS analysis (4 min, basic): rt=2.01 min, m / z=390.3 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 8.07(dt, J=7.9, 1.3Hz, 1H), 8.02 - 7.88(m, 1H), 7.65(d, J=7.8Hz, 1H), 7.46(td, J=8.1, 6.1Hz, 1H), 7.39 - 7.31 (m, 1H), 7.28 - 7.15 (m, 2H), 7.13 - 7.03 (m, 1H), 7.03 - 6.94(m, 1H), 6.82(d, J=2.8Hz, 1H), 6.34(t, J=6.0Hz, 1H), 4.14(t, J=4.3Hz, 2H), 3.71(q, J=7.0Hz, 2H), 3.52 - 3.38(m, 2H), 3.06 - 2.92(m, 2H). 19F NMR (376MHz, DMSO-D6) δ -113.94.

[0296] Example 51: 2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 70 mg, 0.197 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 66 mg, 0.295 mmol). The crude product was purified by column chromatography (20 g column) eluting with a 0–100% (v / v) EtOAc gradient in isohexane to give 2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine) as an off-white solid (60 mg, 0.143 mmol, 72.87% yield). UPLC-MS analysis (4 min, basic): rt=2.23 min, m / z=419.2 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.72(s, 1H), 7.96(s, 1H), 7.3(d, J=7.7Hz, 1H), 7.26(dt, J=8.0, 1.0Hz, 1H), 7.03 - 6.95(m, 1H), 6.95 - 6.85(m, 2H), 6.10(d, J=8.2Hz, 1H), 4.49 - 4.33(m, 1H), 4.20 - 4.05(m, 2H), 3.51 - 3.35(m, 2H), 3.02(dd, J=14.9, 5.3Hz, 1H), 2.95 - 2.76(m, 2H), 2.72 - 2.62(m, 1H), 2.60(s, 3H), 2.17 - 2.06(m, 1H), 2.04 - 1.92(m, 1H).

[0297] Example 52: 2-(2,4-dimethylthiazol-5-yl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 100 mg, 0.303 mmol) and 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 109 mg, 0.455 mmol). The crude product was purified by column chromatography (24 g column) eluting with a 0–100% (v / v) EtOAc gradient in isohexane (product eluted with 95–100% EtOAc) to give 2-(2,4-dimethylthiazol-5-yl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (87 mg, 0.214 mmol, 70.58% yield). UPLC-MS analysis (4 min, basic): rt=1.77 min, m / z=407.3 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.8(s, 1H), 7.60 - 7.55(m, 1H), 7.35 - 7.31(m, 1H), 7.15(d, J=2.3Hz, 1H), 7.09 - 7.03(m, 1H), 7.00 - 6.93(m, 1H), 6.79 - 6.75(m, 1H), 6.32(t, J=5.9Hz, 1H), 4.13 - 4.06(m, 2H), 3.62(q, J=6.8Hz, 2H), 3.44 - 3.35(m, 2H), 3.00 - 2.90(m, 2H), 2.70(s, 3H), 2.55(s, 3H).

[0298] Intermediate of Example 53 53.1: tert-Butyl N-[(1R)-1-[[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate [ka] Prepared according to general procedure 2a using tert-butyl N-[(1R)-1-(methoxymethyl)-2-(2,4,6-trichloropyrimidin-5-yl)oxy-ethyl]carbamate (1.00 equiv., 0.20 g, 0.476 mmol) and (R)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (1.10 equiv., 0.097 g, 0.523 mmol) in ethanol (3.4483 mL) at 50°C. The reaction was concentrated to dryness to give an oily residue, which was dispersed in water (20 mL), and the resulting suspension was filtered to give tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate as an off-white solid (0.26 g, 0.461 mmol, 96.89% yield). UPLC-MS analysis (2 min, basic): rt=1.35 min, m / z=536.1 / 538.1 / 540.1 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.74(s, 1H), 7.70(d, J=8.0Hz, 1H), 7.33(d, J=7.8Hz, 1H), 7.25(dt, J=8.0, 0.9Hz, 1H), 7.10(d, J=8.0Hz, 1H), 7.05 - 6.96 (m, 1H), 6.96 - 6.87 (m, 1H), 4.40 - 4.27 (m, 1H), 4.11 - 4.01 (m, 1H), 3.98 - 3.90(m, 1H), 3.40(d, J=5.7Hz, 2H), 3.26(s, 3H), 3.06(dd, J=14.9, 5.3Hz, 1H), 2.94 - 2.79(m, 2H), 2.76 - 2.66(m, 1H), 2.21 - 2.10(m, 1H), 2.09 - 1.93(m, 1H), 1.39(s, 9H), 1.17 - 1.02(m, 1H).

[0299] 53.2: (3R)-N-[5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride [ka] Following general method 3, tert-butyl N-[(1R)-1-[[2,4-dichloro-6-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]pyrimidin-5-yl]oxymethyl]-2-methoxy-ethyl]carbamate (1.00 equiv, 0.25 g, 0.452 mmol) was used to give (3R)-N-[5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride as a beige solid (0.23 g, 0.452 mmol, 100.08% yield). UPLC-MS analysis (2 min, basic): rt=1.21 min, m / z=436.3.0 / 438.2 / 440.3 [M+H]+, purity 93%. 1H NMR (400MHz, DMSO-D6) δ 10.77(s, 1H), 8.57(s, 3H), 8.12(d, J=8.4Hz, 1H), 7.33(d, J= 7.8Hz, 1H), 7.29 - 7.21(m, 1H), 7.05 - 6.96 (m, 1H), 6.93 (td, J=7.4, 1.1Hz, 1H), 4.45 - 4.33 (m, 1H), 4.29 (dd, J=10.2, 4.0Hz, 1H), 4.14 - 4.06 (m, 1H), 3.80 - 3.71 (m, 1H), 3.70 - 3.65(m, 2H), 3.34(s, 3H), 3.11 - 2.95 (m, 2H), 2.95 - 2.76 (m, 3H), 2.12 - 2.04 (m, 1H).

[0300] 53.4: (7R)-2-chloro-7-(methoxymethyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Following general method 4, (3R)-N-[5-[(2R)-2-amino-3-methoxy-propoxy]-2,6-dichloro-pyrimidin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine hydrochloride (1.00 equiv., 200 mg, 0.393 mmol) was used to give (7R)-2-chloro-7-(methoxymethyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (0.16 g, 0.384 mmol, 97.64% yield). UPLC-MS analysis (2 min, basic): rt=1.12 min, m / z=400.3 / 402.3 [M+H]+, purity 96%. 1H NMR (400MHz, DMSO-D6) δ 10.70(s, 1H), 7.41 - 7.27(m, 2H), 7.24(d, J=7.9Hz, 1H), 6.99(t, J=7.4Hz, 1H), 6.91(t, J=7.4Hz, 1H), 6.58(d, J=8.5Hz, 1H), 4.30 - 4.17(m, 1H), 4.12 - 3.93 (m, 2H), 3.65 (s, 1H), 3.38 - 3.34 (m, 1H), 3.29 (s, 3H), 2.94 (dd, J=14.9, 5.3Hz, 1H), 2.88 - 2.76 (m, 2H), 2.69 - 2.56(m, 1H), 2.07 - 1.90(m, 2H), 1.11 - 1.00(m, 1H).

[0301] Example 53: (7R)-7-(Methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using (7R)-2-chloro-7-(methoxymethyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 90 mg, 0.216 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.50 equiv., 73 mg, 0.324 mmol). The crude product was purified by flash column chromatography (20 g column) eluting with a 0–100% (v / v) EtOAc gradient in isohexane followed by EtOAc / MeOH (product eluted with 5–7% MeOH) to give (7R)-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine) as an off-white solid (48 mg, 0.104 mmol, 48.03% yield). UPLC-MS analysis (4 min, basic): rt=1.93 min, m / z=463.4 [M+H]+, purity 98%. 1H NMR (400MHz, DMSO-D6) δ 10.74(s, 1H), 7.96(s, 1H), 7.33(d, J=7.6Hz, 1H), 7.30 - 7.20(m, 1H), 7.0(d, J=3.1Hz, 1H), 7.03 - 6.96(m, 1H), 6.92(td, J=7.5, 1.1Hz, 1H), 6.30(d, J=8.2Hz, 1H), 4.40(s, 1H), 4.12 - 3.98(m, 2H), 3.73 - 3.62(m, 1H), 3.44 - 3.36(m, 2H), 3.30(s, 3H), 3.01(dd, J=15.0, 5.3Hz, 1H), 2.87(d, J=21.8Hz, 2H), 2.66(s, 1H), 2.60(s, 3H), 2.10(d, J=12.4Hz, 1H), 2.02 - 1.89(m, 1H).

[0302] Example 54: [(7R)-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl]methanol [ka] To (7R)-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 23 mg, 0.0497 mmol) in DCM (2 mL) was added boron tribromide in DCM (1 M, 1.00 equiv., 0.050 mL, 0.0497 mmol) and the mixture was stirred at ambient temperature for 24 h. The reaction mixture was carefully quenched by the addition of MeOH (0.5 mL). The crude product was purified by silica column chromatography eluting with a gradient of MeOH (0% to 5% v / v) in DCM to give [(7R)-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl]methanol as a white solid (9.0 mg, 0.0187 mmol, 37.53% yield). UPLC-MS analysis (4 min, basic): rt = 1.67 min, m / z = 449.4 [M+H], purity 93%. 1H NMR (400MHz, DMSO-D6) δ 10.70(s, 1H), 7.95(s, 1H), 7.32(d, J=7.7Hz, 1H), 7.25(dt, J=8.0, 0.9Hz, 1H), 6.99(ddd, J=8.1, 7.0, 1.3Hz, 1H), 6.95 - 6.88(m, 2H), 6.17(d, J=8.2Hz, 1H), 4.93(t, J=5.3Hz, 1H), 4.40(s, 1H), 4.07(d, J=3.3Hz, 2H), 3.56 - 3.45(m, 2H), 3.42 - 3.33 (m, 1H), 3.01 (dd, J=14.9, 5.3Hz, 1H), 2.84 (td, J=16.2, 10.0Hz, 2H), 2.71 - 2.61 (m, 1H), 2.59 (s, 3H), 2.14 - 2.07(m, 1H), 1.96(qd, J=10.8, 5.9Hz, 1H).

[0303] Example 55: N-[2-(1H-indol-3-yl)ethyl]-2-(1-methyltriazol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 200 mg, 0.606 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole (1.00 equiv., 126 mg, 0.606 mmol). The reaction mixture was concentrated, and the product was precipitated in a DCM / EtOAc mixture. The crude product was purified by reverse-phase chromatography (16 g cartridge) eluting with a gradient of MeCN / water from 0% to 95%, followed by preparative HPLC (basic method) to give N-[2-(1H-indol-3-yl)ethyl]-2-(1-methyltriazol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine-4-amine as a white solid (2.3 mg, 0.00599 mmol, 0.98% yield). UPLC-MS analysis (6 min, basic): rt=2.41 min, m / z=377.1 [M+H]+, purity 98%. 1H NMR (400MHz, MeOD) δ 7.98(s, 1H), 7.61(d, J=7.9Hz, 1H), 7.30(d, J=8.1Hz, 1H), 7.07(d, J=7.3Hz, 2H), 7.01(t, J=7.5Hz, 1H), 4.15(t, J=4.5Hz, 2H), 4.11(s, 3H), 3.81(t, J=7.1Hz, 2H), 3.50(t, J=4.3Hz, 2H), 3.03(t, J=7.1Hz, 2H).

[0304] Example 56: (7R)-2-(4-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (55 mg, 0.137 mmol) and 4-fluorobenzeneboronic acid (38 mg, 0.274 mmol). The reaction mixture was reduced to dryness in vacuo. The crude product was purified by column chromatography eluting with 4:1 and 2:1 hexanes:EtOAc to give (7R)-2-(4-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a white solid (22 mg, 0.0508 mmol, 37.09% yield). UPLC-MS analysis (4 min, basic): rt=2.07 min, m / z=434.4 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.80(s, 1H), 8.29 - 8.19(m, 2H), 7.61(d, J=7.8Hz, 1H), 7.34(dt, J=8.1, 1.0Hz, 1H), 7.27 - 7.16(m, 3H), 7.07(ddd, J=8.1, 7.0, 1.2Hz, 1H), 6.98(ddd, J=7.9, 7.0, 1.1Hz, 1H), 6.87(d, J=3. 1Hz, 1H), 6.37(t, J=5.9Hz, 1H), 4.05(qd, J=10.6, 3.5Hz, 2H), 3.69(dt, J=8.9, 6.5Hz, 3H), 3.45 - 3.33(m, 2H), 3.31(s, 3H), 3.03 - 2.94(m, 2H). 19F NMR (376MHz, DMSO-D6) δ -113.49 - -113.60(m)

[0305] Example 57: (7R)-2-(3-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (50 mg, 0.0976 mmol) and 3-fluorobenzeneboronic acid (27 mg, 0.195 mmol). The reaction mixture was reduced to dryness in vacuo. The crude product was purified by column chromatography eluting with 4:1 and 2:1 hexanes:EtOAc to give (7R)-2-(3-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (16 mg, 0.0365 mmol, 37.43% yield). UPLC-MS analysis (4 min, basic): rt=2.09 min, m / z=434.4 [M+H]+, purity 99%. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 8.06(dt, J=7.8, 1.2Hz, 1H), 7.94(ddd, J=11.0, 2.8, 1.4Hz, 1H), 7. 64(d, J=7.8Hz, 1H), 7.45(td, J=8.0, 6.1Hz, 1H), 7.34(dt, J=8.1, 0.9Hz, 1H), 7.28 - 7.16(m, 2H), 7.07(ddd, J=8.1, 6.9, 1.2Hz, 1H), 6.97(ddd, J=8.0, 7.0, 1.1Hz, 1H) , 6.92(d, J=3.0Hz, 1H), 6.44(t, J=5.9Hz, 1H), 4.06(qd, J=10.6, 3.5Hz, 2H), 3.74 - 3.64 (m, 3H), 3.46 - 3.32 (m, 2H), 3.31 (s, 3H), 2.99 (dd, J=8.9, 6.4Hz, 2H). 19F NMR (376MHz, DMSO-D6) δ -113.90 (ddd, J=10.9, 8.6, 6.1Hz).

[0306] Example 58: 5-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1-methyl-pyridin-2-one [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (150 mg, 0.455 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (160 mg, 0.682 mmol). The crude product was purified by column chromatography (40 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane followed by MeOH (0% to 15%; v / v) in EtOAc to give 5-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1-methyl-pyridin-2-one as a beige solid (110 mg, 0.273 mmol, 60.09% yield). UPLC-MS analysis (4 min, basic): rt=1.54 min, m / z=403.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.80(s, 1H), 8.35(d, J=2.5Hz, 1H), 8.16(dd, J=9.5, 2.4Hz, 1H), 7.60(d, J=7.8Hz, 1H), 7.39 - 7.30(m, 1H), 7.19(d, J=2.3Hz, 1H), 7.07(dd, J=8.1, 6.9Hz, 1H), 7.03 - 6.91(m, 1H), 6.66(t, J=2.5Hz, 1H), 6.41(d, J=9.5Hz, 1H), 6.21(t, J=6.0Hz, 1H), 4.09(t, J= 4.3Hz, 2H), 3.67(q, J=7.0Hz, 2H), 3.49(s, 3H), 3.41(q, J=3.0Hz, 2H), 2.96(t, J=7.6Hz, 2H).

[0307] Example 59: (7R)—N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using (7R)-2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (300 mg, 0.746 mmol) and 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (218 mg, 0.970 mmol). The reaction mixture was concentrated to dryness under vacuum. The crude product was purified by column chromatography eluting with 3:1 and 1:1 hexanes:EtOAc to give (7R)—N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine) as a white solid (157 mg, 0.360 mmol, 48.19% yield). UPLC-MS analysis (2 min, basic): rt=1.09 min, m / z=437.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.80(s, 1H), 8.02(s, 1H), 7.65(ddt, J=7.8, 1.3, 0.7Hz, 1H), 7.34(dt, J=8. 1, 0.9Hz, 1H), 7.19(d, J=2.3Hz, 1H), 7.07(ddd, J=8.2, 7.0, 1.2Hz, 1H), 7.03 - 6.95(m, 2H), 6.45(t, J=5.9Hz, 1H), 4.03(qd, J=10.6, 3.5Hz, 2H), 3.70 - 3.57(m, 3H), 3.38(d, J=7.7Hz, 2H), 3.29(s, 3H), 2.95(dd, J=9.0, 6.4Hz, 2H), 2.64(s, 3H).

[0308] Example 60: [(7R)-4-[2-(1H-indol-3-yl)ethylamino]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl]methanol [ka] To (7R)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine) (140 mg, 0.321 mmol) in DCM (4 mL) was added a solution of boron tribromide in DCM (1 M, 0.38 mL, 0.385 mmol), and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was carefully quenched by the addition of MeOH (1 mL) and water (4 mL), then washed twice with DCM. The organics were dried over NaSO, filtered, and concentrated to dryness. The crude product was purified by reverse-phase column chromatography (4 g column) eluting with a water gradient (5% to 95% basic buffer) containing MeCN to give [(7R)-4-[2-(1H-indol-3-yl)ethylamino]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl]methanol as an off-white solid (22 mg, 0.0521 mmol, 16.24% yield). UPLC-MS analysis (4 min, basic): rt=1.56 min, m / z=423.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.80(d, J=2.4Hz, 1H), 8.03(s, 1H), 7.65(ddt, J=7.8, 1.3, 0.7Hz, 1H), 7.34(dt, J=8.1, 0.9Hz, 1H), 7.18(d, J= 2.3Hz, 1H), 7.07(ddd, J=8.2, 7.0, 1.3Hz, 1H), 6.99(ddd, J=7.9, 7.0, 1.1Hz, 1H), 6.91(s, 1H), 6.47(s, 1H), 4.11 - 3.99(m, 2H), 3.62(s, 2H), 3.54 - 3.42(m, 2H), 3.40 - 3.31 (m, 1H), 2.95 (dd, J = 9.0, 6.4 Hz, 2H), 2.64 (s, 3H). 1H not observed.

[0309] Example 61: 2-(2-methylthiazol-5-yl-N-[(4R)-1,3,4,5-tetrahydrobenzo[cd]indol-4-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Assume: 2-(2-methylthiazol-5-yl-N-[(4R)-1,3,4,5-tetrahydrobenzo[cd]indol-4-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (29 mg, 0.0717 mmol, 7.49% yield). Chemical purity: 99.51%, m / z=405.21. Enantiomeric excess: 100. UPLC-MS analysis (4 min, basic): rt=1.75 min, m / z=405.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.60(s, 1H), 7.87(s, 1H), 7.10(d, J=8.1Hz, 1H), 7.01 - 6.91(m, 3H), 6.88(s, 1H), 6.67(d, J=7.0Hz, 1H), 5.96(d, J=8.6Hz, 1H), 4.53(dt, J=9.0, 4.5Hz, 1H), 4.05(t, J=4.1Hz, 2H), 3.35(d, J=4.2Hz, 2H), 3.03(dt, J=12.3, 7.4Hz, 3H), 2.85(dd, J=15.0, 9.6Hz, 1H), 2.54(s, 3H). It is assumed to be optical isomer R.

[0310] Example 62: 2-(2-methylthiazol-5-yl-N-[(4S)-1,3,4,5-tetrahydrobenzo[cd]indol-4-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Assume the following: 2-(2-methylthiazol-5-yl-N-[(4S)-1,3,4,5-tetrahydrobenzo[cd]indol-4-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (36 mg, 0.0881 mmol, 9.20% yield). Chemical purity: 98.75%, m / z=405.21 Enantiomeric excess: 97.0. UPLC-MS analysis (4 min, basic): rt=1.75 min, m / z=405.1 [M+H]+, 100% purity. 1H NMR (400 MHz, DMSO-D6) δ 10.60 (s, 1H), 7.87 (s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.98 - 6.93 (m, 2H), 6.88 (s, 1H), 6.71 - 6.60 (m, 1H), 5.96 (d, J = 8.6 Hz, 1H), 4.53 (dt, J = 9.0, 4.5 Hz, 1H), 4.05 (t, J = 4.2 Hz, 2H), 3.35 (d, J = 4.2 Hz, 2H), 3.09 - 2.95 (m, 3H), 2.86 (dd, J = 15.4, 9.5 Hz, 1H), 2.54 (s, 3H). Expected enantiomer S.

[0311] Example 63: 3-[4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one [ka] Prepared according to general procedure 5b using 2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (75 mg, 0.198 mmol) and (2-oxo-1,2-dihydropyridin-3-yl)boronic acid (1.50 equiv., 41 mg, 0.297 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane followed by MeOH (0% to 15%; v / v) in EtOAc to give 3-[4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one as a yellow solid (24 mg, 0.0579 mmol, 29.23% yield).

[0312] Example 63 is a keto / enol tautomer. It can also exist in the following form: (R)-3-(4-((2,3,4,9-tetrahydro-1H-carbazol-3-yl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.76 min, m / z=415.2 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.73(s, 1H), 8.53 - 8.46(m, 1H), 8.11(dd, J=4.8, 2.1Hz, 1H), 7.37(d, J=7.4Hz, 1H), 7.33(d, J=7.7Hz, 1H), 7.28 - 7.24 (m, 1H), 7.03 - 6.97 (m, 1H), 6.94 - 6.89 (m, 2H), 6.60 - 6.49 (m, 1H), 4.38 (s, 1H), 4.18 (s, 2H), 3.48 (s, 2H), 3.03 (dd, J = 14.9, 5.3 Hz, 1H), 2.87 (q, J = 13.3 Hz, 2H), 2.74 (dd, J = 14.9, 9.5 Hz, 1H), 2.20 - 2.08 (m, 1H), 2.06 - 1.92 (m, 1H). 1H not observed.

[0313] Example 64: N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (80 mg, 0.243 mmol) and (2-methoxy-3-pyridyl)boronic acid (1.50 equiv., 56 mg, 0.364 mmol). An additional amount of boronic acid, catalyst, and ligand was added, and the reaction was stirred at 100 °C for 24 h. The crude product was purified by column chromatography (40 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane followed by MeOH (0% to 5%; v / v) in EtOAc to give N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (45 mg, 0.112 mmol, 46.09% yield). UPLC-MS analysis (4 min, basic): rt=1.62 min, m / z=403.1 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.73(s, 1H), 8.18(dd, J=4.9, 2.0Hz, 1H), 7.81(dd, J=7.3, 2.0Hz, 1H), 7.62 - 7.57 (m, 1H), 7.30 (dt, J=8.1, 0.9Hz, 1H), 7.13 (d, J=2.3Hz, 1H), 7.06 - 7.00 (m, 2H), 6.86 - 6.80 (m, 1H), 6.79 - 6.74(m, 1H), 6.27(t, J=5.9Hz, 1H), 4.17 - 4.08(m, 2H), 3.81(s, 3H), 3.61 - 3.51(m, 2H), 3.45 - 3.35(m, 2H), 2.98 - 2.89(m, 2H).

[0314] Example 65: 2-(5-Fluoro-2-methoxy-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (130 mg, 0.329 mmol) and 5-fluoro-2-methoxypyridine-3-boronic acid (84 mg, 0.493 mmol). The crude material was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane, followed by MeOH (0% to 10%; v / v) in EtOAc to give 2-(5-fluoro-2-methoxy-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a yellow solid (112 mg, 0.251 mmol, 76.29% yield). UPLC-MS analysis (4 min, basic): rt=1.89 min, m / z=447.2 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.64(s, 1H), 8.09(d, J=3.2Hz, 1H), 7.77 - 7.65(m, 1H), 7.28(d, J=7.7Hz, 1H), 7.19(dt, J=8.0, 1.0Hz, 1H), 7.01 - 6.91(m, 1H), 6.91 - 6.81(m, 2H), 5.99(d, J=8.2Hz, 1H), 4.35 - 4.21(m, 1H), 4.10(t, J=4.4Hz, 2H), 3.76(s, 3H), 3.37(d, J=6.1Hz, 2H), 3.00(dd, J=14.9, 5.3Hz, 1H), 2.83 - 2.72 (m, 2H), 2.58 (dd, J=15.0, 9.1Hz, 1H), 2.13 - 2.02 (m, 1H), 2.01 - 1.87 (m, 1H). 19F NMR (376MHz, DMSO-D6) δ -139.81.

[0315] Intermediate of Example 66 66.1: 2-(2-benzyloxy-5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (120 mg, 0.364 mmol) and 2-(benzyloxy)-5-fluoropyridin-3-yl-boronic acid (135 mg, 0.546 mmol). The crude material was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane, followed by MeOH (0% to 15%; v / v) in EtOAc to give 2-(2-benzyloxy-5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (105 mg, 0.190 mmol, 52.30% yield). UPLC-MS analysis (4 min, basic): rt=2.20 min, m / z=497.2 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.71(s, 1H), 8.14(d, J=3.1Hz, 1H), 7.76(dd, J=8.6, 3.1Hz, 1H), 7.55(d, J=7.9Hz, 1H), 7.38 - 7.33(m, 2H), 7.26(dt, J=8.1, 1.0Hz, 1H), 7.21 - 7.13(m, 3H), 7.06(d, J=2.4Hz, 1H), 6.98(ddd, J=8.1, 6.9, 1.2Hz, 1H), 6.82 - 6.73(m, 2H), 6.27(t, J=5.9Hz, 1H), 5.31(s, 2H), 4.09(t, J=4.3Hz, 2H), 3.53(q, J=6.9Hz, 2H), 3.38(q, J=3.7Hz, 2H), 2.91 - 2.82(m, 2H). 19F NMR (376MHz, DMSO-D6) δ -139.38.

[0316] Example 66: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-fluoropyridin-2(1H)-one [ka] To a solution (3.8265 mL) of 2-(2-benzyloxy-5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (95 mg, 0.191 mmol) in ethanol, palladium on activated carbon (10% Pd) (30 mg, 0.191 mmol) was added and the reaction mixture was stirred at room temperature under a molecular hydrogen atmosphere for 18 hours. The suspension was filtered through Celite, and the filtrate was evaporated to dryness. The crude material was purified by column chromatography (20 g cartridge) eluting with a gradient of 0% to 100% EtOAc in isohexane to give 5-fluoro-3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as an off-white solid (49 mg, 0.119 mmol, 62.39% yield). Example 66 is a keto / enol tautomer. It may also exist in the following form: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-fluoropyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.79 min, m / z=407.3 [M+H]+, purity 99%. 1H NMR (400MHz, DMSO-D6) δ 10.84(s, 1H), 8.30(dd, J=9.1, 3.3Hz, 1H), 8.15(d, J=3.2Hz, 1H), 7.60(dd, J=7.8, 1.1 Hz, 1H), 7.42 (d, J=2.7Hz, 1H), 7.34 (dt, J=8.1, 0.9Hz, 1H), 7.20 (d, J=2.4Hz, 1H), 7.11 - 7.04 (m, 1H), 7.02 - 6.94 (m, 1H), 6.84 (t, J=5.9Hz, 1H), 4.21 - 4.11 (m, 2H), 3.72 - 3.60 (m, 2H), 3.47 (q, J = 3.8 Hz, 2H), 3.04 - 2.93 (m, 2H). 1H not observed. 19F NMR (376MHz, DMSO-D6) δ -139.71.

[0317] Example 67: 2-(5-Fluoro-2-methoxy-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (85 mg, 0.232 mmol) and 5-fluoro-2-methoxypyridine-3-boronic acid (59 mg, 0.348 mmol). The crude material was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane, followed by MeOH (0% to 10%; v / v) in EtOAc to give 2-(5-fluoro-2-methoxy-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as an off-white solid (65 mg, 0.155 mmol, 66.65% yield). UPLC-MS analysis (4 min, basic): rt=1.77 min, m / z=421.3 [M+H]+, purity 99%. 1H NMR (400MHz, DMSO-D6) δ 10.82 - 10.68 (m, 1H), 8.18 (dd, J=3.1, 1.0Hz, 1H), 7.80 - 7.71(m, 1H), 7.60(d, J=7.9Hz, 1H), 7.30(dt, J=8.1, 0.9Hz, 1H), 7.13(dd, J=2.3, 1.0Hz, 1H), 7.09 - 6.98(m, 1H), 6.91 - 6.77(m, 2H), 6.38(t, J=5.9Hz, 1H), 4.12(t, J=4.3Hz, 2H), 3.80(d, J=0.9Hz, 3H), 3.56(q, J=6.8Hz, 2H), 3.41(s, 2H), 2.99 - 2.87(m, 2H). 19F NMR (376MHz, DMSO-D6) δ -139.90 (d, J=0.9Hz).

[0318] Example 68: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-methylpyridin-2(1H)-one [ka] To N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-5-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (80 mg, 0.192 mmol) in DCM (2 mL) was added a 1 M solution of boron tribromide in DCM (0.091 mL, 0.960 mmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was carefully quenched by the addition of MeOH (1 mL) and then concentrated to dryness. The crude product was purified by column chromatography (20 g cartridge) eluting with an EtOAc (0% to 100%; v / v) gradient in isohexane and then by preparative HPLC to give the desired product 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-5-methyl-pyridin-2-ol as a white solid (30 mg, 0.0745 mmol, 38.81% yield).

[0319] Example 68 is a keto / enol tautomer. It can also exist in the following forms: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-methylpyridin-2-ol. [ka] UPLC-MS analysis (6 min, basic): rt=3.10 min, m / z=403.2 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.82(s, 1H), 8.34(d, J=2.6Hz, 1H), 7.96 - 7.90(m, 1H), 7.57(d, J=7.9Hz, 1H), 7.31(d, J=8.0Hz, 2H), 7.20 - 7.14(m, 1H), 7.03(ddt, J=8.2, 6.9, 1.4Hz, 1H), 6.99 - 6.90 (m, 1H), 6.73 (t, J = 5.8 Hz, 1H), 4.10 (d, J = 4.5 Hz, 2H), 3.61 (q, J = 7.1 Hz, 2H), 3.42 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.20 (s, 3H). 1H is not observed.

[0320] Example 69: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-(trifluoromethyl)pyridin-2(1H)-one [ka] N-[2-(1H-indol-3-yl)ethyl]-2-[2-methoxy-5-(trifluoromethyl)-3-pyridyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (70 mg, 0.149 mmol) was treated with 4N hydrogen chloride in dioxane (5.0 mL, 20.0 mmol) and the mixture was heated at 70° C. for 18 hours. The reaction was concentrated to dryness and the residue was purified by column chromatography (12 g column) eluting with 15-30% methanol in DCM to give 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-5-(trifluoromethyl)pyridin-2-ol as a yellow solid (39 mg, 0.0836 mmol, 56.22% yield).

[0321] Example 69 is a keto / enol tautomer. It can also exist in the following forms: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-(trifluoromethyl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.50 min, m / z=457.3 [M+H]+, 100% purity. NMR (400 MHz, DMSO-D6) δ 10.84 (s, 1H), 8.69 (s, 1H), 8.49 (s, 1H), 7.59 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.02 (ddd, J = 10.7, 6.0, 2.5 Hz, 2H), 6.93 (td, J = 7.4, 1.1 Hz, 1H), 4.13 (t, J = 4.3 Hz, 2H), 3.62 (q, J = 7.0 Hz, 2H), 3.46 (d, J = 4.7 Hz, 2H), 3.00 - 2.92 (m, 2H). 1H not observed. 19F NMR (376MHz, DMSO-D6) δ -59.66.

[0322] Intermediate of Example 70 70.1: 2-(2-benzyloxy-5-fluoro-3-pyridyl)-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (100 mg, 0.288 mmol) and 2-(benzyloxy)-5-fluoropyridin-3-yl-boronic acid (107 mg, 0.431 mmol). The crude product was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane to give 2-(2-benzyloxy-5-fluoro-3-pyridyl)-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a yellowish solid (80 mg, 0.140 mmol, 48.66% yield). UPLC-MS analysis (2 min, basic): rt=1.23 min, m / z=515.3 [M+H]+, purity 94%. 1H NMR (400MHz, DMSO-D6) δ 10.79(s, 1H), 8.14(dd, J=3.1, 1.8Hz, 1H), 7.81 - 7.70(m, 1H), 7.52(dd, J=8.4, 6.0Hz, 1H), 7.38 - 7.32(m, 2H), 7.19 - 7.13(m, 3H), 7.07 - 6.99(m, 2H), 6.76(s, 1H), 6.63 - 6.56(m, 1H), 6.30(t, J=5.7Hz, 1H), 5.30(s, 2H), 4.08(s, 2H), 3.51(d, J=7.6Hz, 2H), 3.38(s, 2H), 2.84(t, J=7.6Hz, 2H). 19F NMR (376MHz, DMSO-D6) δ -139.36.

[0323] Example 70: 5-Fluoro-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] To a solution of 2-(2-benzyloxy-5-fluoro-3-pyridyl)-N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (90 mg, 0.157 mmol) in ethanol (3.1485 mL) was added palladium-activated carbon paste (5% Pd) (60 mg, 0.157 mmol), and the reaction mixture was stirred at room temperature under a molecular hydrogen atmosphere for 18 hours. The suspension was filtered through Celite, and the filtrate was evaporated to dryness. The crude material was triturated with DCM / MeOH (1:1, 2 mL) to give 5-fluoro-3-[4-[2-(6-fluoro-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as an off-white solid (25 mg, 0.0577 mmol, 36.67% yield). Example 70 is a keto / enol tautomer. It may also exist in the following form: 5-fluoro-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.85 min, m / z=425.3 [M+H]+, purity 99%. 1H NMR (400MHz, DMSO-D6) δ 10.91(s, 1H), 8.25(dd, J=9.0, 3.2Hz, 1H), 8.14(d, J=3.2Hz, 1H), 7.56(dd, J=8.7, 5.5H z, 1H), 7.42 (d, J=3.0Hz, 1H), 7.20 (d, J=2.3Hz, 1H), 7.10 (dd, J=10.2, 2.3Hz, 1H), 6.88 - 6.77(m, 2H), 4.16(t, J=4.2Hz, 2H), 3.65(q, J=7.0Hz, 2H), 3.51 - 3.42(m, 2H), 3.02 - 2.92(m, 2H). 1H is not observed. 19F NMR (376MHz, DMSO-D6) δ -122.36, -139.73.

[0324] Intermediate of Example 71 71.1: 2-(2-benzyloxy-5-fluoro-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (80 mg, 0.202 mmol) and 2-(benzyloxy)-5-fluoropyridin-3-yl-boronic acid (75 mg, 0.304 mmol). The crude material was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane to give the desired product, 2-(2-benzyloxy-5-fluoro-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine, as a yellow solid (50 mg, 0.0957 mmol, 47.28% yield). UPLC-MS analysis (4 min, basic): rt=2.29 min, m / z=523.2 [M+H]+, purity 97%. 1H NMR (400MHz, DMSO-D6) δ 10.62(s, 1H), 8.08(d, J=3.1Hz, 1H), 7.74(dd, J=8.6, 3.1Hz, 1H), 7.37(d, J=1.7Hz, 1H), 7.36 - 7.34 (m, 1H), 7.23 (d, J=7.6Hz, 1H), 7.20 - 7.10(m, 4H), 6.93(ddd, J=8.1, 7.1, 1.3Hz, 1H), 6.85(ddd, J=8.0, 7.0, 1.1Hz, 1H) , 6.80(s, 1H), 5.99(d, J=8.5Hz, 1H), 5.30(s, 2H), 4.36(s, 1H), 4.10(s, 2H), 3.46 - 3.35(m, 2H), 2.90(dd, J=14.9, 5.3Hz, 1H), 2.69(s, 2H), 2.58(dd, J=15.1, 9.2Hz, 1H), 1.95(s, 2H). 19F NMR (376MHz, DMSO-D6) δ -139.32.

[0325] Example 71: (R)-5-fluoro-3-(4-((2,3,4,9-tetrahydro-1H-carbazol-3-yl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one [ka] To a solution of 2-(2-benzyloxy-5-fluoro-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (45 mg, 0.0775 mmol) in ethanol (3.4445 mL) was added palladium-activated carbon paste (5% Pd) (30 mg, 0.0775 mmol), and the reaction mixture was stirred at room temperature under a molecular hydrogen atmosphere for 18 hours. The suspension was filtered through Celite, and the filtrate was evaporated to dryness. The crude material was triturated with DCM / MeOH (1:1, 2 mL) to give 5-fluoro-3-[4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as an off-white solid (13 mg, 0.0301 mmol, 38.79% yield). Example 71 is a keto / enol tautomer. It may also exist in the following form: (R)-5-fluoro-3-(4-((2,3,4,9-tetrahydro-1H-carbazol-3-yl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.97 min, m / z=433.3 [M+H]+, 100% purity. 1H NMR (400MHz, DMSO-D6) δ 10.71(s, 1H), 8.32 - 8.19(m, 1H), 8.08(d, J=3.2Hz, 1H), 7.43(s, 1H), 7.29(d, J=7.8Hz, 1H), 7.22(d, J=8.0Hz, 1H), 6.96(t, J=7.5Hz, 1H), 6.88(t, J=7.4Hz, 1H), 6.62(d, J=8.3Hz, 1H), 4.34(s, 1H), 4.15(s, 2H), 3.45(s, 2H), 3.05 - 2.64(m, 4H), 2.17 - 2.05(m, 1H), 2.04 - 1.88 (m, 1H). 1H not observed. 19F NMR (376MHz, DMSO-D6) δ -139.61.

[0326] Example 72: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-chloropyridin-2(1H)-one [ka] To 2-(5-chloro-2-methoxy-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (80 mg, 0.183 mmol) in DCM (10 mL) was added a 1 M solution of boron tribromide in DCM (0.087 mL, 0.916 mmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was carefully quenched by the addition of MeOH (2 mL) and then concentrated to dryness. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0% to 100%; v / v) in isohexane to give 5-chloro-3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyridin-2-ol as a yellow solid (18 mg, 0.0404 mmol, 22.08% yield).

[0327] Example 72 is a keto / enol tautomer. It can also exist in the following form: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-chloropyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.93 min, m / z=423.3 / 425.3 [M+H]+, purity 95%. 1H NMR (400MHz, DMSO-D6) δ 10.81(s, 1H), 8.47(d, J=2.8Hz, 1H), 8.15(d, J=2.8Hz, 1H), 7.56(dt, J=7.7, 0.9Hz, 1H), 7.42(s, 1H), 7.30(dt, J=8.0, 1.0Hz, 1H), 7.16( d, J=2.3Hz, 1H), 7.03(ddd, J=8.1, 7.0, 1.3Hz, 1H), 6.96(ddd, J=8.0, 7.0, 1.1Hz, 1H), 6.84(t, J=5.9Hz, 1H), 4.12(t, J=4.2Hz, 2H), 3.66 - 3.57 (m, 2H), 3.46 - 3.41 (m, 2H), 2.99 - 2.91 (m, 2H). 1H is not observed.

[0328] Intermediate of Example 73 73.1: N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general method 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (1.00 equiv., 150 mg, 0.455 mmol) and 2-methoxy-6-methylpyridine-3-boronic acid (1.50 equiv., 114 mg, 0.682 mmol). The crude material was purified by column chromatography (20 g cartridge) eluting with a gradient of EtOAc (50% to 100%; v / v) in hexane to give the desired product N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine as a beige solid (76 mg, 0.168 mmol, 37.01% yield). UPLC-MS analysis (2 min, basic): rt=1.17 min, m / z=417.4 [M+H]+, purity 92%. 1H NMR (400MHz, DMSO-D6) δ 10.75(s, 1H), 7.72(dd, J=7.3, 5.0Hz, 1H), 7.60(d, J=7.7Hz, 1H), 7.34 - 7.28(m, 1H), 7.13(s, 1H), 7.03(s, 1H), 6.86(d, J=8.6Hz, 2H), 6.75(s, 1H), 6.25(d, J=5.5Hz, 1H), 4.11(s, 2H), 3.79(d, J=4.4Hz, 3H), 3.55(s, 2H), 3.40(s, 2H), 2.94(s, 2H), 2.43(d, J=4.0Hz, 3H).

[0329] Example 73: 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-6-methyl-1H-pyridin-2-one [ka] N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (76 mg, 0.183 mmol) was treated with 4N hydrogen chloride in dioxane (6.1 mL, 24.6 mmol) and the mixture was heated at 70° C. for 18 hours. The reaction was concentrated to dryness and the residue was purified by column chromatography (12 g cartridge) eluting with EtOAc to give the desired product 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-6-methyl-1H-pyridin-2-one as a yellow solid (55 mg, 0.132 mmol, 72.23% yield).

[0330] Example 73 is a keto / enol tautomer. It can also exist in the following form: 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-6-methylpyridin-2-ol. [ka] UPLC-MS analysis (4 min, basic): rt=1.81 min, m / z=403.4 [M+H]+, purity 96%. 1H NMR 0.12 (400 MHz, DMSO-D6) δ 10.84 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 8.14 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.1 Hz, 1H), 7.20 (s, 1H), 7.13 - 6.94 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 4.18 (s, 2H), 3.71 (s, 2H), 3.52 (s, 2H), 3.00 (s, 2H), 2.38 (s, 3H). 1H not observed.

[0331] Example 74: 2-(2-amino-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine [ka] Prepared according to general procedure 5b using 2-chloro-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (100 mg, 0.294 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (97 mg, 0.441 mmol). The crude material was purified by column chromatography (20 g cartridge) eluting with a MeOH (5% to 10% v / v) gradient in DCM followed by preparative HPLC (General Method) to give the title compound as a yellow solid (52 mg, 0.129 mmol, 43.80% yield). UPLC-MS analysis (4 min, basic): rt=1.66 min, m / z=388.3 [M+H]+, purity 96%. 1H NMR (400MHz, DMSO-D6) δ 10.83(s, 1H), 8.78(dd, J=7.6, 1.8Hz, 1H), 8.05(dd, J=5.8, 1.8Hz, 1H), 7.56(d, J =7.8Hz, 1H), 7.33(dd, J=8.1, 1.0Hz, 1H), 7.20(d, J=2.3Hz, 1H), 7.13(s, 1H), 7.10 - 7.03(m, 1H), 7.02 - 6.96(m, 1H), 6.89(dd, J=7.7, 5.8Hz, 1H), 6.57(t, J=5.9Hz, 1H), 4.20 - 4.09 (m, 2H), 3.66 (q, J = 6.9 Hz, 2H), 3.46 (s, 2H), 2.98 (t, J = 7.5 Hz, 2H). 2H not observed.

[0332] In vitro assay 1: AhR antagonism in U937 cells (Promega P450-Glo® assay) AhR antagonism was evaluated using U937 cells (a myeloid cell line derived from human histiocytic lymphoma). Ligands bind to AhR in the cytoplasm, and the AhR / ligand complex translocates to the nucleus and forms a heterodimer with AhR nuclear translocator (Arnt). This complex binds to the xenobiotic response element (XRE) in the 5' upstream region of the CYP1A1 promoter, promoting CYP1A1 expression. CYP1A1 activity was assessed by assessing the conversion of luciferin-CEE to luciferin, which then reacts with luciferase to produce light. The amount of light produced is directly proportional to cytochrome P450 activity.

[0333] U937 cells in serum-free Ultraculture medium (Lonza) were seeded at 100,000 cells / well in 96-well round-bottom tissue culture plates. Test compounds were added at seven concentrations (1% DMSO final) and incubated for 10 minutes before the addition of 300 μM KYNA. The plates were then placed in an incubator at 37°C, ≥85% humidity, and 5% CO for 24 hours. After aspirating the supernatant, the CYP1A1 substrate luciferin-CEE (83 μM final) was added and incubated for 3 hours. The reaction was then stopped by the addition of luciferin detection reagent. Luminescence readings were taken 20 minutes later.

[0334] In vitro assay 2: CYP1A1 inhibition assay The direct CYP1A1 inhibitory activity of test compounds was also evaluated using the Promega P450-Glo® Assay System. Test compounds were added at seven concentrations to half-area white 96-well plates. Cypex CYP1A1 bactosomes (0.5 pmol final) and the CYP1A1 substrate luciferin-CEE (30 μM final) were prepared in 0.1 M potassium phosphate buffer and incubated with the test compounds at 37°C for 5 minutes. Then, 0.2 mM NADPH was added, and the plate was incubated at 37°C for 10 minutes. The reaction was stopped by adding luciferin detection reagent, and luminescence readings were taken 20 minutes later.

[0335] In vitro assay 3: AhR antagonism in human peripheral blood mononuclear cells (PBMCs) - inhibition of interleukin-22 (IL-22) release PBMCs were isolated from human peripheral blood using Lymphoprep® and cultured at 1 x 10 in RPMI medium containing 10% fetal bovine serum, 1% penicillin-streptomycin, and 1% non-essential amino acids. 6The PBMCs were then activated with a CD3 / CD28 agonist mixture (human T cell TransAct® (Miltenyi Biotec)) at 1 μl / 100,000 cells and seeded at 100,000 cells / well in 96-well round-bottom tissue culture plates. One hour after stimulation, seven concentrations of each test compound or vehicle (final [DMSO] 0.2%) were added. The plates were then placed in an incubator at 37°C, humidity ≥85%, and 5% CO2 for 72 hours, after which the medium was removed and stored at -20°C until cytokine analysis. IL-22 was measured using the human IL-22 DuoSet ELISA (R&D systems) according to the manufacturer's instructions. The results of the in vitro assay are shown in Table 1 below.

[0336] [Table 2]

Claims

1. Compounds of formula (I): 【Chemical 1】 And, where Y is a phenyl or a 3- to 6-membered ring, optionally containing 1, 2, or 3 heteroatoms selected from N, O, and S, and the phenyl or ring is R ５ and R ６ optionally substituted with; R １ But H, C １～３ Alkyl, (-CH ２ ) pCN, -COC １～３ Alkyl, —CO(CH ２ ) qNR ７ R ８ , -SO ２ C １～３ Alkyl, —SO ２ NR ７ R ８ , -(CH ２ ) qPh, C ３～５ Cycloalkyl, C with 1 to 6 halogen groups １～３ Alkyl, OR Ｙ and -NR ７ R ８ C having one or more independently selected from １～３ alkyl, -(CH ２ ) p'OC １～３ Alkyl, —C ０～３ Alkylene C(O)C ０～３ alkyl, wherein the alkyl is OR Ｙ and -NR ７ R ８ oxetane, Z, —C(O)(CH ２ )qZ, -C(O)O(CH ２ )qZ, -C(O)O(CH ２ )pPh, -C(O)(CH ２ )qZ′, -C(O)O(CH ２ ) qZ′; R ２ is H or C １～３ Alkyl, C ３～５ cycloalkyl, halogen and optionally OR Ｙ , halogen and —NR ７ R ８ C having one or more groups independently selected from １～３ is alkyl; R ２ ' is H, C １～３ is alkyl or halogen; R ３ is H or C １～３ is alkyl; R ４ is a 9- to 13-membered heterocyclic ring having at least one heteroatom selected from N, O, and S, and the substituent R ９ , R ９ ' and R １０ having R ５ H, oxo, hydroxy, halogen, CN, C １～３ Alkyl, C ３～５ Cycloalkyl, —OC １～３ alkyl, with 1 to 6 halogen groups -(O) ０～１ C １～３ alkyl, C with one or more ORY groups １～３ Alkyl, —C(O)C １～３ Alkyl NR ７ R ８ , -SO ２ C １～３ Alkyl, —SO ２ NR ７ R ８ , or NR ７ R8; R ６ H, oxo, hydroxy, halogen, CN, C １～３ Alkyl, —C(O)C １～３ Alkyl NR ７ R ８ , -SO ２ C １～３ Alkyl, or —SO ２ NR ７ R ８ and R ７ is H or C １～３ alkyl, or —C(O)ORY; R ８ is H or C １～３ is alkyl; R ９ H, hydroxy, halogen, CN, C １～３ Alkyl, C １～３ Alkoxy, C with 1 to 6 halogen groups １～３ alkyl, C with one or more ORY groups １～３ Alkyl, —C ３～５ cycloalkyl, -(CH ２ ) qOC １～３ Alkyl, -COC １～３ Alkyl NR ７ R ８ , -SO ２ C １～３ Alkyl, or —SO ２ NR ７ R ８ and R ９ ' is H, hydroxy, halogen, CN, C １～３ Alkyl, C １～３ Alkoxy, C having 1 to 6 halo groups １～３ alkyl, C with one or more hydroxy groups １～３ Alkyl, —CO(CH ２ ) qNR ７ R ８ , -SO ２ C １～３ Alkyl, or —SO ２ NR ７ R ８ and R １０ H, hydroxy, halogen, CN, C １～３ Alkyl, —C(O)C １～３ Alkyl NR ７ R ８ , -SO ２ C １～３ Alkyl, or —SO ２ NR ７ R ８ and R １１ But H, C １～３ Alkyl or C ２～６ is hydroxyalkyl; R Ｙ is H or C1-3 alkyl; X is CH ２ , S, -SO ２ , N.R. １１ or O; Z' is a 5- or 6-membered heteroaryl having at least one heteroatom selected from N, O and S, wherein the heteroaryl is optionally hydroxy, halogen, CN, C １～３ It may contain 1, 2 or 3 substituents selected from alkyl; Z is a 3- to 6-membered ring optionally containing 1, 2, or 3 heteroatoms selected from N, O, and S; R ５ and R ６ and optionally hydroxy, halogen, CN, C １～３ a 3- to 6-membered ring, optionally having 1, 2, or 3 substituents selected from alkyl; n is 0 or 1; n' is 0 or 1; m is 0, 1, 2 or 3; p is an integer 1, 2 or 3; p' is an integer 2 or 3; q is 0, 1, 2 or 3; A compound of formula (I) or a pharmaceutically acceptable salt thereof:

2. A compound of formula (I) according to claim 1 , wherein Y contains 1, 2, or 3 heteroatoms selected from N, O, and S; ５ and R ６ is a 5- to 6-membered ring substituted with A compound of formula (I).

3. A compound of formula (I) according to claim 1 or 2, wherein Y is a 5- or 6-membered ring containing nitrogen; A compound of formula (I).

4. A compound of formula (I) according to claim 3, comprising: wherein the ring is an aromatic ring. A compound of formula (I).

5. A compound of formula (I) according to claim 3, comprising: wherein said rings are independently selected from pyrimidine, pyridine, triazole and thiazole; A compound of formula (I).

6. A compound of formula (I) according to claim 5, comprising: Here, R ５ is located at the 5-position of the Y group; A compound of formula (I).

7. A compound according to any one of claims 1 to 2, wherein n is 0.

8. The compound of formula (II) according to claim 1: 【Chemistry 2】 A compound of the formula: Here, X and R １ , R ２ , R ３ , R ４ and m is defined above for compounds of formula (I), A compound of formula (II): or a pharmaceutically acceptable salt thereof.

9. A compound according to any one of claims 1 to 2, comprising: Here, R １ is hydrogen, -C １～３ Alkyl, oxetane, -CH ２ CH ２ OH, -CH ２ CH ２ N (CH ３ ) ２ , and -SO ２ CH3, compound.

10. 10. A compound according to claim 9, comprising: Here, R １ is selected from methyl, ethyl, propyl and isopropyl; compound.

11. A compound according to any one of claims 1 to 2, comprising: Here, R ２ is H, methyl, -CH ２ OCH ３ , -CH ２ OH, CF ３ , -CH ２ N (CH ３ ) ２ are independently selected from compound.

12. A compound according to any one of claims 1 to 2, comprising: Here, R ２ ' is methyl or H; compound.

13. A compound according to any one of claims 1 to 2, comprising: Here, R ４ is a partially saturated 9- or 13-membered ring or aromatic heterocycle selected from indoline, indole, isoindole, indolizine, indazole, benzimidazole, azaindole, pyrazolopyrimidine, purine, benzofuran, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, benzothiadiazole, adenine, guanine, tetrahydroquinoline, dihydroisoquinoline, quinoline, isoquinoline, quinolizine, quinoxaline, phthalazine, cinnoline, naphthyridine, pyridopyrimidine, pyridopyrazine, pteridine, chromene, isochromene, chromenone, benzoxazine, quinolinone, isoquinolinone, dibenzofuran, carbazole, acridine, phenothiazine, and 2,3,4,9-tetrahydro-1H-carbazole; compound.

14. A compound according to any one of claims 1 to 2, comprising: Here, R ５ is oxo, methyl, ethyl, -CF ３ , -OCF ３ , -OCH ３ and halogen-containing groups, compound.

15. A compound according to any one of claims 1 to 2, comprising: Here, R ６ is methyl, ethyl, -OCH ３ and H, compound.

16. A compound according to any one of claims 1 to 2, comprising: Here, R ７ and / or R 8 is H; compound.

17. A compound according to any one of claims 1 to 2, comprising: (i) where R ９ H, methyl, OCF ３ and -C ３～５ cycloalkyl; and / or (ii) where R 9 ' is independently selected from H, F and methyl; and / or (ii) where R 10 is independently selected from H, F and methyl; compound.

18. A compound according to any one of claims 1 to 2, comprising: Here, X is NR １１ That is, compound.

19. A compound according to any one of claims 1 to 2, comprising: Here, R １１ is H, compound.

20. A compound according to any one of claims 1 to 2, comprising: where m is 2 or 1. compound.

21. A compound according to any one of claims 1 to 2, comprising: where n is 1. compound.

22. A compound according to any one of claims 1 to 2, comprising: 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(4-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(3,5-difluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(5-fluoro-3-pyridyl)-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5 ,4-b][1,4]oxazin-4-amine; 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-8-isopropyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine; N-[2-(1H-indol-3-yl)ethyl]-2-(2-methylthiazol-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (7S)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-methyl -7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (7R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; N-[2-(1H-indol-3-yl)ethyl]-2-(4-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-[2-(1H-indol-3-yl)ethyl-[2-(2 -methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl]amino]ethanol; 2-(2-ethyl-4-methyl-thiazol-5-yl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-2-thiazol-2-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(2-methylthiazol-5-yl-N-(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; N-[2-(1H-indol-3-yl)ethyl]-2-(6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(5-fluoro-6-methyl-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2- 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 5-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one; 5-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4- b][1,4]oxazin-2-yl)pyridin-2-ol; 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1-methyl-pyridin-2-one; N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-2-(6-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 3-[4-[2-(6-fluoro-1H-indol-3-yl)ethyl amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one; 3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 2-[2-(difluoromethoxy)-3-pyridyl]-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-5-methyl-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 4-[2-(6-fluoro-1H-indol-3-yl)ethoxy]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine; 3-(4-(2-(1H-indol-3-yl)ethoxy)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine) (R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; 3-(4-(2-(1H-indol-3-yl)ethoxy)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; (R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one ... (R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(hydroxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; (R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(hydroxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; (R)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(hydroxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one (7S)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (6S)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (6R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,7-dimethyl-6,8-dihydropyrimido[5,4-b][1,4]oxazin-4-amine; (7R)-2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(trifluoromethyl) N-[2-(1H-indol-3-yl)ethyl]-2-(2-methylthiazol-5-yl-8-(oxetan-3-yl)-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine; 2-(2-methylthiazol-5-yl-N-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (7R)-8-[2-(dimethylamino)ethyl]-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine; (7R)-8-[2-(dimethylamino)ethyl]-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine 4]oxazin-7-yl]methanol; 2-[2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-8-yl]ethanol; 7-[(dimethylamino)methyl]-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;8-Methylsulfonyl-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-6,7-dihydropyrimido[5,4-b][1,4]oxazin-4-amine; 3-(4-((2-(2-chloro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; 3-(4-((2-(2-chloro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one 3-[4-[2-(7-fluoro-2-methyl-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one; 3-(4-((2-(7-fluoro-2-methyl-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-[4- [2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one; 3-(4-((2-(5,7-difluoro-2-methyl-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-(4-((2-(6-(trifluoromethoxy)-1H-indol-3-yl)ethyl)amino)- 7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; 3-(4-((2-(6-(trifluoromethoxy)-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one;3-(4-((2-(1H-indol-3-yl)ethyl)amino)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; (S)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; (S)-3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; (7R) -2-(5-fluoro-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (R)-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; (R)-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; 3-[(7R)-4-[2-(1H-indol-3-yl)ethoxy]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one; (R)-3-(4-(2-(1H-indol-3-yl)ethoxy)-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; (7R)-2-(3,5-difluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(3-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(2,4-dimethylthiazol-5-yl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (7R)-7-(methoxymethyl)-2-(2-methylthiazol-5-yl-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; [(7R)-2-(2-methylthiazol-5-yl-4-[[(3R)-2,3,4,9- Tetrahydro-1H-carbazol-3-yl]amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl]methanol; N-[2-(1H-indol-3-yl)ethyl]-2-(1-methyltriazol-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (7R)-2-(4-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine (7R)-2-(3-fluorophenyl)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 5-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1-methyl-pyridin-2-one; (7R)-N-[2-(1H-indol-3-yl)ethyl]-7-(methoxymethyl)-2-(2-methylthiazin-4-amine Zol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; (7R)-4-[2-(1H-indol-3-yl)ethylamino]-2-(2-methylthiazol-5-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl]methanol; 2-(2-methylthiazol-5-yl-N-[(4R)-1,3,4,5-tetrahydrobenzo[cd]indol-4-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine;2-(2-methylthiazol-5-yl-N-[(4S)-1,3,4,5-tetrahydrobenzo[cd]indol-4-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 3-[4-[[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl]-1H-pyridin-2-one; (R)-3-(4-((2,3,4,9-tetrahydro-1H-carbazol-3-yl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; N-[2-(1H-indol-3-yl)ethyl]-2-(2-methoxy-3-pyridyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 2-(5-fluoro-2-methoxy-3-pyridyl)-N-[(3 R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-fluoropyridin-2(1H)-one; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro- 6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-fluoropyridin-2-ol; 2-(5-fluoro-2-methoxy-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl )-5-methylpyridin-2(1H)-one; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-methylpyridin-2-ol; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-(trifluoromethyl)pyridin-2(1H)-one; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-(trifluoromethyl)pyridin-2-ol; 5-fluoro-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; 5-fluoro-3-(4-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)- 7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2-ol; (R)-5-Fluoro-3-(4-((2,3,4,9-tetrahydro-1H-carbazol-3-yl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one; (R)-5-Fluoro-3-(4-((2,3,4,9-tetrahydro-1H-carbazol-3-yl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-chloropyridin-2(1H)-one; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-5-chloropyridin-2-ol; 3-[4-[2-(1H-indol-3-yl)ethylamino]-7,8-dihydro-6H-pyrimido[5 ,4-b][1,4]oxazin-2-yl]-6-methyl-1H-pyridin-2-one; 3-(4-((2-(1H-indol-3-yl)ethyl)amino)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)-6-methylpyridin-2-ol, and 2-(2-amino-3-pyridyl)-N-[2-(1H-indol-3-yl)ethyl]-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine, or a pharmaceutically acceptable salt thereof.

23. A compound according to any one of claims 1 to 2, comprising: wherein the compound is 3-(4-(2-(1H-indol-3-yl)ethoxy)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-yl)pyridin-2(1H)-one, or a pharmaceutically acceptable salt thereof; compound.

24. 10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient, diluent, or carrier.

25. A compound according to any one of claims 1 to 2 or a composition according to claim 24 for use in therapy.

26. A compound according to any one of claims 1 to 2 or a composition according to claim 24 for use in the treatment of cancer.

27. A method for preparing a compound according to any one of claims 1 to 2, comprising the following general route: (a) 【Chemistry 3】 wherein R2, R4, and Y are as defined in claim 1 and B is boron; (b) 【Chemistry 4】 wherein R 4 , R 1 and Y are as defined in claim 1 and B is boron; (c) 【Chemistry 5】 wherein R2, R4, R7 and Y are as defined in claim 1 and B is boron; (d) 【Chemistry 6】 wherein R1, R2, R3, R4, R5, R7 and Y are as defined in claim 1 and B is boron; (e) 【Chemistry 7】 wherein R1, R2, R3, R4, R5, R7 and Y are as defined in claim 1 and B is boron; (f) 【Chemistry 8】 wherein R1, R2, R3, R4, R5, R6 and Y are as defined in claim 1 and B is boron; (g) 【Chemistry 9】 wherein R 2 , R 4 and Y are as defined in claim 1 and B is boron; (h) 【Chemistry 10】 wherein R 1 , R 4 and Y are as defined in claim 1 and B is boron; (i) 【Chemistry 11】 wherein R 2 , R 4 and Y are as defined in claim 1 and B is boron; (j) 【Chemistry 12】 wherein R4 and Y are as defined in claim 1 and B is boron; (k) 【Chemistry 13】 wherein R2, R4, R7 and Y are as defined in claim 1 and B is boron; (l) 【Chemistry 14】 wherein R1, R2, R3, R4, R5, R7 and Y are as defined in claim 1 and B is boron; (m) 【Chemistry 15】 wherein R1, R2, R3, R4, R5, R7 and Y are as defined in claim 1 and B is boron; or (n) 【Chemistry 16】 wherein R1, R2, R3, R4, R5, R6 and Y are as defined in claim 1 and B is boron; A method comprising a step selected from any one of the following:

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