Small molecule inhibitors of DYRK / CLK and uses thereof

Abstract

The present invention is in the field of medicinal chemistry. In particular, the present invention relates to a new class of small molecule compounds having a 6,6-heterocyclic structure (e.g., naphthyridine, pyrido-pyridazine, pyrido-pyrazine, quinoline, pyrazino-pyridazine, pyrimido-pyrimidine, quinazoline, quinoxaline, or cinnoline ring system) that inhibit the activity of DYRK1A, DYRK1B, DYRK2, DYRK3, CLK1, CLK2, CLK3, CLK4, CDK7, CDK8 / 19, PI3K, PDGFrA / B, mTOR, WNT, homeodomain-interacting kinase (HIPK), and / or CMGC-kinase. The present invention relates to compounds that function as inhibitors of WNT enzymes, leading to the inhibition of WNT signaling, and the use of those compounds as therapeutic agents for the treatment of Alzheimer's disease, Down's syndrome, Parkinson's disease, Huntington's disease, diabetes, autoimmune diseases, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colon cancer and metastatic colon cancer (e.g., metastatic colon cancer to the liver)), and other diseases.

Description

Detailed Description of the Invention

[0001] [Statement of Government Support] This invention was made with government support under Grant No. AG067926 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] [Technical field] The present invention is in the field of medicinal chemistry. In particular, the present invention relates to a novel class of small molecule compounds (e.g., naphthyridine, pyrido-pyridazine, pyrido-pyrazine, quinoline, pyrazino-pyridazine, pyrimido-pyridine) having a 6,6-heterocyclic structure that function as inhibitors of DYRK1A, DYRK1B, DYRK2, DYRK3, CLK1, CLK2, CLK3, CLK4, CDK7, CDK8 / 19, PI3K, PDGFrA / B, mTOR, WNT, homeodomain-interacting kinase (HIPK), and / or CMGC kinases, leading to the inhibition of WNT signaling. The present invention relates to compounds having a quinazolinone, quinazoline, quinoxaline, or cinnoline ring system and their use as therapeutic agents for the treatment of Alzheimer's disease, Down's syndrome, Parkinson's disease, Huntington's disease, diabetes, autoimmune diseases, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colon cancer and metastatic colon cancer (e.g., metastatic colon cancer to the liver)), and other diseases.

[0003] [Introduction] In the United States, two million new cancer cases are estimated to be diagnosed annually, resulting in more than 600,000 deaths annually. DYRK and CLK kinase inhibition offers promising therapeutic opportunities for a variety of malignancies. Furthermore, small-molecule inhibition of DYRK and CLK kinases may play a role in mitigating the progression of autoimmune and inflammatory disorders, such as osteoarthritis. DYRK1A has been shown to play an important role in the development of dementia and Down syndrome. Dementia, which affects more than 40 million people, currently represents a major unmet medical need and a significant public health burden. 70% of these cases are attributed to Alzheimer's disease (AD), a neurodegenerative pathology whose most prominent symptom is progressive cognitive decline. The underlying treatment of learning and / or memory impairments represents a significant and immense unmet medical need, including the restoration of learning and memory after stroke or severe brain injury.

[0004] The present invention addresses these needs.

[0005] [Summary of the Invention] The proteasome (immune and constitutive), heat shock factor 1, and mammalian target of rapamycin (mTOR) are essential protein complexes responsible for maintaining cell growth, division, and survival in eukaryotes and are required for almost all cellular activities. Impairment of one or more of these complexes often leads to neurodegenerative diseases, cancer, immune disorders, and aging. Targeting these complexes has been clinically proven effective against all forms of cancer. RNA interference, kinome-wide screens, and biochemical studies have demonstrated that inhibition of DYRK2-induced phosphorylation of the 26S proteasome and heat shock factor 1 significantly attenuates proteostasis and impairs cell proliferation (see Guo et al. 2016 Nature Cell Biology; Moreno et al. 2021 Cell death and differentiation; Banerjee et al. PNAS 2018; Banerjee et al. PNAS 2019). Furthermore, inhibition of DYRK3 activity leads to loss of PRAS40 phosphorylation, resulting in loss of mTOR signaling, which reduces cancer cell proliferation. Importantly, loss of DYRK2 and DYRK3 activity significantly inhibited tumor formation in mice (see, for example, Banerjee et al. 2019 PNAS). Therefore, small molecule inhibitors of DYRK kinases, used alone or in combination with existing chemotherapeutics and / or proteasome inhibitors, have unique therapeutic potential for the treatment of growth- and proliferation-modulated human cancers.

[0006] Furthermore, canonical WNT signaling is an important and evolving pathway that has attracted significant interest for therapeutic intervention. The ability to modulate the WNT pathway and thus restore health to diseased tissues offers potential for regenerative therapeutics and oncology. Notably, WNT signaling regulates the function of chondrocytes, osteoblasts, and synoviocytes in osteoarthritis (Tao et al., Theranostics, 2017, 7, 180-195). Indeed, numerous biological processes and targets associated with WNT activation have been reported (Zhan et al., Oncogene 2017, 36, 1461-1473; Ahmed et al., Cancers, 2016, 8, 66). Part of this target set includes the serine / threonine kinase CLK, which has been shown to regulate the Wnt pathway by controlling pre-mRNA splicing (Deshmukh et al., Osteoarthritis Cartilage 2019, 27, 1347-1360, Wang et al., Nature 2008, 456-470-476). CLK consists of four isoforms in mammals (CLK1-CLK4) and belongs to the CMGC family of kinases, which includes DYRKS, cyclin-dependent kinases (CDKs), GSK3, and serine-arginine-rich protein kinases (SRPKs). Because overexpression of CLK proteins affects pre-mRNA splicing site selection, several CLK family inhibitors have been reported to be involved in the regulation of mRNA splicing (Bossard et al., Cancer Res., 2020, 80, 5691; Deshmukh et al., Osteoarthritis Cartilage 2019, 27, 1347-1360). Specifically, two notable CLK inhibitors currently in clinical trials are SM08502 (indication: colorectal cancer, NCT03355066) and SM04690 (indication: knee osteoarthritis, Phase 3, NCT03928184).

[0007] CDKs have also been shown to play a key role in WNT inhibition. In particular, CDK7 enhances the interaction between β-catenin and TCF4 (see Duan et al., Cell Death & Differentiation, 2019, 26, 1442-1452), and CDK8 has been identified in loss-of-function RNAi screens as a gene that controls β-catenin-driven reporter activity (see Rosenbluh et al., Trends Pharmacol Sci. 2014, 35, 103-109). Inhibitors of CDK7, CDK8, and CDK19 have shown utility in colon cancer and liver metastatic colorectal cancer, implicating WNT signaling inhibition. Furthermore, CDK8 selectively promotes the growth of colon cancer metastases in the liver by regulating the gene expression of TIMP3 and matrix metalloproteinases (see Liang et al., Cancer Res. 2018, 78(23), 6594-6606). CDK8 and its paralog CDK19 are two isoforms of mediator kinase, an enzymatic component of the CDK module that binds to the transcriptional mediator complex. Inhibition of CDK8 / 19 mediator kinase sensitizes HER2+ breast cancer to HER2-targeted drugs, preventing resistance in vitro and in vivo (see, e.g., Ding et al., PNAS, 2022, 119 (32), 1-11, e2201073119). Notable CDK8 / CDK19 inhibitors in clinical trials include RVU120 (NCT04021368), TSN084 (NCT05300438), and Senexin B (NCT03065010), the first selective CDK8 / CDK19 inhibitor to enter clinical trials in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS).

[0008] Although numerous clinical trials are being evaluated based on the predominant beta-amyloid hypothesis, small molecule modulation of gamma- and beta-secretase, and numerous immune-based approaches, aberrant phosphorylation of tau protein is thought to contribute significantly to the pathogenesis of AD and therefore offers an alternative approach for therapeutic development. Tau is a cytoplasmic protein that, under normal conditions, is involved in microtubule stabilization. In AD, neuronal tau becomes hyperphosphorylated, resulting in the formation of aggregates of phosphorylated tau protein known as "neurofibrillary tangles" (NFTs). NFTs and amyloid plaques are the most common hallmarks of AD and are correlated with neurofibrillary degeneration, neuronal death, and dementia.

[0009] Interestingly, several protein kinases are involved in neuronal development, and their overexpression and abnormal activation, particularly through tau phosphorylation, have been shown to play an important role in the pathogenesis of AD. Dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A) is important in neuronal development and plays various functional roles in the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21, and current research suggests that overexpression of DYRK1A may be an important factor in causing cognitive impairment in individuals with Alzheimer's disease (AD) and Down syndrome (DS).

[0010] In experiments conducted in the course of developing embodiments of the present invention, compounds having 6,6-heterocyclic structures (e.g., compounds having naphthyridine, pyrido-pyridazine, pyrido-pyrazine, quinoline, pyrazino-pyridazine, pyrimido-pyrimidine, quinazoline, quinoxaline, or cinnoline ring systems) were designed, synthesized, and biologically evaluated for potential use as inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRKS) and CLKs, and as therapeutic agents for AD and other diseases associated with DYRK1A, DYRK1B, DYRK2, DYRK3, and CLK1, CLK2, CLK3, and CLK4 activity (e.g., DS, other neuropathologies, cancers such as glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, triple-negative breast cancer), diabetes, and cognitive impairment). Many of these compounds exhibit activity against dual specificity tyrosine phosphorylation-regulated kinase-1B (DYRK1B), dual specificity tyrosine phosphorylation-regulated kinase-2 (DYRK2) (see Tandon, et al., J. Biol. Chem 296 (2021)), dual specificity tyrosine phosphorylation-regulated kinase-3 (DYRK3) (see Kim, et al., Intl. J. Molecular Sciences 22, 2982 (2021)), and other kinases implicated in various disease states (e.g., the dual specificity protein kinase CLK1 (Clk-1)).

[0011] The DYRK / CLK inhibitors described herein are also considered as potential therapeutic agents for the treatment of developmental diseases such as Down's syndrome, and neurodegenerative diseases such as Parkinson's disease and Huntington's disease. Furthermore, the DYRK inhibitors of the present invention have also been implicated as potential therapeutic agents for the treatment of glioblastoma, highlighting further potential utility in the field of oncology (see, e.g., Ionescu et al., Mini-reviews in Medicinal Chemistry, 2012, 12, 1315-1329).

[0012] These novel DYRK / CLK inhibitors may also be useful as general cognitive enhancers, given the published finding that DYRK1A can phosphorylate sirtuin 1, a key regulator of learning and memory (see, e.g., Michan et al., J. Neurosci. 2010, 30(29), 9695-9707; Guo et al., J. Biol. Chem. 2010, 285 (17), 13223-13232). Furthermore, the efficacy of small molecule inhibition of DYRK1A in attenuating both insoluble tau aggregates and amyloid plaques has been demonstrated (see, e.g., Branca et al., Aging Cell, 2017, 16(5), 1146-1154). The mechanistic basis for this has been previously detailed (Smith et al., ACS Chem. Neuroscience, 2012, 3(11), 857-872). These novel DYRK / CLK inhibitors inhibit DYRK1A-mediated T reg Its identification as a physiologically relevant regulator of cell differentiation, suggesting broader roles for other DYRK family members in immune homeostasis, may have further potential utility, and thus may find novel roles in autoimmune diseases such as inflammatory bowel disease and type 1 diabetes (see, e.g., Khor B, et al., eLife 2015;4:e05920).

[0013] Accordingly, the present invention is a novel class of small molecule compounds having a 6,6-heterocyclic structure (e.g., compounds having naphthyridine, pyrido-pyridazine, pyrido-pyrazine, quinoline, pyrazino-pyridazine, pyrimido-pyrimidine, quinazoline, quinoxaline, or cinnoline ring system) that leads to the inhibition of WNT signaling, including DYRK1A, DYRK1B, DYRK2, DYRK3, CLK1, CLK2, CLK3, CLK4, CDK7, CDK8 / 19, PI3K, PDGFrA / B, mTOR, WNT, and homeodomain-interacting kinases. The present invention relates to such compounds that function as inhibitors of HIPKs, and / or CMGC kinases, and their use as therapeutic agents for the treatment of Alzheimer's disease, Down's syndrome, Parkinson's disease, Huntington's disease, diabetes, autoimmune diseases, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colon cancer and metastatic colon cancer (e.g., metastatic colon cancer to the liver)), and other diseases.

[0014] In certain embodiments, compounds are provided that fall within the scope of the following formulas, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka]

[0015] Formula I is not limited to specific chemical moieties for X, Y, R1, and R2. In some embodiments, the specific chemical moieties for X, Y, R1, and R2 independently include any chemical moiety that enables the resulting compound to inhibit DYRK1A activity. In some embodiments, the specific chemical moieties for X, Y, R1, and R2 independently include any chemical moiety that enables the resulting compound to inhibit one or more of: PI3K / Akt signaling associated with DYRK1A; tau phosphorylation associated with DYRK1A; NFAT phosphorylation associated with DYRK1A; ASK1 / JNK1 pathway activation associated with DYRK1A; p53 phosphorylation associated with DYRK1A; Amph1 phosphorylation associated with DYRK1A; dynamin 1 phosphorylation associated with DYRK1A; synaptojanin phosphorylation associated with DYRK1A; presenilin 1 associated with DYRK1A. (catalytic subunit of gamma-secretase) activity; DYRK1A-associated amyloid precursor protein phosphorylation; DYRK1A-associated SIRT1 activation; heat shock factor 1 and 26S proteasome activity for DYRK2; mTOR activity for DYRK3; DYRK3 phosphorylation (e.g., PRAS40); DYRK1B activity; CMGC / CLK kinase activity; CLK1 activity; CLK2 activity; CLK3 activity; CLK4 activity; CDK7 activity; CDK8 activity; CDK19 activity; PI3K activity; PI3K mutant activity; PDGFrA / B activity; mTOR activity; c-KIT activity; RYK activity; and WNT signaling.

[0016] Such embodiments are not limited to specific definitions of each of the "X" and "Y" substituents.

[0017] In some embodiments, one of the "X" substituents is carbon and the other is nitrogen, or both of the "X" substituents are carbon; and one of the "Y" substituents is nitrogen and the other "Y" substituent is carbon, or two of the "Y" substituents are nitrogen and one "Y" substituent is carbon, or all "Y" substituents are carbon; the resulting structure is one of the following formulas: [ka] [ka]

[0018] In some embodiments, R1 is an aryl or heteroaryl ring.

[0019] In some embodiments, R1 is hydrogen, halogen (e.g., fluorine, bromine, iodine, chlorine), [ka] [ka] [ka] [ka] [ka] is selected from.

[0020] In some embodiments, R2 is hydrogen, halogen (e.g., fluorine, bromine, iodine, chlorine), aryl, substituted aryl, heteroaryl, substituted heteroaryl, [ka] [ka] [ka] and X″ is selected from an alkyl group, a haloalkyl group, an amino group, an alkylamino group, a hydroxy group, a fluoro group, a chloro group, a bromo group, and a cyano group.

[0021] In some embodiments, R, R', and R" are independently selected from hydrogen, halogen (e.g., fluorine, bromine, chlorine, iodine), di-halogen (di-fluorine, di-bromine, di-chlorine, di-iodine), CF3, OCH3, CHF2H, OCF3, methyl, di-methyl, alkoxy, alkylsulfonyl, cyano, carboxy, ester, amide, substituted amide, sulfonamide, substituted sulfonamide, methylenedioxy, heterocyclylalkyl, heterocyclyl, heterocyclylalkylamide, lipophilic moieties including ethers, secondary or tertiary amine moieties consisting of heterocycloalkyl groups that are bioisosteric to secondary amines (e.g., morpholine, piperidine, piperazine).

[0022] In some embodiments, R3 and R4 are independently selected from hydrogen, halogen (eg, fluorine, bromine, chlorine, iodine), methyl, ethyl, and methoxy.

[0023] The KD values for each compound listed in Table 1 were between 0.5 nM and 10 μM (DYRK1A), demonstrating a pan-DYRK and pan-CLK inhibitory profile. Furthermore, many of the compounds listed demonstrate the ability to inhibit WNT signaling, as judged by WNT reporter assay data (see Table 1). WNT reporter assay: Human colon epithelial cells (HCECs) were cultured in 1x DMEM supplemented with 1% penicillin / streptomycin, 1% Glutamax, and 10% fetal bovine serum at 37°C in 5% CO2. These cells were previously engineered to express the TopGFP reporter (Addgene #24304) using second-generation lentiviral technology. For the Wnt reporter assay, cells were seeded at 2000 cells per well in a 384-well black screenstar imaging microplate (Greiner #781866) and allowed to adhere overnight. The next day, cells were stimulated with 10 μM CHIR99021 (Selleck #S1263) to induce the Wnt pathway. Simultaneously, DYR compounds were dose-response administered at concentrations ranging from 0 μM to 30 μM using a Tecan d300e digital dispenser. After 24 hours of incubation, cells were fixed with 4% paraformaldehyde / sucrose solution for 30 minutes. Cells were permeabilized with 0.1% Triton-X in PBS for 10 minutes and stained for DAPI for 30 minutes. Plates were imaged for DAPI, GFP, and mCherry using a Nikon Ti2 Eclipse fluorescence microscope. Analysis was performed using Nikon Elements software, segmenting nuclei based on DAPI and measuring the average intensity per cell for both TopGFP and the internal control (mCherry). To calculate the amount of Wnt activity, the average intensity of TopGFP was taken and divided by the average intensity of mCherry per cell, normalized to individual cells. Curves and EC50 values were plotted and calculated using Graphpad Prism software. KD was obtained from Eurofins. The KdELECT kinase assay panel can quantify the binding affinity of compounds to any kinase assay.Inhibitor binding constants (Kd values) are calculated from duplicate measurements of 11-point dose-response curves performed under optimized conditions to generate true thermodynamic Kd values that facilitate direct comparison of inhibitor affinity between kinases.

[0024] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0025] The present invention further provides a process for preparing any of the compounds of the present invention.

[0026] The present invention also provides for the use of compounds that not only inhibit DYRK1A activity, but also inhibit signaling pathways that depend on DYRK1A phosphorylation (e.g., tau, PI3K / AKT, APP, PSI, ASF, RCAN-1, NFAT, p53, ASK1 / JNK1, SIRT1, GluN2A, and other NMDA receptors), DYRK2 phosphorylation (e.g., 26S proteasome, heat shock factor 1, p53, MYC, and JUN), and DYRK3 phosphorylation (e.g., PRAS40). The present invention also relates to the use of compounds to sensitize cells to additional agents, such as agents known to be effective in treating neurodegenerative diseases.

[0027] In one embodiment, the compound is used as a DYRK protein degrader (see Valazquez, et al, 2019 Molecular Neurobiology 1-12).

[0028] The compounds of the present invention are useful for treating, ameliorating, or preventing disorders associated with DYRK1A, DYRK1B, DYRK2, DYRK3, CLK1, CLK2, CLK3, CLK4, homeodomain-interacting kinase (HIPK), and / or CMGC kinases that lead to inhibition of WNT signaling (e.g., Alzheimer's disease, Down's syndrome, Parkinson's disease, Huntington's disease, diabetes, autoimmune diseases, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colon cancer and metastatic colon cancer (e.g., metastatic colon cancer of the liver)), and other diseases, such as those responsive to inhibition of DYRK isoform activity. In certain embodiments, the compounds may be used to treat, ameliorate, or prevent cancers associated with DYRK2 and DYRK3 activity (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colon cancer, and metastatic colon cancer (e.g., metastatic colon cancer of the liver)). In certain embodiments, the compounds may be used to treat, ameliorate, or prevent autoimmune diseases. In certain embodiments, the compounds may be used to treat, ameliorate, or prevent inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)).

[0029] The present invention also provides pharmaceutical compositions comprising a compound of the present invention in a pharmaceutically acceptable carrier.

[0030] The invention also provides kits comprising a compound of the invention and instructions for administering the compound to an animal, and optionally, other therapeutic agents, such as drugs useful in treating neurodegenerative disorders and / or anti-cancer agents.

[0031] [Detailed Description of the Invention] The DYRK family includes five kinases (DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4). DYRKs belong to the CMGC group of proline-directed kinases, which also includes cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC2-like kinases (CLKs). While the signaling pathways of the CDK and MAPK families have been extensively studied, less is known about how DYRKs and CLKs interact with other proteins and various physiological or pathological processes. The CLK family includes CLK1 through CLK4.

[0032] The DYRK1A gene is located on chromosome 21 (21q22.2), in a region known as the Down syndrome critical region (DSCR) (see, e.g., Hammerle et al., 2011 Development 138, 2543-2554). Underexpression or overexpression of the Dyrk1a gene in mammals, or its orthologous gene, minibrain (mnb), in Drosophila, causes severe delays in central nervous system development and maturation. At the molecular level, DYRK1A phosphorylates nuclear factor of activated T cells (NFAT), counteracting the effects of calcium signaling and maintaining inactive NFAT (see, e.g., Arron et al., 2006 Nature 411, 595-600). DYRK1A has been identified as a negative regulator of the cell cycle, promoting transition to quiescence or differentiation (see, e.g., Chen et al., 2013 Mol. Cell 52, 87-100). In malignant cells, DYRK1A promotes survival through the inhibition of pro-apoptotic proteins (see, e.g., Guo et al., 2010 J. Bio. Chem. 285, 13223-13232; Seifert et al., 2008 FEBS J. 275, 6268-6280).

[0033] In experiments conducted during the course of developing embodiments of the present invention, compounds having a 6,6-heterocyclic structure (e.g., compounds having a naphthyridine, pyrido-pyridazine, pyrido-pyrazine, quinoline, pyrazino-pyridazine, pyrimido-pyrimidine, quinazoline, quinoxaline, or cinnoline ring system) were designed, synthesized, and biologically evaluated as inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs: 1A, 1B, 2, 3, 4) and CLK family members (1, 2, 3, 4) for use against AD, Down's syndrome, multiple malignancies, particularly those associated with inhibition of WNT signaling, and other disorders associated with DYRK / CLK activity (e.g., DS, other neuropathologies, glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, and secondary brain metastases). DYRK1B, notably, is involved in certain cancer cell survival and myoblast differentiation and has been validated as a promising target in CRPC.

[0034] Furthermore, the DYRK / CLK inhibitors of the present invention can be used to treat other cellular pathways involved in psychiatric disorders and neurodegenerative dementia. Specifically, the DYRK / CLK inhibitors of the present invention can be used to inhibit DYRK1A-activated PI3K / Akt signaling, a pathway critically involved in neuronal development, growth, and survival. The DYRK1A inhibitors of the present invention can be used to inhibit DYRK1A-stimulated ASK1 / JNK1 activity, thereby inducing neuronal cell death and apoptosis. Additionally, the DYRK1A inhibitors of the present invention can be used to inhibit DYRK1A phosphorylation of p53 during embryonic brain development, thereby preventing changes in neuronal proliferation. The DYRK1A inhibitors of the present invention can be used to inhibit DYRK1A phosphorylation of synaptic proteins Amph1, Dynamin1, and Synaptojanin, which are involved in regulating endocytosis, thereby preventing changes in the number, size, and morphology of dendritic spines and preserving synaptic plasticity. The DYRK1A inhibitor of the present invention can be used to inhibit presenilin 1 (catalytic subunit of gamma-secretase).The DYRK1A inhibitor of the present invention can be used to inhibit the activity of DYRK2 / 3 and DYRK4.The DYRK1A inhibitor of the present invention can be used to inhibit DYRK1B activity.The DYRK1A inhibitor of the present invention can be used to inhibit CMGC CLK1-4 kinase activity.

[0035] Thus, the present invention addresses the need for effective treatments for GBM, AD, and DS by providing potent, pan-selective DYRK / CLK inhibitors that can penetrate the blood-brain barrier (BBB) and elicit on-mechanism therapeutic responses in animal models. Related diseases include colorectal cancer, castration-resistant prostate cancer, and malignancies associated with WNT signaling inhibition.

[0036] Accordingly, the present invention provides a new class of small molecule compounds having a 6,6-heterocyclic structure (e.g., compounds having a naphthyridine, pyrido-pyridazine, pyrido-pyrazine, quinoline, pyrazino-pyridazine, pyrimido-pyrimidine, quinazoline, quinoxaline, or cinnoline ring system) that inhibit the activity of DYRK1A, DYRK1B, DYRK2, DYRK3, CLK1, CLK2, CLK3, CLK4, CDK7, CDK8 / 19, PI3K, PDGFrA / B, mTOR, WNT, homeodomain-interacting kinase (HIPK), and / or The present invention relates to compounds that function as inhibitors of CMGC kinase, leading to the inhibition of WNT signaling, and the use of those compounds as therapeutic agents for the treatment of Alzheimer's disease, Down's syndrome, Parkinson's disease, Huntington's disease, diabetes, autoimmune diseases, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colon cancer and metastatic colon cancer (e.g., metastatic colon cancer to the liver)), and other diseases.

[0037] The CDC2-like kinase (CLK) family includes four isoforms and is important for regulating the function of the spliceosome complex (see, for example, Fedorov et al., Chem Biol. 201 l;18(l):67-76). This complex, composed of small nuclear RNAs (snRNAs) and numerous associated proteins, controls the splicing of pre-mRNAs to produce mRNAs encoding mature proteins. CLKl is known to regulate spliceosome activity through phosphorylation of component serine-arginine-rich (SR) proteins (see, for example, Bullock et al., Structure. 2009;17(3):352-62). By controlling spliceosome activity in this way, many genes can express multiple mRNAs, leading to a diversity of translated proteins. Alternative isoforms transcribed from the same gene can have distinct activities and physiological functions. Dysregulation of alternative splicing is associated with cancer, where many cancer-related proteins are known to be alternatively spliced (e.g., Druillennec et al., J Nucleic Acids. 2012;2012:639062). An example of an alternatively spliced protein in cancer is Cyclin Dl, which is important for the progression of cancer cells through the cell cycle (e.g., Wang et al., Cancer Res. 2008;68(14):5628-38).

[0038] Alternative splicing regulated by CLKl has also been reported to be involved in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, through phosphorylation of spliceosomal SR proteins (e.g., Jain et al., Curr Drug Targets. 2014;15(5):539-50). In the case of Alzheimer's disease, CLKl is known to regulate the alternative splicing of the microtubule-associated protein TAU, causing an imbalance between TAU isoforms sufficient to cause neurodegeneration and dementia (e.g., Liu et al., Mol Neurodegener. 2008;3:8).

[0039] There is clearly an urgent need for compounds that potently inhibit DYRK and CLK kinases while sparing other closely related kinases in the treatment of both cancer and neurological diseases, and the compounds described herein address this need.

[0040] In certain embodiments, compounds encompassed by the following formula are provided, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka]

[0041] Formula I is not limited to specific chemical moieties for X, Y, R1, and R2. In some embodiments, the specific chemical moieties for X, Y, R1, and R2 independently include any chemical moiety that enables the resulting compound to inhibit DYRK1A activity. In some embodiments, the specific chemical moieties for X, Y, R1, and R2 independently include any chemical moiety that enables the resulting compound to inhibit one or more of: PI3K / Akt signaling associated with DYRK1A; tau phosphorylation associated with DYRK1A; NFAT phosphorylation associated with DYRK1A; ASK1 / JNK1 pathway activation associated with DYRK1A; p53 phosphorylation associated with DYRK1A; Amph1 phosphorylation associated with DYRK1A; dynamin 1 phosphorylation associated with DYRK1A; synaptojanin phosphorylation associated with DYRK1A; presenilin 1 (gamma-secretase activation) associated with DYRK1A. activity of PDK1A-associated amyloid precursor protein (catalytic subunit); phosphorylation of amyloid precursor protein associated with DYRK1A; activation of SIRT1 associated with DYRK1A; activity of heat shock factor 1 and 26S proteasome associated with DYRK2; mTOR activity associated with DYRK3; phosphorylation of DYRK3 (e.g., PRAS40); activity of DYRK1B; activity of CMGC / CLK kinase; activity of CLK1; activity of CLK2; activity of CLK3; activity of CLK4; activity of CDK7; activity of CDK8; activity of CDK19; activity of PI3K; activity of PI3K mutants; activity of PDGFrA / B; activity of mTOR; activity of c-KIT; activity of RYK; and WNT signaling.

[0042] Such embodiments are not limited to specific definitions of each of the "X" and "Y" substituents.

[0043] In some embodiments, one of the substituents of "X" is carbon and the other is nitrogen, or both of the substituents of "X" are carbon; and one of the substituents of "Y" is nitrogen and the other substituent of "Y" is carbon, or two of the substituents of "Y" are nitrogen and one substituent of "Y" is carbon, or all of the substituents of "Y" are carbon; such that the resulting structure is one of the following formulas: [ka] [ka]

[0044] In some embodiments, R1 is an aryl or heteroaryl ring.

[0045] In some embodiments, R1 is hydrogen, halogen (e.g., fluorine, bromine, iodine, chlorine), [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0046] In some embodiments, R2 is hydrogen, halogen (e.g., fluorine, bromine, iodine, chlorine), aryl, substituted aryl, heteroaryl, substituted heteroaryl, [ka] [ka] [ka] and X″ is selected from an alkyl group, a haloalkyl group, an amino group, an alkylamino group, a hydroxy group, a fluoro group, a chloro group, a bromo group, and a cyano group.

[0047] In some embodiments, R, R', and R" are selected from hydrogen, halogen (e.g., fluorine, bromine, chlorine, iodine), dihalogen (di-fluorine, di-bromine, di-chlorine, di-iodine), CF3, OCH3, CHF2H, OCF3, methyl, di-methyl, alkoxy, alkylsulfonyl, cyano, carboxy, ester, amide, substituted amide, sulfonamide, substituted sulfonamide, methylenedioxy, heterocyclylalkyl, heterocyclyl, heterocyclylalkylamide, lipophilic moieties including ethers, secondary or tertiary amine moieties consisting of heterocycloalkyl groups that are bioisosteric to secondary amines (e.g., morpholine, piperidine, piperazine).

[0048] In some embodiments, R3 and R4 are independently selected from hydrogen, halogen (eg, fluorine, bromine, chlorine, iodine), methyl, ethyl, and methoxy.

[0049] In some embodiments, the compounds are compounds 1-64 listed in Table 1.

[0050] The present invention further provides a process for preparing any of the compounds of the present invention.

[0051] In some embodiments, the compositions and methods of the present invention are used to treat diseased cells, tissues, organs, or pathological and / or disease states in animals (e.g., mammalian patients, including, but not limited to, humans and veterinary animals). In this regard, a variety of diseases and conditions may be amenable to treatment or prevention using the methods and compositions of the present invention. A non-limiting, exemplary list of these diseases and conditions includes, but is not limited to, Alzheimer's disease, Down's syndrome, Huntington's disease, Parkinson's disease, autoimmune diseases, cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain), inflammatory disorders (e.g., airway inflammation), neurodegenerative disorders involving DYRK1A, DYRK1B, DYRK2, DYRK3, and / or CLK1, CLK2, CLK3 and CLK4 activity, and any type of cancer involving DYRK1A, DYRK1B, DYRK2, DYRK3, and / or CLK1, CLK2, CLK3 or CLK4 activity, particularly cancers associated with disruption of WNT signaling.

[0052] Some embodiments of the present invention provide methods for administering an effective amount of a compound of the present invention and at least one additional therapeutic agent (including, but not limited to, any agent useful in the treatment of Alzheimer's disease, Down's syndrome, Huntington's disease, Parkinson's disease, autoimmune diseases, inflammatory disorders (e.g., airway inflammation), any neurodegenerative disorder related to the activity of DYRK1A, DYRK1B, DYRK2, DYRK3, and / or CLK1, CLK2, CLK3, or CLK4, particularly any neurodegenerative disorder associated with disruption of WNT signaling).

[0053] Compositions within the scope of the present invention include all compositions containing a compound of the present invention in an amount effective to achieve its intended purpose. While individual needs vary, determining the optimal range of effective amounts of each component is within the skill of one of ordinary skill in the art. Typically, the compound can be orally administered to a mammal, e.g., a human, at a dose of 0.0025 to 50 mg / kg of body weight per day of the mammal being treated for disorders responsive to the induction of apoptosis, or an equivalent amount of a pharmaceutically acceptable salt thereof. In one embodiment, about 0.01 to about 25 mg / kg is orally administered to treat, ameliorate, or prevent such disorders. For intramuscular injection, the dose is generally about half the oral dose. For example, suitable intramuscular doses are about 0.0025 to about 25 mg / kg, or about 0.01 to about 5 mg / kg.

[0054] A unit oral dose may contain from about 0.01 to about 1000 mg, for example, from about 0.1 to about 100 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets or capsules, each containing from about 0.1 to about 10 mg, conveniently about 0.25 to about 50 mg of the compound or solvate thereof.

[0055] In topical formulations, the compound may be present at a concentration of about 0.01-100 mg / g of carrier, hi one embodiment, the compound is present at a concentration of about 0.07-1.0 mg / ml, e.g., about 0.1-0.5 mg / ml, and in one embodiment, about 0.4 mg / ml.

[0056] In addition to administering the compound as a crude chemical, the compound of the present invention can be administered as part of a pharmaceutical formulation containing a suitable pharmaceutically acceptable carrier, including excipients and adjuvants that facilitate processing of the compound into a pharmaceutically usable preparation. Formulations, particularly those that can be administered orally or topically and that can be used for a single type of administration, such as tablets, sustained-release lozenges and capsules, mouthwashes and mouth rinses, gels, liquid suspensions, hair rinses, hair gels, shampoos, and rectally administered preparations such as suppositories, as well as solutions suitable for intravenous infusion, injection, topical or oral administration, contain about 0.01 to 99%, and in one embodiment, about 0.25 to 75%, of the active compound together with the excipients.

[0057] The pharmaceutical compositions of the present invention may be administered to any patient who may experience the beneficial effects of the compounds of the present invention. Foremost among such patients are mammals, such as humans, although the present invention is not intended to be so limited. Other patients include veterinary animals (such as cattle, sheep, pigs, horses, dogs, cats, etc.).

[0058] The compounds of the invention and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, or topical routes. Alternatively, or concurrently, administration may be by oral route. The dosage will depend on the age, health, and weight of the recipient, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect.

[0059] The pharmaceutical preparations of the present invention are prepared in a manner known per se, for example by conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral administration can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, adding suitable adjuvants as desired or necessary, and then processing the granular mixture to obtain tablets.

[0060] Suitable excipients are, in particular, sugars such as lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch pastes using, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrants may be added, such as the above-mentioned starches, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, inter alia, flow regulators and lubricants, such as silica, talc, stearic acid or a salt thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. The dragee cores may, if desired, be provided with a suitable coating that is resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. To produce coatings that are resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dyes or pigments may be added to tablets or dragee coatings, for example, for identification or to characterize the dosage combination of active compounds.

[0061] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active compound in the form of granules, which may be mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the active compound is, in one embodiment, dissolved or suspended in a suitable liquid such as fatty oils or liquid paraffin. Additionally, stabilizers may be added.

[0062] As the pharmaceutical preparation that can be used for rectum, for example, suppositories can be considered, which are made up of one or more active compounds and a suppository base.Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons.In addition, gelatin rectal capsules can be made up of a combination of active compounds and a base.Possible bases include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0063] Suitable formulations for parenteral administration include aqueous solutions of water-soluble active compounds, such as water-soluble salts and alkaline solutions. Additionally, suspensions of the active compounds may be administered as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides or polyethylene glycol-400. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and / or dextran. Optionally, the suspension may also contain stabilizers.

[0064] The topical compositions of the present invention, in one embodiment, are formulated as oils, creams, lotions, ointments, etc., by selection of a suitable carrier. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain oils, animal fats, and high molecular weight alcohols (C12 The carrier may be any suitable carrier in which the active ingredient dissolves. It may also contain emulsifiers, stabilizers, humectants, and antioxidants, and may optionally contain agents that impart color and fragrance. Additionally, these topical formulations may use transdermal penetration enhancers. Examples of such enhancers are found in U.S. Pat. Nos. 3,989,816 and 4,444,762, each of which is incorporated herein by reference in its entirety.

[0065] Ointment can be formulated by mixing the solution of active ingredient in vegetable oil such as almond oil with warm soft paraffin, and then cooling the mixture.The typical example of this ointment is that which contains about 30% by weight of almond oil and about 70% by weight of white soft paraffin.Lotion can be easily prepared by dissolving active ingredient in suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.

[0066] Those skilled in the art will readily recognize that the foregoing represents merely a detailed description of certain preferred embodiments of the invention. Various changes and modifications of the compositions and methods described above can be readily accomplished using expertise available in the art and are within the scope of the invention.

[0067] [Example] The following examples are illustrative, but not limiting, of the compounds, compositions and methods of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy that are obvious to those skilled in the art are within the spirit and scope of the invention.

[0068] Example I This example provides synthesis and characterization information for compounds of the present invention.

[0069] (Formula I) [ka]

[0070] Scheme 1 illustrates the synthesis of the general product (XI) from commercially available nitrobenzene and nitropyridine (I). The first step in the reaction scheme is the synthesis of S with commercially available amine (II). N The Ar reaction affords (III). This substituted nitrobenzene is reduced in a Bechamp-style reaction to give aniline (IV). This aniline is converted to (hetero)aryl bromide (V) via a Sandmeyer reaction. (Hetero)aryl bromide (V) is utilized in a Miyaura borylation reaction to generate pinacol boronate (VII). This boronate is coupled with polyhalogenated heterocycle (VIII) in a Suzuki reaction to give R1-substituted heterocycle (IX), which is further reacted in a Suzuki reaction to give R2,R1-substituted heterocycle (XI).

[0071] In some embodiments, compounds of formula I of the present disclosure can be prepared as depicted in Scheme 2. [ka]

[0072] Scheme 2 describes the synthesis of the advance intermediate (VIIIb), which can be prepared using commercially available or readily prepared (hetero)aryl pinacol boronates (VI) and polyhalogenated bicyclic heteroaryls via Suzuki reaction followed by acid-mediated deprotection.

[0073] In some embodiments, compounds of formula I of the present disclosure can be prepared as depicted in Scheme 3. [ka]

[0074] Scheme 3 illustrates the preparation of pinacol boronate esters (VIIa) via a Sandmeyer-type boronation reaction with anilines (IV).

[0075] In some embodiments, compounds of formula I of the present disclosure can be prepared as depicted in Scheme 4. [ka]

[0076] Scheme 4 describes the synthesis of product (XIV) by Suzuki coupling followed by acid-mediated deprotection.

[0077] [ka] The preparation of the intermediate tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (XVII) is shown in Scheme 5.

[0078] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (XV) (206 mg, 1 eq., 0.937 mmol) was stirred in t-BuOH (4.5 mL) under an argon atmosphere. After 10 min, di-tert-butyl dicarbonate (XVI) (225 mg, 221 μL, 1.1 eq., 1.03 mmol) in t-BuOH (6.5 mL) was slowly added to the reaction flask. The flask was kept under argon for an additional 10 min. The reaction was then placed in an oil bath at 35° C. for 18 h. After completion of the reaction, it was cooled and the solvent was removed under vacuum. The crude material was stirred in water for 5 minutes and collected by filtration to give tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (XVII) (300 mg, 937 μmol, 99%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.20 (d, J = 4.7 Hz, 1H), 8.02 (s, 1H), 7.11 (d, J = 4.7 Hz, 1H), 1.41 (s, 9H), 1.24 (s, 12H). 13 C NMR (126 MHz, DMSO-d6) δ 153.22, 152.67, 147.91, 123.13, 117.53, 84.80, 80.05, 28.49, 25.11.

[0079] The preparation of intermediate 6-bromo-4-(6-chloro-5-fluoropyridin-3-yl)quinazoline (XX) is shown below in Scheme 6. [ka]

[0080] A 100 mL round-bottle mixture of 6-bromo-4-chloroquinazoline (XVIII) (284 mg, 2 eq., 1.17 mmol), 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (XIX) (150 mg, 1 eq., 583 μmol), potassium tirpotassium phosphate (185 mg, 1.5 eq., 874 μmol) and PdCl(dppf) (46 mg, 0.1 eq., 58.3 μmol) in 1,4-dioxane (20 mL) and water (3.3 mL) was heated at 60 °C for 2 h under an argon atmosphere. The reaction was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with saturated sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude product, which was purified by silica gel chromatography (40 g silica gel, eluent EtOAc / Hex = 0 to 100%) to give the product 6-bromo-4-(6-chloro-5-fluoropyridin-3-yl)quinazoline (XX) (152 mg, 449 μmol, 77%). 1H NMR (500 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.36 (dd, J = 9.0, 1.9 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 9.0, 2.1 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 162.52, 155.04, 149.55, 146.03, 138.59, 134.18, 131.04, 128.97, 127.18, 124.29, 122.29.

[0081] The preparation of intermediate 4-(4-chloroquinolin-6-yl)pyridin-2-amine (XXIII) is depicted below in Scheme 7. [ka]

[0082] A mixture of 6-bromo-4-chloroquinoline (XXI) (485 mg, 1 eq., 2.000 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (XXI) (440 mg, 1 eq., 2.000 mmol), potassium phosphate (637 mg, 1.5 eq., 3.000 mmol), and PdCl(dppf) (158 mg, 0.1 eq., 200.0 μmol) in 1,4-dioxane (0.8 mL) and water (0.1 mL) was heated at 90 °C for 2 h under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (5 mL). The aqueous solution was washed with ethyl acetate (10 mL). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude product, which was purified by silica gel chromatography (24 g, ethyl acetate / MeOH=0 10 10%) to give 4-(4-chloroquinolin-6-yl)pyridin-2-amine (XXIII) (381 mg, 1.49 mmol, 75%). LCMS [M+H]+ =256. 1 H NMR (500 MHz, CDCl3) δ 9.03 (d, J = 4.7 Hz, 1H), 8.63 (s, 1H), 8.43 (t, J = 7.8 Hz, 2H), 8.20 (d, J = 8.6 Hz, 1H), 7.90 - 7.58 (m, 2H), 7.07 (s, 1H), 4.98 (brs, 2H). 13 C NMR (126 MHz, CDCl3) δ 159.11, 150.35, 149.12, 149.03, 148.81, 142.92, 138.02, 130.60, 129.28, 126.53, 122.26, 121.80, 112.84, 106.70.

[0083] The preparation of intermediate 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) is shown in Scheme 8. [ka]

[0084] To a vial was added 6-bromo-4-chloroquinazoline (XVIII) (2.10 g, 1 eq., 8.61 mmol), tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (XXIV) (3.50 g, 1 eq., 8.61 mmol), PdCl2dppf (315 mg, 0.05 eq., 431 μmol), and K3PO4 (5.49 g, 3 eq., 25.8 mmol) and purged for 10 minutes. Dioxane (72 mL), water (12 mL) (6:1) was added to the vial and purged for an additional 10 minutes. The reaction was placed in an oil bath at 65 °C for 16 hours. After completion of the reaction, the reaction was cooled, diluted with DCM (19 mL), and 2,2,2-trifluoroacetic acid (7.28 g, 4.890 mL, 20 eq., 63.85 mmol) was added to the vial. The mixture was stirred at 25° C. for 4 hours. After this time, the mixture was poured into DCM and washed with water to give 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) (1.56 g, 1 eq., 3.193 mmol) as a yellow solid. LCMS [M+H] + =388. 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.26 - 8.21 (m, 2H), 7.98 (d, J = 5.4 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.18 (t, J = 8.8 Hz, 1H), 6.81 (dd, J = 5.3, 1.8 Hz, 1H), 6.71 (d, J = 1.7 Hz, 1H), 6.02 (s, 1H), 3.07 (t, J = 4.9 Hz, 4H), 2.84 (q, J = 7.0 Hz, 4H), 1.03 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 167.13, 159.24, 156.49, 154.87, 154.32, 151.19, 149.06, 148.71, 138.37, 132.74, 129.65, 126.87, 124.97, 123.38, 122.99, 118.84, 117.93, 112.59, 106.76, 50.40, 45.96.

[0085] Example 1.1: Preparation of 4-(4-(3-fluoro-4-morpholinophenyl)quinazolin-6-yl)pyridin-2-amine (1) [ka]

[0086] Step A: Preparation of 4-(4-bromo-2-fluorophenyl)morpholine A mixture of 3-fluoro-4-morpholinoaniline (5 g, 30 mmol) and 48% HBr (50 mL) was stirred at 0 °C. NaNO (5 g, 80 mmol) in water (50 mL) was added dropwise to the solution and stirred for an additional 30 minutes. CuBr (8 g, 50 mmol) was added to the reaction solution, and the resulting mixture was heated at 130 °C for 3 hours. The reaction mixture was cooled to room temperature, and NaOH (5.0 N, 50 mL) was added to the solution, followed by extraction with ethyl acetate (150 mL). The solution was filtered through Celite to remove the green copper salts. The organic layer of the filtrate was further collected through a separatory funnel. The aqueous solution was washed with ethyl acetate (60 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was purified on silica gel (liquid, 80 g, eluent: 0-60% ethyl acetate in hexane) to give the desired product. LCMS [M+H] + =259.

[0087] Step B: Preparation of 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine A mixture of 4-(4-bromo-2-fluorophenyl)morpholine (5 g, 1 eq., 0.02 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8 g, 1.7 eq., 0.03 mol), potassium acetate (6 g, 3 eq., 0.06 mol), and PdCl(dppf) (1 g, 0.1 eq., 2 mmol) in 1,4-dioxane (50 mL) was heated at 120 °C for 2.5 h under an argon atmosphere. (Note: TLC plate analysis shows that the product and starting material are similar in polarity, and 20% ethyl acetate in hexane shows an Rf value of 0.3; iodine indicator stains differently.) The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (50 mL). The aqueous solution was washed with ethyl acetate (80 ml), and the combined organic layers were filtered through Celite (due to the dark red color from mixing with water). The organic layers were collected, dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude product (Note: Due to a weak vacuum system, the residue contained a large amount of HOAc from KOAc). The crude product was purified by silica gel chromatography (80 g, 0-60% ethyl acetate in hexanes) to give 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (6 g, 20 mmol) as a white solid. LCMS [M+H] + =307.

[0088] Step C: Preparation of 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)morpholine A mixture of 6-bromo-4-chloroquinazoline (595 mg, 1.5 eq., 2.44 mmol), 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (500 mg, 1 eq., 1.63 mmol), PdCl(dppf) (128 mg, 0.1 eq., 163 μmol), and potassium phosphate tribasic (518 mg, 1.50 eq., 2.44 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was heated at 90° C. under an argon atmosphere for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water (5 mL) and brine (5 mL). The organic layer was dried over NaSO and evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (12 g, eluent 0-10% MeOH in DCM) to give the desired product. However, fractions were not pure based on TLC plate analysis. Therefore, the combined fractions were evaporated, washed with more MeOH (5-10 ml), and filtered to recover the pure product. This was repeated once more to recover the remaining product. The combined product gave a yellow solid, 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)morpholine (338 mg, 871 μmol, 53%). LCMS [M+H] + =389.

[0089] Step D: Preparation of 4-(4-(3-fluoro-4-morpholinophenyl)quinazolin-6-yl)pyridin-2-amine (1) A mixture of 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)morpholine (115 mg, 1 eq., 296 μmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (104 mg, 1.1 eq., 326 μmol), potassium phosphate (94 mg, 1.5 eq., 444 μmol), and PdCl(dppf) (23 mg, 0.1 eq., 29.6 μmol) in 1,4-dioxane (6 mL) and water (1 mL) was heated at 110° C. for 2 h under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL). The aqueous layer was washed with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, and evaporated in vacuo to give a brown solid. The crude product was dissolved in DCM (2 ml) and loaded onto silica gel (24 g, eluent 0–10% MeOH in DCM) to give the desired product, tert-butyl (4-(4-(3-fluoro-4-morpholinophenyl)quinazolin-6-yl)pyridin-2-yl)carbamate (96 mg, 0.19 mmol, 65%), followed by stirring at rt for 16 h with 2,2,2-trifluoroacetic acid (1.5 g, 1.0 ml, 75 eq., 13 mmol) in DCM (3 ml). The reaction mixture was diluted with ethyl acetate (50 ml), washed with 1N NaOH (20 ml), and brine (20 ml). The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude product. TFA (0.24 mL):DCM (0.71 mL) (1:3 v / v) was added to the flask and stirred at 25 °C for 2 h. Upon completion of the reaction, it was diluted with DCM, basified with 1 N NaOH (4.5 g NaOH in 100 mL water), washed with HO, brine, and the organic layer was dried over NaSO. The mixture was concentrated under pressure, and the crude product was purified by column chromatography (DCM / MeOH 0-5%) to give 4-(4-(3-fluoro-4-morpholinophenyl)quinazolin-6-yl)pyridin-2-amine as a yellow solid (46.3 mg, 63% yield, 98% purity). MP 184-186 °C. LCMS [M+H] + =402. 1HNMR (500 MHz, CDCl3) δ 9.39 (d, J = 9.5 Hz, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.26 - 8.18 (m, 1H), 8.09 (dd, J = 8.8, 2.1 Hz, 1H), 7.89 (d, J = 6.4 Hz, 1H), 7.57 (dt, J = 5.2, 2.1 Hz, 2H), 7.13 (t, J = 8.6 Hz, 1H), 7.06 - 6.96 (m, 3H), 3.98 - 3.81 (m, 4H), 3.26 (m, 4H). 13 CNMR (126 MHz, CDCl3) δ 166.96, 158.63, 156.20, 154.23, 151.36, 149.63, 147.36, 141.95, 137.94, 132.47, 130.67, 129.90, 126.78, 124.98, 122.94, 118.49, 118.16, 112.54, 107.05, 66.87, 50.49.

[0090] Example 1.2: Preparation of 4-(4-(6-(1H-pyrrolo[2,3-b]pyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)morpholine (2) [ka]

[0091] Step A: Preparation of 4-(4-(6-(1H-pyrrolo[2,3-b]pyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)morpholine (2) The title compound was isolated as a yellow solid from 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)morpholine in a manner similar to that described in Step D of Example 1.1. MP=264-270° C. 1H NMR (400 MHz, CDCl3) δ 10.85 (s, 1H), 9.45 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 8.33 (d, J = 1.1 Hz, 2H), 7.69 - 7.57 (m, 3H), 7.42 13C NMR (201 MHz, CDCl3) δ 172.77, 167.13, 155.82, 155.51, 154.59, 151.58, 142.10, 137.15, 136.62, 133.56, 130.40, 130.27, 128.11, 127.31, 126.79, 123.07, 118.51, 118.18, 118.06, 115.28, 101.15, 66.86, 50.45.

[0092] Example 1.3: Preparation of 4-(4-(3-fluoro-4-(morpholinomethyl)phenyl)quinazolin-6-yl)pyridin-2-amine (3) [ka]

[0093] Step A: Preparation of 4-(4-(6-bromoquinazolin-4-yl)-2-fluorobenzyl)morpholine The title compound was isolated as a yellow solid from 3-fluoro-4-(4-morpholinylmethyl)phenylboronic acid pinacol ester in a manner similar to that described in Step C of Example 1.1. 1H NMR (500 MHz, CDCl3) δ 9.37 (s, 1H), 8.24 - 8.18 (m, 1H), 8.13 (dd, J = 8.8, 2.0 Hz, 1H), 7.59 (dd, J = 7.7, 1.7 Hz, 1H), 7.53 (dd, J = 10.2, 1.6 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.29 (dd, J = 10.7, 1.8 Hz, 1H), 3.76 (s, 2H), 3.72 (m, 4H), 2.67 - 2.51 (m, 4H).

[0094] Step B: Preparation of 4-(4-(3-fluoro-4-(morpholinomethyl)phenyl)quinazolin-6-yl)pyridin-2-amine (3) The title compound was isolated as a light brown solid from 4-(4-(6-bromoquinazolin-4-yl)-2-fluorobenzyl)morpholine in a manner similar to that described in Step D of Example 1.1. MP=110-116° C. 1 H NMR (400 MHz, CDCl3) δ 9.42 (d, J = 0.9 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.26 - 8.17 (m, 2H), 8.16 (dd, J = 8.5, 1.9 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.57 (dd, J = 10.2, 1.4 Hz, 1H), 6.93 - 6.88 (m, 1H), 6.75 (s, 1H), 4.72 (s, 2H), 3.78 (q, J = 5.9, 5.2 Hz, 4H), 3.74 (s, 2H), 2.65 - 2.51 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 167.07, 162.59, 160.13, 159.00, 154.96, 151.23, 148.85, 138.60, 137.80, 132.86, 131.84, 129.91, 127.00, 125.59, 124.59, 122.96, 116.95, 112.82, 106.70, 66.94, 55.47, 53.52.

[0095] Example 1.4: Preparation of 4-(4-(3-morpholinophenyl)quinazolin-6-yl)pyridin-2-amine (4) [ka]

[0096] Step A: Preparation of 4-(3-bromophenyl)morpholine The title compound was isolated as a yellow solid from 3-morpholinoaniline in a manner similar to that described in Step A of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 6.97 - 6.92 (m, 1H), 6.86 - 6.79 (m, 1H), 6.64 (ddd, J = 8.4, 2.5, 0.9 Hz, 0H), 6.51 (dd, J = 8.9, 2.9 Hz, 1H), 3.75 - 3.62 (m, 4H), 3.00 - 2.90 (m, 4H).

[0097] Step B: Preparation of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine The title compound was isolated as an orange oil from 4-(3-bromo-phenyl)-morpholine in a manner similar to that described in Step B of Example 1.1. 1H NMR (500 MHz, CDCl3) δ 7.30 - 7.22 (m, 1H), 7.23 - 7.14 (m, 1H), 6.91 (ddd, J = 8.2, 2.8, 1.1 Hz, 1H), 6.66 (s, 1H), 3.76 - 3.70 (m, 4H), 3.10 - 2.97 (m, 4H), 2.94 (s, 1H), 1.19 - 1.06 (m, 12H). 13 C NMR (126 MHz, CDCl3) δ 150.58, 129.55, 128.55, 126.66, 121.94, 118.92, 83.28, 66.80, 49.46, 24.65.

[0098] Step C: Preparation of 4-(3-(6-bromoquinazolin-4-yl)phenyl)morpholine The title compound was obtained as a yellow solid from 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine in a manner similar to that described in Step C of Example 1.1. LCMS [M+H] + =372. 1 H NMR (500 MHz, CDCl3) δ 9.36 (s, 1H), 8.28 (d, J = 1.7 Hz, 1H), 7.99 - 7.95 (m, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 3.92 - 3.84 (m, 4H), 3.30 - 3.22 (m, 4H).

[0099] Step D: Preparation of 4-(4-(3-morpholinophenyl)quinazolin-6-yl)pyridin-2-amine (4) The title compound was obtained from 4-(3-(6-bromoquinazolin-4-yl)phenyl)morpholine in a manner similar to that described in Step D of Example 1.1 as a yellow / orange solid. MP=100-105° C. LCMS [M+H] + =384. 1H NMR (500MHz, CDCl3): δ 9.37 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.14 - 8.07 (m, 2H), 7.46 (t, J = 7.9 Hz, 1H), 7.32 (t, J = 2.0 Hz, 1H), 7.21 (dt, J = 7.6, 1.1 Hz, 1H), 7.12 (dd, J = 8.2, 2.6 Hz, 1H), 6.87 (dd, J = 5.4, 1.6 Hz, 1H), 6.70 (d, J = 1.6 Hz, 1H), 4.71 (s, 2H), 3.91 - 3.78 (m, 4H), 3.28 - 3.21 (m, 4H). 13 C NMR (126 MHz, CDCl3): δ 169.25, 158.80, 155.81, 155.05, 151.79, 151.15, 149.18, 148.34, 137.98, 137.81, 132.53, 129.71, 129.38, 125.30, 123.30, 121.46, 117.36, 116.53, 112.68, 106.66, 66.83, 49.02.

[0100] Example 1.5: Preparation of 4-(4-(3-fluoro-5-morpholinophenyl)quinazolin-6-yl)pyridin-2-amine (5) [ka]

[0101] Step A: Preparation of 4-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine The title compound was obtained as a white solid from 4-(3-bromo-5-fluorophenyl)morpholine in a manner similar to that described in Step B of Example 1.1. 1H NMR (500 MHz, CDCl3) δ 7.11 (s, 1H), 6.97 (dd, J = 8.3, 2.3 Hz, 1H), 6.66 (dt, J = 12.1, 2.5 Hz, 1H), 3.87 - 3.78 (m, 4H), 3.18 (dd, J = 6.0, 3.8 Hz, 4H), 1.32 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 164.46, 162.51, 152.49, 117.04, 111.94, 105.32, 84.06, 66.75, 48.99, 24.86.

[0102] Step B: Preparation of 4-(3-(6-bromoquinazolin-4-yl)-5-fluorophenyl)morpholine The title compound was obtained as a yellow solid from 4-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine in a manner similar to that described in Step C of Example 1.1. LCMS [M+H] + =388. 1 H NMR (500 MHz, CDCl3) δ 9.59 (s, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 2.1 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1H), 7.11 (dt, J = 8.3, 1.6 Hz, 1H), 7.04 - 6.99 (m, 1H), 4.13 - 4.06 (m, 4H), 3.52 - 3.46 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 166.87, 164.61, 162.66, 154.64, 153.10, 149.69, 138.64, 137.55, 130.72, 128.91, 124.01, 121.90, 112.04, 107.67, 103.94, 66.57, 48.58.

[0103] Step C: Preparation of 4-(4-(3-fluoro-5-morpholinophenyl)quinazolin-6-yl)pyridin-2-amine (5) The title compound was obtained from 4-(3-(6-bromoquinazolin-4-yl)-5-fluorophenyl)morpholine in a manner similar to that described in Step D of Example 1.1 as a yellow solid. MP=130-135° C. 1 H NMR (500 MHz, CDCl3) δ 9.55 (s, 1H), 8.45 (d, J = 1.9 Hz, 1H), 8.37 (d, J = 8.7 Hz, 1H), 8.34 - 8.29 (m, 2H), 7.25 - 7.22 (m, 1H), 7.10 - 7.07 (m, 1H), 7.05 (dd, J = 5.3, 1.5 Hz, 1H), 6.96 (dt, J = 11.9, 2.4 Hz, 1H), 6.88 (s, 1H), 4.88 (s, 2H), 4.03 (t, J = 4.9 Hz, 4H), 3.43 (t, J = 4.9 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 168.11, 164.56, 162.61, 158.94, 154.90, 153.28, 153.19, 151.11, 148.92, 139.13, 139.06, 138.40, 132.82, 129.80, 124.76, 123.09, 112.65, 111.99, 111.97, 107.77, 106.61, 103.83, 66.60, 48.50.

[0104] Example 1.6: Preparation of 4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)thiomorpholine 1,1-dioxide (6) [ka]

[0105] Step A: Preparation of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiomorpholine 1,1-dioxide The title compound was obtained as a white solid from 4-(4-bromophenyl)thiomorpholine 1,1-dioxide in a manner similar to that described in Step B of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.00 - 3.76 (m, 4H), 3.18 - 2.98 (m, 4H), 1.31 (s, 12H), 1.24 (d, J = 3.1 Hz, 8H), 1.21 (s, 4H). 13 C NMR (126 MHz, CDCl3) δ 149.15, 136.76, 114.50, 83.67, 83.11, 75.08, 50.35, 46.79, 24.85, 24.55.

[0106] Step B: Preparation of 4-(4-(6-bromoquinazolin-4-yl)phenyl)thiomorpholine 1,1-dioxide The title compound was obtained as a yellow solid from 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiomorpholine 1,1-dioxide in a manner similar to that described in Step C of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.32 (d, J = 1.0 Hz, 1H), 8.02 - 7.92 (m, 2H), 7.85 - 7.74 (m, 2H), 7.08 (d, J = 8.9 Hz, 2H), 4.12 - 3.95 (m, 4H), 3.23 - 3.12 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 166.70, 154.44, 149.93, 148.63, 137.23, 131.80, 130.59, 129.15, 128.08, 124.34, 121.68, 115.19, 50.63, 46.48.

[0107] Step C: Preparation of 4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)thiomorpholine 1,1-dioxide (6) The title compound was obtained as a yellow solid from 4-(4-(6-bromoquinazolin-4-yl)phenyl)thiomorpholine 1,1-dioxide in a manner similar to that described in Step D of Example 1.1. 1 H NMR (500 MHz, DMSO-d6) δ 9.32 (d, J = 15.8 Hz, 1H), 8.38 (dd, J = 9.1, 7.3 Hz, 1H), 8.32 - 8.01 (m, 2H), 7.86 (d, J = 8.8 Hz, 1H), 7.67 (t, J = 10.5 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.94 - 6.83 (m, 2H), 6.72 (dt, J = 8.9, 6.9 Hz, 1H), 6.29 (s, 1H), 6.08 (d, J = 16.2 Hz, 1H), 3.98-3.91 (m, 4H), 3.24 - 3.05 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 167.47, 166.86, 160.82, 155.24, 154.62, 149.41, 145.48, 140.28, 138.39, 133.86, 132.82, 132.21, 128.66, 122.02, 116.18, 115.37, 112.88, 110.60, 108.94, 106.01, 50.13, 46.81.

[0108] Example 1.7: Preparation of 4-(4-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (7) [ka]

[0109] Step A: Preparation of 6-bromo-4-(4-(4-methylpiperazin-1-yl)phenyl)quinazoline The title compound was obtained as a yellow solid from 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine in a manner similar to that described in Step C of Example 1.1. 1 H NMR (500 MHz, CDCl3): δ δ 9.46 (s, 1H), 8.52 (t, J = 1.4 Hz, 1H), 8.09 (d, J = 1.3 Hz, 2H), 7.92 - 7.88 (m, 2H), 7.26 - 7.21 (m, 2H), 3.59 - 3.54 (m, 4H), 2.81 - 2.76 (m, 4H), 2.55 (s, 3H).

[0110] Step B: Preparation of 4-(4-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (7) The title compound was obtained as a yellow solid from 6-bromo-4-(4-(4-methylpiperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step D of Example 1.1. LCMS [M+H] + =397. 1 H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H), 8.07 (dd, J = 8.8, 1.9 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 5.1 Hz, 1H), 6.72 (s, 1H), 4.73 (s, 2H), 3.42 (t, J = 5.0 Hz, 4H), 2.68 (t, J = 4.9 Hz, 4H), 2.42 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.16, 155.11, 152.42, 151.31, 137.68, 132.18, 131.59, 129.63, 127.32, 125.44, 123.12, 115.12, 114.99, 112.76, 110.84, 54.70, 47.70, 45.88.

[0111] Example 1.8: Preparation of 4-(4-(3-(morpholinomethyl)phenyl)quinazolin-6-yl)pyridin-2-amine (8) [ka]

[0112] Step A: Preparation of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine The title compound was obtained as an orange oil from 4-(3-bromobenzyl)morpholine in a manner similar to that described in Step B of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 7.63 (dd, J = 4.9, 2.6 Hz, 2H), 7.39 - 7.36 (m, 1H), 7.26 - 7.20 (m, 1H), 3.62 (q, J = 6.8, 5.7 Hz, 4H), 3.44 (s, 2H), 2.38 (t, J = 4.6 Hz, 4H), 1.30 (d, J = 3.4 Hz, 13H), 1.25 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 136.16, 135.82, 133.86, 132.43, 127.72, 83.75, 66.63, 63.15, 53.32, 24.61.

[0113] Step B: Preparation of 4-(3-(6-bromoquinazolin-4-yl)benzyl)morpholine The title compound was obtained as a brown solid from 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine in a manner similar to that described in Step C of Example 1.1. LCMS [M+H] + =386. 1 H NMR (500 MHz, CDCl3) δ 9.36 (s, 1H), 8.23 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 2.9 Hz, 2H), 7.74 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.59 - 7.50 (m, 2H), 3.73 (t, J = 4.7 Hz, 4H), 3.63 (s, 2H), 2.59 - 2.42 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 167.44, 154.86, 149.81, 138.52, 137.25, 136.55, 131.22, 130.77, 130.59, 129.19, 128.91, 128.85, 124.18, 121.59, 66.90, 63.01, 53.59.

[0114] Step C: Preparation of 4-(4-(3-(morpholinomethyl)phenyl)quinazolin-6-yl)pyridin-2-amine (8) The title compound was obtained as a brown solid from 4-(3-(6-bromoquinazolin-4-yl)benzyl)morpholine in a manner similar to that described in Step D of Example 1.1. 1H NMR (500 MHz, CDCl3) δ 9.38 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.12 - 8.09 (m, 2H), 7.77 (d, J = 1.9 Hz, 1H), 7.70 - 7.68 (m, 1H), 7.58 - 7.54 (m, 2H), 6.86 (dd, J = 5.4, 1.6 Hz, 1H), 6.70 (d, J = 1.5 Hz, 1H), 4.73 (s, 2H), 3.70 - 3.65 (m, 4H), 3.64 (s, 2H), 3.46 (s, 1H), 2.51 (t, J = 4.7 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 168.77, 158.88, 155.04, 151.16, 149.18, 148.42, 138.40, 138.19, 136.95, 132.63, 131.21, 130.69, 129.79, 128.93, 128.84, 125.13, 123.26, 112.63, 106.60, 66.86, 63.09, 53.54.

[0115] Example 1.9: Preparation of 4-(4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (9) [ka]

[0116] Step A: Preparation of 6-bromo-4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazoline A mixture of 6-bromo-4-(6-chloro-5-fluoropyridin-3-yl)quinazoline (XX) (223 mg, 1 eq., 659 μmol), 1-methylpiperazine (198 mg, 0.2 mL, 3 eq., 1.98 mmol), and potassium carbonate (182 mg, 2 eq., 1.32 mmol) in THF (10 ml) was heated at 80° C. for 48 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 ml), and washed with brine (20 ml). The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to give 6-bromo-4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazoline (175 mg, 435 μmol, 66%) without further purification. 1 H NMR (500 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.11 (dd, J = 8.9, 2.1 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.92 (dd, J = 14.6, 1.8 Hz, 1H), 3.62 - 3.52 (m, 4H), 2.43 - 2.38 (m, 4H), 2.17 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 163.21, 155.06, 150.04, 149.78, 147.57, 144.73, 137.84, 131.40, 129.16, 125.00, 123.72, 121.45, 95.47, 55.16, 47.32, 46.27.

[0117] Step B: Preparation of 4-(4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (9) A mixture of 6-bromo-4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazoline (85 mg, 1 eq., 0.21 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (56 mg, 1.2 eq., 0.25 mmol), potassium phosphate (67 mg, 1.5 eq., 0.32 mmol), and PdCl(dppf) (17 mg, 0.1 eq., 21 μmol) in 1,4-dioxane (0.8 mL) and water (0.1 mL) was heated at 90 °C for 2 h under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (5 mL). The aqueous solution was washed with ethyl acetate (10 mL). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude product, which was purified by pre-HPLC (5-95% ACN) to give 4-(4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (9) (38 mg, 91 μmol, 43%). 1 H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.47 (d, J = 1.3 Hz, 1H), 8.24 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 14.6 Hz, 2H), 6.82 (s, 1H), 6.73 (s, 1H), 6.02 (s, 2H), 3.59 - 3.54 (m, 4H), 2.42 - 2.36 (m, 4H), 2.17 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 164.40, 161.05, 155.08, 150.88, 149.98, 149.63, 149.25, 147.46, 144.84, 138.71, 133.33, 129.74, 125.27, 124.73, 124.40, 122.88, 110.79, 106.08, 55.17, 47.31, 46.48.

[0118] Example 1.10: 4-(4-(6-morpholinopyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (10) [ka]

[0119] Step A: Preparation of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine The title compound was obtained as a white solid from 4-(5-bromopyridin-2-yl)morpholine in a manner similar to that described in Step B of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 8.50 (d, J = 0.8 Hz, 1H), 7.79 (dd, J = 8.6, 1.6 Hz, 1H), 6.53 (d, J = 8.6 Hz, 1H), 3.88 - 3.68 (m, 4H), 3.61 - 3.46 (m, 4H), 1.26 (s, 6H), 1.18 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 160.48, 154.95, 143.66, 113.75, 105.68, 83.40, 66.82, 45.20, 24.55.

[0120] Step B: Preparation of 4-(5-(6-bromoquinazolin-4-yl)pyridin-2-yl)morpholine The title compound was obtained as a yellow solid from 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in a manner similar to that described in Step C of Example 1.1. 1H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.32 (s, 1H), 8.12 - 8.01 (m, 1H), 7.95 (s, 2H), 6.81 (d, J = 8.9 Hz, 1H), 3.95 - 3.80 (m, 4H), 3.75 - 3.65 (m, 4H). 13 C NMR (125 MHz, CDCl3) δ 164.84, 159.41, 154.85, 149.85, 149.509, 139.37, 137.20, 130.73, 128.68, 123.95, 121.97, 121.53, 106.57, 66.62, 45.27.

[0121] Step C: Preparation of 4-(4-(6-morpholinopyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (10) The title compound was obtained as a yellow solid from 4-(5-(6-bromoquinazolin-4-yl)pyridin-2-yl)morpholine in a manner similar to that described in Step D of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.44 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.97 (s, 2H), 7.79 (d, J = 14.0 Hz, 2H), 3.99 - 3.77 (m, 6H), 3.79 - 3.64 (m, 6H). 13 C NMR (126 MHz, CDCl3) δ 163.57, 154.90, 149.92, 148.09, 144.49, 137.60, 130.58, 128.32, 124.62, 124.45, 124.25, 123.89, 121.99, 67.24, 47.47.

[0122] Example 1.11: 4-(4-(5-fluoro-6-morpholinopyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (11) [ka]

[0123] Step A: Preparation of 4-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine The title compound was obtained as a white solid from 4-(5-bromo-3-fluoropyridin-2-yl)morpholine in a manner similar to that described in Step B of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 8.30 (t, J = 1.6 Hz, 1H), 7.50 (dt, J = 20.8, 10.4 Hz, 1H), 3.90 - 3.69 (m, 4H), 3.67 - 3.48 (m, 4H), 1.29 (s, 6H), 1.23 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 149.45, 148.26, 128.44, 83.79, 83.53, 67.02, 47.92, 25.02, 24.86.

[0124] Step B: Preparation of 4-(5-(6-bromoquinazolin-4-yl)-3-fluoropyridin-2-yl)morpholine The title compound was obtained as a yellow solid from 4-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in a manner similar to that described in Step C of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.44 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.97 (s, 2H), 7.79 (d, J = 14.0 Hz, 2H), 3.99 - 3.77 (m, 6H), 3.79 - 3.64 (m, 6H). 13C NMR (126 MHz, CDCl3) δ 163.57, 154.90, 149.92, 148.09, 144.49, 137.60, 130.58, 128.32, 124.62, 124.45, 124.25, 123.89, 121.99, 67.24, 47.47.

[0125] Step C: Preparation of 4-(4-(5-fluoro-6-morpholinopyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (11) The title compound was obtained as a yellow solid from 4-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in a manner similar to that described in Step D of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.44 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.97 (s, 2H), 7.79 (d, J = 14.0 Hz, 2H), 3.99 - 3.77 (m, 6H), 3.79 - 3.64 (m, 6H). 13 C NMR (126 MHz, CDCl3) δ 163.57, 154.90, 149.92, 148.09, 144.49, 137.60, 130.58, 128.32, 124.62, 124.45, 124.25, 123.89, 121.99, 67.24, 47.47.

[0126] Example 1.12: 4-(4-(3-fluoro-4-morpholinophenyl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine (12) [ka]

[0127] Step A: Preparation of 4-(4-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-2-fluorophenyl)morpholine The title compound was obtained as a yellow solid from 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine in a manner similar to that described in Step C of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 9.51 (d, J = 3.1 Hz, 1H), 8.60 (dd, J = 8.5, 1.9 Hz, 1H), 8.52 (dd, J = 14.9, 2.0 Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.93 (t, J = 8.5 Hz, 1H), 7.24 (t, J = 8.7 Hz, 1H), 4.21 - 3.91 (m, 4H), 3.55 - 3.27 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 163.19, 163.05, 155.54, 151.26, 146.76, 142.75, 140.18, 138.35, 137.37, 129.94, 128.84, 119.57, 117.79, 66.84, 50.31.

[0128] Step B: Preparation of 4-(4-(3-fluoro-4-morpholinophenyl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine (12) The title compound was obtained as a yellow solid from 4-(4-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-2-fluorophenyl)morpholine in a manner similar to that described in Step B of Example 1.9. 1H NMR (500 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.49 (dd, J = 8.6, 5.8 Hz, 2H), 8.45 (t, J = 9.9 Hz, 1H), 8.34 (dd, J = 15.5, 1.8 Hz, 1H), 8.28 (s, 1H), 8.07 (d, J = 5.4 Hz, 1H), 7.23 (dd, J = 11.4, 6.5 Hz, 1H), 7.17 (s, 1H), 6.15 (s, 2H), 3.81 - 3.65 (m, 4H), 3.21 - 3.13 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 163.53, 161.27, 159.15, 156.88, 155.69, 149.41, 149.11, 147.43, 146.10, 142.57, 138.61, 138.20, 129.61, 119.48, 118.65, 118.11, 110.14, 106.21, 66.75, 50.82.

[0129] Example 1.13: 4-(4-(5-fluoro-6-morpholinopyridin-3-yl)quinolin-6-yl)pyridin-2-amine (13) [ka]

[0130] Step A: Preparation of 4-(4-(5-fluoro-6-morpholinopyridin-3-yl)quinolin-6-yl)pyridin-2-amine (13) A mixture of 4-(4-chloroquinolin-6-yl)pyridin-2-amine (XXII) (80 mg, 1 eq., 312.9 μmol), 4-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (96 mg, 1 eq., 312.9 μmol), potassium phosphate (100 mg, 1.5 eq., 469.3 μmol), and PdCl(dppf) (25 mg, 0.1 eq., 31.29 μmol) in 1,4-dioxane (0.8 mL) and water (0.1 mL) was heated at 90° C. for 2 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (5 mL). The aqueous solution was washed with ethyl acetate (10 mL). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (0-10% MeOH in ethyl acetate) to give 4-(4-(5-fluoro-6-morpholinopyridin-3-yl)quinolin-6-yl)pyridin-2-amine. LCMS [M+H] + =402. 1 HNMR (500 MHz, CDCl3) δ 8.86 (d, J = 4.4 Hz, 1H), 8.21 - 8.08 (m, 2H), 8.00 (dd, J = 7.6, 3.7 Hz, 2H), 7.83 (dd, J = 8.8, 2.0 Hz, 1H), 7.51 - 7.26 (m, 2H), 6.83 - 6.75 (m, 1H), 6.63 (s, 1H), 4.99 (d, J = 36.4 Hz, 2H), 3.88 - 3.72 (m, 4H), 3.56 (dd, J = 5.6, 3.8 Hz, 4H). 13 CNMR (126 MHz, CDCl3) δ 171.12, 158.99, 150.49, 149.83, 149.41, 148.71, 148.21, 147.86, 144.08, 142.93, 137.38, 130.82, 128.53, 126.55, 124.34, 123.30, 121.97, 112.64, 106.92, 66.87, 47.76.

[0131] Example 1.14: 4-(4-(2-morpholinopyridin-4-yl)quinazolin-6-yl)pyridin-2-amine (14) [ka]

[0132] Step A: Preparation of 4-(4-(6-bromoquinazolin-4-yl)pyridin-2-yl)morpholine The title compound was obtained as a yellow solid from 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine in a manner similar to that described in Step C of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 9.35 (s, 1H), 8.40 (dd, J = 36.6, 3.8 Hz, 1H), 8.26 - 8.15 (m, 1H), 7.96 (d, J = 7.4 Hz, 2H), 6.89 (d, J = 4.0 Hz, 2H), 3.80 (dd, J = 13.0, 8.0 Hz, 4H), 3.57 (dd, J = 17.2, 12.5 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 166.15, 159.79, 154.81, 149.71, 148.37, 145.61, 137.70, 130.86, 128.55, 123.82, 122.04, 113.85, 106.96, 66.69, 45.46.

[0133] Step B: Preparation of 4-(4-(2-morpholinopyridin-4-yl)quinazolin-6-yl)pyridin-2-amine (14) The title compound was obtained as a yellow solid from 4-(4-(6-bromoquinazolin-4-yl)pyridin-2-yl)morpholine in a manner similar to that described in Step D of Example 1.1. 1H NMR (500 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.40 (dd, J = 8.8, 2.0 Hz, 1H), 8.37 (d, J = 5.0 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 6.6 Hz, 1H), 8.02 (d, J = 6.5 Hz, 2H), 7.24 (dd, J = 6.6, 1.6 Hz, 1H), 7.22 - 7.19 (m, 2H), 7.08 (dd, J = 5.0, 0.8 Hz, 1H), 3.79 - 3.68 (m, 4H), 3.63 - 3.53 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 167.95, 159.81, 155.93, 155.16, 152.97, 151.33, 148.45, 145.84, 138.39, 135.88, 133.29, 130.26, 126.02, 122.64, 114.26, 111.30, 110.68, 107.89, 66.40, 45.50.

[0134] Example 1.15: 4-(4-(3-fluoro-4-morpholinophenyl)quinazolin-6-yl)pyrimidin-2-amine (15) [ka]

[0135] Step A: Preparation of 4-(2-fluoro-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)phenyl)morpholine A mixture of 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)morpholine (250 mg, 1 eq., 644 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (278 mg, 1.7 eq., 1.09 mmol), potassium acetate (190 mg, 3 eq., 1.93 mmol), and PdCl(dppf) (51 mg, 0.1 eq., 64.4 μmol) in 1,4-dioxane (10 ml) was heated at 100° C. for 16 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to give crude product 4-(2-fluoro-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)phenyl)morpholine (137 mg, 315 μmol, 49%). 1 H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 8.59 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.56 - 7.53 (m, 1H), 7.09 (t, J = 8.5 Hz, 1H), 3.88 (dd, J = 15.9, 11.2 Hz, 4H), 3.32 - 3.16 (m, 4H), 1.23 (s, 6H), 1.20 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 167.25, 156.18, 154.98, 154.21, 152.46, 141.83, 138.79, 134.59, 131.02, 130.96, 127.73, 127.02, 122.27, 118.49, 84.47, 82.85, 75.05, 66.90, 50.54, 50.51, 24.87, 24.57.

[0136] Step B: Preparation of 4-(4-(3-fluoro-4-morpholinophenyl)quinazolin-6-yl)pyrimidin-2-amine (15) A mixture of 4-(2-fluoro-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)phenyl)morpholine (50 mg, 1 eq., 0.11 mmol), 4-bromopyrimidin-2-amine (26 mg, 1.3 eq., 0.15 mmol), potassium triphosphate (41 mg, 1.7 eq., 0.20 mmol), and PdCl(dppf) (9.0 mg, 0.1 eq., 11 μmol) in 1,4-dioxane / water (6 / 1, 5 mL) was heated at 90 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude product was further purified to give the desired product 4-(4-(3-fluoro-4-morpholinophenyl)quinazolin-6-yl)pyrimidin-2-amine (24.5 mg, 60.9 μmol, 53%). LCMS [M+H] + =403. 1 H NMR (500 MHz, CDCl3) δ 9.35 (s, 1H), 8.81 (s, 1H), 8.53 (d, J = 8.7 Hz, 1H), 8.38 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.60 (dd, J = 18.6, 12.6 Hz, 2H), 7.18 - 7.00 (m, 2H), 5.31 (d, J = 32.8 Hz, 2H), 3.91 (s, 4H), 3.28 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 167.35, 164.27, 162.77, 158.33, 156.21, 155.46, 154.24, 152.41, 141.95, 136.21, 131.94, 130.66, 129.66, 126.94, 126.04, 122.70, 118.45, 118.09, 107.87, 66.87, 50.49.

[0137] Example 1.16: 4-(4-(4-morpholinophenyl)quinazolin-6-yl)pyridin-2-amine (16) [ka]

[0138] Step A: Preparation of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine The title compound was obtained as a white solid from 4-(4-bromophenyl)morpholine in a manner similar to that described in Step B of Example 1.1. LCMS [M+H] + =390. 1 H NMR (500 MHz, CDCl3) δ 7.73 - 7.67 (m, 2H), 6.88 (d, J = 8.1 Hz, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.24 - 3.16 (m, 4H), 1.30 (s, 12H).

[0139] Step B: Preparation of 4-(4-(6-bromoquinazolin-4-yl)phenyl)morpholine The title compound was obtained as a yellow solid from 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine in a manner similar to that described in Step C of Example 1.1. LCMS [M+H] + =370. 1 H NMR (500MHz CD2Cl3): δ 9.47 (s, 1H), 8.52 (d, J = 1.7 Hz, 1H), 8.11 (d, J = 2.0 Hz, 2H), 7.96 - 7.88 (m, 2H), 7.26 - 7.20 (m, 2H), 4.11 - 4.03 (m, 4H), 3.49 (dd, J = 6.0, 3.8 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 166.85, 154.81, 152.73, 149.84, 136.90, 131.49, 130.59, 129.37, 127.09, 124.05, 121.15, 114.73, 77.32, 77.27, 77.07, 76.82, 66.69, 48.17.

[0140] Step C: Preparation of 4-(4-(4-morpholinophenyl)quinazolin-6-yl)pyridin-2-amine (16) The title compound was obtained from 4-(4-(6-bromoquinazolin-4-yl)phenyl)morpholine in a manner similar to that described in Step B of Example 1.9 as a yellow solid. MP=190-200° C. LCMS [M+H] + =384. 1 H NMR (500 MHz, CDCl3) δ 9.48 (s, 1H), 8.54 (s, 1H), 8.30 (d, J = 7.6 Hz, 2H), 8.23 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.77 - 7.69 (m, 1H), 7.64 - 7.59 (m, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 5.1 Hz, 1H), 6.88 (s, 1H), 4.89 (s, 2H), 4.05 (t, J = 4.8 Hz, 4H), 3.48 (t, J = 4.7 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 168.13, 158.94, 155.09, 152.67, 151.30, 149.28, 148.52, 137.71, 132.21, 131.58, 129.63, 127.55, 125.40, 123.10, 114.75, 112.71, 106.65, 77.29, 77.04, 76.78, 66.72, 48.20.

[0141] Example 1.17: 4-(2-fluoro-4-(6-(2-methylpyridin-4-yl)pyrido[3,2-d]pyrimidin-4-yl)phenyl)morpholine (17) [ka]

[0142] Step A: Preparation of 4-(2-fluoro-4-(6-(2-methylpyridin-4-yl)pyrido[3,2-d]pyrimidin-4-yl)phenyl)morpholine (17) The title compound was obtained as a yellow solid from 4-(4-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-2-fluorophenyl)morpholine and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in a manner similar to that described in Step B of Example 1.9. Mp 218-219°C. LCMS [M+H] + =402. 1 HNMR (500 MHz, CDCl3) δ 9.35 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.54 - 8.38 (m, 3H), 8.29 (d, J = 8.7 Hz, 1H), 7.92 (s, 1H), 7.86 (d, J = 4.3 Hz, 1H), 7.07 (td, J = 8.7, 2.1 Hz, 1H), 3.90 (dd, J = 5.7, 3.5 Hz, 4H), 3.27 (dd, J = 5.7, 3.7 Hz, 4H), 2.72 (s, 3H). 13 CNMR (126 MHz, CDCl3) δ 164.25, 159.33, 155.72, 155.49, 155.31, 153.54, 149.67, 147.24, 145.93, 142.64, 138.38, 129.39, 128.76, 125.01, 121.38, 120.22, 120.03, 118.88, 117.57, 66.87, 50.35, 24.50.

[0143] Example 1.18: 4-(4-(4-(morpholinomethyl)phenyl)quinazolin-6-yl)pyridin-2-amine (18) [ka]

[0144] Step A: Preparation of 4-(4-bromobenzyl)morpholine The title compound was isolated as a cream-colored solid from 4-(morpholinomethyl)aniline in a manner similar to that described in Step A of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 7.27 - 7.22 (m, 2H), 6.81 - 6.77 (m, 2H), 3.88 - 3.82 (m, 4H), 3.55 (s, 2H), 2.58 (t, J = 4.7 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 145.58, 130.49, 127.12, 114.91, 66.96, 53.58.

[0145] Step B: Preparation of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine The title compound was isolated as a white solid from 4-(4-bromobenzyl)morpholine in a manner similar to that described in Step B of Example 1.1. 1 H NMR (500 MHz, CDCl3) δ 7.68 - 7.64 (m, 2H), 7.23 (d, J = 7.8 Hz, 2H), 3.60 (t, J = 4.7 Hz, 5H), 3.41 (s, 2H), 2.34 (d, J = 9.7 Hz, 4H), 1.23 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 140.65, 134.78, 131.37, 130.88, 128.67, 83.61, 66.82, 63.33, 53.51, 24.89.

[0146] Step C: Preparation of 4-(4-(6-bromoquinazolin-4-yl)benzyl)morpholine The title compound was isolated as a yellow solid from 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine in a manner similar to that described in Step C of Example 1.1. LCMS [M+H] + =383.85. 1H NMR (500MHz CD2Cl3): δ δ 9.38 (s, 1H), 8.28 - 8.23 (m, 1H), 8.02 - 7.98 (m, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.60 (dd, J = 7.8, 1.7 Hz, 1H), 7.53 (dd, J = 7.7, 1.7 Hz, 1H), 7.49 (dd, J = 10.2, 1.6 Hz, 1H), 3.77 (t, J = 4.7 Hz, 4H), 3.71 (s, 2H), 2.59 (s, 4H). 13 C NMR δ 165.86, 162.61, 154.82, 149.93, 137.49, 130.91, 128.70, 125.55, 123.92, 121.94, 116.99, 116.76, 77.35, 77.03, 76.71, 75.01, 66.92, 55.40, 53.48, 24.87.

[0147] Step D: Preparation of 4-(4-(4-(morpholinomethyl)phenyl)quinazolin-6-yl)pyridin-2-amine (18) The title compound was isolated as a brown solid from 4-(4-(6-bromoquinazolin-4-yl)benzyl)morpholine in a manner similar to that described in Step D of Example 1.1. LCMS [M+H] + =398. 1 H NMR (500 MHz, CDCl3) δ 9.33 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.17 (t, J = 8.3 Hz, 3H), 7.96 - 7.92 (m, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 5.1 Hz, 1H), 6.91 (s, 1H), 4.94 (s, 2H), 3.75 (t, J = 4.6 Hz, 4H), 3.63 (d, J = 4.8 Hz, 2H), 2.53 (s, 4H). 13C NMR (126 MHz, CDCl3) δ 159.06, 152.33, 148.98, 148.95, 143.75, 142.36, 141.53, 140.66, 140.63, 135.53, 129.97, 129.75, 128.36, 127.56, 127.53, 112.87, 106.61, 67.02, 63.08, 53.69.

[0148] Example 1.19: 4-(4-(5-fluoro-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (19) [ka]

[0149] Step A: Preparation of 4-(1-(5-(6-bromoquinazolin-4-yl)-3-fluoropyridin-2-yl)piperidin-4-yl)morpholine The title compound was isolated as a yellow solid from 6-bromo-4-(6-chloro-5-fluoropyridin-3-yl)quinazoline (XX) in a manner similar to that described in Step A of Example 1.9. 1 HNMR (500 MHz, CDCl3) δ 9.29 (s, 1H), 8.41 (t, J = 1.6 Hz, 1H), 8.33 (t, J = 1.3 Hz, 1H), 7.95 (d, J = 1.7 Hz, 2H), 7.76 (dd, J = 14.1, 2.0 Hz, 1H), 4.45 (dq, J = 11.8, 2.9, 2.5 Hz, 2H), 3.77 (brs, 4H), 3.01 (td, J = 12.9, 2.3 Hz, 2H), 2.65 (brs, 4H), 2.55 (brs, 1H), 2.02 (dd, J = 8.8, 4.8 Hz, 2H), 1.67 (dd, J = 12.6, 4.0 Hz, 2H). 13CNMR (126 MHz, CDCl3) δ 163.21, 154.85, 149.98, 147.94, 144.41, 137.32, 130.86, 128.48, 128.45, 124.39, 123.86, 121.80, 62.39, 49.66, 46.66, 44.84, 34.42, 28.13.

[0150] Step B: Preparation of 4-(4-(5-fluoro-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (19) The title compound was isolated as a yellow solid from 4-(1-(5-(6-bromoquinazolin-4-yl)-3-fluoropyridin-2-yl)piperidin-4-yl)morpholine in a manner similar to that described in Step B of Example 1.9. Mp 202-204°C. LCMS [M+H] + =486. 1 H NMR (500 MHz, CDCl3) δ 9.27 (s, 1H), 8.44 (t, J = 1.7 Hz, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.18 - 8.08 (m, 2H), 8.05 (dd, J = 8.7, 2.0 Hz, 1H), 7.77 (dd, J = 14.1, 1.9 Hz, 1H), 6.86 (dd, J = 5.2, 1.5 Hz, 1H), 6.70 (s, 1H), 4.70 (s, 2H), 4.41 (dq, J = 11.9, 2.3 Hz, 2H), 3.70 (t, J = 4.7 Hz, 4H), 2.98 (td, J = 12.9, 2.3 Hz, 2H), 2.57 (t, J = 4.7 Hz, 4H), 2.46 (ddd, J = 11.2, 7.3, 3.8 Hz, 1H), 1.98 - 1.92 (m, 2H), 1.61 (qd, J = 12.2, 3.9Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 164.41, 159.12, 154.96, 151.25, 150.18, 150.04, 148.93, 147.99, 144.50, 144.46, 138.56, 132.72, 129.80, 124.47, 124.34, 124.13, 122.90, 112.75, 106.58, 67.15, 62.16, 60.37, 49.80, 46.72, 28.36.

[0151] Example 1.20: 4-(4-(6-(2,2-dimethylmorpholino)-5-fluoropyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (20) [ka]

[0152] Step A: Preparation of 4-(5-(6-bromoquinazolin-4-yl)-3-fluoropyridin-2-yl)-2,2-dimethylmorpholine The title compound was isolated as a yellow solid from 6-bromo-4-(6-chloro-5-fluoropyridin-3-yl)quinazoline (XX) in a manner similar to that described in Step A of Example 1.9. LCMS [M+H] + =416.9. 1 HNMR (500 MHz, CDCl3) δ 9.30 (d, J = 2.7 Hz, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.96 (d, J = 2.4 Hz, 2H), 7.77 (d, J = 14.1 Hz, 1H), 3.89 (p, J = 2.9 Hz, 2H), 3.68 (t, J = 4.4 Hz, 3H), 3.52 (s, 2H), 1.31 (d, J = 2.7 Hz, 6H). 13CNMR (126 MHz, CDCl3) δ 163.16, 154.87, 150.49, 144.43, 137.36, 130.90, 128.42, 124.49, 124.32, 123.86, 121.83, 71.50, 60.92, 56.48, 56.43, 46.97, 46.92, 24.42.

[0153] Step B: Preparation of 4-(4-(6-(2,2-dimethylmorpholino)-5-fluoropyridin-3-yl)quinazolin-6-yl)pyridin-2-amine (20) The title compound was isolated as a yellow solid from 4-(5-(6-bromoquinazolin-4-yl)-3-fluoropyridin-2-yl)-2,2-dimethylmorpholine in a manner similar to that described in Step B of Example 1.9. MP 175-177°C. 1 HNMR (500 MHz, CDCl3) δ 9.58 - 9.13 (m, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.26 - 8.01 (m, 3H), 7.82 (d, J = 14.1 Hz, 1H), 6.88 (d, J = 44.4 Hz, 2H), 5.19 (d, J = 78.6 Hz, 2H), 3.95 - 3.84 (m, 2H), 3.68 (d, J = 4.8 Hz, 2H), 3.51 (s, 2H), 1.31 (d, J = 2.7 Hz, 6H). 13 CNMR (126 MHz, CDCl3) δ 164.46, 155.15, 151.43, 150.52, 149.96, 149.77, 147.91, 144.52, 138.09, 132.67, 130.04, 124.57, 124.45, 124.25, 122.92, 71.49, 60.92, 56.53, 56.47, 47.01, 46.97, 24.89, 24.42.

[0154] Example 1.21: 4-(4-(4-methoxy-3-methylphenyl)quinazolin-6-yl)pyridin-2-amine (21) [ka]

[0155] Step A: Preparation of 2-(4-methoxy-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane The title compound was isolated as a brown oil from 4-bromo-1-methoxy-2-methylbenzene in a manner similar to that described in Step B of Example 1.1. LCMS [M+H] + =249. 1 H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 3.71 (d, J = 2.6 Hz, 3H), 2.09 (s, 3H), 1.21 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 160.44, 137.15, 134.34, 125.88, 109.24, 83.50, 55.17, 24.89, 16.03.

[0156] Step B: Preparation of 6-bromo-4-(4-methoxy-3-methylphenyl)quinazoline The title compound was isolated as a white solid from 2-(4-methoxy-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to that described in Example 1.1, Step C. LCMS [M+H] + =328. 1 H NMR (500 MHz, CDCl3) δ 9.55 (s, 1H), 8.56 (s, 1H), 8.18 (s, 2H), 7.85 - 7.78 (m, 2H), 7.26 - 7.21 (m, 1H), 4.16 (d, J = 2.3 Hz, 3H), 2.55 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 167.32, 159.88, 154.74, 149.76, 137.04, 132.18, 130.58, 129.45, 129.31, 128.40, 127.68, 124.19, 121.30, 109.87, 55.57, 16.38.

[0157] Step C: Preparation of 4-(4-(4-methoxy-3-methylphenyl)quinazolin-6-yl)pyridin-2-amine (21) The title compound was isolated as a grey solid from 6-bromo-4-(4-methoxy-3-methylphenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =342. 1 H NMR (500 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.35 - 8.26 (m, 2H), 8.18 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 1H), 6.86 (dd, J = 5.4, 1.7 Hz, 1H), 6.74 (d, J = 1.7 Hz, 1H), 6.09 (s, 2H), 3.93 (s, 3H), 2.30 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 159.9, 159.88, 154.74, 151.98, 149.76, 148.50, 137.04, 132.18, 130.58, 129.45, 129.31, 128.40, 127.68, 124.19, 121.30, 109.87, 107.52, 106.89, 56.05, 16.53.

[0158] Example 1.22: 1-(4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)piperazin-1-yl)ethan-1-one (22) [ka]

[0159] Step A: Preparation of 1-(4-(4-bromophenyl)piperazin-1-yl)ethan-1-one 1-(4-Bromophenyl)piperazine (0.50 g, 1 eq., 2.07 mmol) and triethylamine (0.56 g, 0.77 mL, 2.7 eq., 5.5 mmol) were added to DCM (7.2 mL). The reaction was cooled to 0 °C, and acetyl chloride (0.33 g, 0.29 mL, 2.0 eq., 4.2 mmol) was added slowly. After completion of the reaction, the reaction was quenched with brine solution and diluted with DCM. The organic phase was further washed with brine and water and dried using sodium sulfate. The mixture was concentrated under pressure and purified by column chromatography (EtOAc / Hex). 1-(4-(4-bromophenyl)piperazin-1-yl)ethan-1-one (405 mg, 1.43 mmol, 69%) was isolated as a white solid. LCMS [M+H] + =282. 1 H NMR (500 MHz, CDCl3) δ 7.27 - 7.21 (m, 2H), 6.71 - 6.66 (m, 2H), 3.68 - 3.64 (m, 2H), 3.54 - 3.48 (m, 2H), 3.07 - 2.98 (m, 4H), 2.03 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 168.98, 149.90, 132.04, 118.24, 112.79, 49.54, 49.20, 46.05, 41.16, 21.37.

[0160] Step B: Preparation of 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethan-1-one The title compound was isolated as a brown solid from 1-(4-(4-bromophenyl)piperazin-1-yl)ethan-1-one in a manner similar to that described in Step B of Example 1.1. LCMS [M+H] + =331. 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.9 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 3.76 (t, J = 5.1 Hz, 2H), 3.63 - 3.58 (m, 2H), 3.26 (t, J = 5.0 Hz, 2H), 3.23 (d, J = 5.2 Hz, 2H), 2.12 (s, 3H), 1.31 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 169.11, 152.82, 136.24, 122.18, 114.94, 83.52, 45.99, 41.12, 24.86, 21.41.

[0161] Step C: Preparation of 6-bromo-4-(4-(4-(prop-1-en-2-yl)piperazin-1-yl)phenyl)quinazoline The title compound was isolated as a yellow solid from 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethan-1-one in a manner similar to that described in Step C of Example 1.1. LCMS [M+H] + =410. 1 H NMR (500 MHz, CDCl3) δ 9.47 (s, 1H), 8.50 (s, 1H), 8.10 (s, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 3.98 (t, J = 5.0 Hz, 2H), 3.83 (t, J = 4.9 Hz, 2H), 3.52 (dt, J = 17.9, 5.0 Hz, 4H), 2.33 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.12, 166.80, 154.82, 152.25, 149.86, 136.97, 131.53, 130.64, 129.31, 127.43, 124.05, 121.23, 115.45, 48.20, 45.93, 41.09, 21.24.

[0162] Step D: 1-(4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)piperazin-1-yl)ethan-1-one (22) The title compound was isolated as a yellow solid from 1-(4-(4-(6-bromoquinazolin-4-yl)phenyl)piperazin-1-yl)ethan-1-one in a manner similar to that described in Step B of Example 1.9. MP=120-130° C. LCMS [M+H] + =425. 1 H NMR (500 MHz, CDCl3) δ 9.48 (d, J = 4.6 Hz, 1H), 8.53 (s, 1H), 8.37 - 8.22 (m, 3H), 7.97 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 5.6 Hz, 1H), 6.88 (s, 1H), 4.83 (s, 2H), 3.97 (d, J = 6.5 Hz, 2H), 3.88 - 3.81 (m, 2H), 3.57 - 3.46 (m, 4H), 2.32 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.09, 168.01, 159.04, 155.06, 152.19, 151.28, 149.09, 148.86, 137.90, 132.29, 131.61, 129.64, 127.93, 125.27, 123.09, 115.45, 112.73, 106.49, 48.24, 45.95, 41.10, 21.37.

[0163] Example 1.23: 4-(4-(5-fluoro-6-(2-oxa-8-azaspiro[4.5]decan-8-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine hydrochloride (23) [ka]

[0164] Step A: Preparation of 8-(5-(6-bromoquinazolin-4-yl)-3-fluoropyridin-2-yl)-2-oxa-8-azaspiro[4.5]decane The title compound was isolated as a yellow solid from 6-bromo-4-(6-chloro-5-fluoropyridin-3-yl)quinazoline (XX) in a manner similar to that described in Step A of Example 1.9. LCMS [M+H] + =416.9.

[0165] Step B: Preparation of 4-(4-(5-fluoro-6-(2-oxa-8-azaspiro[4.5]decan-8-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine hydrochloride (23) A mixture of 8-(5-(6-bromoquinazolin-4-yl)-3-fluoropyridin-2-yl)-2-oxa-8-azaspiro[4.5]decane (90 mg, 1 eq., 0.20 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (54 mg, 1.2 eq., 0.24 mmol), potassium phosphate (65 mg, 1.5 eq., 0.30 mmol), and PdCl(dppf) (16 mg, 0.1 eq., 20 μmol) in 1,4-dioxane (0.8 mL) and water (0.1 mL) was heated at 90 °C for 2 h under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The aqueous solution was washed with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude product was purified by silica gel flash column (eluent: 0-10% MeOH in ethyl acetate) to recover the free base product, which was then dissolved in DCM (3 ml) and purged with HCl gas to give 4-(4-(5-fluoro-6-(2-oxa-8-azaspiro[4.5]decan-8-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine hydrochloride (23) (56 mg, 56%). LCMS [M+H] + =457. 1HNMR (500 MHz, DMSO-d6) δ 14.16 (s, 1H), 9.38 (s, 1H), 8.56 (s, 1H), 8.47 (d, J = 1.9 Hz, 1H), 8.36 (dd, J = 8.8, 1.9 Hz, 1H), 8.29 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.14 - 8.02 (m, 2H), 7.36 (s, 1H), 7.33 (d, J = 6.7 Hz, 1H), 5.74 (s, 1H), 3.78 (t, J = 7.0 Hz, 2H), 3.71 (dt, J = 13.6, 5.2 Hz, 2H), 3.66 - 3.56 (m, 2H), 3.52 (s, 2H), 1.79 (t, J = 7.1 Hz, 2H), 1.65 (t, J = 5.6 Hz, 4H). 13 CNMR (126 MHz, DMSO-d6) δ 164.95, 155.61, 154.77, 153.27, 151.37, 147.47, 145.11, 136.85, 135.71, 133.13, 129.90, 126.46, 125.32, 123.81, 122.58, 114.99, 111.47, 111.18, 77.48, 66.93, 45.44, 42.11, 37.19, 34.89.

[0166] Example 1.24: 4-(4-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine hydrochloride (24) [ka]

[0167] Step A: Preparation of 6-bromo-4-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)quinazoline hydrochloride The title compound was isolated from 6-bromo-4-(6-chloro-5-fluoropyridin-3-yl)quinazoline (XX) in a manner similar to that described in Step A of Example 1.9, then dissolved in DCM (3 ml) and purged with HCl gas. LCMS [M-HCl+1] + 388. 1 H NMR (500 MHz, DMSO-d6) δ 9.54 (s, 2H), 9.37 (s, 1H), 8.57 - 8.46 (m, 1H), 8.29 (d, J = 2.1 Hz, 1H), 8.19 (dd, J = 9.0, 2.2 Hz, 1H), 8.11 - 8.02 (, 2H), 3.87 (t, J = 5.1 Hz, 4H), 3.25 (t, J = 4.9 Hz, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 163.35, 155.08, 149.62, 147.80, 144.58, 138.04, 131.11, 128.93, 125.59, 125.42, 123.97, 121.78, 49.04, 44.25, 42.83.

[0168] Step B: Preparation of 4-(4-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)quinazolin-6-yl)pyridin-2-amine hydrochloride (24) The title compound was isolated as an orange solid from 6-bromo-4-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)quinazoline hydrochloride in a manner similar to that described in Step B of Example 1.9. LCMS [M-HCl+1] + 402. 1HNMR (500 MHz, d4-MeOH) δ 9.35 (s, 1H), 8.60 (t, J = 1.5 Hz, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.38 (dd, J = 8.8, 2.0 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.07 (dd, J = 13.7, 1.9 Hz, 1H), 8.00 (d, J = 6.4 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.23 (dd, J = 6.4, 1.7 Hz, 1H), 4.00 (t, J = 5.1 Hz, 4H), 3.45 (t, J = 5.2 Hz, 4H). 13 CNMR (126 MHz, d 4- MeOH) δ 165.04, 156.03, 154.88, 152.83, 151.30, 150.18, 149.20, 148.13, 144.34, 138.84, 136.60, 132.74, 129.32, 125.98, 125.38, 125.05, 124.88, 122.73, 111.30, 109.77, 44.05, 43.11.

[0169] Example 1.25: 4-(4-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (25) [ka]

[0170] Step A: Preparation of 1-(4-bromo-2-fluorophenyl)-4-methylpiperazine The title compound was isolated as a brown solid from 3-fluoro-4-(4-methylpiperazin-1-yl)aniline in a manner similar to that described in Step A of Example 1.1. LCMS [M+H] + =274. 1H NMR (500 MHz, CDCl3) δ 7.24 (s, 2H), 6.88 (t, J = 9.0 Hz, 1H), 3.17 (t, J = 5.1 Hz, 4H), 2.71 - 2.64 (m, 4H), 2.43 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 156.32, 154.33, 139.41, 127.41, 120.00, 119.51, 113.45, 55.01, 50.28, 46.07.

[0171] Step B: Preparation of 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine The title compound was isolated as a brown solid from 1-(4-bromo-2-fluorophenyl)-4-methylpiperazine in a manner similar to that described in Step B of Example 1.1. LCMS [M+H] + =321. 1 H NMR (500 MHz, CDCl3) δ 7.26 (dd, J = 33.9, 10.7 Hz, 2H), 6.97 (d, J = 10.0 Hz, 1H), 6.71 (t, J = 8.2 Hz, 1H), 2.94 (dt, J = 46.3, 4.8 Hz, 4H), 2.44 - 2.36 (m, 4H), 2.16 (s, 3H), 1.12 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 156.13, 154.15, 131.36, 127.45, 121.83, 118.01, 83.74, 55.03, 50.05, 46.05, 24.75.

[0172] Step C: Preparation of 6-bromo-4-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazoline The title compound was isolated as a brown solid from 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine in a manner similar to that described in Step C of Example 1.1. LCMS [M+H] + =402. 1 H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.30 (d, J = 1.4 Hz, 1H), 7.95 (d, J = 1.3 Hz, 2H), 7.54 - 7.48 (m, 2H), 7.10 (t, J = 8.6 Hz, 1H), 3.31 (t, J = 4.7 Hz, 3H), 2.76 - 2.68 (m, 4H), 2.42 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 165.69, 154.82, 149.98, 137.17, 130.81, 128.92, 126.66, 126.64, 123.92, 121.57, 118.84, 118.81, 117.98, 117.80, 54.97, 54.89, 49.72, 45.87.

[0173] Step D: Preparation of 4-(4-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (25) The title compound was isolated as a brown solid from 6-bromo-4-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =415. 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J = 10.1 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.22 - 8.11 (m, 3H), 7.64 - 7.56 (m, 2H), 7.15 (t, J = 8.6 Hz, 1H), 6.91 (d, J = 5.0 Hz, 1H), 6.74 (s, 1H), 4.69 (s, 1H), 3.47 (dt, J = 12.9, 6.4 Hz, 4H), 2.92 (s, 4H), 2.58 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 166.87, 158.97, 156.19, 154.98, 154.22, 151.32, 148.94, 141.60, 138.31, 132.55, 129.82, 126.75, 124.81, 122.96, 118.92, 118.02, 112.77, 106.51, 54.81, 49.46, 45.64.

[0174] Example 1.26: 4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline (26) [ka]

[0175] Step A: Preparation of 4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline The title compound was isolated from 6-bromo-4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazoline in a manner similar to that described in Step A of Example 1.15. LCMS [M+H] + =450.

[0176] Step B: Preparation of 4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline (26) The title compound was isolated from 6-bromo-4-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazoline in a manner similar to that described in Step B of Example 1.15. MP 263-265°C. LCMS [M+H] + =443.

[0177] Example 1.27: 4-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline (27) [ka]

[0178] Step A: Preparation of 4-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline (27) The title compound was isolated from 6-bromo-4-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)quinazoline hydrochloride and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate in a manner similar to that described in Step D of Example 1.1. LCMS [M+H] + =425. 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 9.28 (s, 1H), 8.64 (t, J = 1.6 Hz, 1H), 8.46 (dd, J = 8.8, 2.0 Hz, 1H), 8.38 - 8.31 (m, 2H), 8.28 (dd, J = 8.0, 1.5 Hz, 1H), 8.24 - 8.08 (m, 3H), 7.20 (dd, J = 8.0, 4.6 Hz, 1H), 3.80 (t, J = 4.9 Hz, 4H), 3.23 (d, J = 5.1 Hz, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 163.18, 154.07, 149.69, 149.64, 144.57, 143.81, 135.65, 134.08, 129.41, 127.57, 126.26, 123.41, 121.62, 117.56, 116.90, 113.52, 45.23, 43.54.

[0179] Example 1.28: 8-(5-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-3-fluoropyridin-2-yl)-2,8-diazaspiro[4.5]decan-1-one (30) [ka]

[0180] Step A: Preparation of 8-(5-(6-bromoquinazolin-4-yl)-3-fluoropyridin-2-yl)-2,8-diazaspiro[4.5]decan-1-one The title compound was isolated as a yellow solid from 6-bromo-4-(6-chloro-5-fluoropyridin-3-yl)quinazoline (XX) in a manner similar to that described in Step A of Example 1.9. LCMS [M+H] + =457. 1H NMR (500 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.47 (t, J = 1.8 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 8.9, 2.2 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.98 (dd, J = 14.6, 1.9 Hz, 1H), 7.63 (s, 1H), 4.19 (dt, J = 13.5, 4.0 Hz, 2H), 3.29 - 3.21 (m, 4H), 2.07 (t, J = 6.8 Hz, 2H), 1.81 (ddd, J = 13.2, 11.5, 4.1 Hz, 2H), 1.49 (dt, J = 13.6, 3.2 Hz, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 180.25, 163.29, 155.11, 149.97, 149.61, 147.39, 144.84, 137.83, 131.13, 128.97, 125.07, 124.90, 123.72, 121.59, 44.22, 42.30, 38.41, 32.01, 31.71.

[0181] Step B: Preparation of 8-(5-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-3-fluoropyridin-2-yl)-2,8-diazaspiro[4.5]decan-1-one (30) The title compound was isolated as a yellow oil from 8-(5-(6-bromoquinazolin-4-yl)-3-fluoropyridin-2-yl)-2,8-diazaspiro[4.5]decan-1-one in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =470. 1H NMR (500 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.55 (t, J = 1.7 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.28 (dd, J = 8.8, 1.9 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.08 - 7.93 (m, 2H), 7.64 (s, 1H), 6.89 (dd, J = 5.3, 1.6 Hz, 1H), 6.79 (d, J = 1.5 Hz, 1H), 6.11 (s, 2H), 4.20 (dt, J = 13.5, 4.1 Hz, 2H), 3.29 - 3.20 (m, 4H), 2.07 (t, J = 6.8 Hz, 2H), 1.86 - 1.76 (m, 2H), 1.57 - 1.44 (m, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 180.28, 164.32, 160.93, 155.07, 150.94, 149.97, 149.23, 147.49, 147.47, 144.96,138.66, 133.29, 129.72, 125.19, 124.31, 122.79, 110.77, 106.00, 44.22, 44.17, 42.30, 38.42, 32.04, 31.70.

[0182] Example 1.29: 4-(4-(3-fluoro-4-morpholinophenyl)quinolin-6-yl)pyridin-2-amine (32) [ka]

[0183] Step A: Preparation of 4-(4-(3-fluoro-4-morpholinophenyl)quinolin-6-yl)pyridin-2-amine (32) The title compound was isolated as a grey solid from 4-(4-chloroquinolin-6-yl)pyridin-2-amine (XXIII) in a manner similar to that described in Step A of Example 1.13. LCMS [M+H] + =400. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.07 - 8.03 (m, 1H), 8.00 (d, J = 5.3 Hz, 1H), 7.50 (d, J = 4.5 Hz, 2H), 7.40 (dd, J = 8.3, 2.0 Hz, 1H), 7.24 (t, J = 8.7 Hz, 1H), 6.82 - 6.79 (m, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.05 (s, 2H), 3.82 - 3.78 (m, 5H), 3.15 (dd, J = 4.2, 2.2 Hz, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 159.83, 153.99, 150.00, 148.11, 147.55, 147.08, 145.67, 139.31, 136.30, 130.28, 129.82, 127.52, 125.63, 125.21, 122.21, 121.51, 118.56, 116.60, 109.63, 104.73, 65.56, 49.64.

[0184] Example 1.30: 1-(4-(4-(6-(1H-pyrazol-4-yl)quinazolin-4-yl)phenyl)piperazin-1-yl)ethan-1-one (37) [ka]

[0185] Step A: Preparation of 1-(4-(4-(6-(1H-pyrazol-4-yl)quinazolin-4-yl)phenyl)piperazin-1-yl)ethan-1-one (37) The title compound was isolated as a yellow solid from tert-butyl 1-(4-(4-(6-bromoquinazolin-4-yl)phenyl)piperazin-1-yl)ethan-1-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate in a manner similar to that described in Step D of Example 1.1. LCMS [M+H] + =399. 1 H NMR (500 MHz, CDCl3) δ 9.25 (s, 1H), 8.27 (s, 1H), 8.12 (dd, J = 7.0, 4.5 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.93 (s, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 3.84 - 3.79 (m, 2H), 3.69 - 3.65 (m, 2H), 3.43 - 3.34 (m, 4H), 3.17 (dd, J = 9.7, 5.7 Hz, 1H), 2.16 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.22, 167.45, 153.46, 152.28, 149.57, 132.53, 132.14 131.76, 131.55, 129.01, 127.70, 123.36, 122.45, 115.46, 115.38, 48.35, 48.08, 45.96, 41.14, 21.37.

[0186] Example 1.31: 1-(4-(4-(6-(2-aminopyridin-4-yl)quinolin-4-yl)phenyl)piperazin-1-yl)ethan-1-one (38) [ka]

[0187] Step A: Preparation of 1-(4-(4-(6-(2-aminopyridin-4-yl)quinolin-4-yl)phenyl)piperazin-1-yl)ethan-1-one (38) The title compound was isolated as a grey solid from 4-(4-chloroquinolin-6-yl)pyridin-2-amine (XXIII) and 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethan-1-one in a manner similar to that described in Step A of Example 1.13. LCMS [M+H] + =424. 1 H NMR (500 MHz, CDCl3) δ 8.99 (dd, J = 13.5, 4.5 Hz, 1H), 8.28 (d, J = 7.2 Hz, 1H), 7.95 - 7.77 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.40 (dd, J = 8.3, 4.4 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.12 (d, J = 8.2 Hz, 3H), 6.98 (s, 1H), 6.87 (dt, J = 17.5, 8.5 Hz, 1H), 3.86 - 3.61 (m, 5H), 3.38 - 3.15 (m, 4H), 2.17 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.14, 158.09, 151.03, 150.77, 148.95, 148.77, 145.87, 136.07, 130.78, 130.66, 128.92, 127.92, 126.91, 124.52, 121.89, 116.12, 112.71, 107.45, 75.98, 46.12, 41.27, 21.37.

[0188] Example 1.32: 2-(4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)piperazin-1-yl)ethan-1-ol (41) [ka]

[0189] Step A: Preparation of 2-(4-(4-bromophenyl)piperazin-1-yl)ethan-1-ol The title compound was isolated as a white solid from 1-(4-bromophenyl)piperazine and ethylene bromohydrin in a manner similar to that described in Step A of Example 1.22. LCMS [M+H] + =284. 1 H NMR (500 MHz, CDCl3) δ 7.37 - 7.31 (m, 2H), 6.81 - 6.75 (m, 2H), 3.69 (t, J = 5.3 Hz, 2H), 3.23 - 3.17 (m, 4H), 2.87 (s, 1H), 2.72 (t, J = 5.0 Hz, 4H), 2.65 (t, J = 5.3 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 150.12, 131.93, 117.76, 112.10, 59.41, 57.68, 52.76, 48.93.

[0190] Step B: Preparation of 1-(4-bromophenyl)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazine 2-(4-(4-Bromophenyl)piperazin-1-yl)ethan-1-ol (200 mg, 1 eq., 701 μmol), imidazole (91 mg, 88.1 μL, 1.9 eq., 1.33 mmol), and DCM (3.5 mL) were added to the vial and stirred for 10 minutes. tert-Butyldimethylchlorosilane (159 mg, 175 μL, 1.5 eq., 1.05 mmol) was added and stirring was continued at 25°C for 16 hours. After completion of the reaction, the reaction was diluted with DCM, washed with water, brine, and dried over magnesium sulfate. The reaction was purified by column chromatography to give 1-(4-bromophenyl)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazine (280 mg, 701 μmol, 99%). LCMS [M+H] + =400. 1H NMR (500 MHz, CDCl3) δ 7.27 - 7.22 (m, 2H), 6.73 - 6.66 (m, 2H), 3.73 (t, J = 6.2 Hz, 2H), 3.12 - 3.06 (m, 4H), 2.62 (dd, J = 6.2, 4.1 Hz, 4H), 2.52 (t, J = 6.2 Hz, 2H), 0.83 (s, 9H), 0.00 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 150.33, 131.84, 116.67, 111.71, 61.31, 60.48, 53.64, 48.90, 25.96, 18.30.

[0191] Step C: Preparation of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine The title compound was isolated as a white solid from 1-(4-bromophenyl)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazine in a manner similar to that described in Step B of Example 1.1. LCMS [M+H] + =446. 1 H NMR (500 MHz, CDCl3) δ 7.69 - 7.64 (m, 2H), 6.86 - 6.83 (m, 2H), 3.78 (t, J = 6.2 Hz, 2H), 3.27 - 3.18 (m, 4H), 2.74 - 2.64 (m, 4H), 2.57 (t, J = 6.2 Hz, 2H), 1.20 (s, 12H), 0.87 (s, 9H), 0.04 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 153.30, 136.11, 129.09, 114.34, 83.37, 61.09, 60.42, 53.53, 47.86, 25.93, 24.85, 24.60, 18.27.

[0192] Step D: Preparation of 6-bromo-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazin-1-yl)phenyl)quinazoline The title compound was isolated as a yellow solid from 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine in a manner similar to that described in Step C of Example 1.1. LCMS [M+H] + =528. 1 H NMR (500 MHz, CDCl3) δ 9.46 (s, 1H), 8.53 (t, J = 1.3 Hz, 1H), 8.13 - 8.07 (m, 2H), 7.91 (d, J = 8.7 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.18 - 7.14 (m, 1H), 4.00 (t, J = 6.1 Hz, 2H), 3.56 (t, J = 5.0 Hz, 2H), 2.96 - 2.88 (m, 3H), 2.80 (t, J = 6.3 Hz, 2H), 1.07 (d, J = 2.6 Hz, 9H), 0.24 (d, J = 2.5 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 154.93, 152.68, 149.95, 136.83, 131.47, 130.63, 129.46, 126.17, 124.11, 122.09, 121.05, 114.91, 61.29, 60.49, 53.56, 47.86, 29.71, 25.95, 18.31.

[0193] Step E: Preparation of 2-(4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)piperazin-1-yl)ethan-1-ol (41) A 5 mL MWV was loaded with 6-bromo-4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazin-1-yl)phenyl)quinazoline (30 mg, 1 eq., 57 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (14 mg, 1.1 eq., 63 μmol), PdCl(dppf) (5 mg, 0.1 eq., 5.7 μmol), and potassium phosphate tribasic (18 mg, 1.5 eq., 85 μmol). The vial was capped and degassed for 10 min. After that, degassed 1,4-dioxane (0.19 mL):water (32 μL) (6:1 v / v) was added, degassed for an additional 10 min, and heated to 110 °C in an oil bath for 3 h. The mixture was stirred in THF (0.45 mL) at 25° C. and tetrabutylammonium fluoride (14 mg, 1 eq., 52 μmol) was added. The solution was stirred for 1.5 h. After completion of the reaction, it was basified with 1N NaOH and diluted with DCM. The organics were purified by column chromatography to yield 2-(4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)piperazin-1-yl)ethan-1-ol (41) as a yellow solid. LCMS [M+H] + =427. 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 8.8, 3.9 Hz, 2H), 8.09 (dd, J = 8.8, 2.0 Hz, 2H), 7.84 - 7.76 (m, 2H), 7.09 (d, J = 8.7 Hz, 3H), 6.92 (dd, J = 5.4, 1.6 Hz, 1H), 6.73 (d, J = 1.6 Hz, 2H), 4.67 (s, 1H), 3.73 (t, J = 5.3 Hz, 2H), 3.45 (t, J = 5.1 Hz, 4H), 2.80 (t, J = 5.1 Hz, 4H), 2.71 (t, J = 5.3 Hz, 2H).

[0194] Example 1.33: 4-(4-(3-fluoro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (43) [ka]

[0195] Step A: Preparation of tert-butyl (1R,5S)-3-(2-fluoro-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 1,2-Difluoro-4-nitrobenzene (1.1 g, 0.78 mL, 1 eq., 7.1 mmol), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 1 eq., 7.1 mmol) in DMF (9.0 mL) were stirred at 90 °C for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure to give tert-butyl (1R,5S)-3-(2-fluoro-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.839 g, 5.234 mmol, 74%) as a yellow solid. LCMS [M+H] + =351. 1 H NMR (500 MHz, DMSO-d6) δ 8.04 - 7.95 (m, 2H), 7.14 (t, J = 9.2 Hz, 1H), 4.22 (s, 2H), 3.50 - 3.42 (m, 2H), 3.12 - 3.03 (m, 2H), 1.91 - 1.79 (m, 3H), 1.42 (d, J = 8.1 Hz, 9H). 13 C NMR (126 MHz, DMSO-d6) δ 152.33, 150.41, 145.02, 138.73, 120.58, 117.63, 111.67, 78.37, 60.90, 49.95, 27.47.

[0196] Step B: Preparation of 3-(4-amino-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-(2-fluoro-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.84 g, 1 eq., 5.234 mmol) was added to a mixture of water (8.8 mL):ethanol (35 mL) and stirred for 10 minutes. Iron (877 mg, 3 eq., 15.70 mmol) and ammonium hydrochloride (560 mg, 2 eq., 10.47 mmol) were added to the reaction flask and placed in a 90 °C oil bath for 12 hours. After completion of the reaction, the mixture was diluted with EtOAc and filtered over Celite. The organics were collected and concentrated under pressure to give a solid. The solid was diluted with water and filtered to give a pale purple solid, tert-butyl 3-(4-amino-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.508 g, 4.692 mmol, 90%). LCMS [M+H] + =322.

[0197] Step C: Preparation of tert-butyl (1R,5S)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(4-amino-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1 eq., 3.11 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (869 mg, 1.1 eq., 3.42 mmol), benzoic acid peroxyanhydride (15 mg, 0.02 eq., 62.2 μmol), and tert-butyl nitrite (481 mg, 1.5 eq., 4.67 mmol) were added to a vial in ACN (10 ml). The reaction was stirred at 80 °C for 2 h. The reaction was diluted with EtOAc, washed with water and brine, and dried over sodium sulfate. The reaction mixture was purified by column chromatography (EtOAc / Hex 0-10%) to give tert-butyl (1R,5S)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (364 mg, 842 μmol, 27%). LCMS [M+H] + =433. 1 H NMR (500 MHz, CDCl3) δ 7.45 (dd, J = 8.0, 1.5 Hz, 1H), 7.39 (dd, J = 13.8, 1.5 Hz, 1H), 6.82 (dd, J = 9.5, 6.9 Hz, 1H), 4.26 (s, 2H), 3.26 (d, J = 11.1 Hz, 2H), 2.99 (s, 2H), 2.01 - 1.86 (m, 4H), 1.45 (s, 9H), 1.29 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 155.76, 153.63, 142.24, 131.37, 121.85, 118.20, 83.78, 79.64, 54.99, 49.9, 28.50, 27.73, 25.03.

[0198] Step D: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-6-bromoquinazoline A vial was charged with 6-bromo-4-chloroquinazoline (194 mg, 1 eq., 796 μmol), tert-butyl (1R,5S)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (344 mg, 1 eq., 796 μmol), PdCl2dppf (29 mg, 0.05 eq., 39.8 μmol), and K3PO4 (507 mg, 3 eq., 2.39 mmol) and purged for 10 minutes. Dioxane (8 mL), water (1 mL) (6:1) was added to the vial and purged for an additional 10 minutes. The reaction was placed in a 90 °C oil bath for 16 hours. After completion of the reaction, the reaction was cooled and DCM (2.5 mL) and 2,2,2-trifluoroacetic acid (888 mg, 597 μL, 20 eq., 7.79 mmol) were added to a 5 mL microwave vial. The mixture was stirred at 25° C. for 4 hours. The mixture was then poured into DCM and washed with water to give a solid: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-6-bromoquinazoline. LCMS [M+H] + =414. 1 H NMR (500 MHz, CDCl3) δ 9.54 (s, 1H), 8.55 (t, J = 1.4 Hz, 1H), 8.19 (d, J = 1.4 Hz, 2H), 7.75 - 7.70 (m, 2H), 7.24 (t, J = 8.5 Hz, 1H), 3.91 - 3.84 (m, 2H), 3.65 (dd, J = 11.5, 2.7 Hz, 2H), 3.33 (d, J = 11.0 Hz, 2H), 2.78 (s, 2H), 2.29 (t, J = 6.7 Hz, 2H), 2.10 (dt, J = 7.3, 2.8 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 165.77, 154.82, 153.94, 149.95, 142.10, 137.14, 130.76, 128.99, 126.70, 123.92, 121.52, 118.52, 118.01, 117.83, 56.27, 54.69, 28.69.

[0199] Step E: Preparation of 6-bromo-4-(3-fluoro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)quinazoline 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-6-bromoquinazoline (132 mg, 1 eq., 319 μmol), formaldehyde (14 mg, 13.2 μL, 1.5 eq., 479 μmol), acetic acid (38 mg, 36.6 μL, 2 eq., 639 μmol) were added to DCM (3 mL) in a vial. The reaction was stirred at 25° C. for 1 h. The reaction was cooled, diluted with EtOAc, washed with water, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give 6-bromo-4-(3-fluoro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)quinazoline (80 mg, 0.19 mmol, 59%). LCMS [M+H] + =428. 1 H NMR (500 MHz, CDCl3) δ 9.52 (s, 1H), 8.51 (t, J = 1.3 Hz, 1H), 8.16 (d, J = 1.4 Hz, 2H), 7.73 - 7.67 (m, 2H), 7.24 (t, J = 8.6 Hz, 1H), 3.66 (dd, J = 7.4, 4.1 Hz, 2H), 3.59 (d, J = 2.3 Hz, 4H), 2.69 (s, 3H), 2.35 - 2.25 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 165.68, 154.80, 149.94, 141.45, 137.19, 130.76, 129.67, 128.94, 126.71, 123.91, 121.58, 118.80, 117.98, 117.80, 61.50, 54.34, 40.06, 25.03.

[0200] Step F: Preparation of 4-(4-(3-fluoro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (43) The title compound was isolated as a brown solid from 6-bromo-4-(3-fluoro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)quinazoline in a manner similar to that described in Step D of Example 1.9. LCMS [M+H] + =441. 1 H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.18 - 8.13 (m, 2H), 8.09 (dd, J = 8.8, 2.0 Hz, 1H), 7.56 - 7.53 (m, 1H), 7.52 (s, 1H), 7.00 (t, J = 8.5 Hz, 1H), 6.91 - 6.88 (m, 1H), 6.71 (s, 1H), 4.55 (s, 2H), 3.36 (dd, J = 11.3, 2.8 Hz, 2H), 3.23 (s, 2H), 3.15 (d, J = 10.7 Hz, 2H), 2.34 (s, 3H), 2.05 (dd, J = 8.8, 4.3 Hz, 2H), 1.94 (t, J = 6.5 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 167.04, 159.02, 155.01, 153.84, 151.32, 149.12, 149.00, 138.24, 132.50, 129.75, 126.77, 124.98, 123.86, 122.98, 118.50, 118.09, 117.91, 112.87, 106.48, 61.28, 55.61, 41.06, 25.25.

[0201] Example 1.34: 4-(4-(4-(4-(tert-butyl)piperazin-1-yl)-3-fluorophenyl)quinazolin-6-yl)pyridin-2-amine (45) [ka]

[0202] Step A: Preparation of 1-(tert-butyl)-4-(2-fluoro-4-nitrophenyl)piperazine The title compound was isolated as a yellow solid from 1-(tert-butyl)piperazine in a manner similar to that described in Step A of Example 1.43. LCMS [M+H] + =281. 1 H NMR (400 MHz, CDCl3) δ 7.98 - 7.93 (m, 1H), 7.87 (dd, J = 13.3, 2.6 Hz, 1H), 6.88 (t, J = 8.8 Hz, 1H), 3.35 - 3.26 (m, 4H), 2.74 (t, J = 4.9 Hz, 4H), 1.10 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 154.31, 151.83, 145.79, 121.13, 117.01, 112.47, 50.29, 45.71, 25.91.

[0203] Step B: Preparation of 4-(4-(tert-butyl)piperazin-1-yl)-3-fluoroaniline The title compound was isolated as a purple solid from 1-(tert-butyl)-4-(2-fluoro-4-nitrophenyl)piperazine in a manner similar to that described in Step B of Example 1.43. LCMS [M+H] + =251. 1 H NMR (400 MHz, CDCl3) δ 6.80 (t, J = 8.9 Hz, 1H), 6.42 (d, J = 2.6 Hz, 1H), 6.38 (d, J = 8.1 Hz, 1H), 3.51 (s, 2H), 3.03 (s, 4H), 2.79 (s, 4H), 1.13 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 157.98, 155.54, 142.62, 120.38, 110.77, 103.82, 51.75, 46.04, 25.88.

[0204] Step C: Preparation of 1-(tert-butyl)-4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine The title compound was isolated from 4-(4-(tert-butyl)piperazin-1-yl)-3-fluoroaniline in a manner similar to that described in Step C of Example 1.43. LCMS [M+H] + =363. 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.05 - 7.00 (m, 1H), 3.31 - 3.30 (m, 4H), 2.97 (s, 5H), 1.28 (s, 9H), 1.22 (s, 12H).

[0205] Step D: Preparation of 6-bromo-4-(4-(4-(tert-butyl)piperazin-1-yl)-3-fluorophenyl)quinazoline The title compound was isolated as a yellow solid from 1-(tert-butyl)-4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine in a manner similar to that described in Step C of Example 1.1. LCMS [M+H] + =442. 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.30 (s, 1H), 7.96 (s, 1H), 7.54 - 7.47 (m, 2H), 7.46 - 7.33 (m, 1H), 7.11 (t, J = 8.5 Hz, 1H), 3.46 (s, 1H), 3.42 - 3.36 (m, 4H), 2.96 (m, 4H), 1.25 (s, 9H).

[0206] Step E: Preparation of 4-(4-(4-(4-(tert-butyl)piperazin-1-yl)-3-fluorophenyl)quinazolin-6-yl)pyridin-2-amine (45) The title compound was isolated as a yellow solid from 6-bromo-4-(4-(4-(tert-butyl)piperazin-1-yl)-3-fluorophenyl)quinazoline in a manner similar to that described in Step D of Example 1.9. LCMS [M+H] + =457. 1 H NMR (500 MHz, CDCl3) δ 9.33 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.18 - 8.14 (m, 2H), 8.10 (dd, J = 8.8, 2.0 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.11 (t, J = 8.5 Hz, 1H), 6.89 (d, J = 5.3 Hz, 1H), 6.70 (s, 1H), 4.61 (s, 2H), 3.40 (m, 4H), 2.95 (m, 4H), 1.23 (s, 9H).

[0207] Example 1.35: 1-(5-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one (46) [ka]

[0208] Step A: tert-Butyl (3aR,6aS)-5-(2-fluoro-4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate The title compound was isolated as a yellow solid from tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate in a manner similar to that described in Step A of Example 1.43. LCMS [M+H] + =351. 1 H NMR (400 MHz, CDCl3) δ 7.94 - 7.87 (m, 1H), 7.87 - 7.82 (m, 1H), 6.52 (t, J = 8.9 Hz, 1H), 3.81 (tt, J = 7.2, 2.9 Hz, 2H), 3.65 (dd, J = 11.4, 6.9 Hz, 2H), 3.49 (dt, J = 11.0, 3.4 Hz, 2H), 3.30 (d, J = 11.4 Hz, 2H), 2.99 (dp, J = 8.0, 2.9 Hz, 2H), 1.44 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 154.55, 150.39, 147.96, 142.03, 136.90, 121.87, 113.04, 79.85, 54.00, 49.89, 41.21, 28.56.

[0209] Step B: Preparation of tert-butyl 5-(4-amino-2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate The title compound was isolated as a purple solid from tert-butyl (3aR,6aS)-5-(2-fluoro-4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate in a manner similar to that described in Step B of Example 1.43. LCMS [M+H] + =321.

[0210] Step C: Preparation of tert-butyl 5-(4-amino-2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate The title compound was isolated from tert-butyl 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate in a manner similar to that described in Step C of Example 1.43. LCMS [M+H] + =433. 1 H NMR (400 MHz, CDCl3) δ 7.43 - 7.33 (m, 1H), 7.00 - 6.95 (m, 1H), 6.72 - 6.64 (m, 1H), 3.67 - 3.60 (m, 2H), 3.56 (ddd, J = 9.0, 7.0, 1.9 Hz, 2H), 3.39 - 3.30 (m, 2H), 3.28 (dq, J = 10.0, 2.1 Hz, 2H), 2.93 (h, J = 5.9 Hz, 2H), 1.44 (d, J = 1.5 Hz, 9H), 1.22 (s, 12H).

[0211] Step D: Preparation of 6-bromo-4-(3-fluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)quinazoline The title compound was isolated from tert-butyl 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate in a manner similar to that described in Step D of Example 1.43. LCMS [M+H] +=412. 1 H NMR (400 MHz, CDCl3) δ 9.29 (d, J = 5.7 Hz, 1H), 8.36 - 8.33 (m, 1H), 7.95 (d, J = 1.4 Hz, 2H), 7.57 - 7.46 (m, 3H), 6.88 (t, J = 8.6 Hz, 1H), 3.52 (t, J = 7.4 Hz, 2H), 3.44 (d, J = 10.1 Hz, 2H), 3.27 (d, J = 7.9 Hz, 2H), 2.99 - 2.94 (m, 2H), 1.46 (d, J = 3.6 Hz, 1H), 0.91 - 0.78 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 156.21, 154.91, 150.06, 137.14, 130.81, 129.17, 126.99, 124.11, 124.01, 123.52, 121.49, 118.10, 117.22, 116.45, 55.64, 53.58, 42.74.

[0212] Step E: Preparation of 1-(5-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one The title compound was isolated from 6-bromo-4-(3-fluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)quinazoline in a manner similar to that described in Step A of Example 1.22. LCMS [M+H] + =456. 1H NMR (500 MHz, CDCl3) δ 9.28 (s, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.02 - 7.93 (m, 3H), 7.56 (dd, J = 14.7, 2.1 Hz, 1H), 7.54 - 7.50 (m, 1H), 6.77 (t, J = 8.7 Hz, 1H), 3.84 - 3.76 (m, 4H), 3.53 (ddd, J = 13.1, 6.9, 3.7 Hz, 2H), 3.50 - 3.41 (m, 3H), 3.12 (dt, J = 7.6, 4.9 Hz, 1H), 3.03 (dtd, J = 10.4, 7.6, 3.8 Hz, 1H), 2.07 (s, 3H).

[0213] Step F: Preparation of 1-(5-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one (46) The title compound was isolated as a yellow solid from 1-(5-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =469. 1H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.18 - 8.13 (m, 2H), 8.09 (dd, J = 8.8, 2.0 Hz, 1H), 7.56 - 7.53 (m, 1H), 7.52 (s, 1H), 7.00 (t, J = 8.5 Hz, 1H), 6.91 - 6.88 (m, 1H), 6.72 (s, 1H), 4.63 (s, 2H), 3.84 - 3.76 (m, 4H), 3.53 (ddd, J = 13.1, 6.9, 3.7 Hz, 2H), 3.50 - 3.41 (m, 3H), 3.12 (dt, J = 7.6, 4.9 Hz, 1H), 3.03 (dtd, J = 10.4, 7.6, 3.8 Hz, 1H), 2.11 (s, 3H).

[0214] Example 1.36: 4-(4-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)quinazolin-6-yl)pyridin-2-amine (36) [ka]

[0215] Step A: Preparation of 6-bromo-4-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)quinazoline 6-Bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) (218 mg, 1 eq., 563 μmol) and potassium carbonate (156 mg, 2 eq., 1.13 mmol) were added to acetone (5.6 mL) and stirred under argon for 10 minutes. Iodoethane (97 mg, 49.8 μL, 1.1 eq., 619 μmol) was added and stirred at 25 °C for 24 hours. After completion of the reaction, the mixture was concentrated under pressure and dissolved in DCM. The organic layer was washed with water and brine and dried over sodium sulfate. The collected organic layer was concentrated under pressure and purified by column chromatography (DCM / MeOH 0-10%) to give 6-bromo-4-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)quinazoline (25 mg, 60 μmol, 11%). LCMS [M+H] + =414. 1 H NMR (500 MHz, CDCl3) δ 9.33 (s, 1H), 8.32 (t, J = 1.4 Hz, 1H), 7.97 (d, J = 1.3 Hz, 2H), 7.56 - 7.49 (m, 2H), 7.12 (t, J = 8.7 Hz, 1H), 3.32 (t, J = 4.9 Hz, 4H), 2.72 (t, J = 4.8 Hz, 4H), 2.55 (d, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 165.76, 156.18, 154.83, 154.21, 149.97, 142.10, 137.19, 130.80, 130.00, 128.97, 126.67, 123.94, 121.58, 118.76, 117.87, 52.54, 49.95, 29.71, 11.83.

[0216] Step B: Preparation of 4-(4-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)quinazolin-6-yl)pyridin-2-amine (36) The title compound was isolated as a brown solid from 6-bromo-4-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =429. 1 H NMR (500 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.34 - 8.27 (m, 2H), 8.19 (s, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.25 (t, J = 8.7 Hz, 1H), 6.87 (dd, J = 5.3, 1.6 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.09 (s, 2H), 3.22 (t, J = 4.8 Hz, 5H), 2.58 (t, J = 4.7 Hz, 4H), 2.43 (q, J = 7.2 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.95, 155.08, 151.03, 149.31, 147.49, 144.34, 141.92, 138.55, 133.18, 129.78, 127.65, 124.49, 122.71, 119.35, 118.17, 117.94, 114.25, 110.69, 105.93, 52.72, 52.05, 50.06, 12.33.

[0217] Example 1.37: 4-(4-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (47) [ka]

[0218] Step A: Preparation of 6-bromo-4-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)quinazoline 6-Bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) (60 mg, 1 eq., 0.15 mmol), K2CO3 (43 mg, 2 eq., 0.31 mmol), and methanesulfonyl chloride (18 mg, 1 eq., 0.15 mmol) were added to a vial in DMF (1.5 mL). After completion of the reaction, the mixture was diluted with EtOAc, washed with water, and dried over sodium sulfate. The organic layer was removed under reduced pressure and purified by column chromatography (DCM:MeOH 0-5%) to give 6-bromo-4-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)quinazoline (45 mg, 97 μmol, 62%). LCMS [M+H] + =466. 1 H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.27 (t, J = 1.4 Hz, 1H), 7.96 (d, J = 1.3 Hz, 2H), 7.55 - 7.49 (m, 2H), 7.11 (t, J = 8.6 Hz, 1H), 3.44 (dd, J = 6.1, 3.7 Hz, 4H), 3.33 (dd, J = 6.4, 3.5 Hz, 4H), 2.84 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 165.51, 156.29, 154.81, 154.32, 149.97, 141.26, 137.32, 130.88, 128.79, 126.70, 123.89, 121.74, 119.19, 117.93, 49.87, 45.91, 34.47.

[0219] Step B: Preparation of 4-(4-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (47) The title compound was isolated as a yellow solid from 6-bromo-4-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =478. 1H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 8.7 Hz, 2H), 8.14 (d, J = 8.8 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.16 (t, J = 8.5 Hz, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.79 (s, 1H), 4.87 (s, 2H), 3.48 (dd, J = 6.4, 3.3 Hz, 4H), 3.40 - 3.32 (m, 4H), 2.88 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 166.75, 156.55, 155.02, 154.09, 151.36, 149.31, 148.05, 141.26, 138.23, 132.62, 131.62, 129.92, 128.27, 126.79, 124.80, 122.91, 119.24, 118.00, 112.72, 49.89, 45.91, 34.54.

[0220] Example 1.38: 4-(4-(3-fluoro-4-(4-isobutylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (48) [ka]

[0221] Step A: Preparation of 6-bromo-4-(3-fluoro-4-(4-isobutylpiperazin-1-yl)phenyl)quinazoline 6-Bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) (150 mg, 1 eq., 387 μmol) in THF (3.0 mL) was treated with DIPEA (200 mg, 270 μL, 4 eq., 1.55 mmol) and isobutyraldehyde (140 mg, 0.18 mL, 5 eq., 1.94 mmol) and stirred at room temperature for 1 h. STAB (sodium triacetoxyborohydride) (328 mg, 4 eq., 1.55 mmol) was then added, and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with aqueous sodium bicarbonate (10%) and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with aqueous sodium chloride, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (MeOH:DCM 0-5%) to give 6-bromo-4-(3-fluoro-4-(4-isobutylpiperazin-1-yl)phenyl)quinazoline (139 mg, 314 μmol, 81%). LCMS [M+H] + =444. 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.29 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 1.4 Hz, 2H), 7.55 - 7.45 (m, 2H), 7.07 (dd, J = 9.8, 7.4 Hz, 1H), 3.26 (s, 4H), 2.62 (s, 4H), 2.33 - 2.12 (m, 2H), 1.83 (p, J = 6.9 Hz, 1H), 0.92 (d, J = 6.6 Hz, 6H).

[0222] Step B: Preparation of 4-(4-(3-fluoro-4-(4-isobutylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (48) The title compound was isolated from 6-bromo-4-(3-fluoro-4-(4-isobutylpiperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =457. 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.25 - 8.15 (m, 2H), 8.12 (dd, J = 8.8, 2.0 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.13 (t, J = 8.7 Hz, 1H), 6.91 (dd, J = 5.4, 1.5 Hz, 1H), 6.75 (s, 1H), 3.32 (t, J = 5.0 Hz, 4H), 2.69 (q, J = 5.8 Hz, 4H), 2.24 (d, J = 7.3 Hz, 2H), 1.88 (m, J = 13.6, 6.8 Hz, 1H), 0.97 (d, J = 6.5 Hz, 6H).

[0223] Example 1.39: 4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)-N,N-dimethylpiperazine-1-carboxamide (49) [ka]

[0224] Step A: Preparation of 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-N,N-dimethylpiperazine-1-carboxamide The title compound was isolated from 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) in a manner similar to that described in Step A of Example 1.22. LCMS [M+H] + =459. 1 H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.26 (s, 1H), 7.92 (s, 2H), 7.53 - 7.44 (m, 2H), 7.06 (t, J = 8.5 Hz, 1H), 3.45 - 3.38 (m, 4H), 3.20 (t, J = 4.8 Hz, 4H), 2.84 (s, 6H).

[0225] Step B: Preparation of 4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)-N,N-dimethylpiperazine-1-carboxamide (49) The title compound was isolated from 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-N,N-dimethylpiperazine-1-carboxamide in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =472. 1 H NMR (500 MHz, CDCl3) δ 9.36 (d, J = 3.0 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.68 - 7.41 (m, 2H), 7.15 (s, 1H), 7.08 - 6.99 (m, 1H), 6.95 (s, 1H), 3.44 (s, 4H), 3.24 (s, 4H), 2.86 (d, J = 6.6 Hz, 6H).

[0226] Example 1.40: 4-(4-(3-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (50) [ka]

[0227] Step A: Preparation of 6-bromo-4-(3-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)quinazoline The title compound was isolated from 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) in a manner similar to that described in Step A of Example 1.47. LCMS [M+H] + =430. 1H NMR (500 MHz, CDCl3) δ 9.32 (d, J = 6.2 Hz, 1H), 8.32 - 8.28 (m, 1H), 7.98 - 7.94 (m, 2H), 7.55 - 7.48 (m, 2H), 7.11 (t, J = 8.5 Hz, 1H), 3.43 - 3.32 (m, 3H), 2.95 - 2.80 (m, 4H), 2.04 (m, 1H), 1.22 - 1.15 (m, 6H). 13 C NMR (126 MHz, CDCl3) δ 165.71, 156.18, 154.84, 154.21, 149.98, 141.93, 137.21, 130.82, 128.94, 126.66, 123.93, 121.60, 118.86, 117.80, 48.4, 40.0, 18.1.

[0228] Step B: Preparation of 4-(4-(3-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (50) The title compound was isolated from 6-bromo-4-(3-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step D of Example 1.1. LCMS [M+H] + =442. 1 H NMR (500 MHz, CDCl3) δ 9.35 (s, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.12 (dd, J = 8.8, 2.0 Hz, 1H), 7.59 - 7.56 (m, 2H), 7.16 (t, J = 8.3 Hz, 1H), 6.91 - 6.87 (m, 1H), 6.74 (s, 1H), 4.83 (s, 2H), 3.64 (m, 4H), 3.20 (m, 4H), 1.41 (s, 7H).

[0229] Example 1.41: 4-(4-(3-fluoro-4-(4-(methyl-d3)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (51) [ka]

[0230] Step A: Preparation of 6-bromo-4-(3-fluoro-4-(4-(methyl-d3)piperazin-1-yl)phenyl)quinazoline The title compound was isolated from 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) in a manner similar to that described in Step A of Example 1.47. LCMS [M+H] + =403. 1 H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.30 (t, J = 1.4 Hz, 1H), 7.95 (d, J = 1.3 Hz, 2H), 7.54 - 7.48 (m, 2H), 7.10 (t, J = 8.6 Hz, 1H), 3.31 (t, J = 5.0 Hz, 5H), 2.71 (t, J = 4.4 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 165.71, 156.18, 154.84, 154.21, 149.98, 141.93, 137.21, 130.82, 128.94, 126.66, 123.93, 121.60, 118.86, 117.80, 54.86, 49.69.

[0231] Step B: Preparation of 4-(4-(3-fluoro-4-(4-(methyl-d3)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (51) The title compound was isolated as a yellow solid from 6-bromo-4-(3-fluoro-4-(4-(methyl-d3)piperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =418. 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.18 - 8.13 (m, 2H), 8.09 (dd, J = 8.8, 2.0 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.11 (t, J = 8.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.70 (d, J = 1.5 Hz, 1H), 4.66 - 4.52 (m, 2H), 3.32 (t, J = 4.9 Hz, 4H), 2.72 (t, J = 4.8 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 166.93, 159.02, 156.18, 154.98, 154.2, 151.29, 148.97, 141.74, 138.33, 132.60, 130.64, 129.79, 126.74, 124.86, 122.97, 118.88, 118.10, 112.77, 106.52, 54.83, 49.69, 41.03.

[0232] Example 1.52: Methyl 4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (52) [ka]

[0233] Step A: Preparation of 6-bromo-4-(3-fluoro-4-(4-(methyl-d3)piperazin-1-yl)phenyl)quinazoline The title compound was isolated from 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) in a manner similar to that described in Step A of Example 1.47. LCMS [M+H] + =446. 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.29 (dd, J = 1.8, 0.9 Hz, 1H), 7.97 (t, J = 1.6 Hz, 2H), 7.55 - 7.52 (m, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.09 (t, J = 8.6 Hz, 1H), 3.73 (s, 3H), 3.68 (d, J = 5.1 Hz, 4H), 3.19 (t, J = 5.2 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 165.71, 156.26, 155.90, 154.70, 154.29, 149.84, 141.96, 137.34, 130.75, 128.90, 126.70, 123.90, 121.73, 118.99, 117.92, 52.80, 50.07, 43.77.

[0234] Step B: Preparation of methyl 4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (52) The title compound was isolated as a yellow solid from methyl 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)piperazine-1-carboxylate in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =458. 1 H NMR (500 MHz, CDCl3) δ 9.48 (s, 1H), 8.46 (s, 1H), 8.38 - 8.19 (m, 3H), 7.72 (t, J = 11.2 Hz, 2H), 7.25 (d, J = 8.5 Hz, 1H), 7.03 (s, 1H), 6.86 (s, 1H), 4.89 (s, 2H), 3.88 (s, 3H), 3.83 (m, 4H), 3.34 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 166.89, 158.91, 155.91, 154.97, 151.29, 149.13, 148.54, 141.77, 138.29, 132.62, 131.01, 129.83, 126.74, 124.84, 122.94, 119.02, 118.16, 112.72, 106.69, 52.80, 50.09, 43.83.

[0235] Example 1.42: (4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)piperazin-1-yl)(cyclopropyl)methanone (53) [ka]

[0236] Step A: Preparation of (4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)piperazin-1-yl)(cyclopropyl)methanone The title compound was isolated from 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) in a manner similar to that described in Step A of Example 1.47. LCMS [M+H] + =456. 1 H NMR (500 MHz, CDCl3) δ 9.47 (s, 1H), 8.44 (t, J = 1.3 Hz, 1H), 8.12 (d, J = 1.7 Hz, 2H), 7.71 - 7.64 (m, 2H), 7.24 (t, J = 8.4 Hz, 1H), 4.08 - 3.96 (m, 4H), 3.45 - 3.31 (m, 4H), 1.93 (tt, J = 8.0, 4.7 Hz, 1H), 1.18 - 1.14 (m, 2H), 0.95 (dt, J = 7.9, 3.4 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 172.20, 165.67, 156.25, 154.74, 149.87, 141.69, 137.33, 130.76, 128.89, 126.73, 123.90, 121.73, 118.99, 118.11, 45.56, 42.06, 11.01, 7.61.

[0237] Step B: Preparation of (4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)piperazin-1-yl)(cyclopropyl)methanone (53) The title compound was isolated as a yellow solid from methyl (4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)piperazin-1-yl)(cyclopropyl)methanone in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =469. 1 H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.17 - 8.07 (m, 2H), 7.65 - 7.59 (m, 2H), 7.15 (t, J = 8.5 Hz, 1H), 6.94 (s, 1H), 6.86 (s, 1H), 5.52 (s, 2H), 3.90 (d, J = 16.2 Hz, 4H), 3.37 - 3.19 (m, 4H), 1.82 (tt, J = 7.9, 4.7 Hz, 1H), 1.09 - 1.02 (m, 2H), 0.88 - 0.80 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 172.20, 166.94, 158.36, 156.52, 155.15, 154.06, 151.46, 150.11, 141.71, 137.69, 132.41, 131.02, 130.00, 128.37, 126.83, 125.07, 122.91, 119.04, 60.37, 11.00, 7.57.

[0238] Example 1.43: 4-(4-(3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (54) [ka]

[0239] Step A: 6-Bromo-4-(3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)quinazoline To a solution of 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) (200 mg, (0940) 0.501 mmol) in DMF (3 mL) was added potassium carbonate (139 mg, 1.006 mmol), potassium iodide (83 mg, 0.500 mmol), and 2-bromoethyl methyl ether (70 mg, 0.504 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was cooled to room temperature, diluted with 50 mL of ethyl acetate, and washed twice with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (0-5% MeOH / DCM) to give 6-bromo-4-(3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)quinazoline (125 mg, 281 μmol, 73%). LCMS [M+H] + =446. 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.28 (t, J = 1.3 Hz, 1H), 7.92 (d, J = 1.3 Hz, 2H), 7.53 - 7.44 (m, 2H), 7.07 (t, J = 8.7 Hz, 1H), 3.56 (t, J = 5.5 Hz, 2H), 3.36 (s, 3H), 3.29 (t, J = 5.0 Hz, 4H), 2.73 (t, J = 4.9 Hz, 4H), 2.67 (t, J = 5.5 Hz, 2H).

[0240] Step B: Preparation of 4-(4-(3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (54) The title compound was isolated as a yellow solid from methyl 6-bromo-4-(3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =459. 1 H NMR (400 MHz, CDCl3) δ 9.34 (d, J = 1.4 Hz, 1H), 8.37 - 8.32 (m, 1H), 8.21 - 8.05 (m, 3H), 7.62 - 7.53 (m, 2H), 7.16 - 7.07 (m, 1H), 6.90 (dd, J = 5.4, 1.5 Hz, 1H), 6.72 (s, 1H), 3.60 (td, J = 5.5, 1.5 Hz, 2H), 3.39 (d, J = 1.0 Hz, 3H), 3.32 (d, J = 5.1 Hz, 4H), 2.78 (dd, J = 6.4, 3.3 Hz, 4H), 2.71 (td, J = 5.5, 1.8 Hz, 2H).

[0241] Example 1.44: 4-(4-(3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (55) [ka]

[0242] Step A: 6-Bromo-4-(3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)quinazoline The title compound was isolated from 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (XXV) in a manner similar to that described in Step A of Example 1.48. LCMS [M+H] + =472.1 H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.32 (t, J = 1.4 Hz, 1H), 7.97 (d, J = 1.4 Hz, 2H), 7.58 - 7.49 (m, 2H), 7.11 (t, J = 8.7 Hz, 1H), 4.06 (dd, J = 11.1, 4.4 Hz, 2H), 3.42 (td, J = 11.9, 1.9 Hz, 2H), 3.30 (t, J = 4.9 Hz, 4H), 2.81 (t, J = 4.8 Hz, 4H), 2.66 - 2.46 (m, 2H), 1.92 - 1.76 (m, 1H), 1.65 (m, J = 12.1, 4.5 Hz, 2H).

[0243] Step B: Preparation of 4-(4-(3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (55) The title compound was isolated as a yellow solid from 6-bromo-4-(3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =471. 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 8.8 Hz, 2H), 8.08 (dd, J = 8.7, 2.0 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.08 (t, J = 8.4 Hz, 1H), 6.87 (dd, J = 5.3, 1.5 Hz, 1H), 6.69 (d, J = 1.6 Hz, 1H), 3.99 - 3.87 (m, 2H), 3.79 (q, J = 8.0 Hz, 1H), 3.69 (dd, J = 8.6, 6.7 Hz, 1H), 3.26 (t, J = 5.0 Hz, 4H), 3.05 (p, J = 7.1 Hz, 1H), 2.74 (dt, J = 10.4, 5.0 Hz, 2H), 2.62 (dt, J = 10.7, 4.9 Hz, 2H), 2.07 (dtd, J = 12.1, 7.6, 4.4 Hz, 1H), 1.89 (dq, J = 12.3, 8.0 Hz, 1H).

[0244] Example 1.45: 4-(4-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (56) [ka]

[0245] Step A: 6-Bromo-4-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazoline 6-Bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (51 mg, 1 eq., 0.13 mmol) was dissolved in DCE (0.52 mL), followed by the addition of STAB (42 mg, 1.5 eq., 0.20 mmol), oxentan-3-one (14 mg, 13 μL, 1.5 eq., 0.20 mmol), and acetic acid (1.6 mg, 1.5 μL, 0.2 eq., 26 μmol). The resulting suspension was stirred at 25 °C for 16 h, after which the solvent was removed under reduced pressure. The residue was washed with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated under reduced pressure. 6-Bromo-4-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazoline (17 mg, 38 μmol, 29%) was obtained. LCMS [M+H] + =442. 1 H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.30 (t, J = 1.4 Hz, 1H), 7.96 (d, J = 1.4 Hz, 2H), 7.54 - 7.49 (m, 2H), 7.11 (t, J = 8.7 Hz, 1H), 4.71 (d, J = 6.4 Hz, 4H), 3.64 (s, 1H), 3.33 (m, 4H), 2.60 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 165.69, 156.20, 154.82, 154.23, 149.96, 137.25, 130.82, 128.92, 126.68, 123.93, 121.65, 118.85, 118.02, 117.84, 75.05, 59.25, 49.56.

[0246] Step B: Preparation of 4-(4-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (56) The title compound was isolated as a yellow solid from 6-bromo-4-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =456. 1 H NMR (500 MHz, CDCl3) δ 9.33 (s, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.10 (t, J = 9.2 Hz, 2H), 7.60 - 7.52 (m, 2H), 7.11 (t, J = 8.4 Hz, 1H), 6.90 (d, J = 5.1 Hz, 1H), 6.76 (s, 1H), 4.92 (s, 2H), 4.74 - 4.60 (m, 4H), 3.63 - 3.56 (m, 1H), 3.30 (t, J = 4.7 Hz, 4H), 2.55 (t, J = 4.8 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 167.00, 158.60, 156.20, 155.08, 154.23, 151.38, 149.55, 147.63, 141.89, 137.99, 132.50, 129.91, 126.77, 125.01, 122.96, 118.84, 117.93, 112.68, 106.99, 75.41, 59.22, 49.60.

[0247] Example 1.46: 4-(4-(3-fluoro-4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (64) [ka]

[0248] Step A: 6-Bromo-4-(3-fluoro-4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)phenyl)quinazoline To a microwave vial was added potassium carbonate (107 mg, 2 eq., 775 μmol), 6-bromo-4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazoline (150 mg, 1 eq., 387 μmol), and MeCN (1.5 mL). The solution was heated to 55° C. and stirred for 15 minutes, after which time oxetan-3-ylmethyl 4-methylbenzenesulfonate (174 mg, 1.85 eq., 717 μmol) was added. After the addition, the reaction mixture was stirred for 16 hours at 55° C. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (75 mL), and washed with water (3×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting residue was purified by column chromatography (MeOH:DCM 0-5%) to give 6-bromo-4-(3-fluoro-4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)phenyl)quinazoline (129.3 mg, 282.7 μmol, 73%). LCMS [M+H] + =458. 1 H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.34 (t, J = 1.3 Hz, 1H), 7.99 (d, J = 1.4 Hz, 2H), 7.61 - 7.50 (m, 2H), 7.11 (t, J = 8.7 Hz, 1H), 4.92 - 4.80 (m, 2H), 4.48 (t, J = 6.2 Hz, 2H), 3.39 - 3.23 (m, 5H), 2.85 (d, J = 7.3 Hz, 2H), 2.69 - 2.61 (m, 4H).

[0249] Step B: Preparation of 4-(4-(3-fluoro-4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (64) The title compound was isolated as a yellow solid from 6-bromo-4-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step B of Example 1.9. LCMS [M+H] + =471.1 H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.23 - 8.09 (m, 3H), 7.64 - 7.55 (m, 2H), 7.12 (t, J = 8.6 Hz, 1H), 6.92 (dd, J = 5.3, 1.5 Hz, 1H), 6.74 (s, 1H), 4.85 (dd, J = 7.8, 6.0 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 3.50 (s, 4H), 3.37 - 3.22 (m, 5H), 2.83 (d, J = 7.3 Hz, 2H).

[0250] (Formula II) [ka]

[0251] Scheme 9 describes the synthesis of general product (XI) via Buchwald amination using commercially available amine (II) and bromobenzene (XXVI) to give (hetero)aryl bromide (V). (Hetero)aryl bromide (V) is utilized in Miyaura borylation to generate pinacol boronate (VII). This boronate is coupled with polyhalogenated heterocycle (VIII) in a Suzuki reaction to give R1-substituted heterocycle (IX), which is further reacted in a Suzuki reaction to give R2,R1-substituted heterocycle (XI).

[0252] In some embodiments, compounds of formula II of the present disclosure can be prepared as depicted in Scheme 10. [ka]

[0253] Scheme 10 describes the synthesis of advanced intermediates (Vb), which can be prepared using commercially available or readily prepared bromobromo-(hetero)aryls (V) and bromo-polyhalogenated bicyclic heteroaryls by acid-mediated deprotection (Va) and further functionalization to generate general intermediates (Vb).

[0254] The preparation of intermediate 6-bromo-4-(3-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)quinazoline (XXVIII) is shown below in Scheme 11. [ka]

[0255] To a 5 mL microwave vial was added tert-butyl 6-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (XXVII) (469 mg, 1 eq., 939 μmol), DCM (5.8 mL), and 2,2,2-trifluoroacetic acid (2.14 g, 1.44 mL, 20 eq., 18.8 mmol). The mixture was stirred at 25° C. for 4 hours. After this time, the mixture was poured into DCM and washed with water to give 6-bromo-4-(3-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)quinazoline (XXVIII) (300 mg, 751 μmol, 80%) as a solid. 1 H NMR (500 MHz, CDCl3) δ 9.30 - 9.27 (m, 1H), 8.30 (ddt, J = 4.6, 2.7, 1.7 Hz, 1H), 7.96 - 7.92 (m, 2H), 7.51 - 7.44 (m, 2H), 6.62 - 6.56 (m, 1H), 4.27 - 4.21 (m, 4H), 4.17 - 4.10 (m, 4H), 1.88 (d, J = 5.1 Hz, 1H).

[0256] Example 2.1: 4-(4-(3-fluoro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (28) [ka]

[0257] Step A: 6-(4-bromo-2-fluorophenyl)-2-oxa-6-azaspiro[3.3]heptane The solution was placed in a 100 mL RBF purged and maintained under an inert atmosphere of argon for 24 hours. To 4-bromo-2-fluoro-1-iodobenzene (484 mg, 1 eq., 1.61 mmol) in toluene (9.5 mL) was added Pd2(dba)3 (44 mg, 0.03 eq., 48.3 μmol), cesium carbonate (1.31 g, 2.5 eq., 4.02 mmol), 2-oxa-6-azaspiro[3.3]heptane (160 mg, 1.00 eq., 1.61 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (93 mg, 0.1 eq., 161 μmol). The resulting solution was stirred at 100 °C. The reaction was then quenched by the addition of 25 mL of water and extracted with 25 mL of ethyl acetate. The combined organized layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by automated column chromatography (0-15% EtOAc / Hex) using a CombiFlash to give 6-(4-bromo-2-fluorophenyl)-2-oxa-6-azaspiro[3.3]heptane (0.22 g, 0.81 mmol, 50%) as a yellow solid. LCMS [M+H] + =272.

[0258] Step B: 6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane 6-(4-Bromo-2-fluorophenyl)-2-oxa-6-azaspiro[3.3]heptane (280 mg, 1 Eq., 1.03 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (392 mg, 1.5 Eq., 1.54 mmol), catalyst (17 mg, 0.02 Eq., 20.6 μmol), and potassium acetate (303 mg, 3.0 Eq., 3.09 mmol) were added to a 40 mL MW vial and placed under inert conditions for 10 minutes. 1,4-Dioxane (5 mL) was added to the vial and stirred for an additional 10 minutes under inert conditions. The reaction was placed in an 80 °C oil bath for 12 hours. After cooling the reaction, the contents were diluted with EtOAc and washed with brine (1 x 20 mL) and water (1 x 20 mL). The organic layer was filtered through Celite and dried over sodium sulfate. The desiccant was filtered through a cotton plug, and the solvent was evaporated under pressure. The loaded reaction mixture was purified by column chromatography (0-50% EtOAc / Hex) to isolate 6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane (276 mg, 865 μmol, 84.0%) as an orange solid. LCMS [M+H] + =320.

[0259] Step C: 6-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2-oxa-6-azaspiro[3.3]heptane A vial was charged with 6-bromo-4-chloroquinazoline (73 mg, 1 eq., 0.300 mmol), 6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane (105 mg, 1.1 eq., 330 μmol), PdCl2dppf (22 mg, 0.1 eq., 30.0 μmol), and K3PO4 (127 mg, 2 eq., 600 μmol) and purged for 10 minutes. Dioxane (2.58 mL), water (430 μL) (6:1) was added to the vial and purged for an additional 10 minutes. The reaction was placed in a 90 °C oil bath for 16 hours. After completion, the reaction was cooled and diluted with EtOAc. The organic layer was washed with brine (20 mL) and water (20 mL). The collected organic layer was filtered through Celite and dried over sodium sulfate. The solvent was removed in vacuo and separated by column chromatography (0-10% DCM / MeOH) to give 6-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2-oxa-6-azaspiro[3.3]heptane (53 mg, 0.13 mmol, 44%) as a yellow solid. LCMS [M+H] + =399. 1 H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 8.33 (s, 1H), 7.96 (s, 2H), 7.56 - 7.43 (m, 2H), 6.61 (t, J = 8.6 Hz, 1H), 4.89 (s, 4H), 4.29 (d, J = 2.1 Hz, 4H). 13 C NMR (126 MHz, CDCl3) δ 165.79, 154.74, 153.03, 151.10, 149.93, 140.74, 140.66, 137.04, 130.69, 129.04, 126.80, 121.94, 121.38, 117.53, 113.98, 113.95, 62.82, 39.82.

[0260] Step D: 4-(4-(3-fluoro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (28) To a 5 mL MWV was added 6-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2-oxa-6-azaspiro[3.3]heptane (53 mg, 1 Eq., 0.13 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (32 mg, 1.1 Eq., 0.15 mmol), PdCl2(dppf) (10 mg, 0.1 Eq., 13 μmol), and potassium phosphate tribasic (42 mg, 1.5 Eq., 0.20 mmol). The vial was capped and degassed for 10 minutes. After degassing, the vial was diluted with degassed 1,4-dioxane (0.46 mL):water (77 μL), (6:1 (v / v) solvent was injected, degassed for an additional 10 minutes, and heated to 110 °C in an oil bath for 3 hours. The mixture was diluted with HO and EtOAc, and the aqueous layer was extracted three times with EtOAc. The pooled EtOAc extracts were washed twice with brine, and the EtOAc layer was then evaporated in vacuo, reconcentrated with DCM, dry-loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH 0-10%) to give 4-(4-(3-fluoro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (39 mg, 94 μmol, 71%) as a yellow solid. [M+H] + =414. 1 H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.14 (q, J = 6.8 Hz, 1H), 8.07 (dd, J = 8.7, 1.9 Hz, 1H), 7.59 - 7.51 (m, 1H), 7.51 - 7.42 (m, 1H), 6.89 (d, J = 5.1 Hz, 1H), 6.73 (s, 1H), 6.62 (dd, J = 22.3, 7.3 Hz, 1H), 6.59 - 6.51 (m, 1H), 4.86 (s, 4H), 4.26 (d, J = 2.1 Hz, 4H), 2.71 (d, J = 109.7 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 167.11, 158.80, 155.04, 153.10, 151.28, 149.40, 148.10, 140.63, 138.86, 137.88, 132.36, 129.78, 127.01, 125.10, 122.94, 117.65, 114.00, 112.69, 106.80, 81.02, 62.83, 24.76.

[0261] Example 2.2: 4-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-fluorophenyl)quinazolin-6-yl)pyridin-2-amine (29) [ka]

[0262] Step A: 5-(4-bromo-2-fluorophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane The title compound was isolated as a white solid from 2-oxa-5-azabicyclo[2.2.1]heptane in a manner similar to that described in Step A of Example 2.1. LCMS [M+H] + =271.

[0263] <Step B> (1S,4S)-5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane The title compound was isolated as an orange solid from 5-(4-bromo-2-fluorophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane in a manner similar to that described in Step B of Example 2.1. LCMS [M+H] + =319.

[0264] Step C: (1S,4S)-5-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane The title compound was isolated as a yellow solid from (1S,4S)-5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane in a manner similar to that described in Example 2.1, Step C. LCMS [M+H] + =399. 1 H NMR (500 MHz, CDCl3) δ 9.27 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.02 - 7.92 (m, 2H), 7.56 (dd, J = 14.5, 2.1 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H), 6.76 (t, J = 8.7 Hz, 1H), 4.74 - 4.64 (m, 2H), 4.09 - 4.01 (m, 1H), 3.91 (dd, J = 7.8, 1.5 Hz, 1H), 3.74 (ddd, J = 9.9, 3.1, 1.6 Hz, 1H), 3.39 (dt, J = 10.2, 2.2 Hz, 1H), 2.10 - 2.04 (m, 1H), 2.04 - 1.93 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 165.87, 154.31, 152.61, 150.68, 149.47, 138.24, 138.17, 137.23, 130.34, 129.20, 127.29, 125.28, 123.79, 121.52, 118.36, 115.54, 76.04, 72.57, 59.48, 36.74.

[0265] Step D: 4-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-fluorophenyl)quinazolin-6-yl)pyridin-2-amine (29) The title compound was isolated as a yellow solid from (1S,4S)-5-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane in a manner similar to that described in Step D of Example 2.1. LCMS [M+H] + =414. 1 H NMR (500 MHz, CDCl3) δ 9.29 (s, 1H), 8.38 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.57 - 7.49 (m, 2H), 6.91 (d, J = 4.9 Hz, 1H), 6.80 - 6.72 (m, 2H), 4.67 (d, J = 12.0 Hz, 1H), 4.04 (d, J = 7.7 Hz, 1H), 3.90 (d, J = 7.7 Hz, 1H), 3.74 (dd, J = 10.3, 2.6 Hz, 1H), 3.46 (s, 1H), 3.39 (dd, J = 9.8, 2.7 Hz, 1H), 2.67 - 2.33 (s, 2H), 2.04 (dd, J = 9.9, 2.2 Hz, 1H), 2.00 - 1.94 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 166.99, 158.63, 155.09, 152.69, 151.45, 150.76, 149.66, 148.52, 147.55, 137.97, 137.66, 132.26, 129.78, 127.18, 125.23, 122.92, 117.07, 112.65, 107.00, 72.54, 59.48, 36.73, 29.71, 28.32.

[0266] Example 2.3: 4-(3-Fluoro-4-(piperazin-1-yl)phenyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline (33) [ka]

[0267] Step A: tert-Butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate The title compound was isolated as a brown solid from tert-butyl piperazine-1-carboxylate in a similar manner to Step A of Example 2.1. LCMS [M+H] + =360.

[0268] Step B: tert-Butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate The title compound was isolated from tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate in a manner similar to that described in Step B of Example 2.1. 1 H NMR (500 MHz, CDCl3) δ 7.28 (dd, J = 7.9, 1.5 Hz, 1H), 7.26 - 7.20 (m, 1H), 6.68 (t, J = 8.2 Hz, 1H), 3.53 - 3.25 (m, 4H), 2.86 (t, J = 5.1 Hz, 4H), 1.26 (s, 9H), 1.10 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 155.94, 154.68, 153.99, 142.43, 142.36, 131.41, 131.38, 128.96, 128.38, 121.99, 121.84, 118.22, 118.20, 83.82, 79.85, 50.18, 50.16, 28.43, 25.02.

[0269] Step C: tert-Butyl 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)piperazine-1-carboxylate The title compound was isolated from tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate in a manner similar to that described in Example 2.1, Step C. LCMS [M+H]+ =489. 1 H NMR (500 MHz, CDCl3) δ 9.47 (s, 1H), 8.45 (dd, J = 1.7, 0.9 Hz, 1H), 8.11 (q, J = 2.3, 1.7 Hz, 2H), 7.71 - 7.62 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H), 3.78 (t, J = 5.0 Hz, 4H), 3.33 (t, J = 5.0 Hz, 4H), 1.64 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 155.94, 154.68, 153.99, 142.43, 142.36, 131.41, 131.38, 128.96, 128.38, 121.99, 121.84, 118.22, 118.20, 83.82, 79.85, 50.18, 28.43, 25.02.

[0270] Step D: 4-(3-fluoro-4-(piperazin-1-yl)phenyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline (33) A mixture of tert-butyl 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (130 mg, 1 eq., 267 μmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (110 mg, 1.2 eq., 320 μmol), potassium phosphate (85 mg, 1.5 eq., 400 μmol), and PdCl(dppf) (21 mg, 0.1 eq., 26.7 μmol) in 1,4-dioxane (0.8 mL) and water (0.1 mL) was heated at 90° C. for 2 h under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (5 mL). The aqueous solution was washed with ethyl acetate (10 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude product was passed through a silica gel flash column (eluent, ethyl acetate in hexane = 0-100%) to give the intermediate. The intermediate was further dissolved in DCM (3 ml) and TFA (1 ml), and the reaction solution was stirred at rt for an additional 4 hours. The reaction solvent was removed, and the crude product was purified by pre-HPLC (eluent MeOH:water = 8-100%) to give 4-(3-fluoro-4-(piperazin-1-yl)phenyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline (36 mg, 85 μmol, 32%). Mp 242-244 °C. LCMS [M+H] + =425. 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.19 (s, 1H), 8.37 (dd, J = 8.7, 2.0 Hz, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.25 (dt, J = 5.8, 2.9 Hz, 1H), 8.17 (dd, J = 8.1, 1.6 Hz, 1H), 8.09 - 8.02 (m, 2H), 7.80 - 7.63 (m, 2H), 7.26 (t, J = 8.7 Hz, 1H), 7.14 (dd, J = 8.0, 4.6 Hz, 1H), 3.23 (t, J = 4.6 Hz, 4H), 3.10 (d, J = 4.3 Hz, 4H). 13 C NMR (126 MHz, DMSO-d6) δ 165.41, 155.77, 154.07, 149.73, 149.70, 143.82, 141.39, 135.41, 133.89, 131.28, 129.43, 127.50, 126.16, 123.21, 121.86, 119.56, 118.19, 118.01, 117.53, 116.94, 113.54, 48.90, 44.29.

[0271] Example 2.4: 1-(4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)piperazin-1-yl)ethan-1-one (34) [ka]

[0272] Step A: 1-(4-bromo-2-fluorophenyl)piperazine A solution of 4-bromo-2-fluoro-1-iodobenzene (912 mg, 1 eq., 3.03 mmol) in toluene (18 mL) with Pd(dba) (83 mg, 0.03 eq., 90.9 μmol), cesium carbonate (2.47 g, 2.5 eq., 7.58 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (175 mg, 1 eq., 303 μmol) was placed in a 100 mL RBF purged and maintained under an inert atmosphere of argon for 24 hours. The resulting solution was stirred at 100 °C for 24 hours. The reaction was then quenched by the addition of 25 mL of water and extracted with 25 mL of ethyl acetate. The combined layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by automated column chromatography on a CombiFlash (0-15% EtOAc / Hex) to give tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate (748 mg, 2.08 mmol, 69%) as a pale yellow solid. LCMS [M+H] + =359. tert-Butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate (709 mg, 1 eq., 1.97 mmol) and DCM (20 ml) were added to a vial with stirring. 2,2,2-Trifluoroacetic acid (15 g, 9.97 mL, 66 eq., 130 mmol) was added and the reaction was vented. The reaction was stirred at 25 °C for 3 h. Upon completion, the reaction was basified with 1N NaOH and diluted with DCM (2 x 10 mL). The organic layer was washed with water, dried over sodium sulfate, concentrated under pressure, and purified by column chromatography (DCM / MeOH 0-10%) to give 1-(4-bromo-2-fluorophenyl)piperazine (376 mg, 1.45 mmol, 74%) as a tan solid. LCMS [M+H] + =259. 1 H NMR (500 MHz, CDCl3) δ 9.74 (s, 1H), 7.24 - 7.18 (m, 3H), 6.81 (td, J = 8.7, 1.9 Hz, 1H), 3.33 (d, J = 17.2 Hz, 8H). 13C NMR (126 MHz, CDCl3) δ 155.47, 137.74, 127.85, 120.64, 120.03, 115.74, 77.28, 77.02, 76.77, 47.42, 43.60.

[0273] Step B: 1-(4-(4-bromo-2-fluorophenyl)piperazin-1-yl)ethan-1-one 1-(4-Bromo-2-fluorophenyl)piperazine (0.350 g, 1 eq., 1.35 mmol) and triethylamine (396 mg, 546 μL, 2.9 eq., 3.92 mmol) were added to DCM (4.5 mL). The reaction was cooled to 0 °C, and acetyl chloride (233 mg, 208 μL, 2.2 eq., 2.97 mmol) was added slowly. After complete addition, the reaction was warmed to 25 °C and stirred for 16 h. Upon completion, the reaction was quenched with brine solution and diluted with DCM. The organic phase was further washed with brine and water and dried over sodium sulfate. The mixture was concentrated under pressure and purified by column chromatography (0-5% DCM / MeOH) to isolate 1-(4-(4-bromo-2-fluorophenyl)piperazin-1-yl)ethan-1-one (257 mg, 853 μmol, 63.2%) as a yellow oil. LCMS [M+H] + =302. 1 H NMR (500 MHz, CDCl3) δ 7.30 - 7.21 (m, 2H), 6.87 - 6.83 (m, 1H), 3.86 - 3.76 (m, 2H), 3.76 - 3.65 (m, 2H), 3.13 - 3.09 (m, 2H), 3.09 - 3.03 (m, 2H), 2.19 (s, 4H). 13 C NMR (126 MHz, CDCl3) δ 169.03, 154.38, 138.86, 127.56, 120.34, 119.70, 114.34, 50.71, 50.14, 46.31, 41.35, 21.28.

[0274] <Step C> 1-(4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethan-1-one The title compound was isolated as a pink solid from 1-(4-(4-bromo-2-fluorophenyl)piperazin-1-yl)ethan-1-one in a manner similar to that described in Step B of Example 2.1. LCMS [M+H] + =349. 1 H NMR (500 MHz, CDCl3) δ 7.49 (dd, J = 7.9, 1.5 Hz, 1H), 7.44 (dd, J = 13.2, 1.4 Hz, 1H), 6.91 (t, J = 8.2 Hz, 1H), 3.77 (t, J = 5.2 Hz, 2H), 3.64 - 3.59 (m, 2H), 3.14 - 3.07 (m, 4H), 2.11 (s, 3H), 1.31 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 169.00, 155.96, 154.00, 141.81, 131.44, 122.02, 118.35, 83.91, 50.60, 50.01, 46.31, 41.34, 24.72, 21.35.

[0275] Step D: 1-(4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)piperazin-1-yl)ethan-1-one The title compound was isolated as an orange solid from 1-(4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethan-1-one in a manner similar to that described in Step C of Example 2.1. LCMS [M+H] + =430. 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.28 (d, J = 1.4 Hz, 1H), 7.96 (d, J = 1.4 Hz, 2H), 7.54 - 7.49 (m, 2H), 7.08 (t, J = 8.4 Hz, 1H), 3.82 (t, J = 5.0 Hz, 2H), 3.66 (t, J = 4.9 Hz, 2H), 3.21 (dt, J = 21.9, 5.0 Hz, 4H), 2.15 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.14, 165.60, 156.25, 154.78, 154.28, 149.93, 141.58, 137.29, 130.79, 128.84, 126.68, 123.89, 121.70, 119.01, 118.00, 50.50, 49.91, 46.36, 41.39, 21.38.

[0276] Step E: 1-(4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)piperazin-1-yl)ethan-1-one (34) The title compound was isolated as a yellow solid from 1-(4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)piperazin-1-yl)ethan-1-one in a manner similar to that described in Step D of Example 2.1. LCMS [M+H] + =443. 1H NMR (500 MHz, CDCl3) δ 9.34 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.11 (td, J = 9.2, 3.7 Hz, 2H), 7.61 - 7.54 (m, 2H), 7.10 (t, J = 8.4 Hz, 1H), 6.89 (d, J = 5.2 Hz, 1H), 6.73 (s, 1H), 4.82 (s, 2H), 3.82 (t, J = 5.1 Hz, 2H), 3.67 (t, J = 5.0 Hz, 2H), 3.22 (dt, J = 21.7, 5.1 Hz, 4H), 2.15 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.12, 166.86, 158.69, 155.02, 154.30, 151.34, 149.38, 147.99, 138.18, 132.60, 131.23, 129.90, 126.77, 124.87, 122.94, 119.02, 118.11, 112.70, 106.86, 50.54, 49.91, 46.36, 41.39, 21.37.

[0277] Example 2.5: 4-(4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (35) [ka]

[0278] Step A: tert-Butyl 4-(4-(6-)-2-fluorophenyl)piperazine-1-carboxylate The title compound was isolated as a yellow solid from tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate in a manner similar to that described in Example 2.1, Step C. LCMS [M+H] + =488. 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.30 (dd, J = 1.7, 0.9 Hz, 1H), 7.99 - 7.95 (m, 2H), 7.56 - 7.49 (m, 2H), 7.09 (t, J = 8.6 Hz, 1H), 3.63 (t, J = 5.0 Hz, 4H), 3.17 (t, J = 5.0 Hz, 4H), 1.48 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 165.73, 156.23, 154.69, 154.26, 149.81, 142.04, 137.31, 130.72, 130.39, 128.92, 126.71, 123.89, 121.71, 118.96, 117.98, 80.06, 50.15, 50.12, 28.45.

[0279] Step B: 4-(4-(3-fluoro-4-(piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (35) The title compound was isolated as a yellow solid from tert-butyl 4-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)piperazine-1-carboxylate in a manner similar to that described in Step D of Example 2.3. LCMS [M+H] + =401. 1 H NMR (500 MHz, CDCl3) δ 9.35 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.19 - 8.16 (m, 2H), 8.11 (dd, J = 8.7, 2.0 Hz, 1H), 7.60 - 7.56 (m, 2H), 7.12 (t, J = 8.6 Hz, 1H), 6.91 (dd, J = 5.4, 1.6 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 4.60 (s, 2H), 3.28 (d, J = 4.6 Hz, 1H), 3.25 (dd, J = 6.2, 3.6 Hz, 4H), 3.12 (dd, J = 6.4, 3.4 Hz, 4H). 13C NMR (126 MHz, CDCl3) δ 166.98, 159.03, 156.22, 154.96, 154.25, 151.27, 149.00, 142.41, 138.31, 132.58, 130.45, 129.77, 126.73, 124.87, 122.97, 118.78, 118.00, 112.80, 106.48, 51.22, 46.00, 29.70.

[0280] Example 2.6: 1-((1S,4S)-5-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one (39) [ka]

[0281] Step A: (1S,4S)-2-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]heptane Benzene, 1-bromo-4-iodo-4-(400 mg, 1 eq., 1.41 mmol), and (1S,4S)-2-boc-2,5-diazabicyclo(2,2,1)heptane (140 mg, 0.5 eq., 707 μmol) were suspended in toluene (2.1 mL), and the reaction mixture was degassed with a stream of argon. Sodium 2-methylpropan-2-olate (543 mg, 610 μL, 4 eq., 5.66 mmol) was added, and the reaction mixture was sonicated under a nitrogen atmosphere until most of the solids dissolved and the solution became homogeneous. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (52 mg, 0.05 eq., 70.7 μmol) was added, and the reaction mixture was heated at 90 °C under nitrogen for 16 h. The solution was filtered through Celite, washed with ethyl acetate, and the filtrate was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography using an eluent gradient of 0% to 50% ethyl acetate in hexane to give tert-butyl (1S,4S)-5-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (366 mg, 1.04 mmol, 73%). LCMS [M+H] + =353.

[0282] Step B: (1S,4S)-2-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]heptane tert-Butyl (1S,4S)-5-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (366 mg, 1 eq., 1.04 mmol) and TFA (7.80 g, 5.27 mL, 66 eq., 68.4 mmol) in DCM (10.5 mL) were added under argon and stirred for 10 minutes. The reaction was stirred at 25° C. for 4 hours. The reaction was basified with 1N NaOH and diluted with DCM to yield (1S,4S)-2-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]heptane, 2,2,2-trifluoroacetate (223 mg, 609 μmol, 59%) as the final product. [M+H] + =252.

[0283] Step C: 1-((1S,4S)-5-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one The title compound was isolated as a brown solid from (1S,4S)-2-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]heptane in a manner similar to that described in Step B of Example 2.4. LCMS [M+H] + =294. 1 H NMR (500 MHz, CDCl3) δ 7.30 (t, J = 8.8 Hz, 2H), 6.43 (t, J = 8.2 Hz, 2H), 4.99 (s, 1H), 4.45 (d, J = 13.9 Hz, 1H), 4.39 (s, 1H), 3.66 (d, J = 8.4 Hz, 1H), 3.57 (dd, J = 13.0, 9.8 Hz, 1H), 3.49 (d, J = 16.0 Hz, 2H), 3.19 - 3.08 (m, 1H), 1.92 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 168.74, 145.23, 132.13, 114.44, 109.31, 58.78, 57.77, 56.92, 55.46, 36.98, 29.71.

[0284] <Step D> 1-((1S,4S)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one The title compound was isolated as a purple oil from 1-((1S,4S)-5-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one in a manner similar to that described in Step B of Example 2.1. LCMS [M+H] + =343. 1H NMR (500 MHz, CDCl3) δ 7.67 (dd, J = 11.7, 7.8 Hz, 2H), 6.54 (t, J = 8.8 Hz, 2H), 4.99 (d, J = 6.3 Hz, 1H), 4.55 - 4.42 (m, 2H), 3.58 (p, J = 9.0 Hz, 2H), 3.52 (s, 2H), 3.25 (d, J = 8.8 Hz, 1H), 1.91 (d, J = 7.6 Hz, 3H), 1.32 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 148.68, 136.48, 132.15, 114.23, 111.70, 83.31, 57.42, 57.15, 56.46, 55.54, 37.16, 24.87.

[0285] Step E: 1-((1S,4S)-5-(4-(6-bromoquinazolin-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one The title compound was isolated from 1-((1S,4S)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one in a manner similar to that described in Step C of Example 2.1. LCMS [M+H] + =422. 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.13 (dt, J = 8.9, 1.7 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.76 - 7.73 (m, 2H), 6.86 (dd, J = 8.5, 6.2 Hz, 2H), 4.82 (d, J = 12.4 Hz, 1H), 4.71 (s, 1H), 3.69 - 3.65 (m, 1H), 3.61 (dd, J = 9.4, 1.9 Hz, 1H), 3.45 (s, 1H), 3.13 (s, 1H), 2.54 (s, 3H), 2.04 (m, 1H), 1.85 (m, 1H).

[0286] Step F: 1-((1S,4S)-5-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one (39) The title compound was isolated as a yellow solid from 1-((1S,4S)-5-(4-(6-bromoquinazolin-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one in a manner similar to that described in Step D of Example 2.1. LCMS [M+H] + =436. 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 5.5 Hz, 1H), 7.69 (d, J = 14.9 Hz, 1H), 7.62 (dt, J = 8.6, 2.2 Hz, 1H), 7.01 (td, J = 9.0, 2.7 Hz, 1H), 6.92 (t, J = 5.4 Hz, 1H), 6.82 (s, 1H), 6.26 (s, 2H), 4.80 (s, 1H), 4.67 (d, J = 5.9 Hz, 1H), 3.88 - 3.83 (m, 1H), 3.79 (d, J = 9.6 Hz, 1H), 3.62 (q, J = 9.5 Hz, 2H), 3.27 (dd, J = 9.3, 3.3 Hz, 1H), 2.03 (d, J = 13.6 Hz, 3H), 1.87 (s, 1H).

[0287] Example 2.7: 1-((1S,4S)-5-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one (40) [ka]

[0288] Step A: (1S,4S)-2-(4-bromo-2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane The title compound was isolated as a yellow solid from (1S,4S)-2-boc-2,5-diazabicyclo(2,2,1)heptane in a manner similar to that of Example 2.4, Step A. LCMS [M+H] + =271.

[0289] <Step B> 1-((1S,4S)-5-(4-bromo-2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one The title compound was isolated as a brown solid from (1S,4S)-2-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]heptane in a manner similar to that described in Step B of Example 2.4. LCMS [M+H] + =314. 1 H NMR (500 MHz, CDCl3) δ 7.17 - 7.11 (m, 1H), 7.10 (s, 1H), 6.46 (t, J = 9.1 Hz, 1H), 4.94 (s, 1H), 4.48 - 4.39 (m, 1H), 3.68 - 3.63 (m, 2H), 3.56 - 3.49 (m, 2H), 3.49 - 3.44 (m, 1H), 3.27 - 3.18 (m, 2H), 1.93 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 168.35, 151.51, 134.57, 127.52, 119.81, 116.51, 108.44, 59.39, 58.91, 58.04, 55.04, 37.18, 21.94.

[0290] <Step C> 1-((1S,4S)-5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one The title compound was isolated as a green oil from 1-((1S,4S)-5-(4-bromo-2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one in a manner similar to that described in Step B of Example 2.1. LCMS [M+H] + =361. 1H NMR (500 MHz, CDCl3) δ 7.67 (dd, J = 11.7, 7.8 Hz, 2H), 6.54 (t, J = 8.8 Hz, 2H), 4.99 (d, J = 6.3 Hz, 1H), 4.55 - 4.42 (m, 2H), 3.58 (p, J = 9.0 Hz, 2H), 3.52 (s, 2H), 3.25 (d, J = 8.8 Hz, 1H), 1.91 (d, J = 7.6 Hz, 3H), 1.32 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 168.87, 148.68, 136.48, 132.15, 129.52, 114.23, 111.70, 83.31, 57.42, 57.15, 56.46, 55.54, 37.16, 24.87.

[0291] Step D: 1-((1S,4S)-5-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one The title compound was isolated from 1-((1S,4S)-5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one in a manner similar to that described in Step C of Example 2.1. LCMS [M+H] + =440. 1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.15 (dt, J = 9.1, 1.9 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 14.8, 2.1 Hz, 1H), 7.56 (dt, J = 8.7, 2.1 Hz, 1H), 7.02 (td, J = 9.0, 3.3 Hz, 1H), 4.79 (s, 1H), 4.67 (d, J = 8.5 Hz, 1H), 3.87 - 3.81 (m, 1H), 3.78 (d, J = 9.5 Hz, 1H), 3.61 (d, J = 5.6 Hz, 1H), 3.48 (d, J = 10.9 Hz, 1H), 2.55 (s, 3H), 2.04 (m, 1H), 1.87 (m, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 171.1, 167.08, 164.30, 154.06, 148.81, 143.97, 136.46, 130.12, 128.14, 126.80, 122.60, 120.12, 117.34, 117.17, 115.07, 57.24, 53.93, 51.97, 50.38, 35.35, 21.49.

[0292] Step E: 1-((1S,4S)-5-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one (40) The title compound was isolated as a yellow solid from 1-((1S,4S)-5-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one in a manner similar to that described in Step D of Example 2.1. LCMS [M+H] + =455. 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 5.5 Hz, 1H), 7.69 (d, J = 14.9 Hz, 1H), 7.62 (dt, J = 8.6, 2.2 Hz, 1H), 7.01 (td, J = 9.0, 2.7 Hz, 1H), 6.92 (t, J = 5.4 Hz, 1H), 6.82 (s, 1H), 6.26 (s, 2H), 4.80 (s, 1H), 4.67 (d, J = 5.9 Hz, 1H), 3.88 - 3.83 (m, 1H), 3.79 (d, J = 9.6 Hz, 1H), 3.62 (q, J = 9.5 Hz, 2H), 3.27 (dd, J = 9.3, 3.3 Hz, 1H), 2.03 (d, J = 13.6 Hz, 3H), 1.87 (s, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 168.17, 166.49, 160.44, 155.15, 152.20, 151.20, 148.12, 138.03, 132.94, 129.75, 128.00, 125.63, 125.44, 124.81, 122.60, 115.99, 110.75, 106.31, 58.59, 55.01, 53.15, 51.55, 36.48, 21.95.

[0293] Example 2.8: 4-(4-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (42) [ka]

[0294] Step A: 1-(4-bromophenyl)-4-(oxetan-3-yl)piperazine The title compound was isolated from 1-(oxetan-3-yl)piperazine in a manner similar to that described in Step A of Example 2.6. LCMS [M+H] + =297. 1 H NMR (500 MHz, CDCl3) δ 7.35 - 7.32 (m, 2H), 6.81 - 6.76 (m, 2H), 4.69 (t, J = 6.6 Hz, 2H), 4.65 (t, J = 6.1 Hz, 2H), 3.22 - 3.16 (m, 4H), 2.50 - 2.46 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 150.21, 131.92, 117.74, 112.07, 75.42, 59.19, 49.49, 48.73.

[0295] <Step B> 1-(oxetan-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine The title compound was isolated as a brown solid from 1-(4-bromophenyl)-4-(oxetan-3-yl)piperazine in a manner similar to that described in Step B of Example 2.1. LCMS [M+H] + =345. 1 H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 4.73 - 4.67 (m, 2H), 4.65 (d, J = 5.7 Hz, 2H), 3.30 (t, J = 5.0 Hz, 4H), 2.53 - 2.44 (m, 4H), 1.22 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 153.17, 136.15, 129.17, 114.48, 83.79, 75.36, 59.21, 49.47, 47.81, 24.85.

[0296] Step C: 6-Bromo-4-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazoline The title compound was isolated as a yellow solid from 1-(oxetan-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine in a manner similar to that described in Step C of Example 2.1. LCMS [M+H] + =427. 1 H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 8.34 (s, 1H), 7.94 (s, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.74 (m, 4H), 3.49 (m, 4H), 2.73 - 2.60 (m, 3H).

[0297] Step D: 4-(4-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (42) The title compound was isolated as a yellow solid from 6-bromo-4-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step D of Example 2.1. LCMS [M+H] + =439. 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.21 (dd, J = 8.8, 2.0 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 5.3 Hz, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.82 (dd, J = 5.3, 1.7 Hz, 1H), 6.71 (s, 1H), 6.05 (s, 2H), 4.54 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.0 Hz, 2H), 3.42 (t, J = 6.3 Hz, 1H), 2.46 (t, J = 5.0 Hz, 4H), 2.39 (t, J = 5.0 Hz, 4H). 13C NMR (101 MHz, DMSO-d6) δ 167.72, 161.06, 155.25, 152.71, 151.17, 149.41, 147.65, 138.16, 132.87, 132.09, 129.76, 126.41, 124.92, 122.76, 114.77, 110.66, 105.90, 74.89, 58.99, 49.47, 47.25.

[0298] Example 2.9: 41-(6-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (44) [ka]

[0299] Step A: tert-Butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate The title compound was isolated from 2,6-diazaspiro[3.3]heptane-2-carboxylic acid in a manner similar to that described in Step A of Example 2.6. LCMS [M+H] + =353.

[0300] Step B: 2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane The title compound was isolated from tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate in a manner similar to that described in Step B of Example 2.6. LCMS [M+H] + =253.

[0301] Step C: 1-(6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one The title compound was isolated as a brown solid from 2-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane in a manner similar to that described in Step B of Example 2.4. LCMS [M+H] + =294. 1 H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.2 Hz, 2H), 6.28 (d, J = 8.4 Hz, 2H), 4.25 (s, 2H), 4.11 (s, 2H), 3.92 (s, 4H), 1.84 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 170.52, 149.91, 131.80, 113.45, 110.44, 62.18, 60.73, 57.92, 33.04.

[0302] Step D: 1-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one The title compound was isolated as a brown solid from 1-(6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one in a manner similar to that described in Step B of Example 2.1. LCMS [M+H] + =343. 1 H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 7.9 Hz, 2H), 6.41 (d, J = 8.0 Hz, 2H), 4.27 (s, 2H), 4.14 (s, 2H), 4.00 (d, J = 10.9 Hz, 4H), 1.86 (s, 3H), 1.22 (d, J = 7.9 Hz, 12H). 13 C NMR (126 MHz, CDCl3) δ 170.55, 152.96, 136.03, 129.07, 110.78, 83.37, 61.91, 58.04, 33.12, 29.70, 24.85.

[0303] Step E: 1-(6-(4-(6-bromoquinazolin-4-yl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one The title compound was isolated as a yellow solid from 1-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one in a manner similar to that described in Step C of Example 2.1. LCMS [M+H] + =424. 1 H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.33 (d, J = 1.8 Hz, 1H), 7.96 (s, 2H), 7.73 (d, J = 7.9 Hz, 2H), 6.61 (d, J = 8.0 Hz, 2H), 4.35 (s, 2H), 4.21 (s, 2H), 4.15 (s, 2H), 4.04 (s, 2H), 1.90 (s, 3H).

[0304] Step F: 41-(6-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (44) The title compound was isolated as a yellow solid from 1-(6-(4-(6-bromoquinazolin-4-yl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one in a manner similar to that described in Step D of Example 2.1. LCMS [M+H] + =437. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.21 (dd, J = 8.9, 2.0 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 5.3 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 6.81 (dd, J = 5.3, 1.7 Hz, 1H), 6.70 (s, 1H), 6.62 (d, J = 8.5 Hz, 2H), 6.05 (s, 2H), 4.30 (s, 2H), 4.08 (s, 4H), 4.02 (s, 3H), 1.73 (s, 3H).

[0305] Example 2.10: 4-(4-(3-fluoro-4-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (57) [ka]

[0306] Step A: 6-Bromo-4-(3-fluoro-4-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)quinazoline 6-Bromo-4-(3-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)quinazoline (XXVIII) (50 mg, 1 eq., 0.13 mmol) was dissolved in DCE (0.52 mL), followed by the addition of STAB (40 mg, 1.5 eq., 0.19 mmol), oxentan-3-one (14 mg, 12 μL, 1.5 eq., 0.19 mmol), and acetic acid (1.5 mg, 1.4 μL, 0.2 eq., 25 μmol). The resulting suspension was stirred at 25 °C for 16 h, after which the solvent was removed under reduced pressure. The residue was washed with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated under reduced pressure. A yellow solid was obtained: 6-bromo-4-(3-fluoro-4-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)quinazoline (17 mg, 37 μmol, 30%). LCMS [M+H] + =456. 1 H NMR (500 MHz, CDCl3) δ 9.27 (d, J = 4.4 Hz, 1H), 8.32 - 8.27 (m, 1H), 7.93 (dd, J = 4.0, 1.3 Hz, 2H), 7.52 - 7.43 (m, 2H), 6.61 - 6.55 (m, 1H), 4.85 (q, J = 5.6 Hz, 1H), 4.80 (t, J = 6.6 Hz, 1H), 4.70 (t, J = 6.8 Hz, 1H), 4.57 - 4.48 (m, 2H), 4.21 - 4.17 (m, 2H), 3.53 (s, 2H), 2.04 (s, 4H). 13 C NMR (126 MHz, CDCl3) δ 154.71, 149.90, 137.12, 130.61, 129.11, 126.90, 123.91, 121.43, 117.43, 113.97, 74.51, 63.29, 60.28, 58.64, 29.70.

[0307] Step B: 4-(4-(3-fluoro-4-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (57) The title compound was isolated as a yellow solid from 6-bromo-4-(3-fluoro-4-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)quinazoline in a manner similar to that described in Step D of Example 2.1. LCMS [M+H] + =468. 1 H NMR (500 MHz, CDCl3) δ 9.30 (d, J = 4.5 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.17 - 8.10 (m, 2H), 8.08 (dd, J = 8.8, 2.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 6.89 (dd, J = 5.5, 1.6 Hz, 1H), 6.71 (s, 1H), 6.59 (t, J = 8.5 Hz, 1H), 4.67 (d, J = 6.3 Hz, 2H), 4.49 (dd, J = 6.7, 5.1 Hz, 2H), 4.21 (d, J = 2.1 Hz, 4H), 3.76 - 3.70 (m, 1H), 3.48 (s, 3H), 3.47 (d, J = 3.9 Hz, 1H).

[0308] Example 2.11: 1-(6-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (58) [ka]

[0309] <Step A> 1-(6-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one The title compound was isolated from 6-bromo-4-(3-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)quinazoline (XXVIII) in a manner similar to that described in Step B of Example 2.4. LCMS [M+H] + =442. 1 H NMR (500 MHz, CDCl3) δ 9.29 (s, 1H), 8.29 (t, J = 1.4 Hz, 1H), 7.94 (d, J = 1.4 Hz, 2H), 7.51 - 7.47 (m, 1H), 7.46 (d, J = 1.9 Hz, 1H), 6.60 (t, J = 8.6 Hz, 1H), 4.34 (s, 2H), 4.24 (d, J = 2.0 Hz, 4H), 4.19 (s, 2H), 1.89 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 170.52, 165.76, 154.81, 153.11, 150.00, 140.57, 137.09, 130.78, 129.01, 126.86, 123.91, 121.44, 117.51, 114.07, 63.37, 57.82, 33.89, 18.87.

[0310] Step B: 1-(6-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (58) The title compound was isolated as a yellow solid from 1-(6-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one in a manner similar to that described in Step D of Example 2.1. LCMS [M+H] + =455. 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.19 - 8.13 (m, 2H), 8.10 (dd, J = 8.6, 2.0 Hz, 1H), 7.57 - 7.51 (m, 2H), 6.91 (d, J = 5.4 Hz, 1H), 6.74 (s, 1H), 6.63 (t, J = 8.5 Hz, 1H), 4.81 - 4.70 (m, 2H), 4.36 (s, 2H), 4.26 (d, J = 2.0 Hz, 4H), 4.23 (s, 2H), 1.90 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 170.66, 167.18, 158.98, 155.16, 151.52, 149.42, 148.89, 148.54, 138.13, 132.54, 129.94, 127.67, 127.06, 125.16, 123.08, 117.91, 117.74, 114.20, 112.87, 106.82, 63.48, 57.93, 41.16, 18.99.

[0311] Example 2.12: (S)-4-(4-(3-fluoro-4-(3-(methylamino)pyrrolidin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (60) [ka]

[0312] Step A: tert-Butyl (S)-(1-(4-bromo-2-fluorophenyl)pyrrolidin-3-yl)(methyl)carbamate The title compound was isolated as a yellow solid from (3S)-3-amino-N-methylpyrrolidine, N-BOC protected, in a manner similar to that described in Example 2.1, Step A. LCMS [M+H] + =373. 1H NMR (500 MHz, CDCl3) δ 7.23 - 7.21 (m, 1H), 6.65 (t, J = 9.0 Hz, 1H), 3.64 (dq, J = 8.4, 2.1 Hz, 1H), 3.57 - 3.47 (m, 2H), 3.41 (q, J = 8.4 Hz, 1H), 2.97 (s, 3H), 2.32 - 2.25 (m, 1H), 2.19 - 2.12 (m, 1H), 1.61 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 155.72, 153.09, 136.07, 128.41, 127.31, 119.51, 116.55, 79.88, 51.86, 50.76, 48.63, 28.94, 28.48, 28.23.

[0313] <Step B> tert-Butyl (S)-(1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)(methyl)carbamate The title compound was isolated from tert-butyl (S)-(1-(4-bromo-2-fluorophenyl)pyrrolidin-3-yl)(methyl)carbamate in a manner similar to that described in Step B of Example 2.1. LCMS [M+H] + =421. 1H NMR (500 MHz, CDCl3) δ 7.43 - 7.38 (m, 1H), 7.38 - 7.33 (m, 1H), 6.59 (t, J = 8.4 Hz, 1H), 3.64 (d, J = 14.6 Hz, 1H), 3.56 (tdd, J = 8.2, 6.4, 3.3 Hz, 1H), 3.50 (ddd, J = 10.5, 7.9, 2.5 Hz, 1H), 3.42 (ddd, J = 10.1, 6.6, 2.7 Hz, 1H), 3.35 (dd, J = 13.1, 5.2 Hz, 1H), 2.80 (s, 3H), 2.16 - 2.06 (m, 1H), 2.00 (dq, J = 12.6, 8.4 Hz, 1H), 1.45 (s, 9H), 1.23 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 155.74, 152.53, 139.15, 134.74, 131.58, 122.03, 114.73, 83.49, 79.87, 53.94, 51.59, 48.48, 28.92, 28.48, 28.33, 25.03.

[0314] Step C: tert-Butyl (S)-(1-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)pyrrolidin-3-yl)(methyl)carbamate The title compound was isolated from tert-butyl (S)-(1-(4-bromo-2-fluorophenyl)pyrrolidin-3-yl)(methyl)carbamate in a manner similar to that described in Step C of Example 2.1. LCMS [M+H] + =502. 1H NMR (500 MHz, CDCl3) δ 9.27 (s, 1H), 8.36 - 8.35 (m, 1H), 7.94 (t, J = 1.5 Hz, 2H), 7.54 (dd, J = 14.6, 2.0 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H), 6.77 (t, J = 8.7 Hz, 1H), 3.72 - 3.62 (m, 2H), 3.52 (ddd, J = 10.1, 7.0, 2.8 Hz, 2H), 2.85 (s, 3H), 2.22 - 2.06 (m, 3H), 1.48 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 154.62, 137.28, 130.76, 130.55, 130.42, 129.88, 129.20, 129.18, 128.90, 127.23, 123.88, 121.35, 118.11, 115.08, 80.04, 54.66, 51.51, 48.55, 29.71, 29.02, 28.50.

[0315] Step D: (S)-4-(4-(3-fluoro-4-(3-(methylamino)pyrrolidin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (60) The title compound was isolated as a yellow solid from tert-butyl (S)-(1-(4-(6-bromoquinazolin-4-yl)-2-fluorophenyl)pyrrolidin-3-yl)(methyl)carbamate in a manner similar to that described in Step D of Example 2.3. LCMS [M+H] + =414. 1H NMR (500 MHz, CH3OH+D2O) δ 9.19 (t, J = 4.6 Hz, 1H), 8.46 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.17 - 8.10 (m, 1H), 8.00 (d, J = 4.9 Hz, 1H), 7.61 (s, 2H), 6.99 (s, 1H), 6.92 (s, 2H), 5.49 (d, J = 2.8 Hz, 1H), 4.55 (s, 2H), 4.02 (s, 5H), 3.34 (d, J = 2.9 Hz, 2H), 2.60 (d, J = 2.8 Hz, 1H), 1.91 (s, 3H).

[0316] Example 2.13: 4-(4-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (61) [ka]

[0317] Step A: 1-(4-bromo-2-methylphenyl)-4-methylpiperazine The title compound was isolated as a brown oil from 1-methylpiperazine and 4-bromo-1-iodo-2-methylbenzene in a manner similar to that described in Step A of Example 2.1. LCMS [M+H] + =270. 1 H NMR (500 MHz, CDCl3) δ 7.20 (d, J = 2.3 Hz, 1H), 7.15 (dd, J = 8.5, 2.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 2.81 (t, J = 4.9 Hz, 4H), 2.50 (s, 4H), 2.28 (s, 3H), 2.17 (s, 3H).

[0318] <Step B> 1-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine The title compound was isolated from 1-(4-bromo-2-methylphenyl)-4-methylpiperazine in a manner similar to that described in Step B of Example 2.1. LCMS [M+H] + =317.

[0319] Step C: 6-Bromo-4-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)quinazoline The title compound was isolated from 1-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine in a manner similar to that described in Step C of Example 2.1. LCMS [M+H] + =397. 1 HNMR (500 MHz, CDCl3) δ 9.36 (s, 1H), 8.37 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 1.4 Hz, 2H), 7.67 (d, J = 2.2 Hz, 1H), 7.61 (dd, J = 8.2, 2.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 3.51 (s, 3H), 3.14 (t, J = 4.8 Hz, 4H), 2.73 (s, 4H), 2.47 (s, 3H).

[0320] Step D: 4-(4-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (61) The title compound was isolated from 6-bromo-4-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step D of Example 2.1. LCMS [M+H] + =411. 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.54 - 7.87 (m, 4H), 7.89 - 7.13 (m, 4H), 6.99 (d, J = 5.9 Hz, 1H), 3.45 - 3.13 (m, 5H), 2.78 (s, 4H), 2.46 (s, 4H), 2.36 (s, 3H).

[0321] Example 2.14: 4-(4-(4-(4-(methylsulfonyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)quinazolin-6-yl)pyridin-2-amine (63) [ka]

[0322] Step A: 1-(4-bromo-2-(trifluoromethyl)phenyl)-4-(methylsulfonyl)piperazine The title compound was isolated from 1-(methylsulfonyl)piperazine, HCl and 4-bromo-1-iodo-2-(trifluoromethyl)benzene in a manner similar to that described in Example 2.1, Step A. LCMS [M+H] + =387. 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H) 7.67 (d, 1H), 7.24 (d, 1H), 3.36 (t, 4H), 3.00 (t, 4H), 2.84 (s, 3H).

[0323] <Step B> 1-(methylsulfonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)piperazine The title compound was isolated from 1-(4-bromo-2-(trifluoromethyl)phenyl)-4-(methylsulfonyl)piperazine in a manner similar to that described in Step B of Example 2.1. LCMS [M+H] + =435. 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.96 (d, 1H), 7.31 (d, 1H), 3.37 (t, 4H), 3.05 (t, 4H), 2.84 (s, 3H), 1.34 (s, 12H).

[0324] Step C: 6-Bromo-4-(4-(4-(methylsulfonyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)quinazoline The title compound was isolated as a cream solid from 1-(methylsulfonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)piperazine in a manner similar to that described in Step C of Example 2.1. LCMS [M+H] + =515. 1 H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 8.00 (s, 2H), 7.94 (d, 1H), 7.55 (d, 1H), 3.42 (s, 4H), 3.16 (s, 4H), 2.86 (s, 3H).

[0325] Step C: 4-(4-(4-(4-(methylsulfonyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)quinazolin-6-yl)pyridin-2-amine (63) The title compound was isolated from 6-bromo-4-(4-(4-(methylsulfonyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)quinazoline in a manner similar to that described in Step C of Example 2.1. LCMS [M+H] + =529. 1 H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.26 (s, 1H), 8.24 (d, 1H), 8.18 (s, 1H), 8.15 (d, 1H), 8.11 (d, 1H), 8.03 (d, 1H), 7.59 (d, 1H), 6.91 (d, 1H), 6.85 (s, 1H), 3.43 (t, 4H), 3.18 (t, 4H), 2.87 (s, 3H). 13CNMR (100 MHz, CDCl3) δ 166.7, 158.3, 158.2, 155.1, 153.2, 151.4, 149.8, 138.2, 134.5, 133.9, 132.8, 130.2, 124.6, 124.5, 122.9, 112.5, 107.5, 52.9, 46.3, 34.5, 24.9.

[0326] (Formula III) [ka]

[0327] Scheme 12 illustrates an alternative synthesis to substituted aryl bromides (XXXIII). Anilines (XXIX) were converted to piperazines (XXXI) by double substitution with bis(2-chloroethyl)amine (XXX). The piperazine analogs (XXXI) were functionalized by substitution, and the (hetero)aryl bromides (XXXIII) were then utilized in a Miyaura borylation reaction to generate pinacol boronates (VII). The boronates were then coupled with polyhalogenated heterocycles (VIII) in a Suzuki reaction to give R1-substituted heterocycles (IX), which were further reacted in a Suzuki reaction to give R2,R1-substituted heterocycles (XI).

[0328] Example 3.1: 4-(4-(3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (31) [ka]

[0329] Step A: 1-(4-bromo-2,6-difluorophenyl)piperazine To a 5 mL MW vial was added bis(2-chloroethyl)amine, HCl (1.96 g, 1.1 eq., 11.0 mmol), 4-bromo-2,6-difluoroaniline (2.08 g, 1 eq., 10.0 mmol), and diethylene glycol monomethyl ether (2.0 mL). The reaction mixture was heated to 150 °C overnight. The resulting mixture was cooled and dissolved in a minimal amount of MeOH (7 mL). Ether was added until the product was extruded from solution (100 mL) and filtered. The product was further washed with ether, extracted with DCM / water, dried over MgSO4, filtered, and concentrated to give 1-(4-bromo-2,6-difluorophenyl)piperazine (400 mg, 14.4%), which was carried on to the next step without further purification. LCMS [M+H] + =278.

[0330] Step B: 1-(4-bromo-2,6-difluorophenyl)-4-methylpiperazine A mixture of 1-(4-bromo-2,6-difluorophenyl)piperazine hydrochloride (570.0 mg, 1 eq., 1.818 mmol) and sodium hydride (0.17 g, 50% Wt, 2 eq., 3.636 mmol) in THF (10 ml) was stirred at room temperature for 30 minutes, and iodomethane (284 mg, 124 μL, 1.1 eq., 2.000 mmol) was added to the solution. The resulting mixture was stirred at room temperature for 2 hours. 1 H NMR (500 MHz, DMSO-d6) δ 7.38 (d, J = 8.8 Hz, 2H), 3.33 (s, 4H), 3.10 (t, J = 4.9 Hz, 4H), 2.23 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 116.67, 116.45, 55.51, 50.74, 46.25, 39.84, 39.74.

[0331] <Step C> 1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine A mixture of 1-(4-bromo-2,6-difluorophenyl)-4-methylpiperazine (400 mg, 1 eq., 1.37 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (593 mg, 1.7 eq., 2.34 mmol), potassium acetate (405 mg, 3 eq., 4.12 mmol), and PdCl(dppf) (108 mg, 0.1 eq., 137 μmol) in DMF (4 mL) was heated at 80 °C for 2 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL × 2). The organic layer was dried over sodium sulfate, filtered, and evaporated to give the crude product. The crude product was purified by silica gel chromatography (eluent: ethyl acetate:hexane = 0 to 100%, then methanol:ethyl acetate = 0 to 20%) to give 1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (270 mg, 798 μmol, 58.1%). LCMS [M+H] + =339.

[0332] Step D: 6-Bromo-4-(3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazoline A 100 mL round-bottle mixture of 6-bromo-4-chloroquinazoline (389 mg, 2 eq., 1.60 mmol), 1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (270 mg, 1 eq., 798 μmol), tripotassium phosphate (254 mg, 1.5 eq., 1.20 mmol), and PdCl(dppf) (63 mg, 0.1 eq., 79.8 μmol) in 1,4-dioxane (20 mL) and water (3.3 mL) was heated at 60 °C under argon for 2 h. The reaction was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with saturated sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (40 g silica gel, eluent ethyl acetate / hexane = 0 to 100%) to obtain the product 6-bromo-4-(3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazoline (192 mg, 458 μmol, 57%). 1 H NMR (500 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.26 (d, J = 2.3 Hz, 1H), 8.22 - 8.15 (m, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 8.4 Hz, 2H), 3.26 (d, J = 41.8 Hz, 4H), 2.58 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 164.68, 163.70, 158.26, 155.03, 149.72, 137.99, 131.21, 130.90, 129.91, 128.94, 123.72, 121.77, 114.79, 114.58, 55.36, 50.55, 45.97.

[0333] Step E: 4-(4-(3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (31) A mixture of 6-bromo-4-(3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazoline (192 mg, 1 eq., 458 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (111 mg, 1.1 eq., 504 μmol), potassium phosphate (146 mg, 1.5 eq., 687 μmol), and PdCl(dppf) (36 mg, 0.1 eq., 45.8 μmol) in 1,4-dioxane (9 mL) and water (1 mL) was heated at 90° C. for 2 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The aqueous solution was washed with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude product. The crude product was purified by column chromatography (DCM / MeOH 0-10%) to give 4-(4-(3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (109 mg, 252 μmol, 55%). Mp 105-107°C. LCMS [M+H] + =433. 1 H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.33 - 8.25 (m, 2H), 8.19 (d, J = 17.0 Hz, 3H), 8.04 (d, J = 5.3 Hz, 1H), 7.66 - 7.51 (m, 2H), 6.87 (dd, J = 5.4, 1.7 Hz, 1H), 6.77 (d, J = 1.7 Hz, 1H), 3.32 (t, J = 4.7 Hz, 4H), 2.62 (t, J = 4.7 Hz, 4H), 2.35 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 165.69, 163.79, 160.90, 158.17, 155.98, 154.98, 150.96, 149.20, 147.43, 138.75, 133.43, 131.37, 129.80, 124.25, 122.64, 114.87, 110.72, 106.00, 55.28, 50.45, 45.83.

[0334] Example 3.2: 4-(4-(3-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (59) [ka]

[0335] Step A: 1-(4-bromo-2-chlorophenyl)piperazine The title compound was isolated from bromo-2-chloroaniline in a manner similar to that described in Example 3.1, Step A. LCMS [M+H] + =275.

[0336] Step B: 1-(4-bromo-2-chlorophenyl)-4-(methylsulfonyl)piperazine To a 100 mL RBF was added 1-(4-bromo-2-chlorophenyl)piperazine (918 mg, 1 eq., 3.33 mmol), TEA (674 mg, 929 μL, 2 eq., 6.66 mmol), and DCM (15.0 mL). The reaction was cooled to 0 °C, and methanesulfonyl chloride (572 mg, 389 μL, 1.5 eq., 5.00 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 2 h. The mixture was further diluted with DCM and HO, the layers were separated, and the aqueous layer was washed again with DCM. The combined organic layers were then washed with brine, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica chromatography (35% EtoAc in hexanes) to give 1-(4-bromo-2-chlorophenyl)-4-(methylsulfonyl)piperazine (407 mg, 1.15 mmol, 35%). LCMS[M+H] + =353. 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, 1H), 7.36 (dd, 1H), 6.91 (d, 1H), 3.41 (t, 4H), 3.12 (t, 4H), 2.84 (s, 3H).

[0337] Step C: 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(methylsulfonyl)piperazine The title compound was isolated from 1-(4-bromo-2-chlorophenyl)-4-(methylsulfonyl)piperazine in a manner similar to that described in Example 3.1, Step C. LCMS [M+H] + =401. 1 H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.66 (d, 1H), 7.01 (d, 1H), 3.42 (t, 4H), 3.19 (t, 4H), 2.84 (s, 3H) 1.33 (s, 12H).

[0338] Step D: 6-Bromo-4-(3-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)quinazoline The title compound was isolated from 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(methylsulfonyl)piperazine in a manner similar to that described in Step D of Example 3.1. LCMS [M+H] + =481. 1 H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.26 (t, 1H), 8.00 (d, 2H), 7.87 (d, 1H), 7.67 (dd, 1H), 7.24 (d, 1H), 3.48 (t, 4H), 3.30 (t, 4H), 2.88 (s, 3H).

[0339] Step E: 4-(4-(3-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (59) The title compound was isolated from 6-bromo-4-(3-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step E of Example 3.1. LCMS [M+H] + =495. 1 H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.28 (s, 1H), 8.21-8.12 (m, 3H), 7.92 (s, 1H), 7.72 (d, 1H), 7.24 (d, 1H), 6.90 (d, 1H), 6.71 (s, 1H), 4.61 (bs, 2H), 3.48 (t, 4H), 3.30 (t, 4H), 2.87 (s, 3H). 13 CNMR (100 MHz, CDCl3) δ l66.7, 159.0, 154.9, 151.2, 150.3, 149.1, 148.9, 138.6, 132.9, 132.8, 132.4, 129.9, 129.6, 129.3, 124.6, 123.0, 120.7, 112.8, 106.5, 75.0, 50.7, 46.1, 34.5, 24.9.

[0340] Example 3.3: 4-(4-(3-chloro-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (62) [ka]

[0341] Step A: 1-(4-bromo-2-chlorophenyl)-4-methylpiperazine A solution of 1-(4-bromo-2-chlorophenyl)piperazine (1.28 g, 1 eq., 4.6456 mmol), formaldehyde (209 mg, 192.0 μL, 1.5 eq., 6.97 mmol) (37%), and acetic acid (558 mg, 531.9 μL, 2 eq., 9.29 mmol) in DCM (46.5 mL) was treated with sodium triacetoxyborohydride (3.94 g, 4 eq., 18.58 mmol) at 25 °C for 1 h. The reaction was quenched with aqueous NaHCO3. The resulting mixture was concentrated and purified on silica to give 1-(4-bromo-2-chlorophenyl)-4-methylpiperazine (722 mg, 2.49 mmol, 54%). LCMS [M+H] + =290. 1 HNMR (500 MHz, CDCl3) δ 7.41 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.6, 2.3 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 3.08 (s, 4H), 2.74 (s, 4H), 2.41 (s, 3H).

[0342] <Step B> 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine The title compound was isolated from 1-(4-bromo-2-chlorophenyl)-4-methylpiperazine in a manner similar to that described in Example 3.1, Step C. LCMS [M+H] + =337. 1HNMR (500 MHz, CDCl3) δ 8.00 (d, J = 1.5 Hz, 1H), 7.86 (dd, J = 8.0, 1.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 3.36 (s, 4H), 2.89 (s, 4H), 2.60 (s, 3H), 1.54 (s, 12H).

[0343] Step C: 6-Bromo-4-(3-chloro-4-(4-methylpiperazin-1-yl)phenyl)quinazoline The title compound was isolated from 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine in a manner similar to that described in Step D of Example 3.1. LCMS [M+H] + =418. 1 H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.20 (t, J = 1.4 Hz, 1H), 7.89 (d, J = 1.4 Hz, 2H), 7.75 (d, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.3, 2.1 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 3.17 (t, J = 4.9 Hz, 4H), 2.62 (t, J = 4.8 Hz, 4H), 2.34 (s, 3H).

[0344] Step E: 4-(4-(3-chloro-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-6-yl)pyridin-2-amine (62) The title compound was isolated from 6-bromo-4-(3-chloro-4-(4-methylpiperazin-1-yl)phenyl)quinazoline in a manner similar to that described in Step E of Example 3.1. LCMS [M+H] + =431. 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.22 - 7.97 (m, 3H), 7.87 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.3, 2.1 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 5.4, 1.6 Hz, 1H), 6.69 (d, J = 1.1 Hz, 1H), 4.66 (s, 2H), 3.29 (s, 4H), 2.79 (s, 4H), 2.47 (s, 3H).

[0345] [Incorporated by reference] The entire disclosure of each patent document and scientific article referred to herein is incorporated by reference for all purposes.

[0346] [Equivalent] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore considered in all respects to be illustrative rather than limiting on the invention described herein. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A compound comprising one of the following formulas, including a pharmaceutically acceptable salt, solvate, and / or prodrug: 【Chemistry 1】 X, Y, R1, and R2 are each independently compounds containing any chemical moiety that enables the resulting compound to inhibit DYRK1A, DYRK1B, DYRK2, DYRK3, CLK1, CLK2, CLK3, CLK4, homeodomain interaction kinase (HIPK), and / or CMGC kinase, thereby leading to inhibition of WNT signaling.

2. The compound according to claim 1, wherein X, Y, R1, and R2 each independently contain any chemical moiety that enables the resulting compound to inhibit one or more of the following: DYRK1A activity; PI3K / Akt signaling related to DYRK1A; Phosphorylation of tau related to DYRK1A; Phosphorylation of NFAT related to DYRK1A; Activation of the ASK1 / JNK1 pathway related to DYRK1A; Phosphorylation of p53 related to DYRK1A; Phosphorylation of Amph1 related to DYRK1A; Phosphorylation of dynamin 1 related to DYRK1A; Phosphorylation of synaptojanin associated with DYRK1A; Activity of presenilin 1 (a catalytic subunit of γ-secretase) associated with DYRK1A; Phosphorylation of amyloid precursor proteins related to DYRK1A; Activation of SIRT1 related to DYRK1A; Activity of heat shock factor 1 and 26S proteasome in relation to DYRK2; mTOR activity related to DYRK3; DYRK3 phosphorylation (e.g., PRAS40); DYRK1B activity; CMGC / CLK kinase activity; CLK1 activity; CLK2 activity; CLK3 activity; CLK4 activity; CDK7 activity; CDK8 activity; CDK19 activity; CDK8 / 19 activity; PI3K activity; PI3K mutant activity; PDGFrA / B activity; mTOR activity; c-KIT activity; RYK activity; and, WNT signaling.

3. The compound according to claim 1, wherein X, Y, R1, and R2 each independently comprise an optional chemical moiety that enables the resulting compound to bind to a DYRK or CLK protein.

4. One substituent of "X" is carbon and the other is nitrogen, or both substituents of "X" are carbon; and, One substituent of "Y" is nitrogen and the other substituents of "Y" are carbon, or two substituents of "Y" are nitrogen and one substituent of "Y" is carbon, or all substituents of "Y" are carbon. The compound according to claim 1.

5. The compound obtained above is 【Chemistry 2】 【Transformation 3】 A compound according to claim 4, selected from the above.

6. R1 is hydrogen, halogen (e.g., fluorine, bromine, iodine, chlorine), 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 A compound according to claim 1, selected from the following.

7. R2 is hydrogen, halogen (e.g., fluorine, bromine, iodine, chlorine), aryl, substituted aryl, heteroaryl, substituted heteroaryl, 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 Selected from, The compound according to claim 1, wherein X'' is selected from alkyl groups, haloalkyl groups, amino groups, alkylamino groups, hydroxyl groups, fluoro groups, chloro groups, bromo groups, and cyano groups.

8. The compound according to claim 6 or 7, wherein R, R', and R'' are independently selected from hydrogen, halogens (e.g., fluorine, bromine, chlorine, iodine), dihalogens (difluorine, dibromine, dichlorine, diiodine), CF3, OCH3, CHF2H, OCF3, methyl, dimethyl, alkoxy, alkylsulfonyl, cyano, carboxy, ester, amide, substituted amide, sulfonamide, substituted sulfonamide, methylenedioxy, heterocyclylalkyl, heterocyclyl, heterocyclylalkylamide, ether, and a lipophilic moiety consisting of a heterocycloalkyl group that is biologically equivalent to a secondary amine (e.g., morpholine, piperidine, piperazine).

9. The compound according to claim 6, wherein R3 and R4 are independently selected from hydrogen, halogen (e.g., fluorine, bromine, chlorine, iodine), methyl, ethyl, and methoxy.

10. The compound according to claim 1, wherein the compound is selected from the compounds listed in Table 1 and / or from the group of compounds 1 to 64.

11. A pharmaceutical composition comprising the compound described in claim 1.

12. The pharmaceutical composition according to claim 11 for treating, improving, or preventing disorders related to one or more of the following that lead to inhibition of WNT signaling in a patient: DYRK1A activity, DYRK1B activity, DYRK2 activity, DYRK3 activity, CLK1 activity, CLK2 activity, CLK3 activity, CLK4 activity, CDK7 activity, CDK8 / 19 activity, PI3K activity, PDGFrA / B activity, mTOR activity, WNT signaling activity, HIPK activity, and CMGC kinase activity.

13. The pharmaceutical composition according to claim 12, wherein the above-mentioned disorder is selected from Alzheimer's disease, Down syndrome, diabetes mellitus, autoimmune diseases, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colorectal cancer and metastatic colorectal cancer (e.g., metastatic colorectal cancer to the liver)), and other diseases.

14. The pharmaceutical composition according to claim 12, wherein the patient is a human patient.

15. The pharmaceutical composition according to claim 12, which is used in combination with one or more agents for treating Alzheimer's disease, Down syndrome, diabetes, autoimmune diseases, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colorectal cancer and metastatic colorectal cancer (e.g., metastatic colorectal cancer to the liver)), and other diseases.

16. The compound according to claim 1, A kit comprising instructions for use for administering the above compound to patients having impairments related to one or more of the following, which lead to inhibition of WNT signaling: DYRK1A activity, DYRK1B activity, DYRK2 activity, DYRK3 activity, CLK1 activity, CLK2 activity, CLK3 activity, CLK4 activity, CDK7 activity, CDK8 / 19 activity, PI3K activity, PDGFrA / B activity, mTOR activity, WNT signaling activity, HIPK activity, and CMGC kinase activity.

17. The kit according to claim 16, wherein the above-mentioned disorder is Alzheimer's disease, Down syndrome, diabetes, autoimmune disease, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colorectal cancer and metastatic colorectal cancer (e.g., metastatic colorectal cancer to the liver)), and other diseases.

18. The kit according to claim 17, further comprising one or more agents for treating Alzheimer's disease, Down syndrome, diabetes, autoimmune diseases, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colorectal cancer and metastatic colorectal cancer (e.g., metastatic colorectal cancer to the liver)), and other diseases.

19. A compound comprising the compound described in claim 1, A pharmaceutical composition for inhibiting one or more of the following, which lead to inhibition of WNT signaling in a target: DYRK1A activity, DYRK1B activity, DYRK2 activity, DYRK3 activity, CLK1 activity, CLK2 activity, CLK3 activity, CLK4 activity, CDK7 activity, CDK8 / 19 activity, PI3K activity, PDGFrA / B activity, mTOR activity, WNT signaling activity, HIPK activity, and CMGC kinase activity.

20. The pharmaceutical composition according to claim 19 for inhibiting one or more of the following: DYRK1A activity; PI3K / Akt signaling related to DYRK1A; Phosphorylation of tau related to DYRK1A; Phosphorylation of NFAT related to DYRK1A; Activation of the ASK1 / JNK1 pathway related to DYRK1A; Phosphorylation of p53 related to DYRK1A; Phosphorylation of Amph1 related to DYRK1A; Phosphorylation of dynamin 1 related to DYRK1A; Phosphorylation of synaptojanin associated with DYRK1A; Activity of presenilin 1 (a catalytic subunit of γ-secretase) associated with DYRK1A; Phosphorylation of amyloid precursor proteins related to DYRK1A; Activation of SIRT1 related to DYRK1A; Activity of heat shock factor 1 and 26S proteasome in relation to DYRK2; mTOR activity related to DYRK3; DYRK3 phosphorylation (e.g., PRAS40); DYRK1B activity; CMGC / CLK kinase activity; CLK1 activity; CLK2 activity; CLK3 activity; CLK4 activity; CDK7 activity; CDK8 activity; CDK19 activity; CDK8 / 19 activity; PI3K activity; PI3K mutant activity; PDGFrA / B activity; mTOR activity; c-KIT activity; RYK activity; and, WNT signaling.

21. The pharmaceutical composition according to claim 19, wherein the subject is a human subject suffering from or at risk of developing a disorder related to DYRK1A activity, DYRK1B activity, DYRK2 activity, DYRK3 activity, CLK1 activity, CLK2 activity, CLK3 activity, CLK4 activity, CDK7 activity, CDK8 / 19 activity, PI3K activity, PDGFrA / B activity, mTOR activity, WNT signaling activity, HIPK activity, and CMGC kinase activity, which leads to inhibition of WNT signaling.

22. The pharmaceutical composition according to claim 19, wherein the above-mentioned disorder is Alzheimer's disease, Down syndrome, diabetes mellitus, autoimmune diseases, inflammatory disorders (e.g., airway inflammation, osteoarthritis (e.g., knee-related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colorectal cancer and metastatic colorectal cancer (e.g., metastatic colorectal cancer to the liver)), and other diseases.

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