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, CLK, and CDK 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 WNT-driven cancers 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 mellitus (T1D / T2D), cognitive hyperactivity). 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)), as well as other kinases implicated in various disease states (e.g., the dual specificity protein kinase CLK1 (Clk-1) and the cyclin-dependent kinases CDK7, CDK8, and CDK19).

[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]

[0018] In some embodiments, R1 is hydrogen, [ka] JPEG2025525395000004.jpg72169 is selected from.

[0019] In some embodiments, R2 is hydrogen, halogen (e.g., fluorine, bromine, iodine, chlorine), aryl, substituted aryl, heteroaryl, substituted heteroaryl, [ka] JPEG2025525395000006.jpg80169 is selected from X″ is selected from alkyl, haloalkyl, amino, alkylamino, hydroxy, fluoro, chloro, bromo, and cyano groups.

[0020] In some embodiments, X', Y', and Z' are independently N, C, or CR'.

[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 is selected from hydrogen, halogen (eg, fluorine, bromine, chlorine, iodine), methyl, ethyl, and methoxy.

[0023] In some embodiments, R4 is [ka] is selected from.

[0024] The KD values for each compound listed in Table 1 were between 0.5 nM and 10 μM (DYRK1A) and demonstrated pan-DYRK and pan-CLK inhibitory profiles. Several compounds were shown to exhibit significant activity against CDK7, CDK8, and CDK19. Furthermore, many of the exemplified compounds demonstrated 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 at 37°C in 5% CO2 in 1x DMEM supplemented with 1% penicillin / streptomycin, 1% Glutamax, and 10% fetal bovine serum. 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.

[0025] [Table 1] JPEG2025525395000009.jpg237169 JPEG2025525395000010.jpg255168 JPEG2025525395000011.jpg255164 JPEG2025525395000012.jpg255160 JPEG2025525395000013.jpg255164 JPEG2025525395000014.jpg255160 JPEG2025525395000015.jpg255165 JPEG2025525395000016.jpg129169

[0026] The present invention further provides a process for preparing any of the compounds of the present invention.

[0027] 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.

[0028] In one embodiment, the compound is used as a DYRK protein degrader (see Valazquez, et al, 2019 Molecular Neurobiology 1-12).

[0029] 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 brain metastases, colorectal cancer). 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)).

[0030] The present invention also provides pharmaceutical compositions comprising a compound of the present invention in a pharmaceutically acceptable carrier.

[0031] 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.

[0032] [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. Cyclin-dependent kinases (CDKs) are a family of multifunctional enzymes that can modify various protein substrates involved in cell cycle progression, including CDK1 through CDK19.

[0033] 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).

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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).

[0039] 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).

[0040] Cyclin-dependent kinases (CDKs) have 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). CDK8 has been identified in loss-of-function RNAi screens as a gene that controls the activity of a β-catenin-driven reporter (see Rosenbluh et al., Trends Pharmacol Sci. 2014, 35, 103-109). Furthermore, CDK8 selectivity promotes the growth of colorectal 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). Indeed, 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, targeted at patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS).

[0041] Thus, there is clearly an urgent need for compounds that potently inhibit DYRK and CLK kinases, as well as CDK7, 8, and 19, while sparing other closely related kinases, in the treatment of both cancer and neurological diseases. The compounds described herein address this need.

[0042] In certain embodiments, compounds encompassed by the following formula are provided, including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka]

[0043] 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.

[0044] Such embodiments are not limited to specific definitions of each of the "X" and "Y" substituents.

[0045] 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]

[0046] In some embodiments, R1 is hydrogen, [ka] JPEG2025525395000020.jpg70169 is selected from.

[0047] In some embodiments, R2 is hydrogen, halogen (e.g., fluorine, bromine, iodine, chlorine), aryl, substituted aryl, heteroaryl, substituted heteroaryl, [ka] JPEG2025525395000022.jpg80169 wherein X″ is selected from alkyl, haloalkyl, amino, alkylamino, hydroxy, fluoro, chloro, bromo, and cyano groups.

[0048] In some embodiments, X', Y', and Z' are independently N, C, or CR'.

[0049] 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).

[0050] In some embodiments, R3 is selected from hydrogen, halogen (eg, fluorine, bromine, chlorine, iodine), methyl, ethyl, and methoxy.

[0051] In some embodiments, R4 is [ka] is selected from.

[0052] In some embodiments, the compound is listed in Table 1. In some embodiments, the compound is one of compounds 1-67 listed in Example I.

[0053] The present invention further provides a process for preparing any of the compounds of the present invention.

[0054] 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, CLK1, CLK2, CLK3, CLK4 activity, and / or CDK7, CDK8, CDK19, and all types of cancer involving DYRK1A, DYRK1B, DYRK2, DYRK3, CLK1, CLK2, CLK3, CLK4, and / or CDK7, CDK8, CDK19 activity, particularly cancers associated with disruption of WNT signaling.

[0055] 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).

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.).

[0061] The compounds of the present invention and their pharmaceutical compositions may be administered by any means that achieve their intended purpose. For example, administration may be parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, or topical. Alternatively, or concurrently, administration may be oral. The dosage depends on the recipient's age, health, and weight, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] [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.

[0071] Example I. This example provides synthesis and characterization information for compounds of the present invention.

[0072] General Scheme 1: [ka] In General Scheme 1, 68 was converted to 70 via standard SNAr chemistry by coupling with commercially available or synthetically prepared amines. 70 was then converted to 72 via Suzuki cross-coupling chemistry by coupling with commercially available or synthetically prepared boronic acids and boronic esters (X=CH or N, Q=Cl or Br, Z=CH or N, Y=N or CH).

[0073] General Scheme 2: Four compounds (29, 30, 33, 34) were prepared by the following general route.

[0074] [ka] In general Scheme 1, 68 was converted to 73 via Suzuki cross-coupling with commercially available boronic acids and boronic esters. 73 was then converted to 72 via standard SNAr chemistry by coupling with commercially available or synthetically prepared secondary amines (X = CH or N, Z = CH or N, Y = N or CH).

[0075] General Scheme 3: Two compounds (32, 67) were prepared by the following general route.

[0076] [ka] In General Scheme 3, 73 was converted to 74 via Boc protection followed by Ullmann coupling with commercially available aryl halides. 76 was then converted to 77 by Boc deprotection. A second Ullmann coupling reaction was used to give 79. 79 was converted to 80 via Suzuki cross-coupling chemistry by coupling with commercially available or synthesized boronic acids and boronic esters (X = CH or N, Q = Cl or Br, Z = CH or N, Y = N or CH).

[0077] General Scheme 4: Two compounds (52, 53) were prepared by the following general route.

[0078] [ka] In general Scheme 4, 81 was converted to 82 by demethylation, followed by a chlorination reaction to give 83. Standard SnAr chemistry was used to convert 81 to 85 using commercially available or synthetically prepared secondary amines. 85 was then converted to 86 via Suzuki cross-coupling chemistry by coupling with commercially available or synthetically prepared boronic acids and boronic esters.

[0079] 2-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 87.

[0080] [ka] Bis(pinacolato)diborane (210 mg, 1.1 eq, 825 μmol), potassium acetate (147 mg, 2.0 eq, 1.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (61 mg, 0.10 eq, 75.0 μmol), and 4-bromo-α,α-difluoro-2-picoline (156 mg, 95 μL, 1 eq, 750 μmol) were charged into a 5 mL Biotage™ microwave vial. The vial was capped, purged with argon, and then charged with degassed 1,4-dioxane (5.0 mL, 0.14 M) and heated to 80 °C for 12 h. The reaction was cooled, concentrated, and the residue was taken up with saturated NH4Cl, extracted with EtOAc, and recrystallized from 75:25 hexanes:DCM to give 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 87, as a white solid, which was used without further characterization.

[0081] Step 1, General Scheme 1 [ka]

[0082] 1-(4-(6-bromoquinazolin-4-yl)piperazin-1-yl)ethan-1-one, 90. [ka] In a 5 mL microwave vial, 6-bromo-4-chloroquinazoline (300 mg, 1 eq, 1.23 mmol), sodium bicarbonate (259 mg, 2.5 eq, 3.08 mmol), and 1-(piperazin-1-yl)ethan-1-one (205 mg, 1.3 eq, 1.60 mmol) were added. The mixture was capped, EtOH (1.2 mL) was added, and the mixture was stirred at 25 °C for 48 h overnight. After this time, the mixture was poured into 20 mL of HO, and the vial was washed with 5 mL of HO x 4, filtered, washed with HO (5 mL x 3), hexane (5 mL x 5), and dried under vacuum for 15 min to give 1-(4-(6-bromoquinazolin-4-yl)piperazin-1-yl)ethan-1-one, 90 (214 mg, 639 μmol, 52%). 1 HNMR (400 MHz, CDCl3) δ8.76 (s, 1H), 8.02 (dd, J = 1.9, 0.7 Hz, 1H), 7.88 - 7.77 (m, 2H), 3.85 - 3.80 (m, 4H), 3.79 - 3.70 (m, 4H), 2.18 (s, 3H). 13 CNMR (101 MHz, CDCl3) δ168.36, 163.90, 154.58, 150.20, 139.55, 132.16, 127.72, 121.01, 118.01, 55.60, 49.18, 45.75, 40.58, 23.92.

[0083] Step 2, General Scheme 1 1-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperazin-1-yl)ethan-1-one, 1. [ka] A 5 mL microwave vial was charged with 1-(4-(6-bromoquinazolin-4-yl)piperazin-1-yl)ethan-1-one (150 mg, 1 eq, 447 μmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (158 mg, 1.1 eq, 492 μmol), PdCl(dppf) (35 mg, 0.1 eq, 44 μmol), and potassium phosphate tribasic (256 mg, 2.7 eq, 1.21 mmol). The vial was capped and degassed for 10 min. After that, degassed 1,4-dioxane (1.2 mL):water (0.30 mL) (4:1 v / v) was added, degassed for an additional 10 min, and heated to 130 °C in an oil bath for 60 min. The reaction was cooled, a vent needle was placed, and concentrated HCl (2.20 g, 1.48 mL, 37 wt %, 50 eq, 22.4 mmol) was added. The mixture was stirred for 1 h, and then 10% NaOH was added until basic. 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 evaporated under vacuum, reconcentrated with DCM, dry-loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-30%) to give 1-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperazin-1-yl)ethan-1-one, 1, (58 mg, 0.17 mmol, 37%) as a brown powder, eluted with (0-10% DCM / MeOH). Mp 82-86 °C. LCMS [M+H] + 349. 1HNMR (400 MHz, CDCl3) δ8.79 (s, 2H), 8.18 (d, J = 5.4 Hz, 2H), 8.06 (d, J = 1.7 Hz, 2H), 8.03 - 7.94 (m, 4H), 6.94 - 6.90 (m, 2H), 6.77 (s, 2H), 4.76 (s, 3H), 3.88 (dd, J = 6.8, 4.0 Hz, 4H), 3.85 (s, 3H), 3.74 (dd, J = 6.6, 3.7 Hz, 4H). 13 CNMR (100 MHz, CDCl3) δ21.42, 41.19, 45.81, 49.10, 50.14, 106.34, 112.46, 116.62, 122.83, 129.64, 131.48, 136.19, 148.66, 149.23, 152.02, 154.41, 159.04, 164.68, 169.38

[0084] 4-(4-(4-phenylpiperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 2. Compound 2 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0085] 6-Bromo-4-(4-phenylpiperazin-1-yl)quinazoline, 91.

[0086] [ka] A 5 mL microwave vial was charged with 6-bromo-4-chloroquinazoline (200 mg, 1 eq, 821 μmol), sodium bicarbonate (173 mg, 2.5 eq, 2.05 mmol), and 1-phenylpiperazine (150 mg, 141 μL, 1.13 eq, 925 μmol). The mixture was capped, iPrOH (1.2 mL) was injected, and the mixture was stirred at 25 °C for 3 h overnight. After this time, the mixture was poured into 20 mL of HO, and the vial was washed with HO (5 mL × 4), filtered, washed with HO (5 mL × 3), hexane (5 mL × 5), and dried under vacuum for 15 min to give 6-bromo-4-(4-phenylpiperazin-1-yl)quinazoline, 91, (247 mg, 669 μmol, 81%) as a white solid. δ8.78 (s, 1H), 8.10 (d, J = 1.4 Hz, 1H), 7.86 (d, J = 1.3 Hz, 2H), 7.39 - 7.30 (m, 2H), 7.01 (d, J = 8.1 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 4.00 (t, J = 5.1 Hz, 4H), 3.45 (dd, J = 6.3, 3.9 Hz, 4H). 13 CNMR (100 MHz, CDCl3) δ163.47, 156.12, 154.00, 150.84, 143.99, 136.12, 130.27, 129.31, 127.26, 120.46, 118.87, 117.63, 116.34, 49.70, 49.18.

[0087] 4-(4-(4-phenylpiperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 2.

[0088] [ka] A 5 mL microwave vial was charged with 6-bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline (100 mg, 1 eq, 0.27 mmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (95 mg, 1.10 eq, 0.297 mmol), potassium phosphate tribasic (83 mg, 1.5 eq, 0.41 mmol), and PdCl(dppf) (19 mg, 0.1 eq, 27 μmol). The mixture was capped, charged with dioxane (0.9 mL), and stirred at 130 °C for 30 min. After this time, the mixture was poured into 20 mL of HO, the vial was washed with HO (5 mL x 4), filtered, washed with HO (5 mL x 3), hexane (5 mL x 5), and dried on vacuum for 15 min to give 4-(4-(4-phenylpiperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 2, as a brown solid. MP 94-100°C. LCMS [M+H] + 383. 1 HNMR (400 MHz, CDCl3) δ8.78 (s, 1H), 8.10 (d, J = 1.4 Hz, 1H), 7.86 (d, J = 1.3 Hz, 2H), 7.39 - 7.30 (m, 2H), 7.01 (d, J = 8.1 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 4.00 (t, J = 5.1 Hz, 4H), 3.45 (dd, J = 6.3, 3.9 Hz, 4H). 13 CNMR (101 MHz, CDCl3) δ163.47, 156.12, 154.00, 150.84, 143.99, 136.12, 130.27, 129.31, 127.26, 120.46, 118.87, 117.63, 116.34, 49.70, 49.18.

[0089] 4-(4-(4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 3.

[0090] Compound 3 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0091] 6-Bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 92.

[0092] [ka] To a 5 mL microwave vial, 6-bromo-4-chloroquinazoline (200 mg, 1 eq, 0.821 mmol) and 1-(pyridin-2-yl)piperazine (146 mg, 0.136 mL, 1.09 eq, 893 μmol) were added. The mixture was capped, EtOH (1.2 mL) was injected, and the mixture was stirred at 25 °C for 48 h. After this time, the mixture was poured into 20 mL of HO, and the vial was washed with HO (5 mL x 4), filtered, washed with HO (5 mL x 3), hexane (5 mL x 5), and dried under vacuum for 15 min to give 6-bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 92, (258 mg, 697 μmol, 85%) as a brown powder. Mp 100-105 °C. 1 HNMR (400 MHz, CDCl3) δ8.80 (s, 1H), 8.25 (dd, J = 5.0, 1.8 Hz, 1H), 8.17 (dd, J = 16.8, 3.6 Hz, 2H), 8.03 - 7.95 (m, 2H), 7.56 (ddd, J = 8.8, 7.1, 2.0 Hz, 1H), 6.95 (d, J = 5.1 Hz, 1H), 6.79 (s, 1H), 6.75 - 6.68 (m, 2H), 4.79 (s, 1H), 4.00 (dd, J = 6.7, 3.7 Hz, 4H), 3.84 (dd, J = 6.5, 3.7 Hz, 4H). 13CNMR (101 MHz, CDCl3) δ164.74, 159.15, 154.53, 152.04, 149.45, 149.20, 148.50, 148.01, 137.70, 135.80, 131.29, 129.51, 123.15, 116.68, 113.94, 112.54, 107.20, 106.37, 49.49, 45.02.

[0093] 4-(4-(4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 3.

[0094] [ka] A 5 mL microwave vial was charged with 6-bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline (100 mg, 1 eq, 0.270 mmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (95 mg, 1.10 eq, 0.297 mmol), potassium phosphate tribasic (83 mg, 1.5 eq, 0.41 mmol), and PdCl(dppf) (19 mg, 0.1 eq, 27.0 μmol). The mixture was capped, charged with dioxane (0.9 mL), and stirred at 130 °C for 30 min. After this time, the mixture was poured into 20 mL of HO, the vial was rinsed with HO (5 mL x 4), filtered, washed with HO (5 mL x 3), hexane (5 mL x 5), and dried under vacuum for 15 min to give 4-(4-(4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 3, as a brown solid. Mp 100-105 °C. LCMS [M+H] + 384. 1HNMR (400 MHz, CDCl3) δ8.80 (s, 1H), 8.25 (dd, J = 5.0, 1.8 Hz, 1H), 8.17 (dd, J = 16.8, 3.6 Hz, 2H), 8.03 - 7.95 (m, 2H), 7.56 (ddd, J = 8.8, 7.1, 2.0 Hz, 1H), 6.95 (d, J = 5.1 Hz, 1H), 6.79 (s, 1H), 6.75 - 6.68 (m, 2H), 4.79 (s, 1H), 4.00 (dd, J = 6.7, 3.7 Hz, 4H), 3.84 (dd, J = 6.5, 3.7 Hz, 4H). 13 CNMR (101 MHz, CDCl3) δ164.74, 159.15, 154.53, 152.04, 149.45, 149.20, 148.50, 148.01, 137.70, 135.80, 131.29, 129.51, 123.15, 116.68, 113.94, 112.54, 107.20, 106.37, 49.49, 45.02.

[0095] 4-(4-(4-phenylpiperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 4.

[0096] Compound 4 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0097] 6-Chloro-4-(4-phenylpiperazin-1-yl)pyrido[3,2-d]pyrimidine, 93.

[0098] [ka] To a 5 mL Biotage microwave vial containing a stir bar, sodium bicarbonate (33 mg, 15 μL, 1 eq, 400 μmol), and 1-phenylpiperazine (71 mg, 67 μL, 1.1 eq, 440 μmol) were added along with EtOH (1.0 mL, 0.4 M) and stirred for 10 min. 4,6-Dichloropyrido[3,2-d]pyrimidine (80 mg, 1 eq, 0.40 mmol) was added, and the vial was sealed and heated at 25 °C for 12 h. Upon completion, the reaction was diluted with water and filtered to give 6-chloro-4-(4-phenylpiperazin-1-yl)pyrido[3,2-d]pyrimidine, 93, (0.11 g, 0.34 mmol, 84%) as a white solid. LCMS [M+H] + 326.1H NMR (500 MHz, DMSO) δ8.59 (d, J = 2.8 Hz, 1H), 8.20 (dd, J = 8.7, 2.8 Hz, 1H), 7.89 (dd, J = 8.7, 2.8 Hz, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H), 4.50 (s, 4H), 3.35 (t, J = 4.3 Hz, 4H), 151.12, 146.92, 145.43, 140.47, 132.75, 129.46, 119.53, 115.89, 48.65, 40.50, 40.33, 40.16, 40.00, 39.83, 39.66, 39.50.

[0099] 4-(4-(4-phenylpiperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 4.

[0100] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (83 mg, 4.0 eq, 994 μmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (1 mg, 0.08 eq, 19 μmol), 6-chloro-4-(4-phenylpiperazin-1-yl)pyrido[3,2-d]pyrimidine (81 mg, 1 eq, 249 μmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (65 mg, 1.2 eq, 298 μmol). The vial was capped, purged with argon, and then charged with degassed 4:1 dioxane:HO (2.5 mL, 0.1 M) and heated to 80° C. for 12 h. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-20%) to give 4-(4-(4-phenylpiperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 4, (90 mg, 0.23 mmol, 94%) as a brown solid. LCMS [M+H] + 384.1H NMR (500 MHz, DMSO) δ8.58 (d, J = 2.1 Hz, 1H), 8.33 (dd, J = 8.9, 2.2 Hz, 1H), 8.24 (dd, J = 8.9, 2.2 Hz, 1H), 8.13 - 8.08 (m, 1H), 7.29 - 7.21 (m, 3H), 7.19 (s, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H), 6.31 (s, 2H), 4.64 (s, 4H), 3.43 (t, J = 4.9 Hz, 4H).13C NMR (126 MHz, DMSO) δ160.89, 159.11, 155.31, 151.16, 147.23, 146.40, 137.69, 133.33, 129.49, 125.15, 119.44, 115.81, 109.85, 105.65, 48.69, 40.48, 40.31, 40.14, 39.98, 39.81, 39.64, 39.48.

[0101] 4-(4-(4-(pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 5.

[0102] Compound 5 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0103] 6-Chloro-4-(4-(pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 94.

[0104] [ka] A 5 mL Biotage microwave vial with a stir bar was charged with sodium bicarbonate (33 mg, 15 μL, 1 eq, 400 μmol) and 1-(pyridin-2-yl)piperazine (65 mg, 61 μL, 1.0 eq, 400 μmol) along with EtOH (1.0 mL, 0.4 M) and stirred for 10 minutes. 4,6-Dichloropyrido[3,2-d]pyrimidine (8 mg, 1 eq, 0.4 mmol) was added, the vial was sealed, and stirred at 25 °C for 12 hours. Upon completion, the reaction was diluted with water and filtered to give 6-chloro-4-(4-(pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 94, (0.11 g, 0.34 mmol, 84%) as a white solid. LCMS [M+H] +327.1H NMR (500 MHz, DMSO) δ8.60 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.15 (dd, J = 5.0, 1.9 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.57 (ddd, J = 13C NMR (126 MHz, DMSO) δ159.16, 158.21, 155.46, 148.05, 146.91, 145.44, 140.42, 138.08, 132.78, 129.43, 113.64, 107.55, 44.84, 40.50, 40.33, 40.16, 40.00, 39.83, 39.66, 39.50.

[0105] 4-(4-(4-(pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 5.

[0106] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (83 mg, 4 eq, 991 μmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (14 mg, 0.08 eq, 19 μmol), 6-chloro-4-(4-(pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine (0.0810 g, 1 eq, 248 μmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (65 mg, 1.2 eq, 297 μmol). The vial was capped and purged with argon, then charged with degassed 4:1 dioxane:HO (2.5 mL, 0.1 M) and heated to 80° C. for 12 h. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-20%) to give 4-(4-(4-(pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 5, (90 mg, 0.23 mmol, 94%) as a brown solid. LCMS [M+H] +385.1H NMR (500 MHz, DMSO) δ8.58 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.25 - 7.18 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 6.68 (t, J = 6.1 Hz, 1H), 6.33 (s, 2H), 4.60 (s, 4H), 3.79 (t, J = 5.1 Hz, 4H).13C NMR (126 MHz, DMSO) δ160.85, 159.15, 155.30, 151.76, 148.78, 148.05, 147.22, 146.45, 138.09, 137.63, 133.37, 125.13, 113.54, 109.86, 107.43, 105.74, 44.88, 40.48, 40.31, 40.24, 40.15, 39.98, 39.81, 39.65, 39.48.

[0107] 4-(4-(4-(pyridin-4-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 6.

[0108] Compound 6 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0109] 6-Bromo-4-(4-(pyridin-4-yl)piperazin-1-yl)quinazoline, 95.

[0110] [ka] A 5 mL Biotage™ microwave vial was charged with a stir bar, sodium bicarbonate (42 mg, 1 eq, 500 μmol), and 1-(pyridin-4-yl)piperazine (97 mg, 1.2 eq, 600 μmol), and EtOH (2.0 mL, 0.4 M) and stirred for 5 minutes. 6-Bromo-4-chloroquinazoline (122 mg, 1 eq, 0.5 mmol) was added, and the vial was sealed and heated at 50° C. for 12 hours. Upon completion, the reaction was diluted with water and extracted with DCM (10 mL×3) to give 6-bromo-4-(4-(pyridin-4-yl)piperazin-1-yl)quinazoline, 82, (0.15 g, 0.41 mmol, 81%) as a white solid. LCMS [M+H] + 370. This compound was used without further purification or characterization.

[0111] 4-(4-(4-(pyridin-4-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 6.

[0112] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (90 mg, 4.0 eq, 1.08 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (15 mg, 0.08 eq, 21 μmol), 6-bromo 4-(4-(pyridin-4-yl)piperazin-1-yl)quinazoline (0.1 g, 1 eq, 270 μmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (71 mg, 1.2 eq, 324 μmol). The vial was capped, purged with argon, and then charged with degassed 4:1 MeOH:HO (2.7 mL, 0.1 M) and heated to 80° C. for 12 h. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry-loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-30%) to give 4-(4-(4-(pyridin-4-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 6, (96 mg, 0.25 mmol, 93%) as a brown solid. LCMS[M+H] 384.1H NMR (500 MHz, DMSO) δ8.67 (s, 1H), 8.24 (s, 2H), 8.10 (d, J = 8.9 Hz, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 6.93 (t, J = 7.2 Hz, 3H), 6.86 (s, 1H), 6.09 (s, 2H), 4.07 - 4.01 (m, 4H), 3.71 (t, J = 5.0 Hz, 5H).13C NMR (126 MHz, DMSO) δ163.73, 161.03, 155.07, 154.46, 151.94, 149.15, 147.94, 147.52, 135.56, 131.49, 129.22, 123.42, 116.22, 110.52, 105.72, 48.49, 45.25, 40.48, 40.31, 40.14, 39.98, 39.81, 39.64, 39.48.

[0113] 6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 7.

[0114] Compound 7 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0115] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (68 mg, 4.0 eq, 0.81 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (12 mg, 0.08 eq, 16 μmol), 6-bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline (0.075 g, 1 eq, 0.20 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (51 mg, 1.2 eq, 0.24 mmol). The vial was capped, purged with argon, and then charged with degassed 4:1 dioxane:HO (2.0 mL, 0.1 M) and heated to 160 °C for 25 min. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-20%) to give 6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 7, (61 mg, 0.16 mmol, 81%) as a brown solid. LCMS [M+H] +372.1H NMR (500 MHz, DMSO) δ8.53 (s, 1H), 8.27 (s, 1H), 8.09 (dd, J = 5.0, 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 8.6, 1.9 Hz, 1H), 7.97 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.52 (ddd, J = 8.9, 7.0, 2.0 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.61 (dd, J = 7.1, 4.9 Hz, 1H), 3.83 (d, J = 5.6 Hz, 7H), 3.71 (dd, J = 6.8, 3.7 Hz, 4H).13C NMR (126 MHz, DMSO) δ163.97, 159.27, 153.46, 148.09, 138.09, 136.96, 131.14, 130.53, 129.10, 128.98, 121.65, 120.03, 116.87, 113.61, 107.48, 49.24, 44.70, 40.37, 40.29, 40.21, 40.04, 39.87, 39.70, 39.54, 39.22.

[0116] 6-(2-(difluoromethyl)pyridin-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 8.

[0117] Compound 8 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0118] [ka] In this procedure, boronate 87 was used. To a 5 mL Biotage™ microwave vial was added sodium bicarbonate (90 mg, 4.0 eq, 1.08 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (15 mg, 0.08 eq, 21 μmol), 6-bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline (100 mg, 1.0 eq, 270 μmol), and 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (75 mg, 1.1 eq, 297 μmol). The vial was capped and purged with argon before being charged with degassed 4:1 dioxane:HO (2.7 mL, 0.1 M) and heated to 160 °C for 25 min. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry-loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-20%) to give 6-(2-(difluoromethyl)pyridin-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 8, (58 mg, 0.14 mmol, 51%) as a brown solid. LCMS [M+H] +419.1H NMR (500 MHz, DMSO) δ8.80 (d, J = 5.2 Hz, 1H), 8.67 (s, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.29 (dd, J = 8.7, 2.0 Hz, 1H), 8.18 - 8.11 (m, 2H), 8.11 - 8.04 (m, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.58 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 7.05 (s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 7.1, 4.9 Hz, 1H), 4.11 - 4.00 (m, 4H), 3.80 - 3.76 (m, 4H).13C NMR (126 MHz, DMSO) δ163.95, 159.13, 154.90, 152.50, 150.97, 148.33, 148.10, 138.10, 133.57, 131.78, 129.44, 124.80, 124.10, 118.76, 116.28, 114.26, 113.56, 107.39, 49.03, 44.58, 40.54, 40.38, 40.21, 40.04, 39.88, 39.71, 39.54, 0.57.

[0119] 4-(4-(4-(pyrimidin-4-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 9.

[0120] Compound 9 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0121] 6-Bromo-4-(4-(pyrimidin-4-yl)piperazin-1-yl)quinazoline, 96.

[0122] [ka] A 5 mL Biotage™ microwave vial was charged with a stir bar, sodium bicarbonate (42 mg, 1 eq, 500 μmol), 4-(piperazin-1-yl)pyrimidine (98 mg, 1.2 eq, 600 μmol), and EtOH (2.0 mL, 0.4 M) and stirred for 5 minutes. 6-Bromo-4-chloroquinazoline (122 mg, 1 eq, 0.5 mmol) was added, and the vial was sealed and heated at 50° C. for 12 hours. Upon completion, the reaction was diluted with water and extracted with DCM (10 mL×3) to give 6-bromo-4-(4-(pyrimidin-4-yl)piperazin-1-yl)quinazoline, 96, (0.15 g, 0.40 mmol, 81%) as a yellow solid. LCMS [M+H] + 371. This compound was used without further purification or characterization.

[0123] 4-(4-(4-(pyrimidin-4-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 9.

[0124] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (90 mg, 4.0 eq, 1.08 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (15 mg, 0.08 eq, 2 μmol), 6-bromo-4-(4-(pyrimidin-4-yl)piperazin-1-yl)quinazoline (0.1 g, 1 eq, 269 μmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (71 mg, 1.2 eq, 324 μmol). The vial was capped, purged with argon, and then charged with degassed 4:1 MeOH:HO (2.7 mL, 0.1 M) and heated to 80° C. for 12 h. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-30%) to give 4-(4-(4-(pyrimidin-4-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 9, (99 mg, 0.26 mmol, 96%) as a brown solid. LCMS [M+H] + 385.1H NMR (500 MHz, DMSO) δ8.67 (s, 1H), 8.55 (s, 1H), 8.24 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 5.4 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 5.4 Hz, 1H), 6.85 (d, J = 15.2 Hz, 2H), 6.08 (s, 2H), 4.03 - 3.97 (m, 4H), 3.89 (t, J = 5.2 Hz, 4H).13C NMR (126 MHz, DMSO) δ163.88, 161.32, 161.01, 158.36, 156.02, 154.46, 151.96, 149.21, 147.55, 135.64, 131.52, 129.24, 123.41, 110.56, 105.68, 79.65, 48.74, 43.18, 40.48, 40.31, 40.14, 39.98, 39.81, 39.64, 39.48.

[0125] 4-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 10.

[0126] Compound 10 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0127] 6-Bromo-4-(4-(pyrimidin-2-yl)piperazin-1-yl)quinazoline, 97.

[0128] [ka] A 5 mL Biotage microwave vial was charged with a stir bar, sodium bicarbonate (34 mg, 16 μL, 1 eq, 413 μmol), 2-(piperazin-1-yl)pyrimidine (8 mg, 1.2 eq, 496 μmol), and EtOH (2.0 mL, 0.4 M) and stirred for 5 minutes. 6-Bromo-4-chloroquinazoline (100 mg, 1 eq, 413 μmol) was added, and the vial was sealed and heated at 50 °C for 12 hours. Upon completion, the reaction was diluted with water and filtered to give 6-bromo-4-(4-(pyrimidin-2-yl)piperazin-1-yl)quinazoline, 97, (0.12 g, 0.32 mmol, 78%) as a white solid. LCMS [M+H] + 371. This compound was used without further purification or characterization.

[0129] 4-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 10.

[0130] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (85 mg, 4.0 eq, 1.01 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (14 mg, 0.08 eq, 20 μmol), 6-bromo-4-(4-(pyrimidin-2-yl)piperazin-1-yl)quinazoline (0.0940 g, 1 eq, 253 μmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (66 mg, 1.2 eq, 304 μmol). The vial was capped, purged with argon, and then charged with degassed 4:1 MeOH:HO (2.5 mL, 0.1 M) and heated to 80 °C for 12 h. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-30%) to give 4-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 10, (0.091 g, 0.24 mmol, 93%) as a brown solid. LCMS [M+H] + 385.1H NMR (500 MHz, DMSO) δ8.67 (s, 1H), 8.42 (d, J = 4.7 Hz, 2H), 8.22 (s, 1H), 8.10 (dd, J = 8.7, 1.9 Hz, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 5.4 Hz, 1H), 6.85 (s, 1H), 6.69 (t, J = 4.8 Hz, 1H), 6.14 (s, 2H), 4.02 - 3.92 (m, 8H). 13C NMR (126 MHz, DMSO) δ164.09, 161.59, 160.84, 158.48, 154.48, 151.97, 148.86, 147.74, 135.61, 131.53, 129.24, 123.44, 116.31, 110.89, 110.62, 105.86, 49.22, 43.49, 40.48, 40.31, 40.15, 39.98, 39.81, 39.65, 39.48.

[0131] 4-(4-(4-(oxetan-3-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 11.

[0132] Compound 11 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0133] 6-Bromo-4-(4-(oxetan-3-yl)piperazin-1-yl)quinazoline, 98.

[0134] [ka] A 5 mL Biotage microwave vial equipped with a stir bar was charged with 1-(oxetan-3-yl)piperazine (70 mg, 64 μL, 1.2 eq, 493 μmol), sodium bicarbonate (34 mg, 1 eq, 411 μmol), and EtOH (2.0 mL, 0.2 M) and stirred for 5 minutes. 6-Bromo-4-chloroquinazoline (0.1 g, 1 eq, 411 μmol) was added, the vial was sealed, and heated at 50 °C for 12 hours. Upon completion, the reaction was diluted with water and extracted with DCM (10 mL x 3) to give 6-bromo-4-(4-(oxetan-3-yl)piperazin-1-yl)quinazoline, 98, (0.13 g, 0.37 mmol, 91%) as a brown solid. LCMS [M+H] + 349. This compound was used without further purification or characterization.

[0135] 4-(4-(4-(oxetan-3-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 11.

[0136] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (144 mg, 4.0 eq, 1.7 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (25 mg, 0.08 eq, 34 μmol), 6-bromo-4-(4-(oxetan-3-yl)piperazin-1-yl)quinazoline (0.15 g, 1 eq, 429 μmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (104 mg, 1.1 eq, 472 μmol). The vial was capped, purged with argon, and then charged with degassed 4:1 MeOH:HO (4.3 mL, 0.1 M) and heated to 80 °C for 12 h. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-30%) to give 4-(4-(4-(oxetan-3-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 11, (0.15 g, 0.41 mmol, 96%) as a brown solid. LCMS [M+H] +363.1H NMR (500 MHz, DMSO) δ8.65 (s, 1H), 8.11 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 5.3 Hz, 1H), 6.80 (s, 1H), 6.12 (s, 2H), 4.58 (t, J = 6.6 Hz, 2H), 4.49 (t, J = 6.1 Hz, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.50 (p, J = 6.4 Hz, 1H), 2.48 (d, J = 5.3 Hz, 4H). 13C NMR (126 MHz, DMSO) δ164.21, 160.89, 154.48, 151.95, 149.03, 147.69,135.73, 131.56, 129.31, 123.22, 116.28, 110.54, 105.76, 74.78, 58.81, 49.45, 49.42, 40.49, 40.32,40.15, 39.99, 39.82, 39.65, 39.49.

[0137] 6-(2-methylpyridin-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 12.

[0138] Compound 12 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0139] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (68 mg, 4.0 eq, 0.81 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (12 mg, 0.08 eq, 16 μmol), 6-bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline (0.075 g, 1 eq, 0.20 mmol), and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (53 mg, 1.2 eq, 0.24 mmol). The vial was capped, purged with argon, and then charged with degassed 4:1 dioxane:HO (2.0 mL, 0.1 M) and heated to 160 °C for 25 min. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-20%) to give 6-(2-methylpyridin-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 12, (0.064 g, 0.17 mmol, 83%) as a brown solid. LCMS [M+H] +383.1H NMR (500 MHz, DMSO) δ8.67 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.23 (dd, J = 8.7, 2.0 Hz, 1H), 8.16 (dd, J = 4.8, 2.0 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.66 (dd, J = 5.3, 1.9 Hz, 1H), 7.59 (ddd, J = 8.9, 7.1, 2.1 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 7.1, 4.9 Hz, 1H), 4.04 - 3.99 (m, 4H), 3.81 - 3.75 (m, 4H), 2.58 (s, 3H). 13C NMR (126 MHz, DMSO) δ163.98, 159.25, 159.14, 154.66, 152.19, 150.15, 148.09, 138.10, 131.76, 129.31, 124.08, 121.22, 119.19, 116.33, 113.56, 107.41, 49.08, 44.59, 40.54, 40.37, 40.21, 40.04, 39.87, 39.71, 39.54, 24.66.

[0140] 6-(2-fluoropyridin-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 13.

[0141] Compound 13 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0142] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (68 mg, 4.0 eq, 0.81 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (12 mg, 0.08 eq, 16 μmol), 6-bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline (0.075 g, 1 eq, 0.20 mmol), and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (54 mg, 1.2 eq, 0.24 mmol). The vial was capped, purged with argon, and then charged with degassed 4:1 dioxane:HO (2.0 mL, 0.1 M) and heated to 160 °C for 25 min. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-20%) to give 6-(2-fluoropyridin-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 13, (0.054 g, 0.14 mmol, 69%) as a cream solid. LCMS [M+H] +387.1H NMR (500 MHz, DMSO) δ8.72 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.33 (dd, J = 8.7, 2.0 Hz, 1H), 8.21 (dd, J = 4.9, 2.0 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.91 (dd, J= 5.2, 2.0 Hz, 1H), 7.76 (s, 1H), 7.64 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.73 (dd, J = 7.1, 4.9 Hz, 1H), 4.11 - 4.06 (m, 4H), 3.86 - 3.80 (m, 4H). 13C NMR (126 MHz, DMSO) δ163.89, 163.68, 159.13, 154.95, 152.60, 148.77, 148.65, 148.10, 138.09, 133.10, 131.76, 129.34, 124.90, 120.50, 116.19, 113.55, 107.68, 107.38, 48.99, 44.57, 40.54, 40.37, 40.20, 40.04, 39.87, 39.70, 39.54.

[0143] 6-(1H-pyrazol-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 14.

[0144] Compound 14 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0145] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (68 mg, 4.0 eq, 0.81 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (12 mg, 0.08 eq, 16 μmol), 6-bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline (0.075 g, 1 eq, 0.20 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (47 mg, 1.2 eq, 0.24 mmol). The vial was capped, purged with argon, and then charged with degassed 4:1 dioxane:HO (2.0 mL, 0.1 M) and heated to 160 °C for 25 min. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-20%) to give 6-(1H-pyrazol-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 14, (52 mg, 0.15 mmol, 72%) as a brown solid. LCMS [M+H] + 358.1H NMR (500 MHz, DMSO) δ13.12 (s, 1H), 8.66 (s, 1H), 8.45 (s, 1H), 8.24 - 8.14 (m, 4H), 7.87 (d, J = 8.7 Hz, 1H), 7.64 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 6.92 (d, J= 8.6 Hz, 1H), 6.74 (dd, J = 7.1, 4.9 Hz, 1H), 3.96 (dd, J = 6.8, 3.7 Hz, 4H), 3.83 (dd, J = 6.7, 3.6 13C NMR (126 MHz, DMSO) δ163.95, 159.27, 153.41, 150.39, 148.09, 138.09, 131.41, 130.86, 129.01, 120.97, 120.17, 116.85, 113.59, 107.46, 49.23, 44.68, 40.54, 40.37, 40.20, 40.04, 39.87, 39.70, 39.54.

[0146] 4-(4-(4-(2-fluorophenyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 15.

[0147] Compound 15 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0148] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (9 mg, 4.0 eq, 1.08 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (15 mg, 0.08 eq, 2 μmol), 6-bromo-4-(4-(2-fluorophenyl)piperazin-1-yl)quinazoline (0.105 g, 1 eq, 271 μmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (6 mg, 1.1 eq, 298 μmol). The vial was capped, purged with argon, and then charged with degassed 4:1 MeOH:HO (2.8 mL, 0.1 M) and heated to 80 °C for 12 h. The reaction was cooled, diluted with DCM / MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-30%) to give 4-(4-(4-(2-fluorophenyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 15, (77 mg, 0.19 mmol, 71%) as a cream solid. LCMS [M+H] +401.1H NMR (500 MHz, DMSO) δ8.61 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.02 (dd, J = 8.7, 2.0 Hz, 1H), 7.96 (d, J = 5.3 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.14 - 7.09 (m, 1H), 7.05 (td, J = 7.4, 4.8 Hz, 2H), 6.98 - 6.90 (m, 1H), 6.86 (dd, J = 5.3, 1.7 Hz, 1H), 6.76 (s, 1H), 5.98 (s, 2H), 3.92 (t, J = 13C NMR (126 MHz, DMSO) δ164.26, 161.01, 154.49, 151.99, 149.23, 147.56, 135.87, 131.60, 129.35, 125.39, 125.36, 123.19, 119.96, 116.59, 116.43, 116.36, 110.60, 105.71, 50.51, 49.75, 40.55, 40.38, 40.21, 40.05, 39.88, 39.71, 39.54.

[0149] 4-(4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 16.

[0150] Compound 16 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0151] 6-Chloro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 99.

[0152] [ka] Sodium bicarbonate (63 mg, 1 eq, 750 μmol) and 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (173 mg, 1.0 eq, 750 μmol) were added to a 5 mL Biotage microwave vial along with EtOH (1.8 mL, 0.4 M) and stirred for 10 minutes. 4,6-Dichloropyrido[3,2-d]pyrimidine (150 mg, 1 eq, 750 μmol) was added, the vial was sealed, and stirred at 25° C. for 12 hours. Upon completion, the reaction was diluted with water and filtered to give 6-chloro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 99, (0.187 g, 0.474 μmol, 63%) as a white solid. LCMS [M+H] + 395.1H NMR (500 MHz, DMSO) δ8.60 (s, 1H), 8.48 - 8.42 (m, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 9.1, 2.6 Hz, 1H), 7.00 (d, J = 9.1 Hz, 1H), 4.46 (s, 4H), 3.97 - 3.76 (m, 4H).

[0153] 4-(4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 16.

[0154] [ka] To a 5 mL microwave vial was added 6-chloro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine (54 mg, 1 eq, 0.14 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (36 mg, 1.2 eq, 0.16 mmol), potassium phosphate tripotassium (87 mg, 3 eq, 0.41 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (9.0 mg, 0.08 eq, 11.0 μmol). The mixture was capped and purged with argon before being charged with degassed 1,4-dioxane (0.8 mL) and water (0.2 mL) and heated at 80 °C for 12 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 3). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-20% MeOH / DCM) to give 4-(4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 16, (49 mg, 110 μmol, 81%) as a brown solid. LCMS [M+H] + 452.95. 1 H NMR (500 MHz, CDCl3) δ8.66 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 5.3 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.69 (dd, J = 9.0, 2.5 Hz, 1H), 7.28 (d, J = 5.4 Hz, 1H), 7.17 (s, 1H), 6.70 (d, J = 8.9 Hz, 1H), 5.06 (s, 2H), 4.69 (s, 4H), 3.94 (t, J = 5.3 Hz, 4H). 13C NMR (126 MHz, CDCl3) δ160.21, 159.61, 158.87, 155.58, 151.47, 148.21, 147.48, 145.92, 137.66, 134.86, 133.80, 124.53, 123.58, 115.74, 111.81, 106.62, 105.64, 44.64.

[0155] 4-(4-(pyridin-2-yl)piperazin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline, 17.

[0156] Compound 17 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0157] [ka] A 5 mL Biotage™ microwave vial was charged with sodium bicarbonate (55 mg, 4.0 eq, 0.65 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (62 mg, 1.1 eq, 0.18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (11 mg, 0.08 eq, 13 μmol), and 6-bromo-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline (61 mg, 1.0 eq, 0.16 mmol). The vial was capped and purged with argon before being charged with degassed 1,4-dioxane (1.5 mL, 0.14 M) and heated to 80 °C for 12 h. The reaction was cooled, concentrated, diluted with DCM / MeOH, filtered through Celite, concentrated, dry-loaded onto silica gel, and purified on a 12 g silica gel column (DCM / MeOH, 0-20%) to give tert-butyl 3-(4-(4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. LCMS [M+H] + 508. This was then subjected to 1M HCl in EtOAc, resulting in precipitation of 4-(4-(pyridin-2-yl)piperazin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline, 17, (23 mg, 56 μmol, 34%) as a brown solid. LCMS [M+H] +408.1H NMR (500 MHz, DMSO) δ12.09 (s, 1H), 8.64 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 4.5 Hz, 1H), 8.24 (d, J = 6.8 Hz, 2H), 8.16 (d, J = 4.8 Hz, 1H), 8.11 (s, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.24 (dd, J = 8.0, 4.6 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 7.1, 13C NMR (126 MHz, DMSO) δ163.99, 159.27, 153.48, 150.28, 149.71, 148.10, 138.10, 133.00, 132.37, 129.13, 125.56, 121.13, 117.63, 116.94, 113.63, 107.49, 49.32, 44.77, 40.54, 40.38, 40.30, 40.21, 40.14, 40.04, 39.87, 39.71, 39.54, 0.57.

[0158] 6-(1H-pyrazol-3-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 18.

[0159] Compound 18 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0160] [ka] A 5 mL Biotage™ microwave vial was charged with tripotassium phosphate (0.14 g, 3 eq, 0.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (15 mg, 0.08 eq, 18 μmol), 6-chloro-4-(4-(pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine (74 mg, 1 eq, 0.23 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (53 mg, 1.2 eq, 0.27 mmol). The vial was capped, purged with argon, and then charged with degassed 4:1 dioxane:HO (2 mL, 0.1 M) and heated to 80 °C for 12 h. The reaction was cooled, diluted with DCM:MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 12 g column (DCM / MeOH 0-20%) to give 6-(1H-pyrazol-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 18, (17 mg, 48.0 μmol, 21%) as a pale yellow solid. LCMS [M+H] + 356.1H NMR (500 MHz, DMSO) δ13.23 (s, 1H), 8.50 (d, J = 5.7 Hz, 2H), 8.21 - 8.12 (m, 3H), 8.09 (d, J = 8.8 Hz, 1H), 7.58 (ddd, J = 8.8, 13C NMR (126 MHz, DMSO) δ158.82, 158.38, 153.59, 149.17, 147.58, 145.46, 137.76, 137.58, 136.60, 132.73, 128.16, 124.77, 121.88, 113.08, 107.04, 44.55.

[0161] 4-(4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 19.

[0162] Compound 19 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0163] 6-chloro-4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 100.

[0164] [ka] Sodium bicarbonate (71 mg, 1 eq, 850 μmol) and 1-(2-fluorophenyl)piperazine (153 mg, 134 μL, 1.0 eq, 850 μmol) were added to a 5 mL Biotage microwave vial along with EtOH (2.0 mL, 0.4 M) and stirred for 10 minutes. 4,6-Dichloropyrido[3,2-d]pyrimidine (170 mg, 1 eq, 850 μmol) was added, the vial was sealed, and the mixture was stirred at 25° C. for 12 hours. Upon completion, the reaction was diluted with water and filtered to give 6-chloro-4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 100, (0.193 g, 0.561 μmol, 66%) as a white solid. LCMS [M+H] + 344.1H NMR (500 MHz, DMSO) δ8.59 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.21 - 7.13 (m, 1H), 7.09 (qd, J = 7.4, 1.7 Hz, 2H), 7.00 (tdd, J = 7.6, 4.7, 2.2 Hz, 1H), 4.51 (s, 4H), 3.20 (t, J = 5.0 Hz, 4H).

[0165] 4-(4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 19.

[0166] [ka] A 5 mL microwave vial was charged with 6-chloro-4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidine (40 mg, 1 eq, 0.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (31 mg, 1.2 eq, 0.14 mmol), potassium phosphate tripotassium (99 mg, 4 eq, 0.47 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (7 mg, 0.08 eq, 9 μmol). The mixture was capped and purged with argon, then injected with degassed 4:1 dioxane:HO (0.7 mL, 0.2 M) and heated at 80 °C for 12 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 3). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-20% MeOH / DCM) to give 4-(4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 19, (36 mg, 90 μmol, 78%) as a pale yellow solid. LCMS [M+H] +402.1H NMR (500 MHz, CDCl3) δ8.65 (s, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 5.6 Hz, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.31 - 7.27 (d, 1H), 7.19 (s, 1H), 7.11 - 7.04 (m, 2H), 7.02 - 6.95 (m, 2H), 5.13 (s, 2H), 4.74 (s, 4H), 3.35 - 3.28 (t, 4H).

[0167] 4-(4-(2-fluorophenyl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrido[3,2-d]pyrimidine, 20.

[0168] Compound 20 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0169] [ka] A 5 mL Biotage™ microwave vial was charged with tripotassium phosphate (0.12 g, 4 eq, 0.58 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (9 mg, 0.08 eq, 12 μmol), 6-chloro-4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidine (50 mg, 1 eq, 0.15 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36 mg, 1.2 eq, 0.17 mmol). The vial was capped and purged with argon before being charged with degassed 4:1 dioxane:HO (0.7 mL, 0.2 M) and heated to 80 °C for 12 h. The reaction was cooled, diluted with DCM:MeOH, filtered through Celite, concentrated, dry-loaded onto silica gel, and purified on a 12 g column (DCM / MeOH 0-20%) to give 4-(4-(2-fluorophenyl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrido[3,2-d]pyrimidine, 20 (26 mg, 67 μmol, 46%) as a brown solid. LCMS [M+H] + 390.1H NMR (500 MHz, DMSO) δ8.50 (s, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 8.09 (s, 2H), 7.21 - 7.08 (m, 3H), 7.01 (dtd, J = 8.1, 4.8, 13C NMR (126 MHz, DMSO) δ158.32, 156.00, 154.05, 153.55, 148.83, 145.49, 139.66, 139.60, 137.69, 136.75, 132.71, 130.29, 124.87, 124.85, 124.56, 122.66, 122.59, 122.36, 119.54, 116.06, 115.90, 73.49, 50.40, 24.94.

[0170] 6-(1-Methyl-1H-pyrazol-3-yl)-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 21.

[0171] Compound 21 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0172] [ka] To a 5 mL Biotage™ microwave vial was added tripotassium phosphate (0.11 g, 4 eq, 0.51 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (8 mg, 0.08 eq, 10 μmol), 6-chloro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine (50 mg, 1 eq, 0.13 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32 mg, 1.2 eq, 0.15 mmol). The vial was capped and purged with argon before being charged with degassed 4:1 dioxane:HO (0.7 mL, 0.2 M) and heated to 80 °C for 12 h. The reaction was cooled, diluted with DCM:MeOH, filtered through Celite, concentrated, dry-loaded onto silica gel, and purified on a 12 g column (DCM / MeOH 0-20%) to give 6-(1-methyl-1H-pyrazol-3-yl)-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 21, (21 mg, 48 μmol, 39%) as a white solid. LCMS [M+H] +441.1H NMR (500 MHz, DMSO) δ8.50 (s, 1H), 8.47 - 8.45 (m, 1H), 8.44 (s, 1H), 8.18 - 8.13 (m, 1H), 8.10 (s, 2H), 7.86 (dd, J = 9.1, 2.6 Hz, 1H), 7.01 (d, J = 9.1 Hz, 1H), 4.56 (s, 4H), 3.94 (s, 3H), 3.92 (t, J = 5.3 Hz, 4H).

[0173] 6-(1H-pyrazol-3-yl)-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 22.

[0174] Compound 22 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0175] [ka] A 5 mL Biotage™ microwave vial was charged with tripotassium phosphate (0.15 g, 4 eq, 0.71 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (12 mg, 0.08 eq, 14 μmol), 6-chloro-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d] (70 mg, 1 eq, 0.18 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (63 mg, 1.2 eq, 0.21 mmol). The vial was capped and purged with argon before being charged with degassed 4:1 dioxane:HO (1.0 mL, 0.2 M) and heated to 80 °C for 12 h. The reaction was cooled, diluted with DCM:MeOH, filtered through Celite, and concentrated. A mixture of DCM:TFA (1:2, 1 mL) was added to the crude mixture, stirred at room temperature overnight, and basified with 1N NaOH. The mixture was extracted with DCM, washed with 10% NaOH, water, and brine. The organic layer was dried over sodium sulfate, concentrated, dry-loaded onto silica gel, and purified on a 12 g column (DCM / MeOH 0–20%) to give 6-(1H-pyrazol-3-yl)-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 22, (14 mg, 34 μmol, 19%) as a brown solid. LCMS[M+H] + 427.1H NMR (500 MHz, DMSO) δ13.23 (s, 1H), 8.52 (s, 1H), 8.51 (s, 1H), 8.48 - 8.44 (m, 1H), 8.20 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 9.1, 2.6 Hz, 1H), 7.02 (d, J = 9.1 Hz, 1H), 4.56 (s, 4H), 4.00 - 3.82 (m, 4H).

[0176] 4-(4-(2-fluorophenyl)piperazin-1-yl)-6-(1H-pyrazol-3-yl)pyrido[3,2-d]pyrimidine, 23.

[0177] Compound 23 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0178] [ka] To a 5 mL Biotage™ microwave vial was added tripotassium phosphate (0.17 g, 4 eq, 0.81 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (13 mg, 0.08 eq, 16 μmol), 6-chloro-4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidine (70 mg, 1 eq, 0.20 mmol), and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (72 mg, 1.2 eq, 0.24 mmol). The vial was capped and purged with argon before being charged with degassed 4:1 dioxane:HO (1.0 mL, 0.2 M) and heated to 80 °C for 12 h. The reaction was cooled, diluted with DCM:MeOH, filtered through Celite, and concentrated. A mixture of DCM:TFA (1:2, 1.2 mL) was added to the crude mixture, stirred at room temperature overnight, and basified with 1N NaOH. The mixture was extracted with DCM, washed with 10% NaOH, water, and brine. The organic layer was dried over sodium sulfate, concentrated, dry-loaded onto silica gel, and purified on a 12 g column (DCM / MeOH 0-20%) to give 4-(4-(2-fluorophenyl)piperazin-1-yl)-6-(1H-pyrazol-3-yl)pyrido[3,2-d], 23, (64 mg, 173 μmol, 85%) as a yellow / orange solid. LCMS [M+H] +376.1H NMR (500 MHz, DMSO) δ8.76 (s, 1H), 8.40 (s, 2H), 8.29 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.13 13C NMR (126 MHz, DMSO) δ158.73, 158.46, 156.41, 154.47, 151.18, 150.35, 139.64, 139.58, 138.67, 131.75, 131.52, 126.75, 125.40, 125.37, 123.32, 123.26, 121.65, 120.07, 120.05, 116.63, 116.47, 50.76.

[0179] 4-(4-(4-(4-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 24.

[0180] Compound 24 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0181] 6-Chloro-4-(4-(4-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 101.

[0182] [ka] To a 5 mL Biotage microwave vial was added sodium bicarbonate (55 mg, 1 eq, 760 μmol) and 1-(4-fluorophenyl)piperazine (117 mg, 1.0 eq, 650 μmol) along with EtOH (1.6 mL, 0.4 M) and stirred for 10 min. 4,6-Dichloropyrido[3,2-d]pyrimidine (130 mg, 1 eq, 650 μmol) was added, the vial was sealed, and stirred at 25 °C for 12 h. Upon completion, the reaction was diluted with water and filtered to give 6-chloro-4-(4-(4-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidine, 101, (0.140 g, 0.407 μmol, 63%). LCMS [M+H] + 344.1H NMR (500 MHz, DMSO) δ8.59 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.08 (t, J = 8.8 Hz, 2H), 7.02 (dd, J = 9.2, 4.7 Hz, 2H), 4.64 - 4.38 (s, 4H), 3.29 (t, J = 5.2 Hz, 4H).

[0183] 4-(4-(4-(4-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 24.

[0184] [ka] A 5 mL microwave vial was charged with 6-chloro-4-(4-(4-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidine (50 mg, 1 eq, 0.15 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (38 mg, 1.2 eq, 0.17 mmol), potassium phosphate tripotassium (120 mg, 4 eq, 0.58 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (9 mg, 0.08 eq, 12.0 μmol). The mixture was capped and purged with argon, then injected with degassed 4:1 dioxane:HO (1.0 mL, 0.1 M) and heated at 80 °C for 12 h. After this time, the 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 x 3). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-20% MeOH / DCM) to give 4-(4-(4-(4-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)pyridin-2-amine, 24, (43 mg, 109 μmol, 75%) as an orange solid. LCMS [M+H] +402.1H NMR (500 MHz, DMSO) δ8.56 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.20 (d, J = 5.4 Hz, 1H), 7.15 (s, 1H), 7.09 (t, J = 8.8 Hz, 2H), 7.03 (dd, J = 9.3, 4.6 Hz, 2H), 6.18 (s, 2H), 4.63 (s, 4H), 3.36 (t, J = 5.1 Hz, 4H). 13C NMR (126 MHz, DMSO) δ161.20, 159.11, 157.55, 155.68, 155.25, 151.96, 149.47, 148.11, 148.09, 147.22, 146.15, 137.69, 133.32, 125.11, 117.72, 117.66, 115.92, 115.74, 109.85, 105.43, 49.58.

[0185] 4-(4-(4-phenylpiperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 25.

[0186] Compound 25 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0187] 6-Bromo-4-(4-phenylpiperazin-1-yl)quinoline, 102.

[0188] [ka] To a 5 mL microwave vial containing 1-phenylpiperazine (1.2 g, 1.17 mL, 6 eq, 7.42 mmol) dissolved in isopropyl alcohol (3.0 mL, 0.4 M) was added N,N-diisopropylethylamine (799 mg, 1.1 mL, 5 eq, 6.19 mmol) and 6-bromo-4-chloroquinoline (300 mg, 1 eq, 1.24 mmol). The reaction mixture was stirred at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was poured into water, extracted with EtOAc (20 mL × 2), washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry loaded onto silica gel and purified on a 24 g silica gel column (5-50% EtOAc / hexanes) to give 6-bromo-4-(4-phenylpiperazin-1-yl)quinoline, 102, (350 mg, 0.95 mmol, 77%). LCMS [M+H] + 369.1H NMR (500 MHz, CDCl3) δ8.75 (d, J = 5.0 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.75 (dd, J = 9.0, 2.3 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.09 - 6.99 (m, 2H), 6.97 - 6.88 (m, 2H), 3.53 - 3.44 (m, 4H), 3.40 (dd, J = 6.3, 3.4 Hz, 4H). 13C NMR (126 MHz, CDCl3) δ155.96, 151.17, 151.06, 148.17, 132.64, 131.86, 129.29, 126.03, 124.86, 120.41, 119.63, 116.45, 109.70, 52.25, 49.40.

[0189] 4-(4-(4-phenylpiperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 25.

[0190] [ka] A 5 mL microwave vial was charged with 6-bromo-4-(4-phenylpiperazin-1-yl)quinoline (80 mg, 1 eq, 0.22 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (57 mg, 1.2 eq, 0.26 mmol), potassium phosphate tripotassium (180 mg, 4 eq, 0.87 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (14 mg, 0.08 eq, 17.0 μmol). The mixture was capped and purged with argon, then injected with degassed 4:1 dioxane:HO (2.0 mL, 0.1 M) and heated at 80 °C for 6 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 3). The aqueous layer was washed with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-20% MeOH / DCM) to give 4-(4-(4-phenylpiperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 25, (38 mg, 101 μmol, 47%) as a yellow solid. LCMS [M+H] +382.1H NMR (500 MHz, CDCl3) δ8.79 (d, J = 5.1 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.90 (dd, J = 8.6, 2.0 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.04 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 5.6 Hz, 1H), 6.97 (d, J = 5.1 Hz, 1H), 6.94 (t, J = 7.3 Hz, 1H), 6.87 (s, 1H), 5.10 (s, 2H), 3.51 (d, J = 5.1 Hz, 4H), 3.48 (d, J = 5.4 Hz, 4H). 13C NMR (126 MHz, DMSO) δ160.56, 156.29, 151.42, 150.89, 149.09, 148.76, 147.51, 135.02, 130.45, 129.00, 127.47, 122.75, 121.07, 119.25, 115.66, 110.04, 109.67, 105.07, 51.79, 48.33.

[0191] 4-(4-phenylpiperazin-1-yl)-6-(1H-pyrazol-4-yl)quinoline, 26.

[0192] Compound 26 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0193] [ka] A 5 mL Biotage™ microwave vial was charged with tripotassium phosphate (0.22 g, 4 eq, 1.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (17 mg, 0.08 eq, 20 μmol), 6-bromo-4-(4-phenylpiperazin-1-yl)quinoline (94 mg, 1 eq, 0.26 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (90 mg, 1.2 eq, 0.31 mmol). The vial was capped, purged with argon, and then charged with degassed 4:1 dioxane:HO (1.5 mL, 0.1 M) and heated to 80 °C for 5 h. The reaction was cooled, diluted with DCM:MeOH, filtered through Celite, and concentrated. A mixture of DCM:TFA (1:2, 1.5 mL) was added to the crude mixture, stirred at room temperature overnight, and basified with 1N NaOH. The mixture was extracted with DCM, washed with 10% NaOH, water, and brine. The organic layer was dried over sodium sulfate, concentrated, dry-loaded onto silica gel, and purified on a 12 g column (DCM / MeOH 0-20%) to give 4-(4-phenylpiperazin-1-yl)-6-(1H-pyrazol-4-yl)quinoline, 26, (12 mg, 35 μmol, 14%) as a reddish-brown solid. LCMS [M+H] + 356. LCMS [M+H] + 356.1H NMR (500 MHz, DMSO) δ13.11 (s, 1H), 8.65 (d, J = 5.8 Hz, 1H), 8.40 (s, 1H), 8.21 (d, J = 1.9 Hz, 1H), 8.11 (dd, J = 8.9, 1.8 Hz, 2H), 7.96 (d, J = 8.7 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.13 (d, J = 5.8 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.83 (t, J = 7.3 Hz, 1H), 3.66 (s, 4H), 3.50 (t, J = 5.0 Hz, 4H).

[0194] 4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperazin-1-yl)phenol, 27.

[0195] Compound 27 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0196] 4-(4-(6-bromoquinazolin-4-yl)piperazin-1-yl)phenol, 103. [ka] Sodium bicarbonate (45 mg, 1 eq, 0.534 mmol) and 4-(piperazin-1-yl)phenol (95 mg, 1.0 eq, 0.534 mmol) were added to a 5 mL Biotage microwave vial along with EtOH (1.3 mL, 0.4 M) and stirred for 10 minutes. 6-Bromo-4-chloroquinazoline (130 mg, 1 eq, 0.534 mmol) was added, the vial was sealed, and stirred at 25 °C for 12 hours. Upon completion, the reaction was diluted with water and filtered to give 4-(4-(6-bromoquinazolin-4-yl)piperazin-1-yl)phenol, 103, (0.158 g, 0.410 mmol, 77%) as a brown solid. LCMS [M+H] + 386.1H NMR (500 MHz, CDCl3) δ8.54 (t, J = 4.3 Hz, 1H), 8.29 (s, 1H), 7.91 (t, J = 4.1 Hz, 1H), 7.67 (d, J = 4.9 Hz, 2H), 7.25 (d, J = 4.8 Hz, 1H), 6.73 (s, 1H), 6.64 (dt, J = 8.6, 4.2 Hz, 2H), 3.84 (s, 4H), 3.09 (p, J = 4.5 Hz, 4H).

[0197] 4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperazin-1-yl)phenol, 27.

[0198] [ka] A 5 mL microwave vial was charged with 4-(4-(6-chloroquinazolin-4-yl)piperazin-1-yl)phenol (50 mg, 1 eq, 0.15 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (39 mg, 1.2 eq, 0.18 mmol), potassium phosphate tripotassium (120 mg, 4 eq, 0.59 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (9 mg, 0.08 eq, 12 μmol). The mixture was capped and purged with argon, then charged with degassed 4:1 dioxane:HO (1.0 mL, 0.1 M) and heated at 80 °C for 12 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 3). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-10% MeOH / DCM) to give 4-(4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperazin-1-yl)phenol, 27, (24 mg, 60 μmol, 41%) as a light brown solid. LCMS [M+H] +399.1H NMR (500 MHz, DMSO) δ8.89 (s, 1H), 8.67 (s, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.09 (dd, J = 8.7, 2.0 Hz, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 6.92 (dd, J = 5.3, 1.7 Hz, 1H), 6.90 - 6.83 (m, 2H), 6.82 (dd, J = 1.7, 0.7 Hz, 1H), 6.72 - 6.65 (m, 2H), 6.06 (s, 2H), 3.94 (t, J = 5.0 Hz, 4H), 3.20 (t, J = 5.1 Hz, 4H). 13C NMR (126 MHz, DMSO) δ163.80, 160.55, 154.03, 151.46, 151.27, 148.78, 147.09, 143.89, 135.31, 131.10, 128.85, 122.69, 118.15, 115.89, 115.53, 110.05, 105.16, 50.07, 49.33.

[0199] 4-(4-(6-(2-aminopyridin-4-yl)pyrido[3,2-d]pyrimidin-4-yl)piperazin-1-yl)phenol, 28.

[0200] Compound 28 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0201] 4-(4-(6-chloropyrido[3,2-d]pyrimidin-4-yl)piperazin-1-yl)phenol, 104.

[0202] [ka] To a 20 mL Biotage microwave vial was added sodium bicarbonate (189 mg, 1 eq, 2.25 mmol) and 4-(piperazin-1-yl)phenol (401 mg, 1.0 eq, 2.25 mmol) along with EtOH (5.0 mL, 0.4 M) and stirred for 10 minutes. 4,6-Dichloropyrido[3,2-d]pyrimidine (450 mg, 1 eq, 2.25 mmol) was added, the vial was sealed, and stirred at 25 °C for 2 days. Upon completion, the reaction was diluted with water and filtered to give 4-(4-(6-chloropyrido[3,2-d]pyrimidin-4-yl)piperazin-1-yl)phenol, 104, (0.429 g, 1.26 mmol, 56%) as a brown solid. LCMS [M+H] + 342.1H NMR (500 MHz, DMSO) δ8.86 (s, 1H), 8.57 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 6.89 - 6.81 (m, 2H), 6.73 - 6.61 (m, 2H), 4.47 (s, 4H), 3.24 - 3.02 (m, 4H). 13C NMR (126 MHz, DMSO) δ157.60, 154.96, 151.22, 146.46, 144.90, 143.78, 140.00, 132.25, 128.95, 118.07, 115.48, 50.24.

[0203] 4-(4-(6-(2-aminopyridin-4-yl)pyrido[3,2-d]pyrimidin-4-yl)piperazin-1-yl)phenol, 28.

[0204] [ka] A 20 mL microwave vial was charged with 4-(4-(6-chloropyrido[3,2-d]pyrimidin-4-yl)piperazin-1-yl)phenol (429 mg, 1 eq, 1.26 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (331 mg, 1.2 eq, 1.51 mmol), potassium phosphate tripotassium (1.07 g, 4 eq, 5.02 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (82 mg, 0.08 eq, 100 μmol). The mixture was capped and purged with argon, then charged with degassed 4:1 dioxane:HO (10 mL, 0.1 M) and heated at 80 °C for 5 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 3). The aqueous layer was washed with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 24 g silica gel column (0-20% MeOH / DCM) to give 4-(4-(6-(2-aminopyridin-4-yl)pyrido[3,2-d]pyrimidin-4-yl)piperazin-1-yl)phenol, 28, (200 mg, 501 μmol, 40%) as a brown solid. LCMS [M+H] + 400.1H NMR (500 MHz, DMSO) δ8.90 (s, 1H), 8.56 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 5.3 Hz, 1H), 7.19 (dd, J = 5.4, 1.6 Hz, 1H), 7.15 (dd, J = 1.7, 0.8 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.72 - 6.65 (m, 2H), 6.17 (s, 2H), 4.61 (s, 5H), 3.22 (t, J = 4.8 Hz, 4H).

[0205] Step 1, General Scheme 2 [ka]

[0206] 4-(4-chloroquinolin-6-yl)pyridin-2-amine, 107.

[0207] [ka] A 100 mL RBF was charged with tripotassium phosphate (1.05 g, 1.5 eq, 4.95 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (270 mg, 0.1 eq, 330 μmol), 6-bromo-4-chloroquinoline (800 mg, 1 eq, 3.30 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (799 mg, 1.1 eq, 3.63 mmol). The mixture was charged with degassed 4:1 dioxane:HO (16 mL, 0.2 M), purged with argon for 10 min, and refluxed at 80 °C for 12 h. The reaction was cooled, diluted with DCM:MeOH, filtered through Celite, concentrated, dry loaded onto silica gel, and purified on a 24 g column (DCM / MeOH 0-8%) to give 4-(4-chloroquinolin-6-yl)pyridin-2-amine, 107 (428 mg, 1.67 mmol, 51%). LCMS [M+H] + 256.1H NMR (500 MHz, CDCl3) δ8.82 (d, J = 4.7 Hz, 1H), 8.44 (d, J = 1.9 Hz, 1H), 8.26 - 8.10 (m, 2H), 7.99 (dd, J = 8.8, 2.0 Hz, 1H), 7.55 (d, J = 4.7 Hz, 1H), 7.04 (d, J = 5.0 Hz, 1H), 6.90 (s, 1H), 4.95 (s, 2H).

[0208] Step 2, General Scheme 2 4-(4-(4-phenylpiperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 29.

[0209] [ka] To a 5 mL microwave vial containing 1-(pyridin-2-yl)piperazine (0.11 g, 0.10 mL, 6 eq, 0.68 mmol) dissolved in isopropyl alcohol (0.8 mL, 0.1 M) was added N,N-diisopropylethylamine (73 mg, 99 μL, 5 eq, 0.57 mmol) and 4-(4-chloroquinolin-6-yl)pyridin-2-amine (29 mg, 1 eq, 0.11 mmol). The reaction was stirred at 100 °C for 12 h. After cooling to room temperature, the reaction was poured into water (10 mL), extracted with EtOAc (40 mL), washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry loaded onto silica gel and purified on a 12 g silica gel column (0-20% MeOH / DCM) to give 4-(4-(4-phenylpiperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 29, (33 mg, 0.11 mmol, 77%) as a brown solid. LCMS [M+H] + 383.1H NMR (500 MHz, DMSO) δ8.74 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.17 (dd, J = 5.1, 1.9 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.99 (dd, J = 8.8, 2.0 Hz, 1H), 7.60 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 7.10 (d, J = 5.0 Hz, 1H), 6.97 - 6.89 (m, 2H), 6.86 (d, J = 1.7 Hz, 1H), 6.71 (dd, J = 7.1, 4.9 Hz, 1H), 6.06 (s, 2H), 3.81 (d, J = 5.5 Hz, 4H), 3.35 (d, J = 5.0 Hz, 4H).

[0210] 4-(4-(4-(4-fluorophenyl)piperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 30.

[0211] Compound 30 was prepared according to general scheme 2 via a two-step procedure reported for the preparation of compound 29. The second step is reported below.

[0212] [ka] 4-(4-(4-Phenylpiperazin-1-yl)quinolin-6-yl)pyridin-2-amine, prepared in a manner similar to Step 2, General Scheme 2, as described for 29. 4-(4-(4-(4-Fluorophenyl)piperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 30, (13 mg, 0.16 mmol, 21%) was obtained as a brown solid. LCMS [M+H] + 400.1H NMR (500 MHz, CDCl3) δ8.78 (d, J = 5.0 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.88 (dd, J = 8.7, 2.0 Hz, 1H), 6.99 (dddd, J = 17.3, 12.6, 7.5, 3.7 Hz, 6H), 6.82 (s, 1H), 4.82 (s, 2H), 3.48 - 3.37 (m, 8H). 13C NMR (101 MHz, CDCl3) δ158.85, 158.75, 157.11, 156.37, 151.39, 150.25, 149.60, 148.07, 147.69, 147.67, 135.59, 130.79, 127.99, 123.48, 121.92, 118.28, 118.21, 115.83, 115.61, 112.71, 109.49, 106.64, 52.35, 50.40.

[0213] 4-(4-(4-(4-fluorophenyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 31.

[0214] Compound 31 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0215] 6-Bromo-4-(4-(4-fluorophenyl)piperazin-1-yl)quinazoline, 108.

[0216] [ka] In a 5 mL Biotage microwave vial, 1-(4-fluorophenyl)piperazine (96 mg, 96 μL, 1.0 eq, 534 μmol) and sodium bicarbonate (45 mg, 1 eq, 534 μmol) were dissolved in EtOH (1.3 mL, 0.4 M) and stirred for 10 min. 6-Bromo-4-chloroquinazoline (130 mg, 1 eq, 534 μmol) was added, the vial was capped, and the mixture was stirred at 25 °C for 12 h. After this time, the mixture was cooled to room temperature, diluted with water, and filtered to give 6-bromo-4-(4-(4-fluorophenyl)piperazin-1-yl)quinazoline, 108 (169 mg, 437 μmol, 82%) as a brown solid. LCMS [M+H] + 388.1H NMR (500 MHz, CDCl3) δ8.75 (s, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.94 - 7.78 (m, 2H), 7.07 - 6.97 (m, 2H), 6.97 - 6.90 (m, 2H), 3.99 (t, J = 5.1 Hz, 4H), 3.51 - 3.24 (m, 4H).

[0217] 4-(4-(4-(4-fluorophenyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 31.

[0218] [ka] A 5 mL microwave vial was charged with 6-chloro-4-(4-(4-fluorophenyl)piperazin-1-yl)quinazoline (60 mg, 1 eq, 0.18 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (46 mg, 1.2 eq, 0.21 mmol), potassium phosphate tripotassium (0.15 mg, 4 eq, 0.7 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (11 mg, 0.08 eq, 14 μmol). The mixture was capped and purged with argon, then charged with degassed 4:1 dioxane:HO (1.5 mL, 0.1 M) and heated at 80 °C for 6 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 3). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-10% MeOH / DCM) to give 4-(4-(4-(4-fluorophenyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 31, (28 mg, 0.18 mmol, 40%) as a yellow solid. LCMS [M+H] +401.1H NMR (500 MHz, CDCl3) δ8.79 (s, 1H), 8.13 (d, J = 5.5 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.96 (dd, J = 8.7, 1.9 Hz, 1H), 7.04 - 6.97 (m, 2H), 6.97 - 6.91 (m, 3H), 6.81 (d, J = 1.6 Hz, 1H), 4.98 (s, 2H), 4.00 (t, J = 5.0 Hz, 4H), 3.34 (t, J = 5.0 Hz, 4H). 13C NMR (101 MHz, CDCl3) δ164.94, 159.01, 158.91, 156.53, 154.72, 152.23, 149.75, 148.41, 147.77, 147.74, 135.99, 131.46, 129.74, 123.26, 118.43, 118.35, 116.86, 116.00, 115.78, 112.67, 106.60, 50.40, 50.01.

[0219] Step 1, General Scheme 3

[0220] [ka] tert-Butyl 3-oxopiperazine-1-carboxylate, 111.

[0221] [ka] To a 100 mL RBF was added piperazin-2-one (600 mg, 1.0 eq, 5.99 mmol) in DCM (40 mL, 0.15 M). Di-tert-butyl dicarbonate (1.44 g, 1.41 mL, 1.1 eq, 6.59 mmol) was added via syringe and stirred at room temperature for 3 h. Upon completion, the reaction was diluted with DCM (30 mL) and washed with water (50 mL). The aqueous layer was washed with DCM (50 × 2 mL). The combined organic layers were washed with brine (30 × 2 mL), dried over sodium sulfate, and evaporated in vacuo to give tert-butyl 3-oxopiperazine-1-carboxylate, 111, (1.2 g, 5.5 mmol, 92%) as a white solid. LCMS [M+H] + 101.1H NMR (500 MHz, CDCl3) δ6.68 (s, 1H), 4.08 (s, 2H), 3.62 (t, J = 5.4 Hz, 2H), 3.38 (td, J = 5.3, 2.6 Hz, 2H), 1.47 (s, 9H).

[0222] Step 2, General Scheme 3

[0223] [ka] tert-Butyl 3-oxo-4-phenylpiperazine-1-carboxylate, 113.

[0224] [ka] To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (300 mg, 1.2 eq, 1.50 mmol), iodobenzene (255 mg, 140 μL, 1 eq, 1.25 mmol), N,N'-dimethylethylenediamine (11 mg, 14 μL, 0.1 eq, 125 μmol), and potassium phosphate tribasic (530 mg, 2 eq, 2.50 mmol) in toluene (2.3 mL, 0.6 M) was added copper iodide (11 mg, 0.05 eq, 62 μmol). The reaction mixture was heated to 80 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with DCM, and filtered through a plug of silica using 40% EtOAc / hexanes as eluent to give tert-butyl 3-oxo-4-phenylpiperazine-1-carboxylate, 113, (191 mg, 0.693 mmol, 56%) as a white solid. LCMS [M+H] + 277.1H NMR (500 MHz, CDCl3) δ7.42 (dd, J = 8.7, 7.1 Hz, 2H), 7.32 - 7.26 (m, 3H), 4.26 (s, 2H), 3.79 (dd, J = 6.6, 3.7 Hz, 2H), 3.74 (dd, J = 6.9, 4.4 Hz, 2H), 1.50 (s, 9H).

[0225] Step 3, General Scheme 3

[0226] [ka] 1-Phenylpiperazin-2-one, 114.

[0227] [ka] A mixture of DCM:TFA (1:4, 14.6 mL) was added to the crude mixture and stirred at room temperature overnight. After completion, the remaining TFA was removed by evaporation in vacuo to give 1-phenylpiperazin-2-one (128 mg, 662 μmol, 34%) as the TFA salt. LCMS [M+H] +195.1H NMR (500 MHz, CDCl3) δ7.25 (d, J = 2.9 Hz, 1H), 6.95 (tq, J = 6.9, 2.3 Hz, 2H), 6.84 (dddd, J = 10.0, 8.4, 3.6, 2.1 Hz, 2H), 3.48 (d, J = 5.3 Hz, 2H), 3.46 (d, J = 4.5 Hz, 2H), 3.12 (dd, J = 6.6, 4.3 Hz, 2H).

[0228] Step 4, General Scheme 3

[0229] [ka] 4-(6-bromoquinazolin-4-yl)-1-phenylpiperazin-2-one, 115.

[0230] [ka] To a solution of 1-phenylpiperazin-2-one, trifluoroacetic acid (100 mg, 1.2 eq, 345 μmol), 6-bromo-4-chloroquinazoline (69 mg, 1.0 eq, 287 μmol), N,N'-dimethylethylenediamine (2.5 mg, 3 μL, 0.1 eq, 28 μmol), and KPO (122 mg, 2 eq, 574 μmol) in toluene (0.8 mL, 0.4 M) was added copper iodide (2 mg, 0.05 eq, 14 μmol). The reaction mixture was heated to 80 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with DCM, and filtered through a plug of silica using 5% MeOH:DCM as the eluent. The filtrate was dry loaded onto silica gel and purified on a 12 g column (DCM / MeOH 0-8%) to give 4-(6-bromoquinazolin-4-yl)-1-phenylpiperazin-2-one, 115 (76 mg, 198 μmol, 69%). LCMS [M+H] +384.1H NMR (500 MHz, CDCl3) δ8.82 (s, 1H), 8.17 (s, 2H), 7.93 (s, 1H), 7.49 - 7.39 (m, 2H), 7.38 - 7.28 (m, 3H), 4.73 (s, 2H), 4.31 (s, 2H), 4.00 (t, J = 5.1 Hz, 2H).

[0231] 4-(6-(1H-pyrazol-4-yl)quinazolin-4-yl)-1-phenylpiperazin-2-one, 32.

[0232] Compound 32 was prepared in a five-step procedure according to general scheme 3. The fifth step is reported below.

[0233] [ka] A 5 mL Biotage™ microwave vial was charged with tripotassium phosphate (96 mg, 4 eq, 455 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (7.4 mg, 0.08 eq, 9.09 μmol), 4-(6-chloroquinazolin-4-yl)-1-phenylpiperazin-2-one (38 mg, 1 eq, 114 μmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (40 mg, 1.2 eq, 136 μmol). The vial was capped, purged with argon, and then charged with degassed 4:1 dioxane:HO (1.5 mL, 76 mM) and heated at 80° C. for 12 h. The reaction was cooled, diluted with DCM:MeOH, filtered through Celite, and concentrated. A mixture of DCM:TFA (1:2, 1.5 mL) was added to the crude mixture, stirred at room temperature overnight, and basified with 1N NaOH. The mixture was extracted with DCM, washed with 10% NaOH, water, and brine. The organic layer was dried over sodium sulfate, concentrated, dry-loaded onto silica gel, and purified on a 12 g column (DCM / MeOH 0-10%) to give 4-(6-(1H-pyrazol-4-yl)quinazolin-4-yl)-1-phenylpiperazin-2-one, 32 (22 mg, 59 μmol, 52%) as a brown solid. LCMS [M+H] +371.1H NMR (500 MHz, DMSO) δ13.08 (s, 1H), 8.63 (s, 1H), 8.43 (s, 1H), 8.20 (d, J = 1.9 Hz, 1H), 8.17 - 8.12 (m, 2H), 7.84 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 5.3 Hz, 4H), 7.28 (ddd, J = 10.2, 5.8, 3.1 Hz, 1H), 4.55 (s, 2H), 4.24 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.2 Hz, 2H).13C NMR (126 MHz, CD3OD_SPE) δ176.88, 167.02, 163.03, 152.74, 149.59, 141.63, 131.48, 131.15, 128.99, 127.63, 127.17, 125.83, 121.19, 120.01, 116.46, 52.65, 49.01, 46.46.

[0234] 4-(4-(4-(2-fluorophenyl)piperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 33.

[0235] Compound 33 was prepared according to general scheme 2 via a two-step procedure reported for the preparation of compound 29. The second step is reported below.

[0236] [ka] Prepared in a manner similar to Step 2, General Scheme 2, used for compound 29. 4-(4-(4-(2-fluorophenyl)piperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 33, (31 mg, 0.16 mmol, 49%) was obtained as a brown solid. LCMS [M+H] +400.1H NMR (500 MHz, CDCl3) δ8.79 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 5.4 Hz, 1H), 7.89 (dd, J = 8.7, 2.0 Hz, 1H), 7.21 - 7.05 (m, 3H), 7.04 - 6.99 (m, 2H), 6.98 (d, J = 5.1 Hz, 1H), 6.86 (s, 1H), 4.99 (s, 2H), 3.49 (dd, J = 5.8, 3.3 Hz, 4H), 3.45 - 3.39 (m, 4H). 13C NMR (126 MHz, CDCl3) δ158.88, 157.23, 156.81, 154.85, 151.45, 150.21, 149.62, 148.34, 139.75, 139.68, 135.59, 130.81, 127.98, 124.62, 124.59, 123.50, 123.12, 123.06, 121.98, 119.22, 119.20, 116.41, 116.25, 112.84, 109.55, 106.59, 52.46, 50.64.

[0237] 4-(4-(4-(2,4-dimethylphenyl)piperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 34.

[0238] Compound 34 was prepared according to general scheme 2 via a two-step procedure reported for the preparation of compound 29. The second step is reported below.

[0239] [ka] Prepared in a manner similar to Step 2, General Scheme 2 used for compound 29. 4-(4-(4-(2,4-dimethylphenyl)piperazin-1-yl)quinolin-6-yl)pyridin-2-amine, 34, (33 mg, 80 μmol, 41%) was obtained as a brown solid. LCMS [M+H] +410.1H NMR (400 MHz, CDCl3) δ8.77 (d, J = 5.1 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 5.7 Hz, 1H), 7.89 (dd, J = 8.8, 2.1 Hz, 1H), 7.10 - 7.03 (m, 3H), 7.03 - 6.99 (m, 1H), 6.97 (d, J = 5.2 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 5.21 (s, 2H), 3.48 (dt, J = 5.4, 2.3 Hz, 4H), 3.24 - 3.15 (m, 4H), 2.33 (s, 3H), 2.30 (s, 3H).

[0240] 4-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)quinazolin-6-yl)pyridin-2-amine, 35.

[0241] Compound 35 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0242] [ka] A microwave vial was charged with tribasic potassium phosphate (318 mg, 3 eq, 1.50 mmol), PdCl(dppf) (36 mg, 0.1 eq, 50 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (121 mg, 1.1 eq, 550 μmol), and 6-bromo-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)quinazoline (200 mg, 1 eq, 500 μmol), and the vial was sealed. The solid was dissolved in 1,4-dioxane (2.0 mL) and water (0.40 mL), and the reaction mixture was heated to 90 °C and stirred there for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a thick pad of Celite. The filtrate was collected and concentrated by rotary evaporation. The resulting residue was dissolved in 50 mL of ethyl acetate and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude concentrate was purified by column chromatography (0-10% MeOH / DCM) to give 4-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)quinazolin-6-yl)pyridin-2-amine, 35, (157 mg, 380 μmol, 76%). LCMS: [M+H] + 414. 1 H NMR (400 MHz, MeOD) δ8.60 (s, 1H), 8.21 (s, 1H), 8.03 (dd, J = 16.2, 7.0 Hz, 2H), 7.86 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 5.4 Hz, 1H), 6.90 - 6.67 (m, 3H), 4.01 (d, J = 5.9 Hz, 2H), 3.70 (d, J = 9.4 Hz, 6H), 3.02 (t, J = 5.8 Hz, 2H), 2.48 (s, 2H).

[0243] 4-(4-(4-Fluorobenzyl)-1,4-diazepan-1-yl)-6-(1H-pyrazol-4-yl)quinazoline, 36.

[0244] Compound 36 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0245] [ka] Potassium acetate (156 mg, 3 eq, 1.59 mmol), PdCl(dppf) (38 mg, 0.1 eq, 53 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (171 mg, 1.1 eq, 583 μmol), and 6-bromo-4-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)quinazoline (220 mg, 1 eq, 530 μmol) were added to a MWV. The solids were degassed and then dissolved in degassed 1,4-dioxane (1.75 mL) and water (350 μL). The solution was heated to 90 °C and stirred magnetically for 16 h. After this time, the solution was diluted with EtOAc and filtered through a pad of Celite. The filtrate was then concentrated by rotary evaporation, and the residue was dissolved in EtOAc and washed twice with water and once with brine. The organic layer was collected and dried over sodium sulfate. It was then concentrated in vacuo, and the residue was further purified using flash chromatography (MeOH / DCM 0-20%) to give a black sludge. Crude tert-butyl 4-(4-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)quinazolin-6-yl)-1H-pyrazole-1-carboxylate (66 mg, 1 eq, 0.13 mmol) was suspended in DCM (5 mL) and TFA (75 mg, 51 μL, 5 eq, 0.66 mmol) was added. The solution was stirred at room temperature for 2 h, after which time the reaction mixture was concentrated by rotary evaporation. The residue was dissolved in ethyl acetate and washed with 2 M NaOH solution (2 × 75 mL). The organic layer was collected, dried over sodium sulfate, filtered, and concentrated to give 4-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)-6-(1H-pyrazol-4-yl)quinazoline, 36, (48 mg, 0.12 mmol, 91%). LCMS [M+H] + 403.1 H NMR (400 MHz, DMSO-D6) δ13.06 (s, 1H), 8.39 (s, 1H), 8.18 - 8.09 (m, 3H), 7.98 (dd, J = 8.6, 1.8 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.27 (ddd, J = 8.8, 5.6, 2.6 Hz, 2H), 7.07 (td, J = 9.1, 2.5 Hz, 2H), 3.95 (q, J = 5.8 Hz, 4H), 3.54 (d, J = 3.6 Hz, 2H), 2.86 - 2.79 (m, 2H), 2.58 - 2.51 (m, 2H), 2.04 - 1.93 (m, 2H).

[0246] 4-(4-(4-(pyridin-3-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 37.

[0247] Compound 37 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0248] [ka] A 5 mL microwave vial was charged with 6-chloro-4-(4-(pyridin-3-yl)piperazin-1-yl)quinazoline (30 mg, 1 eq, 93 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (24 mg, 1.2 eq, 112 μmol), potassium phosphate tripotassium (79 mg, 4 eq, 374 μmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (6 mg, 0.08 eq, 7.5 μmol). The mixture was capped and purged with argon, then charged with degassed 4:1 dioxane:HO (1.4 mL, 67 mM) and heated at 80 °C for 12 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 2). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-10% MeOH / DCM) to give 4-(4-(4-(pyridin-3-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 37, (17 mg, 93 μmol, 49%) as a yellow solid. LCMS [M+H] +384.1H NMR (500 MHz, CDCl3) δ8.80 (s, 1H), 8.39 (d, J = 2.9 Hz, 1H), 8.18 - 8.13 (m, 2H), 8.12 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.7, 1.9 Hz, 1H), 7.26 - 7.24 (m, 1H), 7.22 (dd, J = 8.4, 4.5 Hz, 1H), 6.94 (dd, J = 5.5, 1.6 Hz, 1H), 6.81 (d, J = 1.6 Hz, 1H), 4.96 (s, 2H), 4.02 (t, J = 5.1 Hz, 4H), 3.51 - 3.43 (m, 4H). 13C NMR (126 MHz, CDCl3) δ164.78, 158.72, 154.58, 152.08, 149.73, 147.89, 146.63, 141.31, 138.67, 135.90, 131.41, 129.68, 123.65, 123.08, 122.73, 116.70, 112.51, 106.61, 77.28, 77.02, 76.77, 49.57, 48.46.

[0249] 4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-1-phenylpiperazin-2-one, 38.

[0250] Compound 38 was prepared via general scheme 3, as shown in the preparation of compound 32. The fifth step is reported below.

[0251] [ka] Prepared in a manner similar to step 5, general scheme 3 used for compound 32. 4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)-1-phenylpiperazin-2-one, 38, (18 mg, 46 μmol, 41%) was obtained as a brown solid. LCMS [M+H] +397.1H NMR (500 MHz, MeOD) δ7.97 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.8, 2.0 Hz, 1H), 7.30 (d, J = 5.5 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.74 (t, J = 7.8 Hz, 2H), 6.70 - 6.65 (m, 2H), 6.65 - 6.59 (m, 1H), 6.31 (dd, J = 5.5, 1.7 Hz, 1H), 6.26 (d, J = 1.7 Hz, 1H), 4.05 (s, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.30 (t, J = 5.3 Hz, 2H). 13C NMR (126 MHz, CD3OD_SPE) δ166.74, 163.13, 160.16, 153.79, 151.12, 149.03, 147.40, 141.58, 136.25, 131.66, 128.99, 127.82, 127.18, 125.78, 123.17, 115.96, 110.99, 106.49, 52.72, 48.91, 46.35.

[0252] 4-(4-(4-(2,4-difluorophenyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 39.

[0253] Compound 39 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0254] 6-Bromo-4-(4-(2,4-difluorophenyl)piperazin-1-yl)quinazoline, 116.

[0255] [ka] To a 5 mL Biotage microwave vial, sodium bicarbonate (17 mg, 1 eq, 0.20 mmol) and 1-(2,4-difluorophenyl)piperazine (40 mg, 1 eq, 0.20 mmol) were added along with EtOH (0.5 mL, 0.4 M) and stirred for 10 min. 6-Bromo-4-chloroquinazoline (49 mg, 1 eq, 0.20 mmol) was added, the vial was sealed, and stirred at 25 °C for 12 h. Upon completion, the reaction was extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0–10% EtOAc / hexanes) to give 6-bromo-4-(4-(2,4-difluorophenyl)piperazin-1-yl)quinazoline, 116 (48 mg, 120 μmol, 59%). LCMS [M+H] + 406.1H NMR (500 MHz, CDCl3) δ8.73 (s, 1H), 8.07 (d, J = 2.1 Hz, 2H), 7.89 (dd, J = 8.7, 2.1 Hz, 1H), 6.95 (td, J = 9.0, 5.6 Hz, 1H), 6.85 (tdd, J = 11.9, 8.5, 2.9 Hz, 2H), 4.12 (s, 4H), 3.25 (t, J = 4.9 Hz, 4H).

[0256] 4-(4-(4-(2,4-difluorophenyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 39.

[0257] [ka] A 5 mL microwave vial was charged with 6-chloro-4-(4-(2,4-difluorophenyl)piperazin-1-yl)quinazoline (49 mg, 1 eq, 0.14 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (36 mg, 1.2 eq, 0.16 mmol), potassium phosphate tripotassium (120 mg, 4 eq, 0.54 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (8.9 mg, 0.08 eq, 11 μmol). The mixture was capped and purged with argon, then charged with degassed 4:1 dioxane:HO (0.8 mL, 0.2 M) and heated at 80 °C for 6 h. After this time, the 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 x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-10% MeOH / DCM) to give 4-(4-(4-(2,4-difluorophenyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 39, (27 mg, 65 μmol, 48%) as a light brown solid. LCMS [M+H] + 419.1H NMR (400 MHz, CDCl3) δ8.78 (s, 1H), 8.14 (d, J = 5.4 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 8.03 - 7.76 (m, 2H), 7.01 - 6.89 (m, 2H), 6.89 - 6.77 (m, 3H), 4.91 (s, 2H), 4.01 (t, J = 4.9 Hz, 4H), 3.24 (t, J = 4.9 Hz, 4H).

[0258] 4-(4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)isoxazole, 40.

[0259] Compound 40 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0260] [ka] A 5 mL microwave vial was charged with 6-bromo-4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidine (60 mg, 1 eq, 0.15 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (36 mg, 1.2 eq, 0.19 mmol), potassium phosphate tripotassium (130 mg, 4 eq, 0.62 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.0 mg, 0.08 eq, 12 μmol). The mixture was capped and purged with argon, then injected with degassed 4:1 dioxane:HO (1.0 mL, 0.2 M) and heated at 65 °C for 4 h. After this time, the 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 × 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (60-70% EtOAc / hexanes) to give 4-(4-(4-(2-fluorophenyl)piperazin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)isoxazole, 40, (9.7 mg, 26 μmol, 17%) as a yellow solid. LCMS [M+H] +377.1H NMR (400 MHz, DMSO) δ9.78 (s, 1H), 9.30 (s, 1H), 8.55 (s, 1H), 8.23 (d, J = 2.0 Hz, 2H), 7.23 - 7.09 (m, 3H), 7.01 (ddd, J = 8.9, 13C NMR (101 MHz, DMSO-D6) δ158.33, 158.28, 156.23, 154.45, 153.80, 148.53, 146.22, 145.25, 139.67, 139.59, 137.33, 132.78, 125.69, 124.90, 124.87, 122.67, 122.59, 121.55, 119.52, 119.50, 116.11, 115.91, 50.42.

[0261] 4-(4-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)quinazolin-6-yl)pyridin-2-amine, 41.

[0262] Compound 41 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0263] [ka] Potassium acetate (156 mg, 3 eq, 1.59 mmol), PdCl(dppf) (38 mg, 0.1 eq, 53 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (128 mg, 1.1 eq, 583 μmol), and 6-bromo-4-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)quinazoline (220 mg, 1 eq, 530 μmol) were added to a MWV. The solids were degassed and then dissolved in degassed water (350 μL) and 1,4-dioxane (1.75 mL). The solution was heated to 60 °C and stirred magnetically for 16 h. After this time, the solution was diluted with EtOAc and filtered through a pad of Celite. The filtrate was then concentrated by rotary evaporation, and the residue was dissolved in EtOAc and washed twice with water and once with brine. The organic layer was collected and dried over sodium sulfate. It was then concentrated in vacuo, and the residue was further purified using flash chromatography (MeOH / DCM 0-20%) to give a black sludge. This was then further purified by dissolving in 1:1:1 DCM:MeOH:IPA and adding a metal scavenger silica, stirring for 72 hours, after which the silica was filtered off and concentrated to give 4-(4-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)quinazolin-6-yl)pyridin-2-amine, 41, (45 mg, 0.11 mmol, 20%) as a white fluffy powder. LCMS [M+H] + 429. 1 H NMR (400 MHz, DMSO) δ8.46 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.97 (t, J = 6.4 Hz, 2H), 7.78 (d, J = 8.6 Hz, 1H), 7.29 (dd, J = 8.3, 5.6 Hz, 2H), 7.08 (t, J = 8.7 Hz, 2H), 6.83 (d, J = 5.4 Hz, 1H), 6.74 (s, 1H), 3.98 (m, 4H), 3.56 (m, 2H), 2.86 (m, J = 5.6 Hz, 2H), 2.61 - 2.53 (m, 2H), 2.01 (m, 2H).

[0264] 4-(4-(4-fluorobenzyl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)quinazoline, 42.

[0265] Compound 42 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0266] [ka] Potassium phosphate tribasic (198 mg, 3 eq, 935 μmol), PdCl(dppf) (22.8 mg, 0.1 eq, 31 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (71 mg, 1.1 eq, 343 μmol), and 6-bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline (125 mg, 1 eq, 312 μmol) were added to a MWV. The solids were degassed and then dissolved in degassed water (0.30 mL) and 1,4-dioxane (1.5 mL). The solution was heated to 90 °C and stirred magnetically for 16 h. After this time, the solution was diluted with EtOAc and filtered through a pad of Celite. The filtrate was then concentrated by rotary evaporation, and the residue was dissolved in EtOAc and washed twice with water and once with brine. The organic layer was collected and dried over sodium sulfate. It was then concentrated in vacuo, and the residue was further purified using flash chromatography (MeOH / DCM 0-20%) to give a black sludge. This was then further purified by dissolving it in 1:1:1 DCM:MeOH:IPA and adding a metal scavenger silica, stirring for 72 hours, after which the silica was filtered off to give 4-(4-(4-fluorobenzyl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)quinazoline, 42, (101 mg, 251 μmol, 80%) as a white fluffy powder. LCMS [M+H] + 403. 1H NMR (400 MHz, DMSO) δ8.53 (s, 1H), 8.26 (s, 1H), 8.02 - 7.91 (m, 3H), 7.75 (d, J = 8.7 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.18 - 7.08 (m, 2H), 3.85 (s, 3H), 3.78 - 3.69 (m, 4H), 3.51 (s, 2H), 2.55 (t, J = 4.8 Hz, 4H).

[0267] 4-(4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 43.

[0268] Compound 43 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0269] 6-Bromo-4-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)quinazoline, 117.

[0270] [ka] To a microwave vial was added 6-bromo-4-chloroquinazoline (0.300 g, 1 eq, 1.23 mmol), 1-(4-fluorobenzyl)-1,4-diazepane (513 mg, 478 μL, 2 eq, 2.46 mmol), and a stir bar, and the vial was capped. NMP (8.0 mL) was added to the reaction vial, followed by TEA (312 mg, 429 μL, 2.5 eq, 3.08 mmol), and the solution was heated to 80 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL x 4). The organic layer was separated, 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-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)quinazoline (0.420 g, 1.01 mmol, 82%). LCMS [M+H] + 416. This compound was used without further characterization.

[0271] 4-(4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 43.

[0272] [ka] Potassium phosphate tribasic (198 mg, 3 eq, 935 μmol), PdCl(dppf) (22.8 mg, 0.1 eq, 31.2 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (75 mg, 1.1 eq, 343 μmol), and 6-bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline (125 mg, 1 eq, 312 μmol) were added to a MWV. The solids were degassed and then dissolved in degassed water (0.30 mL) and 1,4-dioxane (1.5 mL). The solution was heated to 90 °C and stirred magnetically for 16 h. After this time, the solution was diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated by rotary evaporation, and the residue was dissolved in EtOAc and washed twice with water and once with brine. The organic layer was collected and dried over sodium sulfate. It was then concentrated in vacuo, and the residue was further purified using flash chromatography (MeOH / DCM 0-20%) to give a black sludge. This was then further purified by dissolving it in 1:1:1 DCM:MeOH:IPA (3 mL) and adding a metal scavenger silica, stirring for 72 hours, and then filtering off the silica to give 4-(4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 43, (84 mg, 0.20 mmol, 65%) as a white fluffy powder. LCMS [M+H] + 415. 1 H NMR (400 MHz, DMSO) δ8.59 (s, 1H), 8.10 - 7.94 (m, 3H), 7.84 (d, J = 8.7 Hz, 1H), 7.33 (t, J = 6.9 Hz, 2H), 7.12 (t, J = 8.7 Hz, 2H), 6.84 (d, J = 5.3 Hz, 1H), 6.75 (s, 1H), 3.76 (s, 4H), 3.49 (s, 2H), 2.56 - 2.48 (m, 4H).

[0273] (R)-4-(4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 44.

[0274] Compound 44 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0275] (R)-6-Bromo-4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 118.

[0276] [ka] To a 5 mL microwave vial was added 6-bromo-4-chloroquinazoline (96 mg, 1 eq, 0.39 mmol), sodium bicarbonate (100 mg, 3 eq, 1.2 mmol), and (R)-3-methyl-1-(pyridin-2-yl)piperazine (70 mg, 1.0 eq, 0.39 mmol). The mixture was capped, DMSO (1.0 mL, 0.4 M) was injected, and the mixture was stirred at 60 °C for 18 h overnight. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL × 3). The aqueous layer was washed with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 3), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry loaded onto silica gel and purified on a 12 g silica gel column (0-50% EtOAc / hexanes) to give (R)-6-bromo-4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 118 (105 mg, 0.273 mmol, 69%). LCMS [M+H] +385.1H NMR (500 MHz, CDCl3) δ8.72 (s, 1H), 8.25 - 8.17 (m, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.87 (dd, J = 8.9, 2.1 Hz, 1H), 7.68 - 7.56 (m, 1H), 6.73 (s, 2H), 4.89 (s, 1H), 4.43 - 4.24 (m, 3H), 4.17 (d, J = 12.9 Hz, 1H), 3.87 (t, J = 12.2 Hz, 1H), 3.54 (d, J = 12.9 Hz, 1H), 3.41 - 3.30 (m, 1H), 1.52 (d, J = 6.7 Hz, 3H).

[0277] (R)-4-(4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 44.

[0278] [ka] A 5 mL microwave vial was charged with (R)-6-bromo-4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazoline (105 mg, 1 eq, 0.273 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (72 mg, 1.2 eq, 0.328 mmol), potassium phosphate tripotassium (232 mg, 4 eq, 1.09 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 0.08 eq, 21.9 μmol). The mixture was capped and purged with argon, then injected with degassed 4:1 dioxane:HO (1.4 mL, 0.2 M) and heated at 80 °C for 6 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 2). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-5% MeOH / DCM) to give (R)-4-(4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 44, (57 mg, 0.14 mmol, 52%) as a yellow solid. LCMS [M+H] + 398.1H NMR (500 MHz, CDCl3) δ8.76 (s, 1H), 8.20 (dd, J = 5.0, 1.8 Hz, 1H), 8.12 (s, 2H), 7.97 (q, J = 8.7 Hz, 2H), 7.60 - 7.43 (m, 1H), 6.99 - 6.81 (m, 2H), 6.74 - 6.56 (m, 2H), 5.24 (s, 2H), 4.88 - 4.75 (m, 1H), 4.34 - 4.19 (m, 2H), 4.08 (dd, J = 12.9, 3.0 Hz, 1H), 3.90 - 3.78 (m, 1H), 3.30 (td, J = 12.1, 3.6 Hz, 1H), 2.61 (s, 1H), 1.48 (d, J = 6.6 Hz, 3H).

[0279] (S)-4-(4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 45.

[0280] Compound 45 was prepared according to General Scheme 1 via the two-step procedure reported for the preparation of compound 1. However, this compound requires an additional SnAR step to add the pyridyl group, as shown below.

[0281] (S)-6-Bromo-4-(2-methylpiperazin-1-yl)quinazoline, 119.

[0282] [ka] Sodium bicarbonate (311 mg, 3 eq, 3.70 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (247 mg, 1 eq, 1.23 mmol) were added to a 5 mL Biotage microwave vial along with DMSO (3.08 mL, 0.4 M) and stirred for 10 min. 6-Bromo-4-chloroquinazoline (300 mg, 1 eq, 1.23 mmol) was added, the vial was sealed, and the mixture was stirred at 60 °C for 6 h. Upon completion, the reaction was extracted into EtOAc, washed with brine, dried over sodium sulfate, concentrated, dry loaded onto silica, and purified on a 12 g silica gel column (0-15% EtOAc:hexanes) to afford tert-butyl (S)-4-(6-bromoquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (369 mg, 907.7 μmol, 73.7%) as a yellow solid. LCMS [M+H] +407.1H NMR (400 MHz, CDCl3) δ8.72 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.83 (dd, J = 9.0, 2.0 Hz, 1H), 4.65 (s, 1H), 4.32 - 3.79 (m, 3H), 3.62 (t, J = 13.4 Hz, 1H), 3.39 - 3.01 (m, 2H), 1.49 (s, 9H), 1.41 (d, J = 6.9 Hz, 3H). To a scintillation vial, tert-butyl (S)-4-(6-bromoquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (369 mg, 1.0 eq, 907 μmol) was dissolved in DCM:TFA (4:1, 9.5 mL), stirred overnight at room temperature, and basified with 1N NaOH. The mixture was extracted with DCM, washed with 10% NaOH, water, and brine, and the organic layer was dried over sodium sulfate and concentrated to give (S)-6-bromo-4-(2-methylpiperazin-1-yl)quinazoline, 119, (213 mg, 693 μmol, 56%). LCMS [M+H] + 307.1H NMR (400 MHz, CDCl3) δ8.73 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.84 - 7.73 (m, 3H), 4.56 (td, J = 7.0, 3.7 Hz, 1H), 3.99 (dt, J = 13.7, 3.1 Hz, 1H), 3.63 (ddd, J = 13.6, 11.4, 3.2 Hz, 1H), 3.18 (td, J = 12.0, 3.5 Hz, 2H), 3.05 (td, J = 11.9, 3.4 Hz, 1H), 2.95 (dt, J = 12.4, 1.7 Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H).

[0283] (S)-6-Bromo-4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 120.

[0284] [ka] A 5 mL Biotage microwave vial was charged with potassium carbonate (297 mg, 3 eq, 2.08 mmol) and (S)-6-bromo-4-(2-methylpiperazin-1-yl)quinazoline (213 mg, 1 eq, 0.693 mmol) in DMSO (1.39 mL, 0.5 M) and stirred at room temperature for 15 minutes. 2-Fluoropyridine (202 mg, 0.18 mL, 3 eq, 2.08 mmol) was then added via syringe, purged with nitrogen, and heated at 140 °C for 24 hours. The reaction mixture was then cooled to room temperature and extracted into EtOAc. The combined organic layers were washed with brine (x3) and water (x3), dried over sodium sulfate, filtered, concentrated, dry-loaded onto silica gel, and purified on a 12 g column (hexanes / EtOAc 0-10%) to give (S)-6-bromo-4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 120, (81 mg, 0.21 mmol, 30%) as a yellow-orange oil. LCMS [M+H] + 385.1H NMR (500 MHz, CDCl3) δ8.72 (s, 1H), 8.22 (dt, J = 7.5, 3.7 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.99 (s, 1H), 7.88 (dd, J = 8.8, 2.0 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 6.74 (t, J = 6.8 Hz, 2H), 4.90 (s, 1H), 4.45 - 4.24 (m, 2H), 4.18 (d, J = 12.9 Hz, 1H), 3.88 (t, J = 12.3 Hz, 1H), 3.54 (d, J = 13.0 Hz, 1H), 3.38 (s, 1H), 1.52 (d, J = 6.6 Hz, 3H).

[0285] (S)-4-(4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 45.

[0286] [ka] A 5 mL microwave vial was charged with (S)-6-bromo-4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazoline (81 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 tripotassium (180 mg, 4 eq, 0.84 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg, 0.08 eq, 17 μmol). The mixture was capped and purged with argon, then charged with degassed 4:1 dioxane:HO (1.1 mL, 0.2 M) and heated at 80 °C for 18 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 2). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-5% MeOH / DCM) to give (S)-4-(4-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 45, (29 mg, 0.75 mmol, 35%) as a brown solid. LCMS [M+H] +398.1H NMR (400 MHz, CDCl3) δ8.76 (s, 1H), 8.24 - 8.17 (m, 1H), 8.16 (s, 1H), 8.09 - 7.85 (m, 3H), 7.53 (t, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.96 (d, J = 5.4 Hz, 1H), 6.77 - 6.62 (m, 2H), 4.87 (s, 1H), 4.29 (t, J = 14.9 Hz, 2H), 4.10 (d, J = 12.7 Hz, 1H), 3.88 (t, J = 12.3 Hz, 1H), 3.52 (d, J = 13.0 13C NMR (126 MHz, DMSO) δ163.42, 160.58, 159.10, 153.94, 151.63, 148.71, 147.53, 147.15, 137.58, 135.09, 130.96, 128.82, 122.67, 116.11, 112.86, 110.07, 106.73, 105.21, 52.29, 48.57, 44.27, 43.79, 15.73.

[0287] (4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperazin-1-yl)(2-fluorophenyl)methanone, 46.

[0288] Compound 46 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0289] (4-(6-bromoquinazolin-4-yl)piperazin-1-yl)(2-fluorophenyl)methanone, 121.

[0290] [ka] Prepared in a similar manner to compound 117. (4-(6-Bromoquinazolin-4-yl)piperazin-1-yl)(2-fluorophenyl)methanone, 121, (287 mg, 0.691 mol, 84%). LCMS [M+H] + 416. 1 H NMR (400 MHz, CDCl3) δ8.67 (s, 1H), 7.92 (s, 1H), 7.73 (s, 2H), 7.40 - 7.31 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.80 (t, J = 5.1 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 3.50 (d, J = 6.3 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ165.51, 163.55, 159.37, 156.91, 154.04, 150.24, 136.27, 131.81, 130.51, 129.38, 126.99, 124.99, 123.69, 119.23, 117.70, 116.03, 115.82, 49.92, 49.63, 46.65, 41.81.

[0291] (4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperazin-1-yl)(2-fluorophenyl)methanone, 46.

[0292] [ka] A microwave vial was charged with tribasic potassium phosphate (276 mg, 3 eq, 1.30 mmol), PdCl(dppf) (31 mg, 0.1 eq, 43 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (105 mg, 1.1 eq, 477 μmol), and (4-(6-bromoquinazolin-4-yl)piperazin-1-yl)(2-fluorophenyl)methanone (180 mg, 1 eq, 433 μmol) and sealed. The solid was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and the reaction mixture was heated to 90 °C and stirred there for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a thick pad of Celite. The filtrate was collected and concentrated by rotary evaporation. The resulting residue was dissolved in 50 mL of ethyl acetate and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude concentrate was purified by column chromatography (0-10% MeOH / DCM) to give (4-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperazin-1-yl)(2-fluorophenyl)methanone, 46, (118 mg, 275 μmol, 63%). LCMS [M+H] + 429. 1 H NMR (400 MHz, CDCl3) δ8.74 (s, 1H), 8.08 (d, J = 5.4 Hz, 1H), 8.02 (s, 1H), 7.98 - 7.87 (m, 2H), 7.39 (q, J = 6.7 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.89 - 6.79 (m, 2H), 3.99 (s, 2H), 3.90 (t, J = 4.9 Hz, 2H), 3.78 (t, J = 5.0 Hz, 2H), 3.54 (t, J = 4.8 Hz, 2H).

[0293] 4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(1-methyl-1H-pyrazol-4-yl)quinazoline, 47.

[0294] Compound 47 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0295] 6-Bromo-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)quinazoline, 122.

[0296] [ka] Prepared in a similar manner to compound 117. 6-Bromo-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)quinazoline, 122, (486 mg, 1.21 mol, 85%). LCMS [M+H] + 401. This compound was used without further characterization.

[0297] 4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(1-methyl-1H-pyrazol-4-yl)quinazoline, 47.

[0298] [ka] In a microwave vial, add tribasic potassium phosphate (318 mg, 3 eq, 1.50 mmol), PdCl (2)(dppf) (36.6 mg, 0.1 eq, 50.0 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (114 mg, 1.1 eq, 550 μmol), and 6-bromo-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)quinazoline (200 mg, 1 eq, 500 μmol) were added and the vial was sealed. The solid was dissolved in 1,4-dioxane (2.0 mL) and water (0.40 mL), and the reaction mixture was heated to 90 °C and stirred there for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a thick pad of Celite. The filtrate was collected and concentrated by rotary evaporation. The resulting residue was dissolved in 50 mL of ethyl acetate and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude concentrate was purified by column chromatography (0-10% MeOH / DCM) to give 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(1-methyl-1H-pyrazol-4-yl)quinazoline, 47 (169 mg, 421 μmol, 84%). LCMS [M+H] + 402. 1 H NMR (400 MHz, CDCl3) δ8.61 (s, 1H), 8.34 (s, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.09 - 7.97 (m, 2H), 7.81 (d, J = 8.6 Hz, 1H), 6.90 (s, 1H), 6.82 (s, 1H), 4.90 (s, 2H), 4.01 (t, J = 5.7 Hz, 2H), 3.95 (s, 3H), 3.77 (d, J = 7.4 Hz, 6H), 3.08 (t, J = 5.7 Hz, 2H).

[0299] 4-(4-(4-(2-fluorophenyl)piperidin-1-yl)quinazolin-6-yl)pyridin-2-amine, 48.

[0300] Compound 48 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0301] 6-Bromo-4-(4-(2-fluorophenyl)piperidin-1-yl)quinazoline, 123.

[0302] [ka] Prepared in a similar manner to compound 126. 6-Bromo-4-(4-(2-fluorophenyl)piperidin-1-yl)quinazoline, 123, (143 mg, 370 μmol, 66%). LCMS [M+H] + 387.1H NMR (500 MHz, CDCl3) δ8.73 (s, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.28 (dd, J = 7.6, 1.8 Hz, 1H), 7.22 (tdd, J = 7.4, 5.2, 1.8 Hz, 1H), 7.13 (td, J = 7.5, 1.3 Hz, 1H), 7.05 (ddd, J = 10.7, 8.2, 1.3 Hz, 1H), 4.53 (dt, J = 13.4, 2.3 Hz, 2H), 3.37 - 3.28 (m, 2H), 3.25 (ddt, J = 11.7, 8.2, 4.2 Hz, 1H), 2.08 - 1.94 (m, 4H).

[0303] 4-(4-(4-(2-fluorophenyl)piperidin-1-yl)quinazolin-6-yl)pyridin-2-amine, 48.

[0304] [ka] A 5 mL microwave vial was charged with 6-bromo-4-(4-(2-fluorophenyl)piperidin-1-yl)quinazoline (143 mg, 1 eq, 0.370 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (97 mg, 1.2 eq, 0.444 mmol), potassium phosphate tripotassium (314 mg, 4 eq, 1.48 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 0.08 eq, 29 μmol). The mixture was capped and purged with argon, then charged with degassed 4:1 dioxane:HO (1.9 mL, 0.2 M) and heated at 80 °C for 18 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 2). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-5% MeOH / DCM) to give 4-(4-(4-(2-fluorophenyl)piperidin-1-yl)quinazolin-6-yl)pyridin-2-amine, 48, (39 mg, 98 μmol, 26%) as a pale yellow solid. LCMS [M+H] +400.1H NMR (500 MHz, CDCl3) δ8.76 (s, 1H), 8.10 (d, J = 2.1 Hz, 2H), 7.98 (d, J = 8.7 Hz, 1H), 7.94 (dd, J = 8.7, 1.9 Hz, 1H), 7.29 (dd, J = 7.5, 1.8 Hz, 1H), 7.22 (tdd, J = 7.4, 5.2, 1.8 Hz, 1H), 7.13 (td, J = 7.5, 1.3 Hz, 1H), 7.05 (ddd, J = 10.6, 8.2, 1.3 Hz, 1H), 6.94 (dd, J = 5.6, 1.5 Hz, 1H), 13C NMR (126 MHz, CDCl3) δ164.98, 161.77, 159.82, 158.44, 154.81, 152.20, 150.49, 146.60, 135.16, 131.87, 131.75, 131.20, 129.50, 128.15, 128.08, 127.75, 127.71, 124.49, 124.46, 123.74, 116.76, 115.76, 115.58, 112.51, 107.12, 50.88, 35.97, 32.05.

[0305] 4-(4-(4-fluorobenzyl)piperazin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline, 49.

[0306] Compound 49 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0307] 6-Bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline, 124. [ka] Prepared in a similar manner to compound 117. 6-Bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline, 124, (mg quantity, mol, 99%). LCMS [M+H] + 402. This compound was used without further characterization.

[0308] 4-(4-(4-fluorobenzyl)piperazin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline, 49.

[0309] [ka] Potassium phosphate tribasic (198 mg, 3 eq, 935 μmol), PdCl(dppf) (22.8 mg, 0.1 eq, 31.2 μmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (118 mg, 1.1 eq, 343 μmol), and 6-bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline (125 mg, 1 eq, 312 μmol) were added to a MWV. The solids were degassed and then dissolved in degassed water (350 μL) and 1,4-dioxane (1.75 mL). The solution was heated to 90 °C and stirred magnetically for 16 h. After this time, the solution was diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated by rotary evaporation, and the residue was dissolved in EtOAc and washed twice with water and once with brine. The organic layer was collected and dried over sodium sulfate. It was then concentrated in vacuo, and the residue was further purified using flash chromatography (MeOH / DCM 0-20%) to give a black sludge, which was then purified by dissolving in 1:1:1 DCM:MeOH:IPA, adding a metal scavenger silica, stirring for 72 hours, and filtering off the silica to give 4-(4-(4-fluorobenzyl)piperazin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline, 49, (50 mg, 0.11 mmol, 37%) as a white fluffy powder. LCMS [M+H] + 439. 1 H NMR (400 MHz, DMSO) δ12.06 (s, 1H), 8.56 (s, 1H), 8.26 (dd, J = 17.6, 6.3 Hz, 2H), 8.15 (d, J = 8.7 Hz, 1H), 8.08 (s, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.56 - 7.41 (m, 1H), 7.37 - 7.29 (m, 2H), 7.13 (dt, J = 17.3, 8.2 Hz, 2H), 3.78 - 3.71 (m, 4H), 3.50 (s, 2H), 2.56 (t, J = 4.7 Hz, 4H).

[0310] 4-(4-(4-(thiazol-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 50.

[0311] Compound 50 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0312] 2-(4-(6-bromoquinazolin-4-yl)piperazin-1-yl)thiazole, 125.

[0313] [ka] Prepared in a similar manner to compound 117. 2-(4-(6-bromoquinazolin-4-yl)piperazin-1-yl)thiazole, 125, (112 mg, 0.298 mol, 32%) LCMS [M+H] + 377. This compound was used without further characterization.

[0314] 4-(4-(4-(thiazol-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 50.

[0315] [ka] A microwave vial was charged with tribasic potassium phosphate (190 mg, 3 eq, 893 μmol), PdCl(dppf) (21.8 mg, 0.1 eq, 29.8 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (72 mg, 1.1 eq, 327 μmol), and 2-(4-(6-bromoquinazolin-4-yl)piperazin-1-yl)thiazole (112 mg, 1 eq, 298 μmol) and sealed. The solid was dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), and the reaction mixture was heated to 90 °C and stirred there for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a thick pad of Celite. The filtrate was collected and concentrated by rotary evaporation. The resulting residue was dissolved in 50 mL of ethyl acetate and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude concentrate was purified by column chromatography (0-10% MeOH / DCM) to give 4-(4-(4-(thiazol-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 50, (74 mg, 0.19 mmol, 64%). LCMS [M+H] + 390. 1 H NMR (400 MHz, DMSO) δ8.69 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.13 - 7.99 (m, 2H), 7.93 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 3.6 Hz, 1H), 6.95 (dd, J = 5.4, 1.6 Hz, 1H), 6.87 (dd, J = 17.4, 2.6 Hz, 2H), 3.95 (dd, J = 6.7, 3.8 Hz, 4H), 3.72 - 3.64 (m, 4H).

[0316] 4-(4-(4-phenylpiperidin-1-yl)quinazolin-6-yl)pyridin-2-amine, 51.

[0317] Compound 51 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0318] 6-Bromo-4-(4-phenylpiperidin-1-yl)quinazoline, 126.

[0319] [ka] A solution of 6-bromo-4-chloroquinazoline (300 mg, 1.2 eq, 1.23 mmol), 4-phenylpiperidine (166 mg, 1.0 eq, 1.03 mmol), and potassium carbonate (426 mg, 3.0 eq, 3.08 mmol) in DMSO (2.46 mL, 0.4 M) was stirred at 60 °C for 6 h. After cooling to room temperature, the reaction was extracted with EtOAc, washed with brine (×3) and water (×3), dried over anhydrous sodium sulfate, filtered, concentrated, and dry-loaded onto silica gel. Purification on a 12 g silica gel column (0-10% EtOAc / hexane) gave 6-bromo-4-(4-phenylpiperidin-1-yl)quinazoline, 126, (347 mg, 0.942 mmol, 92%). LCMS [M+H] + 367.1H NMR (400 MHz, CDCl3) δ8.63 (d, J = 2.6 Hz, 1H), 8.28 (t, J = 5.8 Hz, 1H), 8.06 (t, J = 2.4 Hz, 1H), 7.92 (dt, J = 9.0, 2.4 Hz, 1H), 7.33 (qd, J = 8.5, 2.3 Hz, 3H), 7.24 (d, J = 4.2 Hz, 2H), 4.89 (s, 2H), 3.51 (t, J = 13.0 Hz, 2H), 3.13 - 2.92 (m, 1H), 2.19 (s, 2H), 1.94 (tdd, J = 15.7, 9.8, 3.5 Hz, 2H).

[0320] 4-(4-(4-phenylpiperidin-1-yl)quinazolin-6-yl)pyridin-2-amine, 51.

[0321] [ka] A 5 mL microwave vial was charged with 6-chloro-4-(4-phenylpiperidin-1-yl)quinazoline (57 mg, 1 eq, 0.18 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (46 mg, 1.2 eq, 0.21 mmol), potassium phosphate tripotassium (150 mg, 4 eq, 0.70 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.08 eq, 14 μmol). The mixture was capped and purged with argon before being injected with degassed 4:1 dioxane:HO (0.9 mL, 0.2 M) and heated at 80 °C for 18 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 2). The aqueous layer was washed with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-5% MeOH / DCM) to give 4-(4-(4-phenylpiperidin-1-yl)quinazolin-6-yl)pyridin-2-amine, 51, (23 mg, 0.18 mmol, 34%) as a pale yellow solid. LCMS [M+H] +382.1H NMR (400 MHz, CDCl3) δ8.74 (s, 1H), 8.12 (d, J = 5.5 Hz, 1H), 8.08 (s, 1H), 7.93 (q, J = 8.6 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.27 (s, 1H), 7.21 (d, J = 7.3 Hz, 2H), 6.91 (d, J = 5.3 Hz, 1H), 6.77 (s, 1H), 4.87 (s, 2H), 4.54 (d, J = 13.1 Hz, 2H), 3.36 - 3.21 (m, 2H), 2.94 - 2.81 (m, 1H), 2.10 - 1.89 (m, 4H). 13C NMR (101 MHz, CDCl3) δ165.06, 159.02, 154.76, 152.16, 149.70, 148.48, 145.28, 135.58, 131.24, 129.45, 128.76, 126.93, 126.73, 123.53, 116.85, 112.63, 106.51, 50.89, 42.98, 33.43.

[0322] Step 1, General Scheme 4 [ka] 8-Bromo-1,5-naphthyridin-2-ol, 82 [ka] To a 5 mL microwave vial was added 8-bromo-2-methoxy-1,5-naphthyridine (54 mg, 1 eq, 0.23 mmol), followed by dropwise addition of hydrogen bromide (0.37 g, 0.25 mL, 20 eq, 4.5 mmol) at room temperature. The resulting mixture was heated at 85 °C for 12 h. Upon completion, excess hydrogen bromide was evaporated in vacuo. The resulting crude mixture was dissolved in DCM:MeOH (9:1) and filtered to give 8-bromo-1,5-naphthyridin-2-ol, 82, (37 mg, 0.16 mmol, 73%) as a brown solid. LCMS [M+H] +226.1H NMR (500 MHz, DMSO) δ8.34 (d, J = 5.0 Hz, 1H), 7.97 (d, J = 9.7 Hz, 1H), 7.90 (d, J = 5.0 Hz, 1H), 6.86 (d, J = 9.7 Hz, 1H), 4.41 (s, 1H).

[0323] Step 2, General Scheme 4 [ka] 8-Bromo-2-chloro-1,5-naphthyridine, 83.

[0324] [ka] A mixture of 8-bromo-1,5-naphthyridin-2-ol (165 mg, 1 eq, 733 μmol) in phosphoryl trichloride (674 mg, 411 μL, 6 eq, 4.40 mmol) was refluxed in a 5 mL microwave vial for 2 h. Upon completion, the reaction mixture was added dropwise to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine (20×2 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0–50% EtOAc / hexanes) to give 8-bromo-2-chloro-1,5-naphthyridine, 83, (94 mg, 386 μmol, 40%). LCMS [M+H] + 244.1H NMR (500 MHz, CDCl3) δ8.85 (d, J = 4.8 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 4.7 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H).

[0325] Step 3, General Scheme 4 [ka] 2-Chloro-8-(4-(2-fluorophenyl)piperazin-1-yl)-1,5-naphthyridine, 128.

[0326] [ka] A 5 mL Biotage microwave vial was charged with 1-(2-fluorophenyl)piperazine (18 mg, 16 μL, 1.2 eq, 99 μmol) and cesium carbonate (54 mg, 2 eq, 0.16 mmol), and then DMF (0.8 mL, 0.1 M) was added and stirred for 10 min. 8-Bromo-2-chloro-1,5-naphthyridine (20 mg, 1 eq, 82 μmol) was added, and the vial was capped and heated at 100 °C for 3 h. After this time, the 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 × 2). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry loaded onto silica gel and purified on a 12 g silica gel column (0-5% MeOH / DCM) to give 2-chloro-8-(4-(2-fluorophenyl)piperazin-1-yl)-1,5-naphthyridine, 128, (24 mg, 69 μmol, 84%). LCMS [M+H] + 343.1H NMR (500 MHz, CDCl3) δ8.46 (d, J = 5.0 Hz, 1H), 7.67 (s, 1H), 7.33 (t, J = 9.5 Hz, 1H), 7.19 - 7.03 (m, 3H), 7.03 - 6.95 (m, 2H), 4.05 (s, 4H), 3.29 - 3.22 (m, 4H).

[0327] Step 4, General Scheme 4

[0328] 4-(8-(4-(2-fluorophenyl)piperazin-1-yl)-1,5-naphthyridin-2-yl)pyridin-2-amine, 52.

[0329] [ka] A 5 mL Biotage microwave vial was charged with 2-chloro-8-(4-(2-fluorophenyl)piperazin-1-yl)-1,5-naphthyridine (23 mg, 1 eq, 67 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (16 mg, 1.2 eq, 74 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (5.5 mg, 0.08 eq, 6.7 μmol), and cesium carbonate (66 mg, 3 eq, 200 μmol). The vial was capped, purged with nitrogen, and then charged with degassed 4:1 dioxane:HO (1.3 mL, 52 mM) and heated at 95 °C for 12 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (20 mL). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (50-100% EtOAc / hexanes) to give 4-(8-(4-(2-fluorophenyl)piperazin-1-yl)-1,5-naphthyridin-2-yl)pyridin-2-amine, 52, (11 mg, 94 μmol, 28%) as a yellow solid. LCMS [M+H] +401.1H NMR (500 MHz, CDCl3) δ8.71 (d, J = 4.4 Hz, 1H), 8.18 (dd, J = 9.4, 4.6 Hz, 1H), 7.92 (d, J = 6.3 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.30 (d, J = 9.4 Hz, 1H), 7.23 (dd, J = 6.2, 1.4 Hz, 1H), 7.17 (s, 1H), 7.07 (dd, J = 12.2, 6.7 Hz, 2H), 6.98 (qd, J = 7.5, 4.9 Hz, 2H), 6.54 (s, 1H), 3.89 - 3.81 (m, 4H), 3.20 (t, J = 5.2 Hz, 4H).

[0330] 4-(8-(4-phenylpiperazin-1-yl)-1,5-naphthyridin-2-yl)pyridin-2-amine, 53.

[0331] 2-Chloro-8-(4-phenylpiperazin-1-yl)-1,5-naphthyridine, 129.

[0332] Compound 53 was prepared according to general scheme 4 via a four-step procedure reported for the preparation of compound 52. Steps 3 and 4 are reported below.

[0333] [ka] Prepared in a similar manner to step 3, general scheme 4 used for compound 52. 2-Chloro-8-(4-phenylpiperazin-1-yl)-1,5-naphthyridine, 129, (32 mg, 99 μmol, 80%). LCMS [M+H] +325.1H NMR (500 MHz, CDCl3) δ8.47 (d, J = 4.8 Hz, 1H), 8.17 (d, J = 9.4 Hz, 1H), 7.59 (d, J = 4.8 Hz, 1H), 7.41 - 7.28 (m, 3H), 7.01 (d, J = 8.2 Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H), 4.03 (t, J = 5.2 Hz, 4H), 3.37 (dd, J = 6.1, 4.2 Hz, 4H).

[0334] 4-(8-(4-phenylpiperazin-1-yl)-1,5-naphthyridin-2-yl)pyridin-2-amine, 53.

[0335] [ka] Compound 53 was prepared in a manner similar to step 4 of compound 52 according to general scheme 4. 4-(8-(4-phenylpiperazin-1-yl)-1,5-naphthyridin-2-yl)pyridin-2-amine, 53, (11 mg, 98 μmol, 31%) was obtained as a yellow solid. LCMS [M+H] +383.1H NMR (500 MHz, CDCl3) δ8.68 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 9.3 Hz, 1H), 8.14 (d, J = 5.5 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.33 - 7.27 (m, 3H), 7.13 (dd, J = 5.4, 1.4 Hz, 1H), 7.01 - 6.94 (m, 3H), 6.89 (q, J = 8.4 Hz, 1H), 4.86 (s, 2H), 3.86 (dd, J = 6.5, 3.8 Hz, 4H), 3.30 (t, J = 5.2 Hz, 4H).13C NMR (101 MHz, CDCl3) δ157.88, 156.56, 151.05, 148.26, 146.07, 145.68, 142.00, 140.82, 140.48, 139.04, 129.26, 123.57, 120.29, 116.40, 115.98, 112.77, 110.31, 77.32, 77.00, 76.68, 49.21, 45.05.

[0336] 4-(4-((1R,5S)-3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)quinazolin-6-yl)pyridin-2-amine, 54.

[0337] Compound 54 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0338] 6-Bromo-4-((1R,5S)-3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)quinazoline, 130. [ka] Potassium carbonate (178 mg, 3 eq, 1.29 mmol) and (1R,5S)-3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane, trifluoroacetic acid (130 mg, 1 eq, 429 μmol) were added to a 5 mL Biotage microwave vial along with DMF (2.14 mL, 0.2 M) and stirred for 10 minutes. 6-Bromo-4-chloroquinazoline (104 mg, 1 eq, 429 μmol) was added, the vial was sealed, and the mixture was stirred at 110°C for 18 hours. After this time, the 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 the crude product. The crude product was dry loaded onto silica gel and purified on a 12 g silica gel column (0-10% EtOAc / hexanes) to give 6-bromo-4-((1R,5S)-3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)quinazoline, 130, (20 mg, 51 μmol, 12%). LCMS [M+H] + 397.1H NMR (400 MHz, CDCl3) δ8.68 (s, 1H), 8.20 (dd, J = 5.2, 1.9 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.84 - 7.72 (m, 2H), 7.50 (ddd, J = 9.0, 7.1, 2.0 Hz, 1H), 6.71 - 6.60 (m, 2H), 4.96 (t, J = 3.4 Hz, 2H), 4.10 (dd, J = 12.0, 2.4 Hz, 2H), 3.39 (dd, J = 11.9, 2.3 Hz, 2H), 2.05 - 1.85 (m, 4H).

[0339] 4-(4-((1R,5S)-3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)quinazolin-6-yl)pyridin-2-amine, 54.

[0340] [ka] To a solution of (1R,5S)-3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (100 mg, 1.0 eq, 0.528 mmol) in NMP (2.64 mL, 0.18 M) was added triethylamine (134 mg, 184 μL, 2.5 eq, 1.32 mmol) and tert-butyl (4-(4-chloroquinazolin-6-yl)pyridin-2-yl)carbamate (189 mg, 1 eq, 0.528 mmol). The mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction was extracted with EtOAc, washed with brine (×3) and water (×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. A mixture of DCM:TFA (4:1, 2.2 mL) was added to the crude mixture, stirred at room temperature overnight, and basified with 1N NaOH. The mixture was extracted with DCM, washed with 10% NaOH, water, brine, and the organic layer was dried over sodium sulfate, concentrated, dry-loaded onto silica gel, and purified on a 12 g column (DCM / MeOH 0-10%) to give 4-(4-((1R,5S)-3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)quinazolin-6-yl)pyridin-2-amine, 54, (22 mg, 55 μmol, 19%) as a yellow solid. LCMS [M+H] +410.1H NMR (500 MHz, CDCl3) δ8.71 (s, 1H), 8.24 - 8.16 (m, 2H), 8.11 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 1.7 Hz, 2H), 7.51 (ddd, J = 8.9, 7.1, 1.9 Hz, 1H), 6.92 (dd, J = 5.5, 1.5 Hz, 1H), 6.80 (s, 1H), 6.70 - 6.60 (m, 2H), 5.08 (s, 2H), 5.01 (d, J = 4.0 Hz, 2H), 4.12 (dd, J = 12.0, 2.4 Hz, 2H), 3.43 (dd, J = 11.9, 2.2 Hz, 2H), 2.04 - 1.86 (m, 4H).13C NMR (126 MHz, CDCl3) δ163.08, 159.89, 158.65, 155.08, 151.95, 150.14, 147.90, 147.24, 137.77, 135.73, 131.51, 129.48, 123.28, 117.03, 113.80, 112.50, 106.89, 57.79, 51.53, 41.17, 27.13.

[0341] 4-(4-((1R,4R)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazolin-6-yl)pyridin-2-amine, 55.

[0342] Compound 55 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0343] 6-Bromo-4-((1R,4R)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazoline, 131.

[0344] [ka] To a solution of (1S,4S)-2-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane (43.5 mg, 1.0 eq, 0.248 mmol) in NMP (1.24 mL, 0.18 M) was added triethylamine (62.8 mg, 86.5 μL, 2.5 eq, 0.621 mmol) and 6-bromo-4-chloroquinazoline (60 mg, 1 eq, 0.248 mmol). The mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the reaction was extracted with EtOAc, washed with brine (x3) and water (x3), dried over anhydrous sodium sulfate, filtered, concentrated, dry loaded onto silica gel, and purified on a 12 g column (hexanes / EtOAc 50%) to give 6-bromo-4-((1R,4R)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazoline, 131, (91 mg, 0.24 mmol, 96%). LCMS [M+H] + 383.1H NMR (500 MHz, CDCl3) δ8.55 (s, 1H), 8.12 - 8.02 (m, 2H), 7.74 - 7.60 (m, 2H), 7.39 (ddd, J = 8.8, 7.1, 1.9 Hz, 1H), 6.52 (dd, J = 7.1, 5.0 Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 5.39 (t, J = 1.8 Hz, 1H), 5.13 (s, 1H), 4.24 (dd, J = 9.1, 1.9 Hz, 1H), 3.91 (d, J = 9.1 Hz, 1H), 3.71 (dd, J = 9.4, 2.1 Hz, 1H), 3.58 (d, J = 9.4 Hz, 1H), 2.13 (s, 2H).

[0345] 4-(4-((1R,4R)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazolin-6-yl)pyridin-2-amine, 55.

[0346] [ka] To a 5 mL microwave vial was added 6-bromo-4-((1S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazoline (65 mg, 1 eq, 0.17 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (45 mg, 1.2 eq, 0.2 mmol), potassium phosphate tripotassium (140 mg, 4 eq, 0.68 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.08 eq, 14 μmol). The mixture was capped and purged with argon before being injected with degassed 4:1 dioxane:HO (0.85 mL, 0.2 M) and heated at 90 °C for 6 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 2). 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 the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-5% MeOH / DCM) to give 4-(4-((1R,4R)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazolin-6-yl)pyridin-2-amine, 55, (39 mg, 98 μmol, 26%) as a white solid. LCMS [M+H] +396.1H NMR (500 MHz, CDCl3) δ8.61 (d, J = 1.3 Hz, 1H), 8.22 (d, J = 3.3 Hz, 1H), 8.07 (dd, J = 5.4, 1.9 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.88 (d, J = 1.7 Hz, 2H), 7.48 - 7.37 (m, 1H), 6.96 (d, J = 11.6 Hz, 1H), 6.87 (d, J = 5.6 Hz, 1H), 6.55 (dt, J = 7.6, 4.1 Hz, 1H), 6.35 (dd, J = 8.6, 4.0 Hz, 1H), 5.67 (s, 2H), 5.50 - 5.40 (m, 1H), 5.16 (s, 1H), 4.43 (d, J = 9.4 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.77 (dt, J = 9.5, 2.5 Hz, 1H), 3.65 (d, J = 9.3 Hz, 1H), 2.27 - 2.12 (m, 2H). 13C NMR (126 MHz, CDCl3) δ160.34, 157.77, 156.44, 154.98, 151.88, 151.08, 147.40, 143.53 138.09, 134.10, 130.87, 129.14, 123.70, 116.51, 112.71, 111.77, 108.01, 107.49, 60.64, 59.56, 57.16, 54.30, 36.73.

[0347] 4-(4-(4-(pyridin-2-yl)-1,4-diazepan-1-yl)quinazolin-6-yl)pyridin-2-amine, 56.

[0348] Compound 56 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0349] 6-Bromo-4-(4-(pyridin-2-yl)-1,4-diazepan-1-yl)quinazoline, 132.

[0350] [ka] Prepared in a similar manner to compound 131. 6-Bromo-4-(4-(pyridin-2-yl)-1,4-diazepan-1-yl)quinazoline, 132, (167 mg, 434 μmol). LCMS [M+H] + 385.1H NMR (500 MHz, CDCl3) δ8.58 (s, 1H), 8.12 (t, J = 1.3 Hz, 1H), 8.08 (dt, J = 4.9, 1.7 Hz, 1H), 7.85 - 7.74 (m, 2H), 7.44 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 6.59 - 6.49 (m, 2H), 4.18 (t, J = 5.3 Hz, 2H), 4.07 (t, J = 5.4 Hz, 2H), 4.00 - 3.91 (m, 2H), 3.77 (t, J = 6.0 Hz, 2H), 2.30 - 2.15 (m, 2H).

[0351] 4-(4-(4-(pyridin-2-yl)-1,4-diazepan-1-yl)quinazolin-6-yl)pyridin-2-amine, 56.

[0352] [ka] Specifically, compound 56 was prepared under the same conditions as compound 31 (28 mg, 70 μmol, 18% yield). LCMS [M+H] +398.1H NMR (500 MHz, CDCl3) δ8.62 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.91 (s, 2H), 7.44 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 5.1 Hz, 1H), 6.84 (s, 1H), 6.63 - 6.47 (m, 2H), 5.12 (s, 2H), 4.22 (d, J = 5.5 Hz, 2H), 4.10 (d, J = 5.3 Hz, 2H), 3.99 (d, J = 5.7 Hz, 2H), 3.79 (t, J = 6.2 Hz, 2H), 2.26 (s, 2H).

[0353] 4-(4-(3-fluoropyridin-2-yl)piperazin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline, 57.

[0354] Compound 57 was prepared via general scheme 1 via two procedures reported for the preparation of compound 1. The two steps are reported below.

[0355] 6-Bromo-4-(4-(3-fluoropyridin-2-yl)piperazin-1-yl)quinazoline, 133.

[0356] [ka] Prepared in the same manner as compound 117. (mg amount, mol, 68%). LCMS [M+H] + 389. 1 H NMR (400 MHz, CDCl3) δ8.67 (s, 1H), 7.99 - 7.90 (m, 2H), 7.76 - 7.65 (m, 2H), 7.24 - 7.12 (m, 1H), 6.72 (ddd, J = 7.9, 4.8, 3.1 Hz, 1H), 3.94 - 3.80 (m, 4H), 3.68 - 3.58 (m, 4H). 13C NMR (101 MHz, CDCl3) δ163.45, 154.23, 151.25, 150.46, 149.49, 148.70, 142.80, 135.76, 130.46, 127.13, 123.37, 123.18, 118.60, 117.68, 116.33, 49.54, 47.36.

[0357] 4-(4-(3-fluoropyridin-2-yl)piperazin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline, 57.

[0358] [ka] tert-Butyl 3-(4-(4-(3-fluoropyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (163 mg, 1 eq, 311 μmol) was suspended in DCM (3 mL) and TFA (710 mg, 479 μL, 20 eq, 6.229 mmol) was added. The solution was stirred at room temperature for 2 h, after which time the reaction mixture was concentrated by rotary evaporation. The residue was dissolved in ethyl acetate and washed twice with 2 M NaOH solution (2 × 75 mL). The organic layer was collected, dried over sodium sulfate, filtered, and concentrated to give 4-(4-(3-fluoropyridin-2-yl)piperazin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline, 57, (120 mg, 282 μmol, 90%). LCMS [M+H] + 426. 1H NMR (500 MHz, MeOD) δ8.53 (s, 1H), 8.27 (dd, J = 7.9, 1.5 Hz, 1H), 8.24 - 8.15 (m, 2H), 8.09 (dd, J = 8.7, 1.9 Hz, 1H), 7.92 (dt, J = 4.9, 1.4 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.71 (s, 1H), 7.30 (ddd, J = 13.1, 7.9, 1.5 Hz, 1H), 7.18 (dd, J = 8.0, 4.8 Hz, 1H), 6.79 (ddd, J = 8.0, 4.9, 3.2Hz, 1H), 4.00 - 3.95 (m, 4H), 3.67 - 3.61 (m, 4H).

[0359] 1-(1-(6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one, 58.

[0360] Compound 58 was prepared via general scheme 1 using the procedure reported for the preparation of compound 1, but an additional step was required to remove the BOC protecting group. The second and final steps are reported below.

[0361] 1-(1-(6-bromoquinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one, 134.

[0362] [ka] Prepared in a similar manner to compound 117. 1-(1-(6-bromoquinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one, 134, (556 mg, 1.44 mol, 86%). LCMS [M+H] + 386. 1H NMR (500 MHz, CDCl3) δ8.41 (s, 1H), 7.84 (dd, J = 5.1, 2.0 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.26 (ddd, J = 8.9, 7.1, 2.1 Hz, 1H), 6.54 (dd, J = 7.1, 5.0 Hz, 1H), 6.43 (d, J = 8.3 Hz, 1H), 5.10 (tt, J = 7.6, 3.8 Hz, 1H), 3.75 (ddd, J = 13.5, 7.3, 3.6 Hz, 2H), 3.42 - 3.34 (m, 2H), 1.92 (ddt, J = 14.3, 7.4, 3.7 Hz, 2H), 1.71 (dtd, J = 11.9, 7.8, 3.6 Hz, 2H).

[0363] tert-Butyl 3-(4-(4-(2-oxopyridin-1(2H)-yl)piperidin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, 135.

[0364] [ka] A microwave vial was charged with tribasic potassium phosphate (306 mg, 3 eq, 1.44 mmol), PdCl(dppf) (35 mg, 0.1 eq, 48.0 μmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (174 mg, 1.05 eq, 504 μmol), and 1-(1-(6-bromoquinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one (185 mg, 1 eq, 480 μmol) and the vial was sealed. The solid was dissolved in 1,4-dioxane (2.0 mL) and water (0.40 mL), and the reaction mixture was heated to 90 °C and stirred there for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a thick pad of Celite. The filtrate was collected and concentrated by rotary evaporation. The resulting residue was dissolved in 50 mL of ethyl acetate and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude concentrate was purified by column chromatography (0-10% MeOH / DCM) to give tert-butyl 3-(4-(4-(2-oxopyridin-1(2H)-yl)piperidin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, 135, (126 mg, 242 μmol, 50%). LCMS [M+H] + 523. This compound was carried forward to the next step without further characterization.

[0365] 1-(1-(6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one, 58.

[0366] [ka] tert-Butyl 3-(4-(4-(2-oxopyridin-1(2H)-yl)piperidin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (126 mg, 1 eq, 242 μmol) was suspended in DCM (2 mL) and TFA (553 mg, 373 μL, 20 eq, 4.85 mmol) was added. The solution was stirred at room temperature for 2 h, after which time the reaction mixture was concentrated by rotary evaporation. The residue was dissolved in ethyl acetate and washed twice with 2 M NaOH solution (2 × 75 mL). The organic layer was collected, dried over sodium sulfate, filtered, and concentrated to give 1-(1-(6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one, 58, (100 mg, 237 μmol, 97%). LCMS [M+H] + 423. 1 H NMR (400 MHz, CDCl3) δ12.20 (s, 1H), 8.78 (s, 1H), 8.49 - 8.43 (m, 1H), 8.30 (dd, J = 8.0, 1.3 Hz, 1H), 8.21 - 8.08 (m, 2H), 8.08 - 7.95 (m, 2H), 7.70 (s, 1H), 7.59 (ddd, J = 8.4, 7.1, 2.0 Hz, 1H), 7.30 - 7.20 (m, 1H), 6.88 (ddd, J = 7.1, 5.0, 1.0 Hz, 1H), 6.77 (dt, J = 8.3, 0.9 Hz, 1H), 5.45 (tt, J = 7.6, 3.8 Hz, 1H), 4.23 - 4.11 (m, 2H), 3.76 (ddd, J = 13.2, 8.2, 3.4 Hz, 2H), 2.29 (ddt, J = 13.8, 7.3, 3.4 Hz, 2H), 2.14 - 2.02 (m, 2H).

[0367] 1-(1-(6-(1H-pyrazol-4-yl)quinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one, 59.

[0368] Compound 59 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0369] [ka] A microwave vial was charged with tribasic potassium phosphate (306 mg, 3 eq, 1.44 mmol), PdCl(dppf) (35.1 mg, 0.1 eq, 48.0 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (148 mg, 1.05 eq, 504 μmol), and 1-(1-(6-bromoquinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one (185 mg, 1 eq, 480 μmol) and the vial was sealed. The solid was dissolved in 1,4-dioxane (2.0 mL) and water (0.40 mL), and the reaction mixture was heated to 90° C. and stirred there for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a thick pad of Celite. The filtrate was collected and concentrated by rotary evaporation. The resulting residue was dissolved in 50 mL of ethyl acetate and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude concentrate was purified by column chromatography (0-10% MeOH / DCM) to give 1-(1-(6-(1H-pyrazol-4-yl)quinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one, 59, (123 mg, 330 μmol, 68%). LCMS [M+H] + 373. 1H NMR (400 MHz, CDCl3) δ8.74 (s, 1H), 8.19 (ddd, J = 5.0, 2.0, 0.8 Hz, 1H), 8.00 - 7.83 (m, 3H), 7.67 - 7.37 (m, 2H), 6.91 (ddd, J = 7.1, 5.1, 1.0 Hz, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 5.46 (tt, J = 7.7, 3.9 Hz, 1H), 4.14 (ddd, J = 11.2, 6.8, 3.6 Hz, 2H), 3.82 - 3.67 (m, 2H), 2.31 (ddd, J = 12.9, 7.2, 3.6 Hz, 2H), 2.08 (dtd, J = 12.2, 8.0, 3.5 Hz, 2H).

[0370] 6-(3-methyl-1H-pyrazol-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 60.

[0371] Compound 60 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0372] [ka] Compound 60 was prepared according to the same procedure as in the synthesis of compound 50. 6-(3-methyl-1H-pyrazol-4-yl)-4-(4-(pyridin-2-yl)piperazin-1-yl)quinazoline, 60, (61 mg, 165 μmol, 41% yield) was obtained as a brown solid. LCMS [M+H] +372.1H NMR (500 MHz, DMSO) δ12.80 (s, 1H), 8.62 (s, 1H), 8.15 (dd, J = 5.0, 2.0 Hz, 1H), 7.99 (d, J = 7.4 Hz, 3H), 7.83 (d, J = 8.8 Hz, 1H), 7.57 (ddd, J = 8.8, 7.1, 2.0 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.67 (dd, J = 7.1, 4.9 Hz, 1H), 3.87 (dd, J = 7.0, 3.6 Hz, 4H), 3.75 (dd, J = 6.9, 3.7 Hz, 4H), 2.50 (d, J = 3.0 Hz, 3H).

[0373] 4-(4-(4-(3-fluoropyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 61.

[0374] Compound 61 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0375] [ka] A microwave vial was charged with tribasic potassium phosphate (328 mg, 3 eq, 1.548 mmol), PdCl(dppf) (37.7 mg, 0.1 eq, 51.5 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (124 mg, 1.1 eq, 567 μmol), and 6-bromo-4-(4-(3-fluoropyridin-2-yl)piperazin-1-yl)quinazoline (200 mg, 1 eq, 515 μmol) and sealed. The solid was dissolved in 1,4-dioxane (2.0 mL) and water (0.40 mL), and the reaction mixture was heated to 90 °C and stirred there for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a thick pad of Celite. The filtrate was collected and concentrated by rotary evaporation. The resulting residue was dissolved in 50 mL of ethyl acetate and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude concentrate was purified by column chromatography (0-10% MeOH / DCM) to give 4-(4-(4-(3-fluoropyridin-2-yl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-amine, 61, (141 mg, 352.0 μmol, 68%). LCMS [M+H] + 402. 1 H NMR (500 MHz, CDCl3) δ8.73 (s, 1H), 8.13 (d, J = 5.4 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.00 (dd, J = 4.8, 1.7 Hz, 1H), 7.95 - 7.85 (m, 2H), 7.27 - 7.19 (m, 1H), 6.89 - 6.84 (m, 1H), 6.77 (ddd, J = 7.9, 4.8, 3.1 Hz, 1H), 6.71 (s, 1H), 3.95 - 3.89 (m, 4H), 3.71 - 3.65 (m, 4H).

[0376] 1-(1-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one, 62.

[0377] Compound 62 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0378] [ka] To a microwave vial was added tribasic potassium phosphate (306 mg, 3 eq, 1.44 mmol), PdCl(dppf) (35 mg, 0.1 eq, 48.0 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (111 mg, 1.05 eq, 504 μmol), and 1-(1-(6-bromoquinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one (185 mg, 1 eq, 480 μmol), and the vial was sealed. The solid was dissolved in 1,4-dioxane (2.0 mL) and water (0.40 mL), and the reaction mixture was heated to 90 °C and stirred there for 16 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a thick pad of Celite. The filtrate was collected and concentrated by rotary evaporation. The resulting residue was dissolved in 50 mL of ethyl acetate and washed with water (3x50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude concentrate was purified by column chromatography (0-10% MeOH / DCM) to give 1-(1-(6-(2-aminopyridin-4-yl)quinazolin-4-yl)piperidin-4-yl)pyridin-2(1H)-one, 62, (142 mg, 358 μmol, 74%). LCMS [M+H] + 402. 1H NMR (500 MHz, CDCl3) δ8.69 (s, 1H), 8.13 - 8.07 (m, 2H), 8.03 - 7.97 (m, 1H), 7.91 - 7.82 (m, 2H), 7.56 - 7.49 (m, 1H), 6.87 - 6.78 (m, 2H), 6.72 - 6.66 (m, 2H), 5.36 (tt, J = 7.8, 3.8 Hz, 1H), 4.08 (ddd, J = 11.9, 7.2, 3.6 Hz, 2H), 3.68 (ddd, J = 12.9, 8.4, 3.3 Hz, 2H), 2.19 (ddt, J = 14.4, 7.5, 3.6 Hz, 2H), 1.98 (dtd, J = 12.2, 8.0, 3.4 Hz, 2H).

[0379] 4-(4-(4-(2,4-difluorophenyl)piperidin-1-yl)quinazolin-6-yl)pyridin-2-amine, 63.

[0380] Compound 63 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0381] 6-Bromo-4-(4-(2,4-difluorophenyl)piperidin-1-yl)quinazoline, 136. [ka] To a solution of 6-bromo-4-chloroquinazoline (74 mg, 1.2 eq, 0.30 mmol) and 4-(2,4-difluorophenyl)piperidine (50 mg, 1.0 eq, 0.25 mmol) in NMP (0.51 mL, 0.4 M) was added triethylamine (64 mg, 88 μL, 2.5 eq, 0.63 mmol). The mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction was extracted with EtOAc, washed with brine (×3) and water (×3), dried over anhydrous sodium sulfate, filtered, concentrated, dry-loaded onto silica gel, and purified on a 12 g silica gel column (0–10% EtOAc / hexanes) to give 6-bromo-4-(4-(2,4-difluorophenyl)piperidin-1-yl)quinazoline, 136, (78 mg, 0.19 mmol, 76%). LCMS[M+H] + 405.1H NMR (400 MHz, CDCl3) δ8.73 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.83 (dd, J = 8.9, 2.1 Hz, 1H), 7.18 (tt, J = 8.3, 6.3 Hz, 1H), 6.88 (t, J = 8.5 Hz, 2H), 4.57 (d, J = 13.1 Hz, 2H), 3.39 (tt, J = 12.4, 3.8 Hz, 1H), 3.29 (t, J = 12.8 Hz, 2H), 2.36 (qd, J = 12.9, 3.8 Hz, 2H), 2.02 - 1.88 (m, 2H).

[0382] 4-(4-(4-(2,4-difluorophenyl)piperidin-1-yl)quinazolin-6-yl)pyridin-2-amine, 63.

[0383] [ka] A 5 mL microwave vial was charged with 6-bromo-4-(4-(2,4-difluorophenyl)piperidin-1-yl)quinazoline (78 mg, 1 eq, 0.19 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (51 mg, 1.2 eq, 0.23 mmol), potassium phosphate tripotassium (160 mg, 4 eq, 0.77 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.08 eq, 15 μmol). The mixture was capped and purged with argon, then charged with degassed 4:1 dioxane:HO (1.0 mL, 0.2 M) and heated at 80 °C for 18 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL x 2). The aqueous layer was washed with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was dry-loaded onto silica gel and purified on a 12 g silica gel column (0-3% MeOH / DCM) to give 4-(4-(4-(2,4-difluorophenyl)piperidin-1-yl)quinazolin-6-yl)pyridin-2-amine, 63, (20 mg, 0.19 mmol, 25%) as a brown solid. LCMS [M+H] +418.1H NMR (500 MHz, CDCl3) δ8.75 (s, 1H), 8.18 - 8.05 (m, 2H), 8.00 - 7.88 (m, 2H), 7.17 (tt, J = 8.3, 6.3 Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H), 6.87 (t, J = 8.5 Hz, 2H), 6.81 (s, 1H), 4.98 (s, 2H), 4.55 (d, J = 13.3 Hz, 2H), 3.37 (ddt, J = 12.4, 7.6, 3.8 Hz, 1H), 3.28 (t, J = 12.8 Hz, 2H), 2.45 - 2.29 (m, 2H), 1.96 - 1.85 (m, 2H). 13C NMR (126 MHz, DMSO) δ163.78, 161.83, 161.75, 160.51, 159.88, 159.80, 154.08, 151.53, 148.60, 147.30, 135.20, 131.05, 128.84, 128.77, 128.68, 122.75, 119.80, 119.66, 119.51, 115.84, 112.19, 111.98, 109.98, 105.38, 50.01, 32.57, 29.88.

[0384] 4-(4-(8-(pyridin-2-yl)-2,8-diazaspiro[4.5]decan-2-yl)quinazolin-6-yl)pyridin-2-amine, 64.

[0385] Compound 64 was prepared according to general scheme 1 via the two-step procedure reported for the preparation of compound 1. However, this compound requires an additional step to add a pyridyl group, as shown below.

[0386] 4-(4-(8-(pyridin-2-yl)-2,8-diazaspiro[4.5]decan-2-yl)quinazolin-6-yl)pyridin-2-amine, 64.

[0387] 2-(6-Bromoquinazolin-4-yl)-2,8-diazaspiro[4.5]decane, 137.

[0388] [ka] Prepared according to a procedure similar to that used for the synthesis of compound 117. tert-Butyl 2-(6-bromoquinazolin-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate, 137, (398 mg, 832 μmol, 100%) LCMS [M+H] + 448.1H NMR (400 MHz, CDCl3) δ8.59 (s, 1H), 8.27 - 8.21 (m, 1H), 7.80 - 7.72 (m, 2H), 4.05 (t, J = 7.0 Hz, 2H), 3.47 (td, J = 6.3, 4.5 Hz, 4H), 3.41 - 3.31 (m, 1H), 2.42 - 2.32 (m, 1H), 2.02 - 1.94 (m, 2H), 1.62 (q, J = 5.5 Hz, 4H), 1.44 (d, J = 0.9 Hz, 9H). Then, tert-butyl 2-(6-bromoquinazolin-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate was added to TFA in DCM (1:4, 7, 8 mL) and stirred at room temperature for 3 hours. Excess TFA was evaporated in vacuo to give 2-(6-bromoquinazolin-4-yl)-2,8-diazaspiro[4.5]decane as the TFA salt (376 mg, 815 μmol, 98%). LCMS [M+H] + 348. This compound was used without further purification or characterization.

[0389] 2-(6-Bromoquinazolin-4-yl)-8-(pyridin-2-yl)-2,8-diazaspiro[4.5]decane, 138.

[0390] [ka] A 5 mL Biotage microwave vial was charged with 2-(6-bromoquinazolin-4-yl)-2,8-diazaspiro[4.5]decane, trifluoroacetic acid (376 mg, 1.0 eq, 815 μmol), and potassium carbonate (338 mg, 3.0 eq, 2.45 mmol). The vial was capped and charged with 2-fluoropyridine (237 mg, 3.0 eq, 2.45 mmol) and DMSO (1.63 mL, 0.5 M). The reaction was heated at 140 °C for 5 h. Upon completion, the reaction was extracted into EtOAc, washed with brine (x3) and water (x3), dried over sodium sulfate, filtered, concentrated in vacuo, dry-loaded onto silica gel, and purified on a 12 g silica gel column (0-20% EtOAc:hexanes) to give 2-(6-bromoquinazolin-4-yl)-8-(pyridin-2-yl)-2,8-diazaspiro[4.5]decane, 138, (144 mg, 339 μmol, 70%). LCMS [M+H] + 425.1H NMR (500 MHz, CDCl3) δ8.39 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.98 (ddd, J = 5.0, 2.0, 0.8 Hz, 1H), 7.54 (dd, J = 8.9, 2.0 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.26 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 6.46 (dd, J = 8.6, 1.0 Hz, 1H), 6.40 (ddd, J = 7.2, 4.9, 0.9 Hz, 1H), 3.84 (t, J = 7.0 Hz, 2H), 3.59 (s, 2H), 3.41 (dtdd, J = 17.7, 13.3, 9.1, 4.4 Hz, 4H), 1.80 (t, J = 7.0 Hz, 2H), 1.64 - 1.47 (m, 4H).

[0391] 4-(4-(8-(pyridin-2-yl)-2,8-diazaspiro[4.5]decan-2-yl)quinazolin-6-yl)pyridin-2-amine, 64.

[0392] [ka] Compound 64 was prepared according to the same procedure as the synthesis of compound 50. 4-(4-(8-(pyridin-2-yl)-2,8-diazaspiro[4.5]decan-2-yl)quinazolin-6-yl)pyridin-2-amine, 64, (76 mg, 173 μmol, 51% yield) was obtained as a brown solid. LCMS [M+H] + 438.1H NMR (500 MHz, CDCl3) δ8.63 (s, 1H), 8.33 (d, J = 1.3 Hz, 1H), 8.22 - 8.15 (m, 2H), 7.90 (d, J = 1.3 Hz, 2H), 7.47 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 6.90 (dd, J = 5.4, 1.6 Hz, 1H), 6.75 - 6.70 (m, 1H), 6.68 (dd, J = 8.6, 1.2 Hz, 1H), 6.61 (ddd, J = 7.2, 4.9, 0.9 Hz, 1H), 4.57 (s, 2H), 4.14 13C NMR (126 MHz, CDCl3) δ160.25, 159.47, 159.18, 155.07, 151.97, 149.86, 149.15, 148.17, 137.67, 135.13, 130.92, 129.11, 123.81, 116.64, 113.29, 112.79, 107.39, 106.28, 60.74, 49.68, 43.03, 41.18, 36.01, 34.15.

[0393] 4-(4-(2-(pyridin-2-yl)-2,8-diazaspiro[4.5]decan-8-yl)quinazolin-6-yl)pyridin-2-amine, 65.

[0394] Compound 65 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The two steps are reported below.

[0395] 8-(6-Bromoquinazolin-4-yl)-2-(pyridin-2-yl)-2,8-diazaspiro[4.5]decane, 139.

[0396] [ka] Prepared in the same manner as compound 131. 8-(6-Bromoquinazolin-4-yl)-2-(pyridin-2-yl)-2,8-diazaspiro[4.5]decane, 139, (263 mg, 620 μmol, 44%). LCMS [M+H] + 425.1H NMR (500 MHz, CDCl3) δ8.53 (s, 1H), 7.98 (dd, J = 5.3, 1.9 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.26 (ddd, J = 8.8, 7.1, 2.0 Hz, 1H), 6.43 - 6.31 (m, 1H), 6.17 (d, J = 8.5 Hz, 1H), 3.76 - 3.63 (m, 2H), 3.50 (ddd, J = 13.1, 7.4, 4.7 Hz, 2H), 3.36 (t, J = 7.0 Hz, 2H), 3.31 (s, 2H), 1.82 (q, J = 6.9 Hz, 2H), 1.71 - 1.57 (m, 4H).

[0397] 4-(4-(2-(pyridin-2-yl)-2,8-diazaspiro[4.5]decan-8-yl)quinazolin-6-yl)pyridin-2-amine, 65.

[0398] [ka] Compound 65 was prepared according to the same procedure as the synthesis of compound 50. 4-(4-(2-(pyridin-2-yl)-2,8-diazaspiro[4.5]decan-8-yl)quinazolin-6-yl)pyridin-2-amine, 65, (79 mg, 181 μmol, 29% yield) was obtained as a brown solid. LCMS [M+H] + 438.1H NMR (500 MHz, CDCl3) δ8.74 (s, 1H), 8.21 - 8.13 (m, 2H), 8.05 (d, J = 1.9 Hz, 1H), 7.99 - 7.89 (m, 2H), 7.45 (ddd, J = 8.8, 7.1, 1.9 Hz, 1H), 6.90 (dd, J = 5.4, 1.5 Hz, 1H), 6.73 (t, J = 1.0 Hz, 1H), 6.55 (ddd, J = 7.1, 5.1, 1.0 Hz, 1H), 6.36 (dt, J = 8.6, 1.0 Hz, 1H), 4.61 (s, 2H), 3.95 (dt, J = 13.5, 5.2 Hz, 2H), 3.75 (ddd, J = 13.0, 7.4, 4.8 Hz, 2H), 3.55 (t, J = 7.0 Hz, 2H), 3.51 (s, 2H), 2.01 (t, J = 7.0 Hz, 2H), 1.91 - 1.81 (m, 4H). 13C NMR (126 MHz, CDCl3) δ165.00, 159.22, 157.40, 154.73, 152.18, 149.44, 149.18, 148.36, 137.22, 135.78, 131.27, 129.50, 123.38, 116.82, 112.71, 111.71, 106.47, 106.29, 56.55, 47.83, 45.17, 41.16, 36.65, 35.20.

[0399] 4-(4-((3aR,6aS)-5-(pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinazolin-6-yl)pyridin-2-amine, 66.

[0400] Compound 66 was prepared according to general scheme 1 via a two-step procedure reported for the preparation of compound 1. The second step is reported below.

[0401] [ka] Compound 66 was prepared according to the same procedure as the synthesis of compound 50. 4-(4-((3aR,6aS)-5-(pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinazolin-6-yl)pyridin-2-amine, 66, (14 mg, 34 μmol, 13% yield) was obtained as a brown solid. LCMS [M+H] + 410.1H NMR (500 MHz, DMSO) δ8.50 - 8.41 (m, 2H), 8.06 (dd, J = 5.3, 1.9 Hz, 1H), 8.03 - 7.94 (m, 2H), 7.79 (d, J = 8.6 Hz, 1H), 7.48 (ddd, J = 8.8, 7.1, 2.0 Hz, 1H), 6.91 (dd, J = 5.3, 1.7 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1H), 6.55 (dd, J = 7.1, 5.0 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 6.01 (s, 2H), 4.30 (dd, J = 11.7, 6.5 Hz, 2H), 3.95 (dd, J = 11.7, 3.9 Hz, 2H), 3.69 (dd, J = 10.7, 6.8 Hz, 2H), 3.43 (dd, J = 10.9, 3.8 Hz, 2H), 3.18 (t, J = 5.3 Hz, 2H). 13C NMR (126 MHz, DMSO) δ160.46, 159.18, 156.95, 154.38, 151.25, 148.63, 147.82, 147.52, 136.95, 134.37, 130.41, 128.16, 123.68, 115.92, 111.42, 110.14, 106.53, 105.13, 54.38, 50.23.

[0402] 4-(6-(2-aminopyridin-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-1-(2-fluorophenyl)piperazin-2-one, 67.

[0403] Compound 67 was prepared using general scheme 3 via the five-step procedure reported for compound 32.

[0404] tert-Butyl 4-(2-fluorophenyl)-3-oxopiperazine-1-carboxylate, 140.

[0405] [ka] tert-Butyl 4-(2-fluorophenyl)-3-oxopiperazine-1-carboxylate, 140, (539 mg, 1.83 mmol, 100%). LCMS [M+H] + 295.1H NMR (500 MHz, CDCl3) δ7.35 - 7.27 (m, 2H), 7.23 - 7.14 (m, 2H), 4.27 (s, 2H), 3.80 (t, J = 5.3 Hz, 2H), 3.68 (t, J = 5.3 Hz, 2H), 1.50 (s, 9H).

[0406] 1-(2-fluorophenyl)piperazin-2-one, 141 [ka] Prepared in a manner similar to step 3 of compound 32, general scheme 3. 1-(2-fluorophenyl)piperazin-2-one, 141, (129 mg, 662 μmol, 34%). LCMS [M+H] + 195. This compound was used without further purification or characterization.

[0407] 4-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-1-(2-fluorophenyl)piperazin-2-one, 142.

[0408] [ka] Prepared in a manner similar to step 4, general scheme 3, as seen for compound 32. 4-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-1-(2-fluorophenyl)piperazin-2-one, 142, (120 mg, 336 μmol, 60%). LCMS [M+H] + 358.1H NMR (500 MHz, DMSO) δ8.27 (s, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.10 (td, J = 7.8, 1.7 Hz, 1H), 7.06 - 6.98 (m, 1H), 6.95 (ddd, J = 10.0, 8.3, 1.5 Hz, 1H), 6.89 (td, J = 7.6, 1.5 Hz, 1H), 4.70 (s, 2H), 4.27 (s, 2H), 3.49 (t, J = 5.3 Hz, 2H).

[0409] 4-(6-(2-aminopyridin-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-1-(2-fluorophenyl)piperazin-2-one, 67.

[0410] [ka] Prepared in a manner similar to step 4, general scheme 3, as described for compound 32. 4-(6-(2-aminopyridin-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-1-(2-fluorophenyl)piperazin-2-one, 67, (34 mg, 83 μmol, 42%) was obtained as a brown solid. LCMS [M+H] +416.1H NMR (500 MHz, DMSO) δ8.64 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 5.3 Hz, 1H), 7.50 (td, J = 7.7, 1.7 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.34 (ddd, J = 10.1, 8.3, 1.5 Hz, 1H), 7.28 (td, J = 7.6, 1.5 Hz, 1H), 7.21 (dd, J = 5.4, 1.6 Hz, 1H), 7.16 (s, 1H), 6.18 (s, 2H), 5.01 (s, 4H), 3.98 (s, 2H).

[0411] [Incorporated by reference] The entire disclosure of each patent document and scientific article referred to herein is incorporated by reference for all purposes.

[0412] [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; Phosphorylation of DYRK3 (e.g., PRAS40); Activity of DYRK1B; CMGC / CLK kinase activity; CLK1 activity; CLK2 activity; CLK3 activity; CLK4 activity; CDK7 activity; CDK8 activity; Activity of CDK19; Activity of CDK8 / 19; PI3K activity; Activity of the PI3K mutant; 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 substituent of "Y" is 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】 A compound according to claim 4, selected from the above.

6. R1 is hydrogen, 【Transformation 3】 【Chemistry 4】 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, 【Transformation 5】 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, wherein X', Y', and Z' are independently N, C, or CR'.

9. The compound according to claim 6 or 7, wherein R, R', and R'' are independently selected from a lipophilic moiety comprising 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, and ether.

10. The compound according to claim 6 or 7, wherein R3 is selected from hydrogen, halogen (e.g., fluorine, bromine, chlorine, iodine), methyl, ethyl, and methoxy.

11. 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.

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

13. A compound comprising the compound described in Claim 1, A therapeutic agent for disorders 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.

14. The therapeutic agent according to claim 13, wherein the above-mentioned disorder is selected from Alzheimer's disease, Down syndrome, diabetes, autoimmune disease, inflammatory disorder, and cancer.

15. The therapeutic agent according to claim 13, further comprising one or more agents for treating Alzheimer's disease, Down syndrome, diabetes, autoimmune diseases, inflammatory disorders, and cancer.

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 disorder, and cancer.

18. The kit according to claim 16, further comprising one or more agents for treating Alzheimer's disease, Down syndrome, diabetes, autoimmune diseases, inflammatory disorders, and cancer.

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