Bicyclic beta-bromodomain inhibitors and uses thereof

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Ser. No. 62 / 259,894, filed November 25, 2015.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was created in the performance of a Cooperative Research and Development Agreement with the National Institutes of Health (NIH), an Agency of the Department of Health and Human Services. The Government of the United States has certain rights in this invention.THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

[0003] This invention is the subject of a joint research agreement between ConverGene, LLC and the National Institutes of Health (NIH), an Agency of the Department of Health and Human Services.FIELD OF THE INVENTION

[0004] The present invention relates to compounds of Formula I as claimed that inhibit bromodomain-containinc proteins from binding acetylated proteins, to pharmaceutical compositions containing these compounds, and to compounds as claimed for use in methods for treating a wide variety of medical conditions, diseases or disorders.BACKGROUND OF THE INVENTION

[0005] Epigenetic chromatin remodeling is a central mechanism for the regulation of gene expression. Pharmacological modulation of epigenetic change represents a new mode of therapeutic interventions for cancer and inflammation. Emerging evidence suggests that such epigenetic modulations may also provide therapeutic means for treatment of obesity, as well as metabolic, cardiovascular, neurodegenerative, psychiatric and infectious diseases.

[0006] The eukaryotic genome is organized into a basic packaging unit called a nucleosome, which is comprised of approximately 147 base pairs of double-stranded DNA helix wound around a histone octamer, which, in turn, consists of two subunits each of H2A, H2B, H3, and H4 proteins. Nucleosomes are further packaged into chromatin structures, which can exist in a relatively loose state of euchromatin or in a tightly packed heterochromatin structure. Transition from heterochromatin to euchromatin allows transcription of genes, although not all of the genes in euchromatin structure are transcribed. This transition from heterochromatin to euchromatin is controlled by post-translational modifications of histone proteins, including acetylation of lysine residues in H3 / H4 proteins. Histone acetylation is catalyzed by histone acetyltransferases (HATs), resulting in open euchromatin structures that allow transcription of genes including tumor suppressor genes. Conversely, histone deacetylation leads to suppression of such genes and this activity is catalyzed by histone deacetylases (HDACs). Inhibition of histone deacetylases is a mode of cancer treatment and vorinostat (Zolinza ®< ), a histone deacetylase inhibitor, has been shown to be an effective drug for cutaneous T-cell lymphoma in humans.

[0007] Histone acetylation also is modulated by bromodomain-containing proteins. A bromodomain is an approximately 110 amino acid-long evolutionarily conserved bundle of four alpha-helices that binds to acetyllysine residues of acetylated proteins. These domains are present in a number of chromatin-associated proteins including HATs. Bromodomains were first identified as a novel structural motif in the brahma protein, a regulator of Drosophila homeotic genes, but are also found in proteins in humans and yeast either as single-copy or contiguously repeated domains, and are thought to confer specificity for the complex pattern of epigenetic modifications known as the histone code (Cell. 1992 Feb 7;68(3):561-72; J. Biomol. Screen. 2011 Dec; 16(10):1170-85). The human genome encodes approximately 50 bromodomain-containing proteins (Bioinformatics. 2004 Jun 12;20(9):1416-27), some of which may be involved in etiology of cancer, inflammation, obesity, metabolic, cardiovascular, neurodegenerative, psychiatric and infectious diseases (Med. Chem. Commun. 2012 Jan 4 3(2):123-134; Curr. Opin. Drug Discov. Devel. 2009 Sep;12(5):659-65; Discov. Med. 2010 Dec;10(55):489-99; FEBS Lett. 2010 Aug 4;584(15):3260-8; J. Virol. 2006 Sep;80(18):8909-19; J Virol. 2005 Jul;79(14):8920-32; Curr. Opin. Pharmacol. 2008 Feb;8(1):57-64). Thus, inhibition and / or modulation of bromodomain-containing proteins may present a new mode of pharmacological intervention for such diseases.

[0008] Of approximately 50 bromodomain-containing proteins encoded by the human genome, BET proteins represent a small protein family that includes BRD2, BRD3, BRD4 and BRDT. BET proteins contain two tandem bromodomains followed by an extraterminal (ET) domain for protein-protein interaction in the carboxy-terminal region (J. Biol Chem. 2007 May 4;282(18):13141-5). BET proteins bind to acetylated nucleosomes and are thought to function by opening chromatin structure and / or by facilitating transcriptional initiation (Front. Biosci. 2001 Aug 1;6:D1008-18).

[0009] Previously, inhibition of BRD4, either by a BRD4-specific RNAi or by a small-molecule BET inhibitor (JQ1), was unequivocally shown to induce suppression of MYC oncogene (Nature 2011 Aug 3;478(7370):524-8). This indirect suppression of MYC gene expression as a secondary effect of BRD4 inhibition comprises the central mechanism of action exerted by a BET inhibitor.

[0010] Inhibition of BET proteins was shown to be an effective mode of intervention in rodent models of human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma and acute myeloid leukemia by suppressing the expression of MYC gene (Nature 2010 Dec 23;468(7327):1067-73; Cell. 2011 Sep 16;146(6):904-1; Proc. Nat.I Acad. Sci. U S A. 2011 Oct 4;108(40):16669-74), as well as MYCN gene (Cancer Discov. 2013 Mar: 3(3) 308-23). MYC and homologous genes are some of the most overexpressed genes in human cancers; however, there has not been a pharmaceutical compound that directly antagonizes the activity of proteins encoded by the MYC gene and homologous genes to date partly due to the lack of effective drug binding sites. Thus, there exists a need for a means of indirect suppression of the expression of the MYC and homologous genes by inhibiting bromodomains of BET proteins which provide an effective mode of treatment for various diseases, disorders or medical conditions, including various cancers.

[0011] WO 2011 / 054846 discloses imidazo [4, 5-c] quinoline derivatives and salts thereof as bromodomain inhibitors, pharmaceutical compositions containing such compounds, and their use in therapy.

[0012] WO 2015 / 015318 relates to quinazolines as bromodomain inhibitors, which are useful for inhibition of BET protein function by binding to bromodomains, and their use in therapy.

[0013] WO 2012 / 143416 discloses quinoline compounds, pharmaceutical compositions containing such compounds, and their use in therapy.

[0014] The publication of Z.-G. Gao et al. in Molecular Pharmacology, vol. 63, no. 6, pages 1021-1031 relates to the identification of essential residues involved in the allosteric modulation of the human A3 adenosine receptor.

[0015] WO 2016 / 120808 discloses heteroarylaminoisoquinolines, as well as to a method for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and / or prevention of conditions associated with the alteration of the activity of β-galactosidase, specially galactosidase beta-1 or GLB1, including GM1 gangliosidoses and Morquio syndrome, type B.

[0016] EP 1 012 166 B relates to 1-amino-7-isoquinoline derivatives as serine protease inhibitors.

[0017] EP 0 393 926 discloses 1-aminoisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy as inhibitors of gastric acid secretion.

[0018] The publication of Yang S.H. et al. in Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 17, pages 5277-5281 relates to the synthesis, in vivo and in vitro evaluation of 3-arylisoquinolinamines as potent antitumor agents.

[0019] The publication of Bhavin Marvania et al. in European Journal of Medicinal Chemistry, vol. 83, pages 695-708 relates to the synthesis and biological evaluation of DNA-directed alkylating agents, phenyl N-mustard-4-anilinoquinoline conjugates containing a urea linker.

[0020] WO 2006 / 121767 discloses 4-aminoquinoline compounds, pharmaceutical compositions of such compounds, kits comprising such compounds, and uses of such compounds for preparing medicaments and treating virus-related conditions in animals.

[0021] EP 2 072 502 relates to sulfoximide substituted chinolin and chinazolin derivatives as kinase inhibitors.

[0022] US 3 755 332 discloses substituted indazolaminoquinolines, acid addition salts thereof as well as N-oxides thereof as anti-inflammatory, anti-hypertensive and anti-malarial agents.

[0023] EP 1 430 030 B1 relates to N-type calcium channel antagonists for the treatment of pain.

[0024] WO 2008 / 117079 discloses antimicrobial compounds based upon 4-aminoquinoline.

[0025] WO 93 / 03030 discloses quinoline derivatives as immunostimulants.

[0026] WO 2008 / 141843 discloses sulphoximine-substituted quinazoline and quinazoline derivatives as kinase inhibitors.

[0027] WO 2011 / 140442 relates to amino-quinolines as kinase inhibitors.

[0028] The publication of Moyer M.P. et al. in Bioorganic & Medicinal Chemistry Letters, vol. 2, no. 12, pages 1589-1594 relates to the synthesis and identification of 4,6-diaminoquinoline derivatives as immunostimulants.

[0029] The publication of Abouzid K. et al. in Bioorganic & Medicinal Chemistry, vol. 16, no. 16, pages 7543-7551 relates to the design, synthesis and in vitro antitumor activity of 4-aminoquinoline and 4-aminoquinazoline derivatives targeting EGFR tyrosine kinase.

[0030] WO 2014 / 089546 discloses covalent, irreversible small-molecule inhibitors that modify the sulfenyl form (i.e., sulfenic acid, RSOH and sulfenamide, RSNR'2) of therapeutically important proteins (particularly kinases and phosphatases), where the compositions include a compound having a substituted aryl or heterocyclic core structure that promotes binding interactions with a specific protein, and a nucleophilic reaction center (carbon, nitrogen, sulfur, or phosphorous) that is capable of forming a covalent bond with a sulfenic acid- or sulfenamide-modified cysteine residue in the protein,

[0031] WO 2013 / 003586 discloses quinazolines as therapeutic compounds and related methods of use, and describes treating disorders using compounds that modulate stri-atal-enriched tyrosine phosphatase (STEP). Exemplary disorders include schizophrenia and cognitive deficit.

[0032] EP 3 056 207 relates to therapeutic compounds and methods of treating disorders by using such compounds that modulate striatal-enriched tyrosine phosphatase (STEP). Exemplary disorders include schizophrenia and cognitive deficit.

[0033] WO 2012 / 040499 provides compounds useful for treating diseases, including neoplasias and metabolic disorders. The compounds modulate GLUTI function and / or AMPK activity.

[0034] EP 2 221 301 discloses heteroaryloxy quinozaline derivatives and their pharmaceutically-acceptable salts, which have an effect of glucokinase activation and are useful in the field of medicines for treatment for diabetes and obesity.

[0035] WO 2012 / 125913 relates to methods and uses of bifunctional enzyme-building clamp-shaped molecules. The compounds are useful agents for inhibiting cell proliferative disorders, especially those disorders characterized by over activity and / or inappropriate activity of a EGFR, including EGFR-related cancers.

[0036] EP 2 650 286 discloses quinazoline derivatives, pharmacologically acceptable salts thereof, and compositions containing such compounds, as well as methods for using the compounds for treatment of hyperproliferative disorders.

[0037] WO 2008 / 054599 relates to inhibitors of ROCKI and ROCK2, which may be selective for ROCK2, and methods of modulating the pharmacokinetic and / or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCKI and / or ROCK2. Also provided are treatments combining inhibitors of ROCKI and / or ROCK2 with statins.

[0038] EP 1 865 958 B1 relates to inhibitors of ROCKI and ROCK2 and methods of modulating the pharmacokinetic and / or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCKI and or ROCK2 that are useful for the treatment of disease.

[0039] EP 1 854 789 discloses quinazoline derivatives having tyrosine kinase inhibitory activity. The compounds inhibits both of EGF receptor tyrosine kinase and HER2 tyrosine kinase.

[0040] The publication of Timothy J. Stuhlmiller et al. in Cell Reports, vol. 11, no. 3, pages 390-404 relates to the inhibition of lapatinib-induced kinome reprogramming in ERBB2-positive breast cancer by targeting BET family bromodomains.SUMMARY OF THE INVENTION

[0041] The invention is defined by the claims.

[0042] The present invention includes compounds as claimed which bind to bromodomain-containing proteins and subsequently modulate the binding of acetylated proteins to bromodomain-containing proteins. In one aspect, the invention provides compounds of Formula I, wherein each of R 1 , R 2 , R 3 , R 4 , L 1 , X, Y, and Z is as defined in the claims, and pharmaceutically acceptable salts, solvates, polymorphs, thereof.DETAILED DESCRIPTION OF THE INVENTION

[0043] According to one aspect of the invention, a compound of claim 1 is provided.

[0044] In some embodiments, R 8 is selected independently for each occurrence from the group consisting of H, OH, SH, halogen, -CN, -CF 3 , -NO 2 , -OR 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , - OC(O)NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 R 12 , -NR 11 C(O)R 12 ,- NR 11 C(O)OR 12 , -NR 11 S(O) 2 R 12 , - NR 11 C(O)NR 12 R 13 , -(CH 2 ) m -R 16 , -(CH 2 ) q -R 17 , -S(O)R 11 , -S(O) 2 R 11 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with one or more R 14 ; provided that when R 8 is attached to a nitrogen atom (e.g., a nitrogen atom of R 1 , R 2 , or a heterocycloalkyl group formed by R 1 and R 2 , together with the included nitrogen atom and L 1 ) R 8 is selected from R 21 , wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or -S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with one or more R 14 .

[0045] In some embodiments, the C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl of R 21 are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0046] In some embodiments, R 21 , is C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)R 11 , -C(O)OR 11 , - C(O)NR 11 R 12 , or-S(O) 2 R 11 , wherein said C 1-6 alkyl may optionally be substituted with NR 11 R 12 .

[0047] In some embodiments, R 21 is C 1-6 alkyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or-S(O) 2 R 11 , wherein said C 1-6 alkyl may optionally be substituted with NR 11 R 12 .

[0048] In some embodiments, R 21 is C(O)CH 3 , S(O) 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , or C(O)NH(cyclopropyl).

[0049] In some embodiments, R 21 is C(O)CH 3 or S(O) 2 CH 3 .

[0050] In some embodiments, R 8 is selected independently for each occurrence from the group consisting of H, OH, SH, halogen, -CN, -CF 3 , -NO 2 , -OR 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , - OC(O)NR 11 R 12 , -C(O)NR 11 R 12 , -NR 11 R 12 , -NR 11 C(O)R 12 ,- NR 11 C(O)OR 12 , -NR H S(O) 2 R 12 , - NR 11 C(O)NR 12 R 13 , -(CH 2 ) m -R 16 , -(CH 2 ) q -R 17 , -S(O)R 11 , -S(O) 2 R 11 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with one or more R 14 ; provided that when R 8 is attached to a carbon atom (e.g., a carbon atom of R 1 , R 2 , or a heterocycloalkyl group formed by R 1 and R 2 , together with the included nitrogen atom and L 1 ) R 8 is selected from R 8a , wherein R 8a is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, or a 5-6 membered heteroaryl, wherein said C 1-6 alkyl, phenyl, and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0051] In some embodiments, R 8a is benzyl, phenyl, or a 5-6 membered heteroaryl, wherein said phenyl and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0052] In some embodiments, R 8a is phenyl or a 5-6 membered heteroaryl, wherein said phenyl and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0053] In some embodiments, R 8a is phenyl or thienyl, wherein said phenyl may optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl; and said thienyl may optionally be substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl.

[0054] The compound is a compound as claimed , or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: and wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or -S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0056] In some embodiments, R 21 is C 1-6 alkyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or-S(O) 2 R 11 , wherein said C 1-6 alkyl may optionally be substituted with NR 11 R 12 .

[0057] In some embodiments, R 21 is C(O)CH 3 , S(O) 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , or C(O)NH(cyclopropyl).

[0058] In some embodiments, R 21 is C(O)CH 3 or S(O) 2 CH 3 .

[0059] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: and wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or-S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0060] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: and wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or-S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0061] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: and wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or-S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0062] In some embodiments, R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)R 11 , -C(O)OR 11 , - C(O)NR 11 R 12 , or-S(O) 2 R 11 , wherein said C 1-6 alkyl may optionally be substituted with NR 11 R 12 .

[0063] In some embodiments, R 21 is C(O)CH 3 , S(O) 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , or C(O)NH(cyclopropyl).

[0064] In some embodiments, R 21 is C(O)CH 3 or S(O) 2 CH 3 .

[0065] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: and wherein R 8 is phenyl; and wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or -S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0066] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: and wherein R 8 is phenyl; and wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or-S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0067] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: and wherein R 8 is phenyl; and wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or-S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0068] In some embodiments, R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)R 11 , -C(O)OR 11 , - C(O)NR 11 R 12 , or -S(O) 2 R 11 , wherein said C 1-6 alkyl may optionally be substituted with NR 11 R 12 .

[0069] In some embodiments, R 21 is C(O)CH 3 , S(O) 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , or C(O)NH(cyclopropyl).

[0070] In some embodiments, R 21 is C(O)CH 3 or S(O) 2 CH 3 .

[0071] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of:

[0072] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of:

[0073] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of:

[0074] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of:

[0075] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of:

[0076] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of:

[0077] In some embodiments, R 3 is selected from the group consisting of H,

[0078] In some embodiments, R 3 is selected from the group consisting of and and R 4 is H.

[0079] In some embodiments, X is CH.

[0080] In some embodiments, X is N.

[0081] In some embodiments, Z is CH.

[0082] In some embodiments, Z is N.

[0083] In some embodiments, X is CH and Z is N.

[0084] In some embodiments, both X and Z are N.

[0085] In some embodiments, X is N; and Z is CH.

[0086] In some embodiments, Y is selected from the group consisting of NR 6 R 7 , -C(O)R 11 , - C(O)NR 11 R 12 , 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said heterocycloalkyl and heteroaryl is optionally be substituted with 1, 2, 3, or 4 independently selected R 8 .

[0087] In some embodiments, Y is NR 6 R 7 .

[0088] In some embodiments, Y is -C(O)R 11 .

[0089] In some embodiments, Y is -C(O)NR 11 R 12 .

[0090] In some embodiments, Y is 4-6 membered heterocycloalkyl, wherein said 4-6 membered heterocycloalkyl may optionally be substituted with one or more R 8 .

[0091] In some embodiments, Y is 4-6 membered heterocycloalkyl, wherein said 4-6 membered heterocycloalkyl may optionally be substituted with 1 or 2 R 8 groups independently selected from the group consisting of C 1-6 alkyl, 5-6 membered heterocycloalkyl, phenyl, OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently seleted R 14 groups; each R 11 of OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 14 ; each R 12 of -C(O)NR 11 R 12 is independently selected from the group consisting of H and C 1-6 alkyl; and each R 14 attached to R 8 or R 11 is independently selected from the group consisting of halogen, C 1-6 alkyl, phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, OR 18 , NR 18 R 19 , C(O)R 18 , C(O)NR 18 R 19 , and S(O) 2 R 18 , wherein said phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 methyl groups.

[0092] In some embodiments, Y is 4-6 membered heterocycloalkyl, wherein said 4-6 membered heterocycloalkyl may optionally be substituted with 1 or 2 R 8 groups independently selected from the group consisting of C 1-3 alkyl, 5-6 membered heterocycloalkyl, phenyl, -C(O)R 11 , - C(O)NHR 11 , S(O) 2 CH 3 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 ; wherein each R 11 of -C(O)R 11 and -C(O)NHR 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 14 ; and wherein each R 14 attached to R 8 or R 11 is independently selected from the group consisting of chloro, methyl, OH, N(CH 3 ) 2 , C(O)CH 3 , C(O)NH 2 , C(O)NHCH 3 , 1-methyl-1H-imidazolyl, 1,3-dimethyl-1H-pyrazolyl, and 1-methylazetidinyl.

[0093] In some embodiments, Y is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may optionally be substituted with one or more R 8 .

[0094] In some embodiments, Y is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 8 groups independently selected from the group consisting of C 1-6 alkyl, 5-6 membered heterocycloalkyl, phenyl, OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently seleted R 14 groups; each R 11 of OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 14 ; each R 12 of -C(O)NR 11 R 12 is independently selected from the group consisting of H and C 1-6 alkyl; and each R 14 attached to R 8 or R 11 is independently selected from the group consisting of halogen, C 1-6 alkyl, phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, OR 18 , NR 18 R 19 , C(O)R 18 , C(O)NR 18 R 19 , and S(O) 2 R 18 , wherein said phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 methyl groups.

[0095] In some embodiments, Y is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl may optionally be substituted with one or more R 8 groups independently selected from the group consisting of C 1-3 alkyl, 5-6 membered heterocycloalkyl, phenyl, -C(O)R 11 , - C(O)NHR 11 , S(O) 2 CH 3 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 ; wherein each R 11 of -C(O)R 11 and -C(O)NHR 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 14 ; and wherein each R 14 attached to R 8 or R 11 is independently selected from the group consisting of chloro, methyl, OH, N(CH 3 ) 2 , C(O)CH 3 , C(O)NH 2 , C(O)NHCH 3 , 1-methyl-1H-imidazolyl, 1,3-dimethyl-1H-pyrazolyl, and 1-methylazetidinyl.

[0096] In some embodiments, Y is H, chloro, methyl, methoxy, NHR 7 , -C(O)R 11 , -C(O)NHR 11 , pyridinyl, piperazinyl, pyrazolyl, piperidinyl, thienyl, isoxazolyl, 1,2,3,6-tetrahydropyridinyl, diazepanyl, 1,1-dioxidothiomorpholinyl, 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl, 7-azaspiro[3.5]nonanyl, 1,8-diazaspiro[4.5]decan-2-onyl, and 4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl, wherein said pyridinyl, piperazinyl, pyrazolyl, piperidinyl, thienyl, isoxazolyl, 1,2,3,6-tetrahydropyridinyl, diazepanyl, 1,1-dioxidothiomorpholinyl, 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl, 7-azaspiro[3.5]nonanyl, 1,8-diazaspiro[4.5]decan-2-onyl, 4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl may optionally be substituted with 1 or 2 R 8 groups independently selected from the group consisting of C 1-3 alkyl, 5-6 membered heterocycloalkyl, phenyl, -C(O)R 11 , -C(O)NHR 11 , and S(O) 2 CH 3 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 ; wherein each R 11 of -C(O)R 11 and -C(O)NHR 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, and 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 14 ; and wherein each R 14 attached to R 8 or R 11 is independently selected from the group consisting of chloro, methyl, OH, N(CH 3 ) 2 , C(O)CH 3 , C(O)NH 2 , C(O)NHCH 3 , 1-methyl-1H-imidazolyl, 1,3-dimethyl-1H-pyrazolyl, and 1-methylazetidinyl.

[0097] In some embodiments, Y is H, -C(O)R 11 , -C(O)NHR 11 , piperazinyl, pyrazolyl, piperidinyl, or thienyl, wherein said piperazinyl, pyrazolyl, piperidinyl, thienyl, may optionally be substituted with 1 or 2 independently selected R 8 groups independently selected from the group consisting of C 1-3 alkyl, 5-6 membered heterocycloalkyl, phenyl, -C(O)R 11 , -C(O)NHR 11 , and S(O) 2 CH 3 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 ; wherein each R 11 of -C(O)R 11 and -C(O)NHR 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 14 ; and wherein each R 14 attached to R 8 or R 11 is independently selected from the group consisting of chloro, methyl, OH, N(CH 3 ) 2 , C(O)CH 3 , C(O)NH 2 , C(O)NHCH 3 , 1-methyl-1H-imidazolyl, 1,3-dimethyl-1H-pyrazolyl, and 1-methylazetidinyl.

[0098] In some embodiments, Y is selected from the group consisting of: and

[0099] In some embodiments, the invention provides a compound of Formula I wherein: X is CH or N; Z is CH or N, with the proviso that when X is CH, Z is not CH; Y is -C(O)NR 11 R 12 or a heterocycloalkyl or heteroaryl selected from: wherein: n is 1 or 2; p is 0, 1 or 2; R 8 is H, C 1 -C 6 alkyl, or -(CH 2 ) m -R 16 or -(CH 2 ) q -R 17 ; m is 1, 2, 3 or 4; q is 2, 3 or 4; R 16 is -CO 2 H or -C(O)NR 6 R 7 ; and R 17 is OH or NR 6 R 7 .

[0100] In some embodiments, the invention provides a compound of Formula I wherein: X is CH or N; Z is CH or N, with the proviso that when X is CH, Z is not CH; Y is a heterocycloalkyl or heteroaryl selected from: wherein: n is 1 or 2; p is 0, 1 or 2; R 8 is H, C 1 -C 6 alkyl, or -(CH 2 ) m -R 16 or -(CH 2 ) q -R 17 ; m is 1, 2, 3 or 4; q is 2, 3 or 4; R 16 is -CO 2 H or -C(O)NR 6 R 7 ; and R 17 is OH or NR 6 R 7 .

[0101] In some embodiments: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, Cl, C 1-6 alkyl, OR 5 , NR 6 R 7 , -C(O)R 11 , - C(O)OR 11 , -C(O)NR 11 R 12 , C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein said C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group as claimed which is optionally substituted with 1 or 2 independently selected R 8 ; R 3 is selected from the group consisting of 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 4 is H R 5 is selected from the group consisting of C 1-6 alkyl and phenyl, wherein said phenyl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; each R 6 is independently selected from the group consisting of H and C 1-6 alkyl; each R 7 is independently selected from the group consisting of H, C 1-6 alkyl, and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl and 4-10 membered heterocycloalkyl may optionally be substituted by 1, 2, 3, or 4 independently selected R 8 ; each R 8 is independently selected from the group consisting of halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, CN, OR 11 , - C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , NR 11 R 12 , and S(O) 2 R 11 , wherein said C 1-6 alkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl may optionally be substituted by 1, 2, 3, or 4 independently selected R 14 ; each R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 12 is independently selected from the group consisting of H and C 1-6 alkyl; each R 14 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, CN, OR 18 , NR 18 R 19 , C(O)R 18 , C(O)OR 18 , C(O)NR 18 R 19 , S(O) 2 R 18 , C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl, wherein said C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl may optionally be substituted with 1, 2, 3, or 5 independently selected R 15 ; each R 15 is independently selected from the group consisting of -CH 3 , halogen, and CN; each R 18 is independently selected from the group consisting of H and C 1-6 alkyl; and each R 19 is independently selected from the group consisting of H and C 1-6 alkyl.

[0102] In some embodiments: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, Cl, C 1-6 alkyl, NR 6 R 7 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , 4-10 membered heterocycloalkyl, phenyl, and 5-10 membered heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl may optionally be substituted with one or more R 8 ; R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group as claimed which is optionally substituted with one or more R 8 ; R 3 is selected from the group consisting of 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 4 is H; each R 6 is independently selected from the group consisting of H and C 1-6 alkyl; each R 7 is an independently selected C 1-6 alkyl group, each of which may optionally be substituted by 1, 2, 3, or 4 independently selected R 8 ; each R 8 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 , wherein said C 1-6 alkyl, 4-10 membered heterocycloalkyl, phenyl, are each optionally substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyloalkyl, and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyloalkyl, 5-10 membered heteroaryl, may optionally be substituted with one or more R 14 ; each R 12 is independently selected from the group consisting of H and C 1-6 alkyl; each R 14 is independently selected from the group consisting of halogen, C 1-6 alkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, OR 18 , NR 18 R 19 , C(O)R 18 , C(O)NR 18 R 19 , and S(O) 2 R 18 , wherein said phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, may optionally be substituted with one or more R 15 ; each R 15 is CH 3 or CN; each R 18 is independently selected from the group consisting of H and C 1-6 alkyl; and each R 19 is independently selected from the group consisting of H and C 1-6 alkyl.

[0103] In some embodiments: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, Cl, NR 6 R 7 , -C(O)R 11 , -C(O)NR 11 R 12 , 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said 4-10 heterocycloalkyl and 5-10 heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group as claimed which is optionally substituted with 1, 2, 3, or 4 independently selected R 8 ; R 3 is selected from the group consisting of H, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 4 is H; each R 6 is independently selected from the group consisting of H and C 1-6 alkyl; each R 7 is an independently selected C 1-6 alkyl group, each of which may optionally be substituted by 1, 2, 3, or 4 independently selected R 8 ; each R 8 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 , wherein said C 1-6 alkyl, 4-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyloalkyl, and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocyloalkyl, and 5-10 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 12 is independently selected from the group consisting of H and C 1-6 alkyl; each R 14 is independently selected from the group consisting of halogen, C 1-6 alkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, OR 18 , NR 18 R 19 , C(O)R 18 , C(O)NR 18 R 19 , and S(O) 2 R 18 , wherein said phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 15 ; each R 15 is CH 3 or CN; each R 18 is independently selected from the group consisting of H and C 1-6 alkyl; and each R 19 is independently selected from the group consisting of H and C 1-6 alkyl.

[0104] In some embodiments: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, NR 6 R 7 , -C(O)R 11 , -C(O)NR 11 R 12 , 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said 4-10 membered heterocycloalkyl and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: and R 3 is selected from the group consisting of 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 4 is H; each R 6 is independently selected from the group consisting of H and C 1-6 alkyl; each R 7 is an independently selected C 1-6 alkyl group, each of which may optionally be substituted by 1, 2, 3, or 4 independently selected R 8 ; each R 8 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 12 is independently selected from the group consisting of H and C 1-6 alkyl; each R 14 is independently selected from the group consisting of halogen, C 1-6 alkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, OR 18 , NR 18 R 19 , C(O)R 18 , C(O)NR 18 R 19 , and S(O) 2 R 18 , wherein said phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 15 ; each R 15 is CH 3 or CN; each R 18 is independently selected from the group consisting of H and C 1-6 alkyl; each R 19 is independently selected from the group consisting of H and C 1-6 alkyl; and wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , or -S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0105] In some embodiments: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, NR 6 R 7 , -C(O)R 11 , -C(O)NR 11 R 12 , 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said heterocycloalkyl and heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: and R 3 is selected from the group consisting of 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 4 is H; each R 6 is independently selected from the group consisting of H and C 1-6 alkyl; each R 7 is an independently selected C 1-6 alkyl group, each of which may optionally be substituted by 1, 2, 3, or 4 independently selected R 8 ; each R 8 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 12 is independently selected from the group consisting of H and C 1-6 alkyl; each R 14 is independently selected from the group consisting of halogen, C 1-6 alkyl, phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, OR 18 , NR 18 R 19 , C(O)R 18 , C(O)NR 18 R 19 , and S(O) 2 R 18 , wherein said phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 15 ; each R 15 is CH 3 or CN; each R 18 is independently selected from the group consisting of H and C 1-6 alkyl; each R 19 is independently selected from the group consisting of H and C 1-6 alkyl; and R 21 is selected from the group consisting of C(O)CH 3 , S(O) 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , and C(O)NH(cyclopropyl).

[0106] In some embodiments: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, NR 6 R 7 , -C(O)R 11 , -C(O)NR 11 R 12 , 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: R 3 is selected from the group consisting of 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 8 ; R 4 is H; each R 6 is independently selected from the group consisting of H and C 1-6 alkyl; each R 7 is an independently selected C 1-6 alkyl group, each of which may optionally be substituted by 1, 2, 3, or 4 independently selected R 8 ; each R 8 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 14 ; each R 12 is independently selected from the group consisting of H and C 1-6 alkyl; each R 14 is independently selected from the group consisting of halogen, C 1-6 alkyl, phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, OR 18 , NR 18 R 19 , C(O)R 18 , C(O)NR 18 R 19 , and S(O) 2 R 18 , wherein said phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R 15 ; each R 15 is CH 3 or CN; each R 18 is independently selected from the group consisting of H and C 1-6 alkyl; and each R 19 is independently selected from the group consisting of H and C 1-6 alkyl.

[0107] In some embodiments: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, NHR 7 , -C(O)R 11 , -C(O)NHR 11 , piperazinyl, pyrazolyl, piperidinyl, and thienyl, wherein said piperazinyl, pyrazolyl, piperidinyl, and thienyl may be optionally substituted with 1 or 2 independently selected R 8 ; R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: R 3 is isoxazolyl, pyrazolyl, 2-oxopyridinyl, 2-hydroxypyridinyl, each of which is optionally substituted by one or two methyl groups; R 4 is H; each R 6 is independently selected from the group consisting of H and C 1-6 alkyl; each R 7 is an independently selected C 1-6 alkyl group, each of which may optionally be substituted by 1 or 2 independently selected R 8 ; each R 8 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O) 2 R 11 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 ; each R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 14 ; each R 12 is independently selected from the group consisting of H and C 1-6 alkyl; each R 14 is independently selected from the group consisting of halogen, C 1-6 alkyl, phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, OR 18 , NR 18 R 19 , C(O)R 18 , C(O)NR 18 R 19 , and S(O) 2 R 18 , wherein said phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 15 ; each R 15 is CH 3 or CN; each R 18 is independently selected from the group consisting of H and C 1-6 alkyl; and each R 19 is independently selected from the group consisting of H and C 1-6 alkyl.

[0108] In some embodiments: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, NHR 7 , -C(O)R 11 , -C(O)NHR 11 , piperazinyl, pyrazolyl, piperidinyl, and thienyl, wherein said piperazinyl, pyrazolyl, piperidinyl, and thienyl may be optionally substituted with 1 or 2 independently selected R 8 ; R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of: R 3 is isoxazolyl, pyrazolyl, 2-oxopyridinyl, 2-hydroxypyridinyl, each of which is optionally substituted by one or two methyl groups; R 4 is H; each R 6 is independently selected from the group consisting of H and C 1-3 alkyl; each R 7 is an independently selected C 1-3 alkyl group, each of which may optionally be substituted by 1 or 2 independently selected R 8 ; each R 8 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, -C(O)R 11 , -C(O)NHR 11 , S(O) 2 CH 3 , wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 ; each R 11 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1 or 2 independently selected R 14 ; and each R 14 is independently selected from the group consisting of chloro, methyl, OH, N(CH 3 ) 2 , C(O)CH 3 , C(O)NH 2 , C(O)NHCH 3 , 1-methyl-1H-imidazolyl, 1,3-dimethyl-1H-pyrazolyl, and 1-methylazetidinyl.

[0109] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of:

[0110] In some embodiments, R 1 and R 2 , together with the included nitrogen atom and L 1 , form a heterocycloalkyl group selected from the group consisting of:

[0111] In some embodiments, the invention provides compounds of Formula I wherein R 3 is selected independently for each occurrence from the group consisting of:

[0112] In some embodiments, the compound is a compound of Formula II: or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, R 3 is

[0114] In some embodiments, the compound is a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 4 and Q is CH or N.

[0115] In some embodiments, R 3 is

[0116] In some embodiments, p is an integer from 0 to 2.

[0117] In some embodiments, p is 0.

[0118] In some embodiments, p is 1.

[0119] In some embodiments, p is 2.

[0120] In some embodiments, the compound is a compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , - C(O)NR 11 R 12 , or -S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 .

[0121] In some embodiments, R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)R 11 , -C(O)OR 11 , - C(O)NR 11 R 12 , or -S(O) 2 R 11 , wherein said C 1-6 alkyl may optionally be substituted with NR 11 R 12 .

[0122] In some embodiments, R 21 is C(O)CH 3 , S(O) 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , or C(O)NH(cyclopropyl).

[0123] In some embodiments, R 21 is C(O)CH 3 or S(O) 2 CH 3 .

[0124] In some embodiments, R 3 is

[0125] In some embodiments, the compound is a compound of Formula V: or a pharmaceutically acceptable salt thereof, wherein R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R 11 , -C(O)OR 11 , - C(O)NR 11 R 12 , or -S(O) 2 R 11 , wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 ; and R 8a is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl, wherein said C 1-6 alkyl, phenyl, and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0126] In some embodiments, R 8a is benzyl, phenyl, or a 5-6 membered heteroaryl, wherein said phenyl and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0127] In some embodiments, R 8a is phenyl or a 5-6 membered heteroaryl, wherein said phenyl and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0128] In some embodiments, R 8a is phenyl or thienyl, wherein said phenyl may optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl; and said thienyl may optionally be substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl.

[0129] In some embodiments, R 21 is C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)R 11 , -C(O)OR 11 , - C(O)NR 11 R 12 , or -S(O) 2 R 11 , wherein said C 1-6 alkyl may optionally be substituted with NR 11 R 12 .

[0130] In some embodiments, R 21 is C(O)CH 3 , S(O) 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , or C(O)NH(cyclopropyl).

[0131] In some embodiments, R 21 is C(O)CH 3 or S(O) 2 CH 3 .

[0132] In some embodiments, R 3 is

[0133] In some embodiments, the compound of Formula V, or a pharmaceutically acceptable salt thereof, is a compound of Formula Va: or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the compound of Formula V, or a pharmaceutically acceptable salt thereof, is a compound of Formula Vb: or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the compound is a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein R 8a is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl, wherein said C 1-6 alkyl, phenyl, and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0136] In some embodiments, R 8a is benzyl, phenyl, or a 5-6 membered heteroaryl, wherein said phenyl, and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0137] In some embodiments, R 8a is phenyl or a 5-6 membered heteroaryl, wherein said phenyl and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0138] In some embodiments, R 8a is phenyl or thienyl, wherein said phenyl may optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl; and said thienyl may optionally be substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl.

[0139] In some embodiments, R 3 is

[0140] In some embodiments, the compound of Formula VI, or a pharmaceutically acceptable salt thereof, is a compound of Formula Vla: or a pharmaceutically acceptable salt thereof,

[0141] In some embodiments, the compound of Formula VI, or a pharmaceutically acceptable salt thereof, is a compound of Formula Vlb: or a pharmaceutically acceptable salt thereof,

[0142] In some embodiments, the compound is a compound of Formula VII: or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the R 8 group attached to the piperidinyl ring formed by R 1 and R 2 , together with the included nitrogen atom and L 1 , is R 8a , wherein R 8a is phenyl or a 5-6 membered heteroaryl, wherein said phenyl and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0144] In some embodiments, R 8a is phenyl or thienyl, wherein said phenyl may optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl; and said thienyl may optionally be substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl.

[0145] In some embodiments, R 3 is

[0146] In some embodiments, the compound is a compound of Formula VIII: or a pharmaceutically acceptable salt thereof, wherein R 8a is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, or a 5-6 membered heteroaryl, wherein said phenyl and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R 14 .

[0147] In some embodiments, R 8a is phenyl or thienyl, wherein said phenyl may optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl; and said thienyl may optionally be substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF 3 , CN, NH 2 , -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl.

[0148] In some embodiments, R 3 is

[0149] In some embodiments, the compound of Formula VIII, or a pharmaceutically acceptable salt thereof, is a compound of Formula Villa: or a pharmaceutically acceptable salt thereof,

[0150] In some embodiments, the compound of Formula VIII, or a pharmaceutically acceptable salt thereof, is a compound of Formula Vlllb: or a pharmaceutically acceptable salt thereof,

[0151] In some embodiments, the compound is selected from the group consisting of: 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinolin-4-amine; N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-methylquinazoline-2,4-diamine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-amine; N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methoxyquinazolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinazolin-4-amine; N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-morpholinoethyl)quinazoline-2,4-diamine; N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-(4-methylpiperazin-1-yl)ethyl)quinazoline-2,4-diamine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 3-((4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)amino)propan-1-ol; N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinolin-4-amine; 6-bromo-N-(3-chlorobenzyl)-2-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine; N-(3-chlorobenzyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(cyclopropyl)methanone; (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone; 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanol; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-isopentylpiperazin-1-yl)quinazolin-4-amine; N4-(3-chlorobenzyl)-N2-(2-(dimethylamino)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-methylquinazoline-2,4-diamine; (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-4-yl)methanol; (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-3-yl)methanol; (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-2-yl)methanol; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine N-(3-chlorobenzyl)-4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-amine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)quinazolin-4-amine; (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(pyridin-4-yl)methanone; 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-4-yl)ethanol; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)-1,4-diazepan-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1,4-diazepan-1-yl)ethanol; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(pyridin-3-yl)methanone; 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-hydroxyethanone; 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethanone; N-(3-chlorobenzyl)-2-(4-((dimethylamino)methyl)piperidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-4-yl)ethanol; N-(3-chlorobenzyl)-3-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-1-amine; 2-(4-(1-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)piperazin-1-yl)ethanol; 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)propan-2-ol; (R)-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1 -yl)propan-2-ol; (S) -1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1 -yl)propan-2-ol; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)ethanol; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-amine; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)acetamide; 2-amino-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone; 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1 -yl)-2-methylpropan-2-ol; 3-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)propanenitrile; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)quinazolin-4-amine; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetonitrile; N-(3-chlorobenzyl)-2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)quinazolin-4-amine; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1 -yl)-2-methylpropan-1 -ol; (5-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)pyridin-2-yl)methanol; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(1H-pyrazol-4-yl)quinazolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine; 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-ol; 2,6-bis(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine; N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methoxybenzyl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(3-methoxybenzyl)quinazolin-4-amine; N-(2-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; N-(3-bromobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(2-fluorobenzyl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(3-fluorobenzyl)quinazolin-4-amine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(5-methylisoxazol-4-yl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(furan-2-ylmethyl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)quinazolin-4-amine; N-((5-chloropyridin-3-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; N-((4-chloropyridin-2-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-fluoropyridin-3-yl)methyl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylpyridin-3-yl)methyl)quinazolin-4-amine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-methylquinazolin-4-amine; 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-3-fluoropyridin-2-ol; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylthiophen-2-yl)methyl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylthiophen-2-yl)methyl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-(thiophen-2-yl)ethyl)quinazolin-4-amine; N-(1-(3-chlorophenyl)ethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-3-methylpyridin-2-ol; N-benzyl-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3-methylisoxazol-4-yl)quinazolin-4-amine; N-((5-chlorothiophen-2-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; N-(4-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-ol; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N, N-dimethylacetamide; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(4-fluorobenzyl)quinazolin-4-amine; 5- (2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide; 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide; 5-(4-((3-chlorobenzyl)amino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 3-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)propanenitrile; 5-(4-((3-chlorobenzyl)amino)-2-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyacetyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(2-(4-(2-aminoacetyl)piperazin-1-yl)-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)acetamide; 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide; 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide; (S)-5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxypropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-((3-chlorobenzyl)amino)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylpyridin-3-yl)methyl)quinazolin-4-amine; 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)acetamide; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanol; 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-((3-chlorobenzyl)amino)-2-(4-(1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-((3-chlorobenzyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)acetamide; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide; N-((5-chloropyridin-3-yl)methyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 2-amino-1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone; 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-hydroxyethanone; and 5-(2-(4-(2-aminoacetyl)piperazin-1-yl)-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol; 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol; 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide; 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)ethanol; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide; 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide; 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 2-(4-(4-((4-chlorophenyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)ethanol; 6-bromo-2-chloro-N-(4-chlorophenyl)quinazolin-4-amine; N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperidin-1-yl)quinazolin-4-amine; N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperidin-1-yl)quinazolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-amine; 1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-4-methylpiperidine-4-carbonitrile; 1-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-4-methylpiperidine-4-carbonitrile; N-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 5-(4-((4-chlorophenyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; N-(4-chlorophenethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 2-(4-(4-(3-benzylazetidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine; N-(4-chlorophenyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxylic acid; 2-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)ethanol; (4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)(4-(2-(dimethylamino)ethyl)piperazin-1-yl)methanone; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetic acid; N4-(3-chlorobenzyl)-N2-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2,4-diamine; N-(4-chlorobenzyl)-4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; N-(3-chlorobenzyl)-2-(4-chlorophenoxy)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; N-(1-(3-chlorophenyl)cyclopropyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4-ylmethyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)quinazoline-2-carboxamide; (S)-2-((2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)amino)-2-phenylethanol; 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpyrrolidin-1-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine; 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpiperidin-1-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine; 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine; N-((1H-imidazol-2-yl)methyl)-4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; N2-((1H-imidazol-2-yl)methyl)-N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2,4-diamine; 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylazetidin-1-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine; N-(1-(3-chlorophenyl)cyclopropyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-amine; 2-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide; 1-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-imidazol-5-yl)methyl)quinazoline-2-carboxamide; 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone; 1-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylpyridin-3-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-((4-chloropyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-((1,5-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-fluoropyridin-3-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylpyridin-3-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)quinazoline-2-carboxamide; 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2-methylthiazol-4-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((6-methylpyridin-3-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)quinazoline-2-carboxamide; N-(1-acetylpiperidin-4-yl)-4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-((2-chloropyridin-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-((6-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-(((5-chloropyridin-3-yl)methyl)amino)-N-((2-chloropyridin-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4-ylmethyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-((3-chloropyridin-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)quinazoline-2-carboxamide; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-N-(1-methylpiperidin-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2-methylthiazol-5-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylthiazol-2-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylthiazol-2-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((3-fluoropyridin-4-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methyloxazol-2-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((3-methylpyridin-4-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methylpyridin-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(6-methylpyridin-3-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(4-methylpyridin-3-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(5-fluoropyridin-3-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-(6-chloropyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(3-fluoropyridin-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(2,6-dimethylpyridin-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methyl-1H-pyrazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(1-methylpiperidin-4-yl)quinoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)quinoline-2-carboxamide; 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2 H-pyran-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)quinoline-2-carboxamide; 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-imidazol-5-yl)methyl)quinazoline-2-carboxamide; 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)quinoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)quinoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2 H-pyran-4-yl)quinoline-2-carboxamide; 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)quinazoline-2-carboxamide; 4-(((5-chloropyridin-3-yl)methyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2 H-thiopyran-4-yl)quinazoline-2-carboxamide; 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)quinazoline-2-carboxamide; 4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)thiomorpholine 1,1-dioxide; 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)quinazoline-2-carboxamide; 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)thiomorpholine 1,1-dioxide; 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-N, N-dimethylpiperazine-1-carboxamide; 4-((1-(3-chlorophenyl)cyclopropyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)quinazoline-2-carboxamide; 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-2-carboxamide; 4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-N, N-dimethylpiperazine-1-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2-methylpyridin-4-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((trans)-4-hydroxycyclohexyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-imidazol-2-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((trans)-3-hydroxycyclobutyl)quinazoline-2-carboxamide; 1-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)piperidine-4-carboxylic acid; 1-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-4-yl)piperidine-4-carboxylic acid; 4-((3-chlorobenzyl)amino)-N-((3,3-difluorocyclobutyl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-N-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylthiazol-5-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((3,5-dimethylisoxazol-4-yl)methyl)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2,4-dimethylthiazol-5-yl)methyl)quinazoline-2-carboxamide; 1-(6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)piperidine-4-carboxylic acid; (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; (R) -1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; 4-(6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine; (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine; (R)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N, N-dimethylethanamine; 1-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-N-methylpiperidine-4-carboxamide; (R)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-yl)-3-phenylmorpholine; (S) -4-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-yl)-3-phenylmorpholine; 1-(6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-N-methylpiperidine-4-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidothietan-3-yl)quinazoline-2-carboxamide; (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide; 6-(3,5-dimethylisoxazol-4-yl)-N-((trans)-4-hydroxycyclohexyl)-4-((S)-3-phenylmorpholino)quinazoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((trans)-4-hydroxycyclohexyl)quinoline-2-carboxamide; (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide; (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)(1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone; (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)quinazolin-4-amine; (S)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-imidazol-5-yl)methyl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide; (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide; (S)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)quinazolin-4-yl)-3-phenylmorpholine; (S)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide; (4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone; (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone; (4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone; (4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone; (4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)quinazolin-4-yl)-3-phenylmorpholine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)quinazolin-4-amine; (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpiperazin-1-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; (S)-5-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-3-phenylmorpholine; (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)ethan-1-one; (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1 -yl)-2-methylpropan-2-ol; (S)-1-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide; (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide; (S)-1-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-N-ethylpiperazine-1-carboxamide; (S)-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone; (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine; (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N, N-dimethylacetamide; (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol; (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-2-hydroxyethan-1-one; (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol; (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)acetamide; (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-((S)-3-phenylmorpholino)quinazolin-2-yl)piperazin-1 -yl)propan-2-ol; (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylpiperazin-1-yl)ethan-1-one; (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(4-(methylsulfonyl)-2-phenylpiperazin-1-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(3-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)quinazolin-4-yl)-3-phenylmorpholine; 1-(4-(4-((3-chlorobenzyl)(cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; (S)-7-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-7-azaspiro[3.5]nonan-2-ol; (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1,8-diazaspiro[4.5]decan-2-one; (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidothietan-3-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide; (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)methanone; (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)(1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)quinazolin-4-yl)-3-phenylmorpholine; tert-butyl (S)-4-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decan-1-one; (S)-(5-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)pyridin-2-yl)methanol; (S)-N-cyclopropyl-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylpiperazine-1-carboxamide; (S)-(5-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)thiophen-2-yl)methanol; (S)-1-(3-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethan-1-one; (S)-4-(2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine; (S)-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)thiophen-2-yl)methanol; (S)-1-(4-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)quinazolin-4-yl)-3-phenylmorpholine; (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-2,8-diazaspiro[4.5]decan-1-one; (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1-methyl-1,8-diazaspiro[4.5]decan-2-one; (S)-N-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide; 1-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-4-yl)-N-methylpiperidine-4-carboxamide; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine; (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine; (S)-3-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)propanenitrile; (S)-8-(4-(4-acetyl-2-phenylpiperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1-methyl-1,8-diazaspiro[4.5]decan-2-one; (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(4-(methylsulfonyl)-2-phenylpiperazin-1-yl)quinazolin-2-yl)-1-methyl-1,8-diazaspiro[4.5]decan-2-one; (S)-5-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(2-phenylpiperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; 1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-morpholinoquinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol; (S)-5-(4-(4-acetyl-2-phenylpiperazin-1-yl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one; or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the compound is selected from the group of compounds that concord with the claims provided in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of a compound provided herein (e.g., a compound of Formula I) is a trifluoroacetic acid salt.

[0153] Certain of the compounds described herein contain one or more chiral centers (e.g., including the compound species of the examples unless otherwise indicated by the chemical name), or may otherwise be capable of existing as multiple stereoisomers. The present disclosure includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically and / or diastereomerically enriched mixtures.

[0154] Compounds provided herein may be present as the (S)-enantiomer.

[0155] Compounds provided herein may be present as the (R)-enantiomer. Also included within the present disclosure are the individual stereoisomers of the compounds represented by Formula I, as well as any wholly or partially equilibrated mixtures thereof. The present disclosure also includes the individual stereoisomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.

[0156] In some embodiments, compounds of the present invention are provided as pharmaceutically acceptable salts which include non-toxic salts of the compounds set forth herein. Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt.

[0157] The salts provided may be in some cases hydrates or solvates. The present invention includes a salt or solvate of the compounds herein described, including combinations thereof such as a solvate of a salt. The compounds of the present disclosure may exist in solvated, for example hydrated or ethanol complexed, as well as un-solvated forms, and the present invention encompasses all such forms. The salts of the present disclosure can be pharmaceutically acceptable salts.

[0158] The compounds or their pharmaceutically acceptable salts as provided herein may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of the present disclosure. Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.

[0159] Although it is possible to administer the compounds of the present disclosure in the form of a bulk active chemical, it is preferred to administer the compound in the form of a pharmaceutical composition or formulation. Thus, pharmaceutical compositions are provided that include one or more compounds of Formula I and / or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0160] There is described herein a process for the preparation of a pharmaceutical composition including admixing one or more compounds of Formula I and / or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0161] In some embodiments, compounds as claimed which bind to and otherwise modulate acetylated protein binding to bromodomain-containing proteins are provided. Such compounds include at least one compound selected from Formula I as provided herein. Exemplary compounds include, but are not limited to, those compounds set forth previously by name.

[0162] In some embodiments, compounds as claimed for use in the treatment or prevention of a disease or condition mediated by inhibiting bromodomain-containing proteins from binding acetylated proteins are provided. In some embodiments, compounds as claimed for use in the treatment of a disease or condition mediated by inhibiting bromodomain-containing proteins from binding acetylated proteins are provided.

[0163] In some embodiments, compounds as claimed for use in the treatment or prevention of a disease or condition mediated by inhibiting acetylated proteins from binding bromodomain-containing proteins are provided. In some embodiments, compounds for use in the treatment of a disease or condition mediated by inhibiting acetylated proteins from binding bromodomain-containing proteins are provided.

[0164] In some embodiments, a compound as claimed for use in a method for the treatment or prevention of a disease is provided that includes the step of administering a compound as provided herein to inhibit the activity of bromodomain-containing proteins.

[0165] In some embodiments, a compound as claimed for use in a method for the treatment or prevention of a disease is provided that includes the step of administering a compound as provided herein to inhibit the activity of bromodomain-containing proteins by inhibiting binding to acetylated proteins. In some embodiments, a compound as claimed for use in the method is a method of treating a disease which includes the step of administering a compound as provided herein to inhibit the activity of bromodomain-containing proteins by inhibiting binding to acetylated proteins.

[0166] In some embodiments, the acetylated protein is an acetylated histone involved in the regulation or dysregulation of gene expression.

[0167] The compounds of the present invention, their pharmaceutically acceptable salts and their pharmaceutical compositions can be used for treating or preventing a wide variety of conditions or disorders. In some embodiments, the compounds of the present invention their pharmaceutically acceptable salts and their pharmaceutical compositions can be used for treating a wide variety of conditions or disorders.

[0168] In some embodiments, the disease or condition subject to prevention or treatment includes human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumors, Merkel cell carcinoma, prostate cancer, ovarian cancer, chordoma, osteoarthritis, rheumatoid arthritis (e.g, juvenile rheumatoid arthritis), Alzheimer's disease, and HIV infection. In some embodiments, the disease or condition subject to treatment includes human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumors, Merkel cell carcinoma, prostate cancer, ovarian cancer, chordoma, osteoarthritis, rheumatoid arthritis (e.g, juvenile rheumatoid arthritis), Alzheimer's disease, and HIV infection.

[0169] In some embodiments, the disease or condition subject to prevention or treatment includes human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumors, Merkel cell carcinoma, prostate cancer, osteoarthritis, rheumatoid arthritis (e.g, juvenile rheumatoid arthritis), Alzheimer's disease, and HIV infection. In some embodiments, the disease or condition subject to treatment includes human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumors, Merkel cell carcinoma, prostate cancer, osteoarthritis, rheumatoid arthritis (e.g, juvenile rheumatoid arthritis), Alzheimer's disease, and HIV infection.

[0170] In some embodiments, the disease or condition subject to prevention or treatment includes Hodgkin Lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and acute lymphocytic leukemia. In some embodiments, the disease to be treated is selected from Hodgkin Lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and acute lymphocytic leukemia.

[0171] In some embodiments, a compound as claimed for use in a method for the treatment or prevention of a disease or condition mediated by bromodomain-containing proteins is provided and includes the step of administering a compound as provided herein. In some embodiments, a compound as claimed for use in a method for the treatment of a disease or condition mediated by bromodomain-containing proteins is provided and includes the step of administering a compound as provided herein. Any of acompound as claimed for use in the methods provided herein may include administering to a subject a therapeutically effective amount of a compound as provided herein, including a salt or polymorph thereof, or a pharmaceutical composition that includes such compounds, salts, or polymorphs.

[0172] The manner in which the compounds or their pharmaceutical composition set forth herein may be administered can vary. In some embodiments, the compounds can be administered orally. Preferred pharmaceutical compositions may be formulated for oral administration in the form of tablets, capsules, caplets, syrups, solutions, and suspensions. Such oral formulations can be provided in modified release dosage forms such as time-release tablet and capsule formulations. Pharmaceutical compositions can also be administered via injection, namely, intravenously, intramuscularly, subcutaneously, intraperitoneally, intraarterially, intrathecally, and intracerebroventricularly. Intravenous administration is a preferred method of injection. Suitable carriers for injection are well known to those of skill in the art and include 5% dextrose solutions, saline, and phosphate buffered saline.

[0173] Pharmaceutical compositions may also be administered using other means, for example, rectal administration. Formulations useful for rectal administration, such as suppositories, are well known to those of skill in the art. The compounds can also be administered by inhalation, for example, in the form of an aerosol; topically, such as, in lotion form; transdermally, such as, using a transdermal patch (for example, by using technology that is commercially available from Novartis and Alza Corporation); by powder injection; or by buccal, sublingual, or intranasal absorption. Pharmaceutical compositions may be formulated in unit dose form, or in multiple or subunit doses.

[0174] The administration of the pharmaceutical compositions described herein can be intermittent, or at a gradual, continuous, constant or controlled rate. The pharmaceutical compositions may be administered to a warm-blooded animal, for example, a mammal such as a human being. In addition, the time of day and the number of times per day that the pharmaceutical composition is administered can vary.

[0175] A compound as claimed use in treating, preventing, delaying the onset of, or slowing the progression of disorders mediated by acetylated proteins involved in the regulation or dysregulation of gene expression, in mammals in need of such treatment are also provided. The methods involve administering to a subject a therapeutically effective amount of a compound as provided herein, including a salt thereof, or a pharmaceutical composition that includes such compounds.

[0176] In some embodiments, the compound as claimed for use in methods for treating, preventing, delaying the onset of, or slowing the progression of disorders mediated by acetylated proteins involved in the regulation or dysregulation of gene expression, in mammals in need of such treatment include the administration of at least one compound as provided herein including, but not limited to, the compounds provided according to Formula I.

[0177] The compounds alone or in a pharmaceutical composition as provided herein may be used in the treatment of a variety of disorders and conditions and, as such, may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions. Thus, in some embodiments, the present disclosure includes the administration of the compound of the present disclosure in combination with other therapeutic compounds. Such a combination of pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds or agents and the relative timings of administration will be selected in order to achieve the desired therapeutic effect. The administration in combination of a compound of the present disclosure with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including two or more compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second. Such sequential administration may be close in time or remote in time.

[0178] In some embodiments, the present disdosure includes a combination as claimed for use in combination therapy comprising administering to the subject a therapeutically or prophylactically effective amount of the compound of the present disclosure and one or more other therapy including chemotherapy, radiation therapy, gene therapy, or immunotherapy.

[0179] The compounds of the present disclosure can be used to mediate the prevention or treatment of various conditions or disorders mediated by inhibiting bromodomain-containing proteins from binding acetylated proteins. In some embodiments, the compounds of the present disclosure can be used to mediate the treatment of various conditions or disorders mediated by inhibiting bromodomain-containing proteins from binding acetylated proteins. The compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of various types of cancer, inflammation, obesity, metabolic, cardiovascular, neurodegenerative, psychiatric and infectious diseases. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of various types of cancer, inflammation, obesity, metabolic, cardiovascular, neurodegenerative, psychiatric and infectious diseases.

[0180] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and viral infections. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and viral infections.

[0181] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of a variety of chronic autoimmune and inflammatory conditions such as Graves' Opthalomapthy, Graves' Disease, Guillain-Barré syndrome, rheumatoid arthritis (e.g. juvenile rheumatoid arthritis), osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and acute rejection of transplanted organs. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of a variety of chronic autoimmune and inflammatory conditions provided herein. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of a wide variety of acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement and acute rejection of transplanted organs. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of a wide variety of acute inflammatory conditions provided herein.

[0182] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, provided herein.

[0183] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebro- vascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of conditions associated with ischaemia-reperfusion injury provided herein.

[0184] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of disorders of lipid metabolism provided herein, via the regulation of APO-A1.

[0185] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma, cardiac fibrosis, cystic fibrosis lung inflammation, and liver fibrosis. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma, and cardiac fibrosis. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of fibrotic conditions such as cystic fibrosis lung inflammation, idiopathic pulmonary fibrosis, and liver fibrosis. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of fibrotic conditions provided herein.

[0186] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of Rubinstein-Taybi syndrome. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of Rubinstein-Taybi syndrome.

[0187] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of a disease selected from juvenile rheumatoid arthritis, cystic fibrosis lung inflammation, idiopathic pulmonary fibrosis, liver fibrosis, Guillain-Barré syndrome, and Rubinstein-Taybi syndrome. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of a disease selected from juvenile rheumatoid arthritis, cystic fibrosis lung inflammation, idiopathic pulmonary fibrosis, liver fibrosis, Guillain-Barré syndrome, and Rubinstein-Taybi syndrome.

[0188] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of viral infections provided herein.

[0189] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of diseases associated with systemic inflammatory response syndrome including sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of diseases associated with systemic inflammatory response syndrome provided herein.

[0190] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of SIRS, the onset of shock, and multi-organ dysfunction syndrome.

[0191] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of sepsis, sepsis syndrome, septic shock and endotoxaemia, acute or chronic pancreatitis, herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus and for the treatment of Human papilloma virus infections of skin or cervical epithelia. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of sepsis, sepsis syndrome, septic shock and endotoxaemia, acute or chronic pancreatitis, herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus and for the treatment of Human papilloma virus infections of skin or cervical epithelia.

[0192] In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment or prevention of various forms of cancer, leukemias and lymphomas including acute myeloid leukemia, NPM1c mutant leukemia, Burkitt's lymphoma, multiple myeloma, T-cell lymphoblastic leukemia and other hematological cancers that involve translocations of mixed-lineage leukemia gene (MLL); solid tumors such as hepatocellular carcinoma, glioblastoma, medulloblastoma, neuroblastoma, NUT midline carcinoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, ovarian cancer, chordoma, neuroendocrine tumors including those involving the pancreas and thymus (PanNETS and NETs), and Merkel cell carcinoma (MCC) and prostate cancer; osteoarthritis and rheumatoid arthritis (e.g. juvenile rheumatoid arthritis); Alzheimer's disease; and HIV infection. In some embodiments, the compounds and their pharmaceutical compositions are particularly useful in the treatment of various forms of cancer, leukemias and lymphomas including acute myeloid leukemia, NPM1c mutant leukemia, Burkitt's lymphoma, multiple myeloma, T-cell lymphoblastic leukemia and other hematological cancers that involve translocations of mixed-lineage leukemia gene (MLL); solid tumors such as hepatocellular carcinoma, glioblastoma, medulloblastoma, neuroblastoma, NUT midline carcinoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, ovarian cancer, chordoma, neuroendocrine tumors including those involving the pancreas and thymus (PanNETS and NETs), and Merkel cell carcinoma (MCC) and prostate cancer; osteoarthritis and rheumatoid arthritis (e.g, juvenile rheumatoid arthritis); Alzheimer's disease; and HIV infection. In some embodiments, the disease is selected from human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, ovarian cancer, chordoma, neuroendocrine tumors, Merkel cell carcinoma, prostate cancer, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, and HIV infection. In some embodiments, the disease is selected from human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumors, Merkel cell carcinoma, prostate cancer, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, and HIV infection.

[0193] It is contemplated and therefore within the scope of the present invention that any feature that is described above can be combined with any other feature that is described above.DEFINITIONS

[0194] The following definitions are meant to clarify, but not limit, the terms defined. If a particular term used herein is not specifically defined, such term should not be considered indefinite. Rather, terms are used within their accepted meanings.

[0195] As used throughout this specification, the preferred number of atoms, such as carbon atoms, will be represented by, for example, the phrase "C x- C y alkyl," which refers to an alkyl group, as herein defined, containing the specified number of carbon atoms. Similar terminology will apply for other preferred terms and ranges as well. Thus, for example, C 1-6 alkyl represents a straight or branched chain hydrocarbon containing one to six carbon atoms. Additional examples include C 1-4 , C 1-3 , and the like.

[0196] As used herein the term "alkyl" refers to a straight or branched chain hydrocarbon, which may be optionally substituted, with multiple degrees of substitution being allowed. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl, and n-pentyl. The alkyl group may contain from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0197] As used herein, the term "alkene" refers to an unsaturated hydrocarbon that includes one or more carbon-carbon double bonds. The term "lower alkene" refers to an alkene that includes from five to twenty carbon atoms, such as from two to ten carbon atoms, while the term "upper alkene" refers to an alkene that includes more than twenty carbon atoms, such as from twenty-one to one hundred carbon atoms. The term "substituted alkene" refers to an alkene that has one or more of its hydrogen atoms replaced by one or more substituent groups, such as halogen. The alkene group may contain 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0198] As used herein, the term "alkyne" refers to an unsaturated hydrocarbon that includes one or more carbon-carbon triple bonds. The term "lower alkyne" refers to an alkyne that includes from five to twenty carbon atoms, such as from two to ten carbon atoms, while the term "upper alkyne" refers to an alkyne that includes more than twenty carbon atoms, such as from twenty-one to one hundred carbon atoms. The term "substituted alkyne" refers to an alkyne that has one or more of its hydrogen atoms replaced by one or more substituent groups, such as halogen. The alkynyl moiety maycontain 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0199] As used herein, the term "cycloalkyl" refers to a fully saturated optionally substituted monocyclic, bicyclic, spirocyclic, or bridged hydrocarbon ring, with multiple degrees of substitution being allowed. Preferably, the ring is three to twelve-membered, more preferably, from five- to six-membered. Exemplary "cycloalkyl" groups as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). In some embodiments, the cycloalkyl is a C 3-10 monocyclic or bicyclic cyclocalkyl.

[0200] The cycloalkyl may be a C 3-10 monocyclic cyclocalkyl.

[0201] As used herein, the term "alkoxy" refers to a group -OR a< , where R a< is "alkyl" as defined herein. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. The alkoxy group may have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0202] As used herein, the term "heterocycloalkyl" or "heterocycle" or "heterocyclyl" refers to an optionally substituted mono- or polycyclic ring system, optionally containing one or more degrees of unsaturation, and also containing one or more heteroatoms, which may be optionally substituted, with multiple degrees of substitution being allowed. Exemplary heteroatoms include nitrogen, oxygen, or sulfur atoms, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is three to twelve-membered, preferably five or six-membered and is either fully saturated or has one or more degrees of unsaturation. Such rings may be optionally fused to one or more of another heterocyclic ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" groups as used herein include, but are not limited to, tetrahydrofuran, pyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene. The heterocycloalkyl may be a mono or bicyclic ring system, which may be spirocyclic, having 4-10 ring members, wherein 1 or 2 ring members of the monocyclic ring system or 1, 2, 3, or 4 ring members of the bicyclic ring system are independently selected from nitrogen, oxygen, and sulfur.

[0203] As used herein, the term "aryl" refers to a single benzene ring or fused benzene ring system which may be optionally substituted, with multiple degrees of substitution being allowed. Examples of "aryl" groups as used include, but are not limited to, phenyl, benzyl, 2-naphthyl, 1-naphthyl, anthracene, and phenanthrene. Preferable aryl rings have five- to ten-members. The term "aryl" also includes a fused benzene ring system, namely where a cyclic hydrocarbon or heterocycle (e.g., a cyclohexane or dioxane ring) or heteroaryl (e.g., pyridine) is fused with an aromatic ring (aryl, such as a benzene ring). The aryl groups may have from 6 to 1 0 carbon atoms.

[0204] As used herein, the term "heteroaryl" refers to a monocyclic five to seven membered aromatic ring, a fused bicyclic aromatic ring system comprising two of such aromatic rings, which may be optionally substituted, with multiple degrees of substitution being allowed, or to a fused bicyclic ring system namely where a cycloalkyl or heterocycle (e.g., a cyclohexane or dioxane ring) is fused with a heteroaryl ring. Preferably, heteroaryl rings contain five- to ten-members. These heteroaryl rings contain one or more nitrogen, sulfur, and / or oxygen atoms. In certain embodiments, the heteroaryl rings contain one to three nitrogen, one to three oxygen, or one or two sulfur atoms. N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. Examples of "heteroaryl" groups as used herein include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, quinoxaline, benzofuran, benzoxazole, benzothiophene, indole, indazole, benzimidazole, imidazopyridine, pyrazolopyridine, and pyrazolopyrimidine.

[0205] The heteroaryl may be a mono or bicyclic ring system having 5-10 ring members, wherein 1, 2, or 3 ring members of the monocyclic ring system or 1, 2, 3, or 4 ring members of the bicyclic ring system are independently selected from nitrogen, oxygen, and sulfur.

[0206] As used herein the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0207] As used herein the term "haloalkyl" refers to a substituted or unsubstituted alkyl group, as defined herein, that is substituted with at least one halogen. Examples of branched or straight chained "haloalkyl" groups as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, for example, fluoro, chloro, bromo, and iodo. The term "haloalkyl" should be interpreted to include such substituents as perfluoroalkyl groups such as -CF 3 . The haloalkyl groupmayhave1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0208] As used herein, the term "sulfhydryl" refers to refers to a -SH group.

[0209] As used herein, the term "thioalkoxy" refers to a group -SR a< , where R a< is "alkyl" as defined herein. The thioalkoxy group may have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0210] As used herein, the term "carboxyamido" refers to -NH-C(O)-W, wherein W is hydrogen or an unsubstituted or substituted alkyl, alkene, alkyne, cycloalkyl, aryl, or heterocycle group.

[0211] As used herein, the term "amine" is given its ordinary meaning and includes primary (e.g., -NH 2 ), secondary (e.g. -NHR) and tertiary amines (e.g. -NRR).

[0212] As used herein, the term "amido" refers to a group of the formula -C(O)NR R , wherein R '< and R "< are substituted or unsubstituted alkyl, cycloalkyl or heterocycle, or R '< and R "< can form cycloalkyl or heterocycle.

[0213] As used herein, the term "sulfamido" refers to the group -SO 2 NR '< R "< , wherein R' and R" are as defined in the definition of "amido".

[0214] As used herein, "optionally substituted", groups may be substituted or unsubstituted. The substituent (or substitution) group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: lower (C 1 -C 6 ) alkyl, lower alkenyl, lower alkynyl, lower aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino, dialkylamino, diarylalkylamino, alkylthio, arylthio, heteroarylthio, oxo, oxa, carbonyl (-C(O)), carboxyesters (-C(O)OR), carboxamido (-C(O)NH 2 ), carboxy, acyloxy, -H, halo, -CN, -NO 2 , -N 3 , -SH, -OH, -C(O)CH 3 , perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, esters, amides, phosphonates, phosphonic acid, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, thioalkyls. An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ). A group may optionally be substituted by 1, 2, 3, 4, or 5 independently selected groups (e.g., the aryl and heteroaryl groups of R 1 may optionally be substituted by 1, 2, 3, 4, or 5 independently selected R 8 groups). A group may optionally be substituted by 1, 2, 3 independently selected groups (e.g., the aryl and heteroaryl groups of R 1 may optionally be substituted by 1, 2, or 3 independently selected R 8 groups). A group may optionally be substituted by 1 or 2 independently selected groups (e.g., the aryl and heteroaryl groups of R 1 may optionally be substituted by 1 or 2 independently selected R 8 groups).

[0215] A group may optionally be substituted by 1 group (e.g., the aryl and heteroaryl groups of R 1 may optionally be substituted by 1 R 8 group).

[0216] As used herein, the term "pharmaceutically acceptable" refers to carrier(s), diluent(s), excipient(s) or salt forms of the compounds of the present disclosure that are compatible with the other ingredients of the formulation of the pharmaceutical composition.

[0217] As used herein, the term "pharmaceutical composition" refers to a compound of the present disclosure optionally admixed with one or more pharmaceutically acceptable carriers, diluents, or excipients. Pharmaceutical compositions preferably exhibit a degree of stability to environmental conditions so as to make them suitable for manufacturing and commercialization purposes.

[0218] As used herein, the terms "effective amount", "therapeutic amount", and "effective dose" refer to an amount of the compound of the present disclosure sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in an effective prevention or treatment of a disorder. Treatment of a disorder may be manifested by delaying or preventing the onset or progression of the disorder, as well as the onset or progression of symptoms associated with the disorder. Treatment of a disorder may also be manifested by a decrease or elimination of symptoms, reversal of the progression of the disorder, as well as any other contribution to the well-being of the patient. The effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.

[0219] The term "prodrug" as used herein is intended to encompass a class of analogs of compounds of the present invention wherein a metabolically labile moiety is attached to said compound of the invention through an available NH, C(O)H, COOH, C(O)NH 2 , OH or SH functionality. The prodrug-forming moieties are removed by metabolic processes and release the active compounds having the free NH, C(O)H, COOH, C(O)NH 2 , OH or SH group in vivo. Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and / or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance. Design and preparation of various forms of prodrugs is known to those skilled in the art, and is described in, for example: a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch. 31 (Academic Press, 1996). b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); 33. c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch. 5, pp. 113-191 (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003). GENERAL METHODS FOR PREPARATION OF COMPOUNDS

[0220] There is described herein a method for the synthesis of compounds of the present disclosure. There is described herein a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the present disclosure. The compounds can be prepared according to the methods described below using readily available starting materials and reagents. In these reactions, variants may be employed which are themselves known to those of ordinary skill in this art but are not described in detail here. Those skilled in the art of organic synthesis will appreciate that there exist multiple means of producing compounds of the present disclosure. Illustrative synthetic methods, including those directed to specific, selected compounds noted in Table 2, are as set forth herein.

[0221] It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures.

[0222] One skilled in the art of organic synthesis understands that vulnerable moieties such as C(O)OH, C(O) and C(O)H, NH, C(O)NH 2 , OH and SH moieties may be protected and deprotected, as necessary. Protecting groups for C(O)OH moieties include, but are not limited to, allyl, benzoylmethyl, benzyl, benzyloxymethyl, tert-butyl, ethyl, methyl, 2,2,2-trichloroethyl, and the like. Protecting groups for C(O) and C(O)H moieties include, but are not limited to, 1,3-dioxylketal, diethylketal, dimethylketal, 1,3-dithianylketal, O-methyloxime, O-phenyloxime and the like. Protecting groups for NH moieties include, but are not limited to, acetyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoryl, formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacetyl, phthaloyl, succinyl, trichloroethoxycarbonyl, triethylsilyl, trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl, para-toluenesulfonyl and the like.

[0223] Protecting groups for OH and SH moieties include, but are not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 3,4-dimethoxybenzyl, 3,4-dimethoxybenzyloxycarbonyl, 1,1-dimethyl-2-propenyl, diphenylmethyl, methanesulfonyl, methoxyacetyl, 4-methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl, para-toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloroethyl, triethylsilyl, trifluoroacetyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-trimethylsilylethyl, triphenylmethyl, 2-(triphenylphosphonio)ethoxycarbonyl and the like.

[0224] A discussion of protecting groups is provided in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York (1999).EXAMPLES General Synthetic Protocols

[0225] The synthesis will now be further described with reference to the following illustrative examples in which, unless stated otherwise, (i) all air or moisture sensitive reactions were performed under positive pressure of nitrogen with oven-dried glassware; (ii) chemical reagents and anhydrous solvents were obtained from commercial sources and used as is; (iii) temperatures are given in degrees Celsius (°C.); operations are carried out at room temperature (RT) or ambient temperature, that is, in a range of 18-25°C; (iv) organic solutions were dried over anhydrous sodium or magnesium sulfate unless otherwise stated; evaporation of organic solvent was carried out using a rotary evaporator under reduced pressure; (v) column chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; (vi) in general, the course of reactions was followed by TLC or liquid chromatography / mass spectroscopy (LC / MS) and reaction times are given for illustration only; (vii) preparative purification was performed on a Waters semi-preparative HPLC with a Phenomenex Luna C18 (5 micron, 30 x 75 mm) column at a flow rate of 45 mL / min, the mobile phase consisted of acetonitrile and water (each containing 0.1% trifluoroacetic acid); a gradient of 10% to 50% acetonitrile over 8 minutes was used during the purification; fraction collection was triggered by UV detection (220 nm); (viii) analytical analysis for purity was determined by two different methods denoted as Final QC Methods 1 and 2; Method 1: analysis was performed on an Agilent 1290 Infinity Series HPLC; UHPLC Long Gradient Equivalent 4% to 100% acetonitrile (0.05% trifluoroacetic acid) in water over 3 minutes, run time of 4.5 minutes with a flow rate of 0.8 mL / min; a Phenomenex Luna C18 column (3 micron, 3 x 75 mm) was used at a temperature of 50 °C; Method 2: analysis was performed on an Agilent 1260 with a 7 minute gradient of 4% to 100% acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) over 8 minute run time at a flow rate of 1 mL / min; a Phenomenex Luna C18 column (3 micron, 3 x 75 mm) was used at a temperature of 50 °C; purity determination was performed using an Agilent Diode Array Detector for both Method 1 and Method 2; mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode; all of the analogs for assay have purity greater than 95% based on both analytical methods; (ix) high resolution mass spectrometry was recorded on Agilent 6210 Time-of-Flight LC / MS system; (x) final products have satisfactory proton nuclear magnetic resonance (NMR) spectra and / or mass spectra data; (xi) when given, NMR data is in the form of delta values for major diagnostic protons, given in part per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, and were obtained on Varian 400 (100) and 600 MHz spectrometers in the solvent indicated; (xii) chemical symbols have their usual meanings; (xiii) in the event that the nomenclature assigned to a given compound does not correspond to the compound structure depicted herein, the structure will control; (xiv) solvent ratio is given in volume:volume (v / v) terms; (xv) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required.Representative Synthetic Schemes

[0226]

[0227] Compounds of Formula I wherein Y is NR 6 R 7 , aryl or heteroaryl may be prepared according to Scheme 1. A dichloride 1 may be allowed to react with an amine, R 1 -L 1 -NH-R 2 , in ethanolic solution, to provide an intermediate compound 2. Coupling of 2 may be performed with a boronic acid or boronate ester in the presence of a palladium catalyst to provide a compound 3. Treatment of 3 with an amine R6R7NH in ethanolic solution will provide an amine of Formula I wherein Y is NR 6 R 7 , while coupling of 3 may be performed with a aryl or heteroaryl boronic acid or boronate ester in the presence of a palladium catalyst to provide a compound of Formula I wherein Y is aryl or heteroaryl.

[0228] In the alternative, compounds of Formula I wherein X and Z are N and Y is NR 6 R 7 may be prepared according to Scheme 2. A dichloride 1 may be allowed to react with potassium tert-butoxide to give a t-butyl ether 4. Coupling of 4 may be performed with a boronic acid or boronate ester in the presence of a palladium catalyst to provide a compound 5. Treatment of 5 with an amine in ethanolic solution, followed by deprotection in the presence of trifluoroacetic acid, will provide an amine 6, which may be coupled with an amine, R 1 -L 1 -NH-R 2 , in the presence of a suitable activating agent, such as PyBrOP, to give a compound of Formula I.

[0229] Compounds as claimed prepared according to Scheme 1 or Scheme 2 are presented in Table 1, and further details of their preparation are subsequently provided in the following Synthetic Procedures. Examples 38-40 and 51 are reference examples. Table 1 Example # Structure Compound Name 1 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine2 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine3 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine4 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinolin-4-amine5 N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-methylquinazoline-2,4-diamine, 2TFA6 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-amine, 2TFA7 N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine, 2TFA8 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methoxyquinazolin-4-amine9 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinazolin-4-amine10 N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-morpholinoethyl)quinazoline-2,4-diamine, 2TFA11 N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-(4-methylpiperazin-1-yl)ethyl)quinazoline-2,4-diamine, 2TFA12 N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA13 3-((4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)amino)propan-1-ol, 2TFA14 N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinolin-4-amine, 2TFA15 6-bromo-N-(3-chlorobenzyl)-2-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine, 2TFA16 N-(3-chlorobenzyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA17 (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(cyclopropyl)methanone, 2TFA18 (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone, 2TFA19 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine, 2TFA20 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanol, 2TFA21 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-isopentylpiperazin-1-yl)quinazolin-4-amine, 2TFA22 N4-(3-chlorobenzyl)-N2-(2-(dimethylamino)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-methylquinazoline-2,4-diamine, 2TFA23 (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-4-yl)methanol, 2TFA24 (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-3-yl)methanol, 2TFA25 (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-2-yl)methanol, 2TFA26 N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine, 2TFA27 N-(3-chlorobenzyl)-4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-amine, 2TFA28 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)quinazolin-4-amine, 2TFA29 (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(pyridin-4-yl)methanone, 2TFA30 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-4-yl)ethanol, 2TFA31 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine, 2TFA32 N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)-1,4-diazepan-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA33 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1,4-diazepan-1-yl)ethanol, 2TFA34 N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA35 (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(pyridin-3-yl)methanone, 2TFA36 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-hydroxyethanone, 2TFA37 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethanone, 2TFA38 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA39 N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA40 2-(4-(4-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanol, 2TFA41 N-(3-chlorobenzyl)-2-(4-((dimethylamino)methyl)piperidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA42 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-4-yl)ethanol, 2TFA43 N-(3-chlorobenzyl)-3-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-1-amine, 2TFA44 2-(4-(1-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)piperazin-1-yl)ethanol, 2TFA45 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)propan-2-ol, 2TFA46 (R)-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)propan-2-ol, 2TFA47 (S)-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)propan-2-ol, 2TFA48 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1 H-pyrazol-1-yl)ethanol, 2TFA49 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-amine, 2TFA50 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide, 2TFA51 2-(4-(4-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide, 2TFA52 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide, 2TFA53 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide, 2TFA54 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)acetamide, 2TFA55 2-amino-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone, 2TFA56 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, 2TFA57 3-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)propanenitrile, 2TFA58 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)quinazolin-4-amine, 2TFA59 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetonitrile, 2TFA60 N-(3-chlorobenzyl)-2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA61 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)quinazolin-4-amine, 2TFA62 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol63 (5-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)pyridin-2-yl)methanol, 2TFA64 N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(1H-pyrazol-4-yl)quinazolin-4-amine, 2TFA65 N-(3-chlorobenzyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine, 2TFA66 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA67 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-ol, 2TFA68 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl69 2,6-bis(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2TFA70 N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA71 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2TFA72 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methoxybenzyl)quinazolin-4-amine, 2TFA73 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(3-methoxybenzyl)quinazolin-4-amine, 2TFA74 N-(2-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA75 N-(3-bromobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA76 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(2-fluorobenzyl)quinazolin-4-amine, 2TFA77 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(3-fluorobenzyl)quinazolin-4-amine, 2TFA78 N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(5-methylisoxazol-4-yl)quinazolin-4-amine, 2TFA79 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(furan-2-ylmethyl)quinazolin-4-amine, 2TFA80 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)quinazolin-4-amine, 2TFA81 N-((5-chloropyridin-3-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA82 N-((4-chloropyridin-2-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA83 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-fluoropyridin-3-yl)methyl)quinazolin-4-amine, 2TFA84 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylpyridin-3-yl)methyl)quinazolin-4-amine, 2TFA85 N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-methylquinazolin-4-amine, 2TFA86 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-3-fluoropyridin-2-ol, 2TFA87 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylthiophen-2-yl)methyl)quinazolin-4-amine, 2TFA88 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylthiophen-2-yl)methyl)quinazolin-4-amine, 2TFA89 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-(thiophen-2-yl)ethyl)quinazolin-4-amine, 2TFA90 N-(1-(3-chlorophenyl)ethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA91 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-3-methylpyridin-2-ol, 2TFA92 N-benzyl-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA93 N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3-methylisoxazol-4-yl)quinazolin-4-amine, 2TFA94 N-((5-chlorothiophen-2-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA95 N-(4-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA96 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-ol, 2TFA97 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide, 2TFA98 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide, 2TFA99 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(4-fluorobenzyl)quinazolin-4-amine, 2TFA100 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA101 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide, 2TFA102 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide, 2TFA103 5-(4-((3-chlorobenzyl)amino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA104 3-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)propanenitrile, 2TFA105 5-(4-((3-chlorobenzyl)amino)-2-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA106 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyacetyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA107 5-(2-(4-(2-aminoacetyl)piperazin-1-yl)-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA108 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)acetamide, 2TFA109 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide, 2TFA110 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide, 2TFA111 (S)-5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxypropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA112 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine113 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one114 5-(4-((3-chlorobenzyl)amino)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one115 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylpyridin-3-yl)methyl)quinazolin-4-amine, 2TFA116 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA117 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)acetamide, 2TFA118 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide, 2TFA119 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide, 2TFA120 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanol, 2TFA121 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA122 5-(4-((3-chlorobenzyl)amino)-2-(4-(1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA123 5-(4-((3-chlorobenzyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA124 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA125 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA126 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA127 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)acetamide, 2TFA128 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide, 2TFA129 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide, 2TFA130 N-((5-chloropyridin-3-yl)methyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA131 2-amino-1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone132 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-hydroxyethanone, 2TFA133 5-(2-(4-(2-aminoacetyl)piperazin-1-yl)-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one134 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA135 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA136 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol, 2TFA137 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol, 2TFA138 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol, 2TFA139 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, 2TFA140 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide, 2TFA141 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide, 2TFA142 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide, 2TFA143 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA144 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)ethanol, 2TFA145 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide, 2TFA146 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N, N-dimethylacetamide, 2TFA147 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide, 2TFA148 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA149 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA150 2-(4-(4-((4-chlorophenyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)ethanol, 2TFA151 2-chloro-N-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA152 N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-amine, 2TFA153 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperidin-1-yl)quinazolin-4-amine, 2TFA154 N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperidin-1-yl)quinazolin-4-amine, 2TFA155 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-amine, 2TFA156 1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-4-methylpiperidine-4-carbonitrile, 2TFA157 1-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-4-methylpiperidine-4-carbonitrile, 2TFA158 N-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA159 5-(4-((4-chlorophenyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, TFA160 N-(4-chlorophenethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA161 2-(4-(4-(3-benzylazetidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine, 2TFA162 N-(4-chlorophenyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA163 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxylic acid, TFA164 2-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)ethanol, 2TFA165 (4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)(4-(2-(dimethylamino)ethyl)piperazin-1-yl)methanone, 2TFA166 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetic acid, TFA167 N4-(3-chlorobenzyl)-N2-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2,4-diamine, 2TFA168 N-(4-chlorobenzyl)-4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA169 N-(3-chlorobenzyl)-2-(4-chlorophenoxy)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA170 N-(1-(3-chlorophenyl)cyclopropyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA171 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4-ylmethyl)quinazoline-2-carboxamide, 2TFA172 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)quinazoline-2-carboxamide, 2TFA173 (S)-2-((2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)amino)-2-phenylethanol, 2TFA174 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpyrrolidin-1-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine, 2TFA175 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpiperidin-1-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine, 2TFA176 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine, 2TFA177 N-((1H-imidazol-2-yl)methyl)-4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA178 N2-((1H-imidazol-2-yl)methyl)-N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2,4-diamine, 2TFA179 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylazetidin-1-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine, 2TFA180 N-(1-(3-chlorophenyl)cyclopropyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-amine, 2TFA181 2-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide, 2TFA182 1-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, 2TFA183 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-imidazol-5-yl)methyl)quinazoline-2-carboxamide, 2TFA184 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone, 2TFA185 1-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone, 2TFA186 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)quinazoline-2-carboxamide, 2TFA187 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylpyridin-3-yl)methyl)quinazoline-2-carboxamide, 2TFA188 4-((3-chlorobenzyl)amino)-N-((4-chloropyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA189 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)quinazoline-2-carboxamide, 2TFA190 4-((3-chlorobenzyl)amino)-N-((1,5-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA191 4-((3-chlorobenzyl)amino)-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA192 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-fluoropyridin-3-yl)methyl)quinazoline-2-carboxamide, 2TFA193 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylpyridin-3-yl)methyl)quinazoline-2-carboxamide, 2TFA194 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)quinazoline-2-carboxamide, 2TFA195 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone, 2TFA196 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2-methylthiazol-4-yl)methyl)quinazoline-2-carboxamide, 2TFA197 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((6-methylpyridin-3-yl)methyl)quinazoline-2-carboxamide, 2TFA198 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)quinazoline-2-carboxamide, 2TFA199 N-(1-acetylpiperidin-4-yl)-4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA200 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)quinazoline-2-carboxamide, 2TFA201 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-carboxamide, 2TFA202 4-((3-chlorobenzyl)amino)-N-((2-chloropyridin-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA203 4-((3-chlorobenzyl)amino)-N-((6-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA204 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)quinazoline-2-carboxamide, 2TFA205 4-((3-chlorobenzyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA206 4-(((5-chloropyridin-3-yl)methyl)amino)-N-((2-chloropyridin-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA207 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4-ylmethyl)quinazoline-2-carboxamide, 2TFA208 4-((3-chlorobenzyl)amino)-N-((3-chloropyridin-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA209 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)quinazoline-2-carboxamide, 2TFA210 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine, 2TFA211 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-N-(1-methylpiperidin-4-yl)quinazoline-2-carboxamide, 2TFA212 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2-methylthiazol-5-yl)methyl)quinazoline-2-carboxamide, 2TFA213 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylthiazol-2-yl)methyl)quinazoline-2-carboxamide, 2TFA214 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylthiazol-2-yl)methyl)quinazoline-2-carboxamide, 2TFA215 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((3-fluoropyridin-4-yl)methyl)quinazoline-2-carboxamide, 2TFA216 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methyloxazol-2-yl)methyl)quinazoline-2-carboxamide, 2TFA217 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((3-methylpyridin-4-yl)methyl)quinazoline-2-carboxamide, 2TFA218 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methylpyridin-4-yl)quinazoline-2-carboxamide, 2TFA219 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(6-methylpyridin-3-yl)quinazoline-2-carboxamide, 2TFA220 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(4-methylpyridin-3-yl)quinazoline-2-carboxamide, 2TFA221 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(5-fluoropyridin-3-yl)quinazoline-2-carboxamide, 2TFA222 4-((3-chlorobenzyl)amino)-N-(6-chloropyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA223 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(3-fluoropyridin-4-yl)quinazoline-2-carboxamide, 2TFA224 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(2,6-dimethylpyridin-4-yl)quinazoline-2-carboxamide, 2TFA225 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methyl-1H-pyrazol-4-yl)quinazoline-2-carboxamide, 2TFA226 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-2-carboxamide, 2TFA227 4-((3-chlorobenzyl)amino)-6-(1- methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(1-methylpiperidin-4-yl)quinoline-2-carboxamide, 2TFA228 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)quinoline-2-carboxamide, 2TFA229 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-2-carboxamide, 2TFA230 4-((3-chlorobenzyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinoline-2-carboxamide, 2TFA231 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)quinoline-2-carboxamide, 2TFA232 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-imidazol-5-yl)methyl)quinazoline-2-carboxamide, 2TFA233 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)quinazoline-2-carboxamide, 2TFA234 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)quinoline-2-carboxamide, 2TFA235 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)quinoline-2-carboxamide, 2TFA236 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide, 2TFA237 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)quinazoline-2-carboxamide, 2TFA238 4-(((5-chloropyridin-3-yl)methyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA239 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)quinazoline-2-carboxamide, 2TFA240 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)quinazoline-2-carboxamide, 2TFA241 4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)thiomorpholine 1,1-dioxide, 2TFA242 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)quinazoline-2-carboxamide, 2TFA243 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)thiomorpholine 1,1-dioxide, 2TFA244 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-N,N-dimethylpiperazine-1-carboxamide, 2TFA245 4-((1-(3-chlorophenyl)cyclopropyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA246 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)quinazoline-2-carboxamide, 2TFA247 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)quinazoline-2-carboxamide, 2TFA248 4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-N,N-dimethylpiperazine-1-carboxamide, 2TFA249 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2-methylpyridin-4-yl)methyl)quinazoline-2-carboxamide, 2TFA250 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1r,4r)-4-hydroxycyclohexyl)quinazoline-2-carboxamide, 2TFA251 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-imidazol-2-yl)methyl)quinazoline-2-carboxamide, 2TFA252 4-((3-chlorobenzyl)amino)-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA253 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1r,3r)-3-hydroxycyclobutyl)quinazoline-2-carboxamide, 2TFA254 1-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)piperidine-4-carboxylic acid, 2TFA255 1-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-4-yl)piperidine-4-carboxylic acid, 2TFA256 4-((3-chlorobenzyl)amino)-N-((3,3-difluorocyclobutyl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA257 4-((3-chlorobenzyl)amino)-N-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide, 2TFA258 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylthiazol-5-yl)methyl)quinazoline-2-carboxamide, 2TFA259 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((3,5-dimethylisoxazol-4-yl)methyl)quinazoline-2-carboxamide, 2TFA260 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2,4-dimethylthiazol-5-yl)methyl)quinazoline-2-carboxamide, 2TFA261 1-(6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)piperidine-4-carboxylic acid262 (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, 2TFA263 (R)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, 2TFA264 4-(6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine, 2TFA265 (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine, 2TFA266 (R)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine, 2TFA267 1-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-N-methylpiperidine-4-carboxamide, 2TFA268 (R)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-yl)-3-phenylmorpholine, 2TFA269 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-yl)-3-phenylmorpholine, 2TFA270 1-(6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-N-methylpiperidine-4-carboxamide, 2TFA271 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidothietan-3-yl)quinazoline-2-carboxamide, TFA272 (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide273 6-(3,5-dimethylisoxazol-4-yl)-N-((1r,4S)-4-hydroxycyclohexyl)-4-((S)-3-phenylmorpholino)quinazoline-2-carboxamide, TFA274 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1r,4r)-4-hydroxycyclohexyl)quinoline-2-carboxamide, TFA275 (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide, TFA276 (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)(1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone, TFA277 (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide, TFA278 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)quinazolin-4-amine279 (S)-6-(3,5-dimethyl isoxazol-4-yl)-N-((1-methyl-1H-imidazol-5-yl)methyl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide, TFA280 (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide, TFA281 (S)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide, TFA282 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA283 (S)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide, TFA284 (4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone, TFA285 (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone, TFA286 (4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone, TFA287 (4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone, TFA288 (4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone, TFA289 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA290 N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)quinazolin-4-amine291 (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpiperazin-1-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, TFA292 (S)-5-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, TFA293 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA294 (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)ethan-1-one, TFA295 (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol, TFA296 (S)-1-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-N-methylpiperidine-4-carboxamide, TFA297 (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide, TFA298 (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide, TFA299 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-N-ethylpiperazine-1-carboxamide, TFA300 (S)-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone, TFA301 (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide, TFA302 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA303 (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide, TFA304 (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol, TFA305 (S)-1-(4-(6-(3, 5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-2-hydroxyethan-1-one, TFA306 (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, TFA307 (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)acetamide, TFA308 (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-((S)-3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)propan-2-ol, TFA309 (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylpiperazin-1-yl)ethan-1-one, TFA310 (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(4-(methylsulfonyl)-2-phenylpiperazin-1-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, TFA311 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(3-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA312 1-(4-(4-((3-chlorobenzyl)(cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, TFA313 (S)-7-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-7-azaspiro[3.5]nonan-2-ol, TFA314 (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1,8-diazaspiro[4.5]decan-2-one, TFA315 (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidothietan-3-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide, TFA316 (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)methanone, TFA317 (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)(1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone, TFA318 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA319 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine, HCl320 (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decan-1-one, TFA321 (S)-(5-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)pyridin-2-yl)methanol, TFA322 (S)-N-cyclopropyl-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylpiperazine-1-carboxamide, TFA323 (S)-(5-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)thiophen-2-yl)methanol, TFA324 (S)-1-(3-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethan-1-one, TFA325 (S)-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)thiophen-2-yl)methanol, TFA326 (S)-4-(2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA327 (S)-1-(4-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethan-1-one, TFA328 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA329 (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-2,8-diazaspiro[4.5]decan-1-one, TFA330 (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1-methyl-1,8-diazaspiro[4.5]decan-2-one, TFA331 (S)-N-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazoline-2-carboxamide332 1-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-4-yl)-N-methylpiperidine-4-carboxamide333 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA334 (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine, TFA335 (S)-3-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)propanenitrile, TFA336 (S)-8-(4-(4-acetyl-2-phenylpiperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1-methyl-1,8-diazaspiro[4.5]decan-2-one, TFA337 (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(4-(methylsulfonyl)-2-phenylpiperazin-1-yl)quinazolin-2-yl)-1-methyl-1,8-diazaspiro[4.5]decan-2-one, TFA338 (S)-5-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(2-phenylpiperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, HCl339 1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-morpholinoquinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol340 (S)-5-(4-(4-acetyl-2-phenylpiperazin-1-yl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, TFA Detailed Synthetic ProceduresExample 1. 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine. STEP 1: 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine.

[0230] To a mixture of 6-bromo-2,4-dichloroquinazoline (278 mg, 1.0 mmol) and (3-chlorophenyl)methanamine (142 mg, 1.0 mmol) in THF (2 ml) was added Et 3 N (0.209 ml, 1.5 mmol). The mixture was stirred at RT for 1 h. The mixture was poured into EtOAc / H 2 O (5 mL / 5 mL). The aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was triturated with hexane and dried to give 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine (360 mg, 0.94 mmol, 94 % yield) as a white solid. MS (M+H) +< = 384.STEP 2: 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0231] In a 2-neck flask was placed 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine (345 mg, 0.9 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (127 mg, 0.9 mmol), PdCl 2 (dppf) (65.9 mg, 0.09 mmol), and K 2 CO 3 (311 mg, 2.250 mmol). The air was removed and re-filled with N 2 (2-3 times). Then a mixture of 1,4-Dioxane (3 ml) and Water (1 ml) was added and stirred at 95 °C (pre-heated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was triturated with 50% CH 2 Cl 2 / hexane to give 48 mg of pure solid product. The filtrate was concentrated and was purified by silica gel chromatography using 20-40% EtOAc / hexane as the eluent, then triturated the product with 5% CH 2 Cl 2 / hexane to give 170 mg of pure solid product. Total 218 mg of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (218 mg, 0.546 mmol, 60.7 % yield) was obtained. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.30 (t, J = 5.9 Hz, 1H), 8.26 (d, J = 1.9 Hz, 1H), 7.83 (dd, J = 8.5, 1.7 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.40 - 7.28 (m, 3H), 4.77 (d, J = 5.7 Hz, 2H), 2.44 (s, 3H), 2.27 (s, 3H); MS (M+H) +< = 400.Example 2. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine. STEP 1: 6-bromo-N-(3-chlorobenzyl)quinazolin-4-amine.

[0232] To a mixture of 6-bromo-4-chloroquinazoline (243 mg, 1.0 mmol) and (3-chlorophenyl)methanamine (142 mg, 1.0 mmol) in THF (2 ml) was added Et 3 N (0.21 ml, 1.5 mmol). The mixture was stirred at RT for 3 h. The mixture was poured into EtOAc / H 2 O (5 mL / 5 mL). The aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was triturated with hexane and dried to give 6-bromo-N-(3-chlorobenzyl)quinazolin-4-amine (342 mg, 0.98 mmol, 98 % yield) as a white solid. MS (M+H) +< = 350.STEP 2: N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0233] In a 2-neck flask was placed 6-bromo-N-(3-chlorobenzyl)quinazolin-4-amine (69.7 mg, 0.2 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (42.3 mg, 0.3 mmol), PdCl 2 (dppf) (14.6 mg, 0.02 mmol), and K 2 CO 3 (83 mg, 0.6 mmol). The air was removed and re-filled with N 2 (2-3 times). Then a mixture of 1,4-Dioxane (1.5 ml) and water (0.5 ml) was added and stirred at 95 °C (pre-heated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 20-40% EtOAc / hexane as the eluent to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (61.5 mg, 0.169 mmol, 84 % yield). 1< H NMR (400 MHz, Chloroform-d) δ 8.70 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.65 - 7.58 (m, 1H), 7.41 (d, J = 1.3 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.28 - 7.22 (m, 2H), 6.82 (s, 1H), 4.92 (d, J = 5.5 Hz, 2H), 2.44 - 2.34 (m, 3H), 2.21 (d, J = 0.6 Hz, 3H); MS (M+H) +< = 365.Example 3. N-(3-chlorobenzvl)-6-(3,5-dimethylisoxazol-4-vl)quinolin-4-amine. STEP 1: 6-bromo-N-(3-chlorobenzyl)quinolin-4-amine.

[0234] In a microwave tube was placed 6-bromo-4-chloroquinoline (242 mg, 1 mmol), (3-chlorophenyl)methanamine (283 mg, 2.0 mmol), DMSO (1 ml), and Hunig's Base (0.349 ml, 2.0 mmol). The tube was sealed and heated at 150 °C for 1 h under microwave irradiation. The mixture was poured into EtOAc / H 2 O (30 mL / 30 mL). The organic layer was washed with H 2 O (30 mL), dried (Na 2 SO 4 ), and filtered. After removal of solvent, the product was triturated with 2% CH 2 Cl 2 / hexane and then dried to give 6-bromo-N-(3-chlorobenzyl)quinolin-4-amine (238 mg, 0.685 mmol, 68.5 % yield). MS (M+H) +< = 349.STEP 2: N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine.

[0235] In a 2-neck flask was placed 6-bromo-N-(3-chlorobenzyl)quinolin-4-amine (87 mg, 0.25 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (70.5 mg, 0.5 mmol), PdCl 2 (dppf) (18.29 mg, 0.025 mmol), and K 2 CO 3 (138 mg, 1.0 mmol). The air was removed and re-filled with N 2 (2-3 times). Then a mixture of 1,4-Dioxane (1.5 ml) and water (0.5 ml) was added and stirred at 95 °C (pre-heated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 0-5% MeOH / EtOAc as the eluent to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine (88.5 mg, 0.243 mmol, 97 % yield). 1< H NMR (400 MHz, Chloroform-d) δ 8.51 (dd, J = 5.5, 1.9 Hz, 1H), 8.09 (dd, J = 8.6, 2.0 Hz, 1H), 7.76 (s, 1H), 7.52 (dt, J = 8.7, 2.0 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.33 - 7.23 (m, 3H), 6.44 (dd, J = 5.5, 2.0 Hz, 1H), 6.01 (s, 1H), 4.60 (dd, J = 5.6, 1.9 Hz, 2H), 2.42 (d, J = 2.0 Hz, 3H), 2.26 (d, J = 1.9 Hz, 3H); MS (M+H) +< = 364.Example 4. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinolin-4-amine. STEP 1: 6-bromo-N-(3-chlorobenzyl)-2-methylquinolin-4-amine.

[0236] In a microwave tube was placed 6-bromo-4-chloro-2-methylquinoline (257 mg, 1 mmol), (3-chlorophenyl)methanamine (283 mg, 2.0 mmol), DMSO (1 ml), and Hunig's Base (0.349 ml, 2.0 mmol). The tube was sealed and heated at 150 °C for 1 h under microwave irradiation. The mixture was poured into EtOAc / H 2 O (30 mL / 30 mL). The organic layer was washed with H 2 O (30 mL), dried (Na 2 SO 4 ), and filtered. After removal of solvent, the product was triturated with 2% CH 2 Cl 2 / hexane and then dried to give 6-bromo-N-(3-chlorobenzyl)-2-methylquinolin-4-amine (211 mg, 0.583 mmol, 58.3 % yield). MS (M+H) +< = 363.STEP 2: N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinolin-4-amine.

[0237] In a 2-neck flask was placed 6-bromo-N-(3-chlorobenzyl)-2-methylquinolin-4-amine (90 mg, 0.25 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (70.5 mg, 0.5 mmol), PdCl 2 (dppf) (18.29 mg, 0.025 mmol), and K 2 CO 3 (138 mg, 1.0 mmol). The air was removed and re-filled with N 2 (2-3 times). Then a mixture of 1,4-Dioxane (1.5 ml) and Water (0.5 ml) was added and stirred at 95 °C (pre-heated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 0-5% MeOH / EtOAc as the eluent to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinolin-4-amine (88.4 mg, 0.234 mmol, 94 % yield). MS (M+H) +< = 378.Example 5. N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-methylquinazoline-2,4-diamine.

[0238] To a suspension of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 39.9 mg, 0.1 mmol) in EtOH (1 ml) was added methanamine (1.0 ml, 2.0 mmol) (2M in THF). The tube was sealed and heated at 75 °C for 16 h. After cooling to rt, the mixture was concentrated and the residue was re-dissolved in DMSO, filtered through a filter, and submitted for purification to give N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-methylquinazoline-2,4-diamine, 2TFA (15.9 mg, 0.026 mmol, 25.6 % yield). MS (M+H) +< = 394.Example 6. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol,4-yl)-2-(4-methylpiperazin-1yl)quinazolin-4-amine.

[0239] To a mixture of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 33.9 mg, 0.085 mmol) and 1-methylpiperazine (102 mg, 1.02 mmol) was added EtOH (1 ml). The tube was sealed and heated at 75 °C for 6 h. After cooling to rt, the mixture was concentrated and the residue was re-dissolved in DMSO, filtered through a filter, and submitted for purification to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-amine, 2TFA (23.1 mg, 0.033 mmol, 39.3 % yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.14 (s, 2H), 8.22 (s, 1H), 7.86 - 7.23 (m, 6H), 4.76 (m, 4H), 4.20 - 2.95 (m, 6H), 2.79 7(s, 3H), 2.43 (s, 3H), 2.26 (s, 3H) (including 1 salt NH); MS (M+H) +< = 463.Example 7. N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine.

[0240] To a mixture of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 33.9 mg, 0.085 mmol) and 1-methylpiperidin-4-amine (116 mg, 1.02 mmol) was added EtOH (1 ml). The tube was sealed and heated at 85 °C for 16 h. After cooling to rt, the mixture was concentrated and the residue was re-dissolved in DMSO, filtered through a filter, and submitted for purification to give N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine, 2TFA (17 mg, 0.024 mmol, 28.4 % yield). MS (M+H) +< = 477.Example 8. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol,4-yl)-2-methoxyquinazolin-4-amine.

[0241] To 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 33.9 mg, 0.085 mmol) was added sodium methoxide (1405 mg, 6.5 mmol) (25 wt% in MeOH, ca. 6.5 M). The tube was sealed and heated at 75 °C for 3 h. After cooling to rt, the mixture was concentrated and then H 2 O (6 mL) was added. The white solid was collected, triturated water (2 mL x 2) and hexane (2 mL), and then dried to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methoxyquinazolin-4-amine (29 mg, 0.073 mmol, 86 % yield). 1< H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 8.8 Hz, 1H), 7.53 (dt, J = 7.5, 1.6 Hz, 2H), 7.39 (s, 1H), 7.29-7.26 (m, 3H), 6.24 (br s, 1H, NH), 4.88 (d, J = 5.5 Hz, 2H), 4.07 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H); MS (M+H) +< = 395.Example 9. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinazolin-4-amine). STEP 1: 6-bromo-N-(3-chlorobenzyl)-2-methylquinazolin-4-amine.

[0242] To a mixture of 6-bromo-2-methylquinazolin-4-ol (120 mg, 0.5 mmol) and bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (583 mg, 1.25 mmol) under N 2 was added 1,4-dioxane (4 ml) and then triethylamine (253 mg, 2.5 mmol). The mixture was stirred at RT for 1 h and (3-chlorophenyl)methanamine (142 mg, 1.0 mmol) was added. The mixture was stirred at RT for 24 h. To the mixture was added H 2 O (5 mL) and the aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layer was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 20-40% EtOAc / hexane as the eluent to give 6-bromo-N-(3-chlorobenzyl)-2-methylquinazolin-4-amine (66 mg, 0.182 mmol, 36.4 % yield). MS (M+H) +< = 364.STEP 2: N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylauinazolin-4-amine.

[0243] In a 2-neck flask was placed 6-bromo-N-(3-chlorobenzyl)-2-methylquinazolin-4-amine (60 mg, 0.165 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (30.3 mg, 0.215 mmol), PdCl 2 (dppf) (12.11 mg, 0.017 mmol), and K 2 CO 3 (68.6 mg, 0.496 mmol). The air was removed and re-filled with N 2 (2-3 times). Then a mixture of 1,4-Dioxane (1 ml) and Water (0.3 ml) was added and stirred at 95 °C (pre-heated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The compined organic layer was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 35-60% EtOAc / hexane as the eluent to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinazolin-4-amine (52.4 mg, 0.138 mmol, 84 % yield). 1< H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 8.6 Hz, 1H), 7.57 (dd, J = 8.6, 1.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.42 (q, J = 1.4 Hz, 1H), 7.29 (qd, J = 4.1, 2.0 Hz, 3H), 6.00 (s, 1H), 4.90 (d, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H); MS (M+H) +< = 379.Example 10. N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-morpholinoethyl)quinazoline-2,4-diamine.

[0244] To a mixture of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 39.9 mg, 0.1 mmol) and 2-morpholinoethanamine (130 mg, 1.0 mmol) was added EtOH (1 ml). The tube was sealed and heated at 90 °C for 16 h. After cooling to rt, the mixture was filtered through a filter, and submitted for purification to give N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-morpholinoethyl)quinazoline-2,4-diamine, 2TFA (23.1 mg, 0.032 mmol, 32.0 % yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.00 (s, 1H), 10.10 (s, 1H), 9.77 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.46 (s, 1H), 7.42 - 7.29 (m, 3H), 4.87 (s, 2H), 3.46 (m, 12H), 2.42 (s, 3H), 2.24 (s, 3H). (including 2 salt NH); MS (M+H) +< = 493.Example 11. N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-(4-methylpiperazin-1-yl)ethyl)quinazoline-2,4-diamine.

[0245] To a mixture of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 39.9 mg, 0.1 mmol) and 2-(4-methylpiperazin-1-yl)ethanamine (143 mg, 1.0 mmol) was added EtOH (1 ml). The tube was sealed and heated at 90 °C for 16 h. After cooling to rt, the mixture was filtered through a filter, and submitted for purification to give N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-(4-methylpiperazin-1-yl)ethyl)quinazoline-2,4-diamine, 2TFA (28.6 mg, 0.039 mmol, 39.0 % yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.81 (s, 1H), 10.07 (s, 1H), 9.62 (d, J = 141.1 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 7.82 (dd, J = 8.4, 1.7 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.46 (t, J = 1.9 Hz, 1H), 7.42 - 7.27 (m, 3H), 4.83 (d, J = 5.7 Hz, 2H), 4.43 - 2.67 (m, 15H), 2.42 (s, 3H), 2.25 (d, J = 1.4 Hz, 3H). (including 1 salt NH); MS (M+H) +< = 506.Example 12. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0246] To a mixture of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 39.9 mg, 0.1 mmol) and N,N-dimethyl-2-(piperazin-1-yl)ethanamine (157 mg, 1.0 mmol) was added EtOH (1 ml). The tube was sealed and heated at 90 °C for 16 h. After cooling to rt, the mixture was filtered through a filter, and submitted for purification to give N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA (21 mg, 0.028 mmol, 28.1 % yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.92 (s, 1H), 10.05 (s, 1H), 9.00 (s, 1H), 8.22 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.47 (t, J = 1.7 Hz, 1H), 7.37 - 7.29 (m, 3H), 4.80 (d, J = 5.7 Hz, 2H), 3.82 (m, 6H), 3.22 (d, J = 6.1 Hz, 2H), 2.80 (s, 6H), 2.72 - 2.50 (m, 4H), 2.42 (s, 3H), 2.25 (s, 3H). (including 2 salt NH); MS (M+H) +< = 520.Example 13. 3-((4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)amino)propan-1-ol.

[0247] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 39.9 mg, 0.1 mmol) and 3-aminopropan-1-o! (75 mg, 1.0 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.33 (s, 1H), 10.01 (s, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.38 - 7.29 (m, 3H), 4.81 (d, J = 5.7 Hz, 2H), 4.56 (s, 1H), 3.44 (d, J = 6.5 Hz, 4H), 2.41 (s, 3H), 2.24 (s, 3H), 1.69 (d, J = 58.0 Hz, 2H). (including 1 salt NH); MS (M+H) +< = 438.Example 14. N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinolin-4-amine.

[0248] To a mixture of 4,4'-(4-chloroquinoline-2,6-diyl)bis(3,5-dimethylisoxazole) (53.1 mg, 0.15 mmol) and (3-chlorophenyl)methanamine (212 mg, 1.5 mmol) was added DMSO (1 ml). The tube was sealed and heated at 160 °C for 1 h under microwave irradiation. The mixture was then filtered through a filter and submitted for purification to give N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinolin-4-amine, 2TFA (17.9 mg, 0.026 mmol, 17.37 % yield). MS (M+H) +< = 459.Example 15. 6-bromo-N-(3-chlorobenzyl)-2-(3,5-dimethylisoxazol,4-yl)quinolin-4-amine.

[0249] To a mixture of 4-(6-bromo-4-chloroquinolin-2-yl)-3,5-dimethylisoxazole (50.6 mg, 0.15 mmol) and (3-chlorophenyl)methanamine (212 mg, 1.5 mmol) was added DMSO (Volume: 1 ml). The tube was sealed and heated at 160 °C for 1 h under microwave irradiation. The mixture was then filtered through a filter and submitted for purification to give 6-bromo-N-(3-chlorobenzyl)-2-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine, 2TFA (15.9 mg, 0.024 mmol, 15.80 % yield). MS (M+H) +< = 442, 444.Example 16. N-(3-chlorobenzyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0250] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine (42.8 mg, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.67 (s, 1H), 8.19 (s, 1H), 7.72 (m, 4H), 7.47 (s, 1H), 7.42 - 7.26 (m, 3H), 4.79 (s, 2H), 3.70 (m, 8H), 3.06 (m, 4H), 2.82 - 2.73 (m, 6H), 2.42 (s, 3H), 2.25 (s, 3H), 1.98 (bs, 2H). (including 2 salt NH); MS (M+H) +< = 534.Example 17. (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(cyclopropyl)methanone.

[0251] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), cyclopropyl(piperazin-1-yl)methanone, HCl (47.7 mg, 0.25 mmol) and Hunig's Base (0.044 ml, 0.250 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 10.10 (s, 1H), 8.23 (s, 1H), 7.79 (m, 2H), 7.50 (d, J = 1.6 Hz, 1H), 7.43 - 7.28 (m, 3H), 4.81 (d, J = 5.6 Hz, 2H), 4.01 - 3.34 (m, 8H), 2.43 (s, 3H), 2.26 (s, 3H), 2.05 - 1.93 (m, 1H), 0.80 - 0.66 (m, 4H). (including 1 salt NH); MS (M+H) +< = 517.Example 18. (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone.

[0252] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), (1-methyl-1H-pyrazol-4-yl)(piperazin-1-yl)methanone, HCl (57.7 mg, 0.25 mmol) and Hunig's Base (0.044 ml, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.99 (s, 1H), 10.10 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.70 (d, J = 0.7 Hz, 1H), 7.50 (s, 1H), 7.44 - 7.28 (m, 3H), 4.81 (d, J = 5.6 Hz, 2H), 3.89 (s, 4H), 3.85 (s, 3H), 3.73 (s, 4H), 2.43 (s, 3H), 2.26 (s, 3H). (including 1 salt NH); MS (M+H) +< = 557.Example 19. 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin,4-amine.

[0253] The title compound was prepared from 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine (19.15 mg, 0.05 mmol) and N,N-dimethyl-2-(piperazin-1-yl)ethanamine (39.3 mg, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.96 (s, 1H), 10.07 (s, 1H), 9.08 (s, 1H), 8.52 (s, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.37 - 7.29 (m, 3H), 4.75 (d, J = 5.6 Hz, 2H), 3.80 (br s, 4H), 3.23 (s, 2H), 2.79 (s, 6H), 2.71 - 2.50 (m, 6H). (including 2 salt NH); MS (M+H) +< = 505.Example 20. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanol.

[0254] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and 2-(piperazin-1-yl)ethanol (32.5 mg, 0.25 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 493.Example 21. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-isopentylpiperazin-1-yl)quinazolin-4-amine.

[0255] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and 1-isopentylpiperazine (39.1 mg, 0.25 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 519.Example 22. N4-(3-chlorobenzyl)-N2-(2-(dimethylamino)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-methylquinazoline-2,4-diamine.

[0256] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and N1,N1,N2-trimethylethane-1,2-diamine (25.5 mg, 0.25 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 465.Example 23. (1-(4-((3-chlorobenzvl)amino)-6-(3,5-dimethylisoxazol-4-vl)quinazolin-2-yl)piperidin-4-yl)methanol.

[0257] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and piperidin-4-ylmethanol (28.8 mg, 0.250 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.72 (s, 1H), 9.99 (s, 1H), 8.20 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.37 - 7.29 (m, 3H), 4.78 (d, J = 5.6 Hz, 2H), 4.50 (br s, 3H), 3.23 (d, J = 5.7 Hz, 2H), 3.11 (m, 2H), 2.42 (s, 3H), 2.25 (s, 3H), 1.76 (d, J = 13.3 Hz, 3H), 1.10 (d, J = 12.5 Hz, 2H). (including 1 salt NH); MS (M+H) +< = 478.Example 24. (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-3-yl)methanol.

[0258] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and piperidin-3-ylmethanol (28.8 mg, 0.250 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.74 (s, 1H), 9.98 (s, 1H), 8.20 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.47 (s, 1H), 7.39 - 7.27 (m, 3H), 4.78 (d, J = 5.7 Hz, 2H), 4.51 (m, 4H), 3.07 (m, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 1.80 - 1.22 (m, 5H).( including 1 salt NH); MS (M+H) +< = 478.Example 25. (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-2-yl)methanol.

[0259] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and piperidin-2-ylmethanol (28.8 mg, 0.250 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 478.Example 26. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine.

[0260] To a mixture of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine (59.7 mg, 0.15 mmol) and N,N-dimethyl-2-(piperazin-1-yl)ethanamine (236 mg, 1.5 mmol) was added DMF (1 ml). The tube was sealed and heated at 180 °C for 1.5 h under microwave irradiation After cooling to rt, the mixture was filtered through a filter, and submitted for purification to give N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine, 2TFA (21.6 mg, 0.029 mmol, 19.27 % yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.72 (s, 1H), 8.94 (s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.76 (dd, J = 8.7, 1.7 Hz, 1H), 7.51 (s, 1H), 7.40 - 7.29 (m, 3H), 6.02 (s, 1H), 4.75 (d, J = 5.9 Hz, 2H), 3.67 (t, J = 4.8 Hz, 4H), 3.23 (t, J = 6.0 Hz, 2H), 2.79 (s, 6H), 2.61 (m, 6H), 2.43 (s, 3H), 2.26 (s, 3H). (including 1 salt NH); MS (M+H) +< = 519.Example 27. N-(3-chlorobenzyl)-4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-amine.

[0261] To a mixture of 4-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-amine (59.7 mg, 0.15 mmol) and N,N-dimethyl-2-(piperazin-1-yl)ethanamine (236 mg, 1.500 mmol) was added DMF (1 ml). The tube was sealed and heated at 180 °C for 1.5 h under microwave irradiation After cooling to rt, the mixture was filtered through a filter, and submitted for purification to give N-(3-chlorobenzyl)-4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-amine, 2TFA (22.8 mg, 0.031 mmol, 20.34 % yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.61 (s, 1H), 9.40 (s, 1H), 7.88 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.51 (s, 1H), 7.46 - 7.35 (m, 3H), 6.44 (s, 1H), 4.76 (d, J = 5.7 Hz, 2H), 3.30 (d, J = 37.4 Hz, 6H), 2.79 (m, 12H), 2.44 (s, 3H), 2.25 (s, 3H). (including 1 salt NH); MS (M+H) +< = 519.Example 28. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)quinazolin-4-amine.

[0262] In a 2-neck flask was placed 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 39.9 mg, 0.1 mmol), 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (61.4 mg, 0.2 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.00 µmol), and K 2 CO 3 (69.1 mg, 0.5 mmol). The air was removed and re-filled with N 2 (2-3 times). Then a mixture of 1,4-dioxane (1.5 ml) and water (0.5 ml) was added and stirred at 95 °C (pre-heated) for 1 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The compined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was dissolved in DMF, filtered through a filter and submitted for purification to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)quinazolin-4-amine, 2TFA (15.2 mg, 0.02 mmol, 19.69 % yield). 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 2H), 8.73 (s, 1H), 8.33 (s, 2H), 7.90 (m, 2H), 7.55 (s, 1H), 7.47 - 7.26 (m, 3H), 4.99 (s, 2H), 4.62 (s, 2H), 3.62 (m, 10H), 2.45 (s, 3H), 2.28 (s, 3H). (including 1 salt NH); MS (M+H) +< = 544.Example 29. (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(pyridin,4-yl)methanone.

[0263] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), piperazin-1-yl(pyridin-4-yl)methanone, 2HCl (66.0 mg, 0.25 mmol), and Hunig's base (0.175 ml, 1.0 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.02 (s, 1H), 10.09 (s, 1H), 8.84 - 8.49 (m, 2H), 8.23 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.46 - 7.41 (m, 2H), 7.38 - 7.24 (m, 3H), 4.78 (d, J = 5.6 Hz, 2H), 4.01 - 3.70 (m, 6H), 3.38 (s, 2H), 2.42 (s, 3H), 2.25 (s, 3H). (including 1 salt NH); MS (M+H) +< = 554.Example 30. 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2-vl)piperidin-4-vl)ethanol,

[0264] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and 2-(piperidin-4-yl)ethanol (32.3 mg, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.89 - 11.54 (m, 1H), 10.00 (s, 1H), 8.20 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.41 - 7.26 (m, 3H), 4.77 (d, J = 5.7 Hz, 2H), 4.46 (m, 3H), 3.53 - 2.92 (m, 4H), 2.42 (s, 3H), 2.25 (s, 3H), 1.75 (m, 3H), 1.33 (m, 2H), 1.16 - 0.96 (m, 2H). (including 1 salt NH); MS (M+H) +< = 492.Example 31. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine. STEP 1: tert-butyl 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate.

[0265] In a 2-neck flask was placed 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 399 mg, 1 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (464 mg, 1.5 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (82 mg, 0.1 mmol), and K 2 CO 3 (622 mg, 4.5 mmol). The air was removed and re-filled with N 2 (2-3 times). Then a mixture of 1,4-Dioxane (6 ml) and Water (3 ml) was added and stirred at 95 °C (pre-heated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 20-40-50% EtOAc / hexane as the eluent to give tert-butyl 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (403 mg, 0.738 mmol, 73.8 % yield). MS (M+H) +< = 546.STEP 2: N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine.

[0266] To a solution of tert-butyl 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (403 mg, 0.738 mmol) in 1,4-Dioxane (2 ml) was added HCl (4M in dioxane, 2 mL). The mixture was stirred at RT for 2 h. Then, hexane (20 mL) was added and carefully removed the solvent (repeat for 3 times). Then the solid was dried in vacuo to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine, 2HCl (390 mg, 0.752 mmol, 102 % crude yield). The material was used for next step without further purification. Submitted 25 mg for purification to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine, 2TFA (as TFA salt) for screening. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.08 (s, 1H), 8.77 (s, 2H), 8.25 (s, 1H), 7.79 (s, 2H), 7.45 (s, 1H), 7.36 - 7.25 (m, 3H), 7.12 (s, 1H), 4.83 (d, J = 5.7 Hz, 2H), 3.83 (br s, 2H), 3.30 (br s, 2H), 2.79 (br s, 2H), 2.45 (s, 3H), 2.28 (s, 3H). (including 1 salt NH); MS (M+H) +< = 446.Example 32. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)-1,4-diazepan-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0267] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and 2-(1,4-diazepan-1-yl)-N,N-dimethylethanamine (42.8 mg, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.79 (s, 1H), 10.08 (s, 1H), 8.23 (s, 1H), 7.83 (s, 2H), 7.46 (s, 1H), 7.34 (m, 3H), 4.78 (d, J = 5.6 Hz, 2H), 3.95 - 2.81 (m, 12H), 2.75 (s, 6H), 2.43 (s, 3H), 2.25 (s, 3H), 2.02 (br s, 1H), 1.69 (br s, 1H). (including 1 salt NH); MS (M+H) +< = 534.Example 33. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2-yl)-1,4-diazepan-1-yl)ethanol.

[0268] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and 2-(1,4-diazepan-1-yl)ethanol (36.1 mg, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.98 (s, 1H), 10.15 (s, 1H), 9.45 (s, 1H), 8.26 (s, 1H), 7.83 (s, 2H), 7.47 (s, 1H), 7.34 (d, J = 10.8 Hz, 3H), 5.39 (s, 1H), 4.79 (d, J = 19.6 Hz, 3H), 4.35 (s, 1H), 3.53 (m, 9H), 2.42 (s, 3H), 2.25 (s, 3H), 2.06 (m, 2H). (including 1 salt NH); MS (M+H) +< = 507.Example 34. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0269] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and N,N-dimethyl-2-(piperidin-4-yl)ethanamine (39.1 mg, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.82 (s, 1H), 10.05 (s, 1H), 9.37 (s, 1H), 8.21 (s, 1H), 7.82 (s, 1H), 7.74 (s, 1H), 7.47 (s, 1H), 7.40 - 7.29 (m, 3H), 4.87 - 4.67 (m, 2H), 4.49 (s, 2H), 3.56 - 2.93 (m, 4H), 2.74 (d, J = 4.6 Hz, 6H), 2.42 (s, 3H), 2.25 (s, 3H), 1.82 - 1.42 (m, 5H), 1.16 (m, 2H). (including 2 salt NH); MS (M+H) +< = 519.Example 35. (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(pyridin-3-yl)methanone.

[0270] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and piperazin-1-yl(pyridin-3-yl)methanone (47.8 mg, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.99 (s, 1H), 10.09 (s, 1H), 8.78 - 8.49 (m, 2H), 8.23 (s, 1H), 7.86 (dd, J = 14.7, 8.2 Hz, 2H), 7.73 (d, J = 8.6 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.41 - 7.26 (m, 3H), 4.79 (d, J = 5.6 Hz, 2H), 3.71 (m, 8H), 2.42 (s, 3H), 2.25 (s, 3H). include 1 salt NH); MS (M+H) +< = 554.Example 36. (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(pyridin-3-yl)methanone.

[0271] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and 2-hydroxy-1-(piperazin-1-yl)ethanone (36.0 mg, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.93 (s, 1H), 10.08 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 7.49 (s, 1H), 7.40 - 7.15 (m, 3H), 4.80 (d, J = 5.2 Hz, 2H), 4.12 (s, 2H), 3.84 (s, 4H), 3.52 (m, 4H), 2.96 (s, 1H), 2.42 (s, 3H), 2.25 (s, 3H). (including 1 salt NH); MS (M+H) +< = 507.Example 37. 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethanone.

[0272] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2HCl (61.0 mg, 0.25 mmol), and Hunig's base (0.175 ml, 1.0 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.04 (s, 1H), 10.14 (s, 1H), 9.54 (s, 1H), 8.22 (s, 1H), 7.75 (s, 2H), 7.48 (s, 1H), 7.35 (t, J = 7.7 Hz, 3H), 4.79 (s, 2H), 4.28 (d, J = 4.4 Hz, 2H), 3.85-3.60 (m, 8H), 2.80 (d, J = 4.1 Hz, 6H), 2.42 (s, 3H), 2.25 (s, 3H). (includine 2 salt NH); MS (M+H) +< = 534.Example 38. 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0273] In a 2-neck flask was placed 7-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine (383 mg, 1 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (223 mg, 1.000 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (82 mg, 0.1 mmol), and K 2 CO 3 (415 mg, 3.0 mmol). The air was removed and re-filled with N 2 (2-3 times). Then a mixture of 1,4-dioxane (3 ml) and water (1.5 ml) was added and stirred at 95 °C (pre-heated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 25-60% EtOAc / hexane as the eluent to give 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (370 mg, 0.927 mmol, 93 % yield). 25 mg of material was submitted for HPLC purification to give TFA salt for screening. MS (M+H) +< = 399.Example 39. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0274] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (19.96 mg, 0.05 mmol) and N,N-dimethyl-2-(piperazin-1-yl)ethanamine (39.3 mg, 0.25 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 520.Example 40. 2-(4-(4-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol,4-yl)quinazolin-2-yl)piperazin-1-yl)ethanol,

[0275] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (19.96 mg, 0.05 mmol) and 2-(piperazin-1-yl)ethanol (32.5 mg, 0.250 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 493.Example 41. N-(3-chlorobenzyl)-2-(4-((dimethylamino)methyl)piperidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0276] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and N,N-dimethyl-1-(piperidin-4-yl)methanamine (35.6 mg, 0.25 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 10.07 (s, 1H), 9.33 (s, 1H), 8.38 - 8.10 (m, 1H), 7.79 (m, 2H), 7.47 (s, 1H), 7.33 (m, 3H), 4.78 (s, 2H), 4.50 (s, 2H), 3.15 (s, 2H), 2.95 (t, J = 6.3 Hz, 2H), 2.79 (s, 3H), 2.77 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 2.12 (s, 1H), 1.79 (s, 2H), 1.18 (m, 2H). (including 2 salt NH); MS (M+H) +< = 505.Example 42. 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2-yl)-1H-pyrazol-4-yl)ethanol.

[0277] To a mixture of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 2-(1H-pyrazol-4-yl)ethanol (28.0 mg, 0.250 mmol) and K 2 CO 3 (34.6 mg, 0.25 mmol) was added DMF (Volume: 1 ml). The tube was sealed and heated at 150 °C for 1.5 h under microwave irradiation. After cooling to rt, the mixture was filtered through a filter, and submitted for purification to give 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-4-yl)ethanol, 2TFA (0.6 mg, 0.854 µmol, 1.707 % yield). MS (M+H) +< = 475.Example 43. N-(3-chlorobenzyl)-3-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-1-amine.

[0278] To a mixture of 3-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-1-amine (0.02 g, 0.05 mmol) and N,N-dimethyl-2-(piperazin-1-yl)ethanamine (0.157 g, 1.0 mmol) was added DMF (1 ml). The tube was sealed and heated at 200 °C for 2 h under microwave irradiation. After cooling to rt, the mixture was filtered through a filter, and submitted for purification to give N-(3-chlorobenzyl)-3-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-1-amine, 2TFA. MS (M+H) +< = 519.Example 44. 2-(4-(1-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)piperazin-1-yl)ethanol.

[0279] To a mixture of 3-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-1-amine (0.02 g, 0.05 mmol) and 2-(piperazin-1-yl)ethanol (0.13 g, 1.0 mmol) was added DMF (1 ml). The tube was sealed and heated at 200 °C for 2 h under microwave irradiation. After cooling to rt, the mixture was filtered through a filter, and submitted for purification to give 2-(4-(1-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)piperazin-1-yl)ethanol, 2TFA. MS (M+H) +< = 492.Example 45. 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)propan-2-ol.

[0280] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and 1-(piperazin-1-yl)propan-2-ol (36.1 mg, 0.25 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 507.Example 46. (R)-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)propan-2-ol.

[0281] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and (R)-1-(piperazin-1-yl)propan-2-ol (36.1 mg, 0.250 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 8.16 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.40 - 7.20 (m, 3H), 5.51 (s, 1H), 4.77 (s, 2H), 4.63 (s, 2H), 4.06 (s, 1H), 3.29 (m, 8H), 2.42 (s, 3H), 2.25 (s, 3H), 1.10 (d, J = 6.1 Hz, 3H).; MS (M+H) +< = 507.Example 47. (S)-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)propan-2-ol.

[0282] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and (S)-1-(piperazin-1-yl)propan-2-ol (36.1 mg, 0.250 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 507.Example 48. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)ethanol.

[0283] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (23.81 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.70 (s, 1H), 8.36 (s, 2H), 7.97 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.48 - 7.40 (m, 1H), 7.40 - 7.25 (m, 2H), 5.01 (s, 3H, including 1 OH), 4.26 (t, J = 5.3 Hz, 2H), 3.77 (t, J = 5.3 Hz, 2H), 2.46 (s, 3H), 2.28 (s, 3H).; MS (M+H) +< = 475.Example 49. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-amine.

[0284] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.81 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 445.Example 50. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide.

[0285] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (25.1 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 488.Example 51. 2-(4-(4-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide.

[0286] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (19.96 mg, 0.05 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (25.1 mg, 0.100 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (34.6 mg, 0.250 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 8.70 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.70 (m, 3H), 7.55 (d, J = 1.9 Hz, 1H), 7.44 (dt, J = 7.5, 1.6 Hz, 1H), 7.40 - 7.20 (m, 3H), 5.01 (s, 2H), 4.91 (s, 2H), 2.51 (m, 3H), 2.31 (s, 3H).; MS (M+H) +< = 488.Example 52. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide.

[0287] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol) and N,N-dimethyl-2-(piperazin-1-yl)acetamide (42.8 mg, 0.250 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 8.18 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.47 (s, 1H), 7.40 - 7.22 (m, 3H), 4.77 (s, 2H), 4.58 (s, 2H), 4.23 (s, 2H), 3.30 (m, 6H), 2.91 (s, 3H), 2.90 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H).; MS (M+H) +< = 534.Example 53. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2- yl)piperazin-1-yl)-N-methylacetamide.

[0288] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), N-methyl-2-(piperazin-1-yl)acetamide, HCl (48.4 mg, 0.25 mmol), and Hunig's base (0.175 ml, 1.0 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.26 (m, 2H), 7.75 (s, 2H), 7.47 (s, 1H), 7.39 - 7.23 (m, 3H), 4.76 (s, 2H), 3.48 (m, 10H), 2.65 (d, J = 4.6 Hz, 3H), 2.42 (s, 3H), 2.25 (s, 3H).; MS (M+H) +< = 520.Example 54. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2-yl)piperazin-1 -yl)acetamide.

[0289] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 2-(piperazin-1-yl)acetamide, HCl (44.9 mg, 0.25 mmol), and Hunig's base (0.175 ml, 1.0 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.07 (s, 1H), 8.18 (s, 1H), 8.01 - 7.52 (m, 4H), 7.47 (s, 1H), 7.41 - 7.25 (m, 3H), 4.76 (s, 2H), 4.14 - 2.86 (m, 10H), 2.42 (s, 3H), 2.25 (s, 3H).; MS (M+H) +< = 506.Example 55. 2-amino-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone.

[0290] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 2-amino-1-(piperazin-1-yl)ethanone, HCl (44.9 mg, 0.25 mmol), and Hunig's base (0.175 ml, 1.0 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.06 (s, 1H), 10.15 (s, 1H), 8.23 (s, 1H), 8.03 (s, 3H), 7.78 (s, 2H), 7.48 (s, 1H), 7.39 - 7.26 (m, 3H), 4.79 (s, 2H), 3.98 - 3.72 (m, 6H), 3.37 (s, 4H), 2.42 (s, 3H), 2.25 (s, 3H). (including 2 salt NH); MS (M+H) +< = 506.Example 56. 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol.

[0291] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (26.6 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 503.Example 57. 3-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)propanenitrile.

[0292] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (24.71 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 484.Example 58. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)quinazolin-4-amine.

[0293] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.2 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.69 (s, 1H), 8.36 (s, 2H), 7.96 (s, 1H), 7.91 - 7.81 (m, 1H), 7.56 (s, 1H), 7.44 (dd, J = 7.5, 1.7 Hz, 1H), 7.40 - 7.26 (m, 3H), 5.01 (s, 2H), 4.39 (s, 2H), 3.72 (t, J = 5.1 Hz, 2H), 3.23 (s, 3H), 2.46 (s, 3H), 2.28 (s, 3H). (including 1 salt NH); MS (M+H) +< = 489.Example 59. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetonitrile.

[0294] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile (23.31 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 470.Example 60. N-(3-chlorobenzyl)-2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0295] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine (0.027 g, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.71 (s, 2H), 8.32 (s, 1H), 7.88 (s, 2H), 7.54 (s, 1H), 7.46 - 7.39 (m, 1H), 7.38-7.31 (m, 2H), 4.98 (br s, 2H), 4.63 (br s, 2H), 3.62 (br s, 2H), 2.82 (s, 6H), 2.45 (s, 3H), 2.28 (s, 3H).; MS (M+H) +< = 502.Example 61. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)quinazolin-4-amine.

[0296] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.01 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 487.Example 62. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol.

[0297] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 39.9 mg, 0.1 mmol), 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (53.2 mg, 0.20 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (83 mg, 0.60 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.85 (s, 1H), 8.19 (s, 2H), 8.01 (s, 1H), 7.72 (s, 2H), 7.52 (s, 1H), 7.41 (dt, J = 7.6, 1.4 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 5.03 (s, 1H), 4.83 (s, 2H), 3.60 (d, J = 5.3 Hz, 2H), 2.45 (s, 3H), 2.28 (s, 3H), 1.49 (s, 6H).; MS (M+H) +< = 503.Example 63. (5-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)pyridin-2-yl)methanol.

[0298] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), (6-(hydroxymethyl)pyridin-3-yl)boronic acid (15.29 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.45 (br s, 1H), 9.38 (dd, J = 2.2, 0.8 Hz, 1H), 8.78 (d, J = 8.2 Hz, 1H), 8.33 (s, 1H), 7.96 - 7.81 (m, 2H), 7.69 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 1.9 Hz, 1H), 7.42 (dt, J = 7.6, 1.4 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.29 (ddd, J = 7.9, 2.1, 1.3 Hz, 1H), 4.95 (d, J = 5.7 Hz, 2H), 4.68 (s, 2H), 2.96 (s, 1H), 2.30 (s, 3H). (One Me peak is overlapped with DMSO.); MS (M+H) +< = 472.Example 64. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(1H-pyrazol-4-yl)quinazolin-4-amine. STEP 1: 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine.

[0299] To a suspension of 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine (575 mg, 1.5 mmol) in EtOH (6 ml) was added N,N-dimethyl-2-(piperazin-1-yl)ethanamine (314 mg, 1.995 mmol) and then Hunig's base (0.348 ml, 1.995 mmol). The tube was sealed and heated at 90 °C for 5 h. After cooling to rt, the mixture was poured into EtOAc / H 2 O (50 mL / 50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layer was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was dried in vacuo to give 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (760 mg, 1.508 mmol, 101 % yield), which was used for next step without further purification. MS (M+H) +< = 505.STEP 2: N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(1H-pyrazol-4-yl)quinazolin-4-amine.

[0300] In a 2-neck flask was placed 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (0.025 g, 0.05 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.029 g, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (0.041 g, 0.30 mmol). The air was removed and re-filled with N 2 (2-3 times). Then added a mixture of 1,4-dioxane (1 ml) and water (0.5 ml) was added and stirred at 95 °C (pre-heated) for 1 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The compined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was filtered through a PL-Thio-resin, eluted with EtOAc, dried, dissolved in DMF, and substmitted for purification using basic condition to give N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(1H-pyrazol-4-yl)quinazolin-4-amine, 2TFA . 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.05 (br s, 1H), 11.78 (s, 1H), 9.99 (s, 1H), 8.50 (s, 1H), 8.07 (br s, 3H), 7.63 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.41 - 7.28 (m, 3H), 4.82 (s, 2H), 3.80 (s, 4H), 3.21 (s, 2H), 2.79 (s, 6H), 2.68 - 2.59 (m, 2H), 2.54 (br s, 4H). (including 1 salt NH.); MS (M+H) +< = 491.Example 65. N-(3-chlorobenzyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine.

[0301] In a 2-neck flask was placed 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), tert-butyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (32.2 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol). The air was removed and re-filled with N 2 (2-3 times). Then added a mixture of 1,4-dioxane (1 ml) and water (0.5 ml) was added and stirred at 95 °C (pre-heated) for overnight. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The compined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was filtered through a PL-Thio-resin, eluted with EtOAc, dried. Then added TFA (0.5 mL) and stirred for 10 min to help complete deprotection. Then the mixture was concentrated to remove most of TFA, dissolved in DMF, and substmitted for purification using basic condition to give N-(3-chlorobenzyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine, 2TFA (3 mg, 4.02 µmol, 8.03 % yield) . 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.83 (s, 1H), 10.01 (s, 1H), 8.13 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.40 - 7.27 (m, 3H), 4.79 (d, J = 5.7 Hz, 2H), 3.81 (br s, 4H), 3.22 (t, J = 6.1 Hz, 2H), 2.79 (s, 6H), 2.69 - 2.60 (m, 2H), 2.55 (br s, 4H), 2.20 (s, 6H); MS (M+H) +< = 519.Example 66. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0302] The title compound was prepared from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (23.51 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 65. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 10.08 (s, 1H), 8.44 (s, 1H), 8.21 (d, J = 2.7 Hz, 1H), 8.05 (s, 1H), 7.90 (dd, J = 9.5, 2.7 Hz, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.40 - 7.28 (m, 3H), 6.56 (d, J = 9.5 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 3.81 (s, 4H), 3.51 (s, 3H), 3.22 ( br s, 2H), 2.79 (s, 6H), 2.64 (br s, 2H), 2.55 (s, 4H). (including 1 salt NH.); MS (M+H) +< = 532.Example 67. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-ol.

[0303] The title compound was prepared from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (22.11 mg, 0.100 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 65. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.03 (s, 1H), 11.83 (s, 1H), 10.06 (s, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 7.92 (dd, J = 9.6, 2.8 Hz, 1H), 7.82 (s, 1H), 7.64 (s, 1H), 7.48 (s, 1H), 7.41 - 7.28 (m, 3H), 6.50 (d, J = 9.6 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 3.81 (s, 4H), 3.22 (s, 2H), 2.79 (s, 6H), 2.68 - 2.60 (m, 2H), 2.55 (s, 4H). (including 1 salt NH.); MS (M+H) +< = 518.Example 68. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-4-ol. STEP 1: 6-bromo-4-(tert-butoxy)-2-chloroquinazoline.

[0304] To a partial suspension of 6-bromo-2,4-dichloroquinazoline (3.47 g, 12.5 mmol) in THF (12 ml) at 0 °C was added KOtBu (13.75 ml, 13.75 mmol) (1M solution in THF). The mixture was stirred at 0 °C for 1.5 h. The mixture was poured into H 2 O / NH 4 Cl aq (25 mL / 25 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 0-5-10% EtOAc / hexane as the eluent to give 6-bromo-4-(tert-butoxy)-2-chloroquinazoline (3.91 g, 12.39 mmol, 99 % crude yield). This material was used for next step without further purification.STEP 2: 4-(4-(tert-butoxy)-2-chloroquinazolin-6-yl)-3,5-dimethylisoxazole.

[0305] In a 2-neck flask was placed 6-bromo-4-(tert-butoxy)-2-chloroquinazoline (1515 mg, 4.8 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1178 mg, 5.28 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (392 mg, 0.48 mmol), and K 2 CO 3 (2189 mg, 15.84 mmol). The air was removed and re-filled with N 2 (2-3 times). Then added a mixture of 1,4-dioxane (12 ml) and water (6 ml) was added and stirred at 95 °C (pre-heated) for 1.5 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 3). The compined organic was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was dried in vacuo to give 4-(4-(tert-butoxy)-2-chloroquinazolin-6-yl)-3,5-dimethylisoxazole (890 mg, 2.68 mmol, 55.9 % yield) ( 1< H NMR (400 MHz, Chloroform-d) δ 7.92 (dd, J = 2.1, 0.6 Hz, 1H), 7.87 (dd, J = 8.6, 0.6 Hz, 1H), 7.67 (dd, J = 8.6, 2.0 Hz, 1H), 2.44 (s, 3H), 2.29 (s, 3H), 1.75 (s, 9H). and 4,4'-(4-(tert-butoxy)quinazoline-2,6-diyl)bis(3,5-dimethylisoxazole) (158 mg, 0.403 mmol, 8.39 % yield) ( 1< H NMR (400 MHz, Chloroform-d) δ 7.96 (dd, J = 2.1, 0.7 Hz, 1H), 7.90 (dd, J = 8.6, 0.7 Hz, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 2.84 (s, 3H), 2.67 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 1.77 (s, 9H).STEP 3: 2-(4-(4-(tert-butoxy)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine.

[0306] To a suspension of 4-(4-(tert-butoxy)-2-chloroquinazolin-6-yl)-3,5-dimethylisoxazole (890 mg, 2.68 mmol) in EtOH (6 ml) was added N,N-dimethyl-2-(piperazin-1-yl)ethanamine (464 mg, 2.95 mmol) and then Hunig's base (0.703 ml, 4.02 mmol). The tube was sealed and heated at 90 °C for 5 h. After cooling to rt, the mixture was concentrated to remove most of EtOH and then poured poured into EtOAc / H 2 O / Na 2 CO 3(aq) (50 mL / 30 mL / 20 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layer was dried (Na 2 SO 4 ) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 0-10-20% MeOH / EtOAc as the eluent to give 2-(4-(4-(tert-butoxy)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine (1030 mg, 2.276 mmol, 85 % yield). 1< H NMR (400 MHz, Chloroform-d) δ 7.72 (dd, J = 2.0, 0.6 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.6, 2.1 Hz, 1H), 3.95 (t, J = 5.1 Hz, 4H), 3.03 (s, 2H), 2.89 (d, J = 6.4 Hz, 2H), 2.78 (s, 6H), 2.64 (t, J = 5.0 Hz, 4H), 2.40 (s, 3H), 2.26 (s, 3H), 1.68 (s, 9H). MS (M+H) +< = 453.STEP 4: 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl.

[0307] To a solution of 2-(4-(4-(tert-butoxy)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethanamine (1240 mg, 2.74 mmol) in CH 2 Cl 2 (6 ml) was added HCl (4M in dioxane, 12 mL). The suspension was stirred vigorously at RT for 5 h. To the mixture was added hexane (40 mL). The solid was filtered and washed with hexane (5 mL x 3). Then the product was transferred to vial (hydroscopic) and dried in vacuo to give 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl as an off-white solid. The material was used for next step without further purification. MS (M+H) +< = 397.Example 69. 2,6-bis(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine. STEP 1: 2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, HCl.

[0308] To a solution of 4,4'-(4-(tert-butoxy)quinazoline-2,6-diyl)bis(3,5-dimethylisoxazole) (500 mg, 1.274 mmol) in CH 2 Cl 2 (2 ml) was added HCl (4M in dioxane, 6 mL). The suspension was stirred at RT for 3 h. To the mixture was added hexane (20 mL). The solid was filtered and washed with hexane (3 mL x 3). Then the product was transferred to vial and dried in vacuo to give 2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, HCl (395 mg, 1.060 mmol, 83 % yield) as an off-white solid. MS (M+H) +< = 337.STEP 2: 2,6-bis(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine.

[0309] To a suspension of 2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, HCl (37.3 mg, 0.1 mmol) and bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (93 mg, 0.20 mmol) in 1,4-dioxane (1 ml) was added Et 3 N (0.139 ml, 1.0 mmol). The mixture was stirred at RT for 2 h and then thiophen-2-ylmethanamine (22.64 mg, 0.20 mmol) was added. The mixture was stirred at 50 °C for another 5 h. The mixture was concentrated, dissolved in DMF (2 mL), filtered theough a filter and submitted for purification to give 2,6-bis(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2TFA (14.1 mg, 0.021 mmol, 21.38 % yield). MS (M+H) +< = 432.Example 70. N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0310] To a suspension of 2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, HCl (37.3 mg, 0.1 mmol) and bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (93 mg, 0.200 mmol) in 1,4-dioxane (1 ml) was added Et 3 N (0.139 ml, 1.0 mmol). The mixture was stirred at RT for 2 h and then (3-chlorophenyl)methanamine (28.3 mg, 0.20 mmol) was added. The mixture was stirred at 50 °C for another 5 h. The mixture was concentrated, dissolved in DMF (2 mL), filtered theough a filter and submitted for purification to give N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA (15.4 mg, 0.022 mmol, 22.38 % yield). MS (M+H) +< = 460.Example 71. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin,4-amine.

[0311] To a suspension of 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol) and Bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.100 mmol) in 1,4-dioxane (1 ml) was added Et 3 N (0.139 ml, 1.0 mmol). The mixture was stirred at RT for 2 h and then thiophen-2-ylmethanamine (11.32 mg, 0.10 mmol) was added. The mixture was stirred at 50 °C for another 5 h. The mixture was concentrated, dissolved in DMF (2 mL), filtered through a filter and submitted for purification to give 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2TFA (11.6 mg, 0.016 mmol, 32.2 % yield). MS (M+H) +< = 492.Example 72. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methoxybenzyl)quinazolin-4-amine.

[0312] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (2-methoxyphenyl)methanamine (13.72 mg, 0.10 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 516.Example 73. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(3-methoxybenzyl)quinazolin-4-amine.

[0313] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (3-methoxyphenyl)methanamine (13.72 mg, 0.10 mmol) according to similar procedure described in Example 71. 1< H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.05 (s, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.99 - 6.89 (m, 2H), 6.88 - 6.76 (m, 1H), 4.76 (d, J = 5.3 Hz, 2H), 3.83 (s, 4H), 3.70 (s, 3H), 3.22 (s, 2H), 2.79 (s, 6H), 2.68 - 2.59 (m, 2H), 2.54 (s, 4H), 2.42 (s, 3H), 2.25 (s, 3H). (imcluding 1 salt NH); MS (M+H) +< = 516.Example 74. N-(2-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0314] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (2-chlorophenyl)methanamine (14.16 mg, 0.10 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 520.Example 75. N-(3-bromobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0315] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (3-bromophenyl)methanamine (18.60 mg, 0.100 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 566.Example 76. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(2-fluorobenzyl)quinazolin-4-amine.

[0316] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (2-fluorophenyl)methanamine (12.51 mg, 0.100 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 504.Example 77. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(3-fluorobenzyl)quinazolin-4-amine.

[0317] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (3-fluorophenyl)methanamine (12.51 mg, 0.100 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 504.Example 78. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(5-methylisoxazol-4-yl)quinazolin-4-amine.

[0318] The title compound was prepared from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (20.9 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 65. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.90 (s, 1H), 10.08 (s, 1H), 8.85 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 7.34 (q, J = 4.8 Hz, 3H), 4.81 (s, 2H), 3.81 (br s, 4H), 3.22 (br s, 2H), 2.79 (s, 6H), 2.68 - 2.60 (m, 5H), 2.54 (br s, 4H). (including 1 salt NH); MS (M+H) +< = 506.Example 79. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(furan-2-ylmethyl)quinazolin-4-amine.

[0319] he title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and furan-2-ylmethanamine (9.71 mg, 0.10 mmol) according to similar procedure described in Example 71. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.91 (s, 1H), 9.98 (s, 1H), 8.22 (s, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.60 (dd, J = 1.8, 0.9 Hz, 1H), 6.47 - 6.33 (m, 2H), 4.79 (d, J = 5.4 Hz, 2H), 3.89 (br s, 4H), 3.24 (br s, 2H), 2.81 (s, 6H), 2.72 - 2.54 (m, 6H), 2.41 (s, 3H), 2.24 (s, 3H). (including 1 salt NH); MS (M+H) +< = 476.Example 80. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)quinazolin-4-amine.

[0320] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and pyridin-3-ylmethanamine (10.81 mg, 0.10 mmol) according to similar procedure described in Example 71. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.89 (s, 1H), 10.08 (s, 1H), 8.64 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.21 (s, 1H), 7.77 (d, J = 37.0 Hz, 3H), 7.42 - 7.32 (m, 1H), 4.83 (d, J = 5.5 Hz, 2H), 3.81 (br s, 4H), 3.22 (br s, 2H), 2.79 (s, 6H), 2.71 - 2.60 (m, 2H), 2.56 (br s, 4H), 2.42 (s, 3H), 2.25 (s, 3H). (including 1 salt NH); MS (M+H) +< = 487.Example 81. N-((5-chloropyridin-3-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0321] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (5-chloropyridin-3-yl)methanamine (14.26 mg, 0.10 mmol) for overnight according to similar procedure described in Example 71. MS (M+H) +< = 521.Example 82. N-((4-chloropyridin-2-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-vl)quinazolin-4-amine.

[0322] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (4-chloropyridin-2-yl)methanamine (14.26 mg, 0.10 mmol) for overnight according to similar procedure described in Example 71. MS (M+H) +< = 521.Example 83. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-fluoropyridin-3-yl)methyl)quinazolin-4-amine.

[0323] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (5-fluoropyridin-3-yl)methanamine (12.61 mg, 0.10 mmol) for overnight according to similar procedure described in Example 71. MS (M+H) +< = 505.Example 84. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylpyridin-3-yl)methyl)quinazolin-4-amine.

[0324] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (4-methylpyridin-3-yl)methanamine (12.22 mg, 0.10 mmol) for overnight according to similar procedure described in Example 71. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 9.86 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.40 (s, 1H), 4.87 (d, J = 4.9 Hz, 2H), 3.82 (br s, 4H), 3.23 (t, J = 6.0 Hz, 2H), 2.80 (s, 6H), 2.73 - 2.52 (m, 6H), 2.41 (br s, 6H), 2.24 (s, 3H). (including 1 salt NH.); MS (M+H) +< = 501.Example 85. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-methylquinazolin,4-amine.

[0325] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and 1-(3-chlorophenyl)-N-methylmethanamine (15.56 mg, 0.100 mmol) for overnight according to similar procedure described in Example 71. MS (M+H) +< = 534.Example 86. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-3-fluoropyridin-2-ol.

[0326] The title compound was prepared from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (0.024 g, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 65. MS (M+H) +< = 536.Example 87. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylthiophen-2-yl)methyl)quinazolin-4-amine.

[0327] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (4-methylthiophen-2-yl)methanamine (12.72 mg, 0.10 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 506.Example 88. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylthiophen-2-yl)methyl)quinazolin-4-amine.

[0328] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (5-methylthiophen-2-yl)methanamine, HCl (16.37 mg, 0.10 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 506.Example 89. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-(thiophen-2-yl)ethyl)quinazolin-4-amine.

[0329] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and 1-(thiophen-2-yl)ethanamine (12.72 mg, 0.10 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 506.Example 90. N-(1-(3-chlorophenyl)ethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0330] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and 1-(3-chlorophenyl)ethanamine (15.56 mg, 0.10 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 534.Example 91. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-3-methylpyridin-2-ol.

[0331] The title compound was prepared from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), (6-hydroxy-5-methylpyridin-3-yl)boronic acid (15.29 mg, 0.100 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 65. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.93 (s, 2H), 10.07 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.82 (dd, J = 2.8, 1.3 Hz, 1H), 7.73 - 7.60 (m, 2H), 7.48 (s, 1H), 7.39 - 7.29 (m, 3H), 4.81 (d, J = 5.7 Hz, 2H), 3.81 (br s, 4H), 3.22 (br s, 2H), 2.79 (s, 6H), 2.70 - 2.51 (m, 6H), 2.06 (s, 3H). (including 1 salt NH); MS (M+H) +< = 532.Example 92. N-benzyl-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0332] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and phenylmethanamine (10.72 mg, 0.10 mmol) for overnight according to similar procedure described in Example 71. MS (M+H) +< = 486.Example 93. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3-methylisoxazol-4-yl)quinazolin-4-amine.

[0333] The title compound was prepared from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (20.90 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 65. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.93 (s, 1H), 10.09 (s, 1H), 9.13 (s, 1H), 8.33 (s, 1H), 7.93 (s, 1H), 7.71 (s, 1H), 7.47 (s, 1H), 7.39 - 7.26 (m, 3H), 4.80 (s, 2H), 3.81 (br s, 4H), 3.22 (br s, 2H), 2.79 (s, 6H), 2.70 - 2.50 (m, 6H), 2.42 (s, 3H). (including 1 salt NH); MS (M+H) +< = 506.Example 94. N-((5-chlorothiophen-2-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0334] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (5-chlorothiophen-2-yl)methanamine, HCl (18.41 mg, 0.10 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 526.Example 95. N-(4-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0335] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (4-chlorophenyl)methanamine (0.014 g, 0.10 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 520.Example 96. 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)pyridin-2-ol.

[0336] The title compound was prepared from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (22.11 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 65. 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 11.67 (s, 1H), 10.18 (s, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 7.71 (s, 1H), 7.49 (s, 2H), 7.41 - 7.26 (m, 3H), 6.77 (s, 1H), 6.61 (d, J = 7.0 Hz, 1H), 4.80 br (s, 2H), 3.82 (br s, 4H), 3.22 (br s, 2H), 2.79 (s, 6H), 2.71 - 2.51 (m, 6H). (including 1 salt NH); MS (M+H) +< = 518.Example 97. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol,4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide.

[0337] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (26.5 mg, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.68 (s, 1H), 8.26 (d, J = 71.6 Hz, 3H), 7.91 (d, J = 36.9 Hz, 2H), 7.55 (s, 1H), 7.46 - 7.40 (m, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.34 - 7.28 (m, 1H), 5.01 (s, 2H), 4.91 (s, 2H), 2.62 (d, J = 4.6 Hz, 3H), 2.46 (s, 3H), 2.28 (s, 3H); MS (M+H) +< = 502.Example 98. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide.

[0338] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (27.9 mg, 0.100 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (8.17 mg, 10.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 8.63 (s, 1H), 8.35 (br s, 2H), 7.91 (m, 2H), 7.55 (s, 1H), 7.46 - 7.40 (m, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 5.26 (s, 2H), 5.01 (s, 2H), 3.04 (s, 3H), 2.85 (s, 3H), 2.46 (s, 3H), 2.28 (s, 3H); MS (M+H) +< = 516.Example 99. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(4-fluorobenzyl)quinazolin-4-amine.

[0339] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and (4-fluorophenyl)methanamine (12.51 mg, 0.10 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 504.Example 100. 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0340] In a 2-neck flask was placed 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine (766 mg, 2 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (517 mg, 2.200 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (163 mg, 0.20 mmol), and K 2 CO 3 (912 mg, 6.6 mmol). The air was removed and re-filled with N 2 (2-3 times). Then added a mixture of 1,4-dioxane (6 ml) and water (3 ml) was added and stirred at 95 °C (pre-heated) for 2 h. After cooling to rt, H 2 O (20 mL) was added and the solid was filtered, washed with H 2 O (3 mL x 2), and then dried. The dried solid was put into 5% EtOAc hexane (30 mL), vigorously stirred for 30 min, and then filtered to give 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (741 mg, 1.441 mmol, 72.1 % crude yield) as yellow solid. The material ca. 80% purity was used without further purification. 20 mg of crude material was submitted for purification for screening. MS (M+H) +< = 411.Example 101. 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide.

[0341] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 0.039 g, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (0.038 g, 0.150 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12 mg, 15 µmol), and K 2 CO 3 (62 mg, 0.45 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 500Example 102. 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide.

[0342] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 0.039 g, 0.075 mmol), N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (39.8 mg, 0.15 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12 mg, 15 µmol), and K 2 CO 3 (62 mg, 0.45 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 514.Example 103. 5-(4-((3-chlorobenzyl)amino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0343] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 0.039 g, 0.075 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (39.9 mg, 0.150 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12 mg, 15 µmol), and K 2 CO 3 (62 mg, 0.45 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 515.Example 104. 3-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)propanenitrile.

[0344] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 0.039 g, 0.075 mmol), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (37.1 mg, 0.15 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12 mg, 15 µmol), and K 2 CO 3 (62 mg, 0.45 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 496.Example 105. 5-(4-((3-chlorobenzyl)amino)-2-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0345] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 0.039 g, 0.075 mmol), 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (39.9 mg, 0.150 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12 mg, 15 µmol), and K 2 CO 3 (62 mg, 0.45 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 515.Example 106. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyacetyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0346] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 38.6 mg, 0.075 mmol) and 2-hydroxy-1-(piperazin-1-yl)ethanone (54.1 mg, 0.375 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 519.Example 107. 5-(2-(4-(2-aminoacetyl)piperazin-1-yl)-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0347] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 38.6 mg, 0.075 mmol), 2-amino-1-(piperazin-1-yl)ethanone, 2HCl (0.081 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 518.Example 108. 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)acetamide.

[0348] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 38.6 mg, 0.075 mmol), 2-(piperazin-1-yl)acetamide, HCl (67.4 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 518.Example 109. 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide.

[0349] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 38.6 mg, 0.075 mmol), N-methyl-2-(piperazin-1-yl)acetamide, HCl (72.6 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 532.Example 110. 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide.

[0350] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 38.6 mg, 0.075 mmol), N,N-dimethyl-2-(piperazin-1-yl)acetamide (64.2 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 546.Example 111. (S)-5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxypropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0351] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 38.6 mg, 0.075 mmol), (S)-1-(piperazin-1-yl)propan-2-ol, HCl (0.068 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 519.Example 112. 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine. STEP 1: 6-bromo-2-chloro-N-((5-chloropyridin-3-yl)methyl)quinazolin-4-amine.

[0352] To a mixture of 6-bromo-2,4-dichloroquinazoline (1.946 g, 7 mmol) in THF (Volume: 20 ml) was added (5-chloropyridin-3-yl)methanamine (0.998 g, 7.0 mmol) and then Et 3 N (1.463 ml, 10.50 mmol) at rt. The mixture was stirred at 0 °C for 15 min and then warmed to RT for 1.5 h (complete by TLC). The mixture was poured into EtOAc / H 2 O (50 mL / 50 mL). The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layer was dried (Na2SO4) and filtered. After removal of solvent, the product was and some EtOAc (5-10 mL), sonicated, and then added hexane (200 mL) slowly. The solid was filtered and triturated with hexane and then dried to give 6-bromo-2-chloro-N-((5-chloropyridin-3-yl)methyl)quinazolin-4-amine (2.31 g, 6.01 mmol, 86 % yield) as a solid.STEP 2: 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[0353] In a 2-neck flask was placed 6-bromo-2-chloro-N-((5-chloropyridin-3-yl)methyl)quinazolin-4-amine (0.960 g, 2.5 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.613 g, 2.75 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.204 g, 0.25 mmol), and K 2 CO 3 (1.140 g, 8.25 mmol). The air was removed and re-filled with N 2 (2-3 times). Then added a mixture of 1,4-dioxane (9 ml) and water (4.5 ml) was added and stirred at 95 °C (pre-heated) for 1.5 h. After cooling to rt, the organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layer was dried (Na 2 SO 4 ) and filtered. The product was triturated with 10% EtOAc / hexane and dried to give crude 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (1.5 g, 2.249 mmol, 90 % crude yield). The crude material contained some impurity was used without further purification. 40 mg of material was submitted for purification for screening. MS (M+H) +< = 400.Example 113. 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0354] In a 2-neck flask was placed 6-bromo-2-chloro-N-((5-chloropyridin-3-yl)methyl)quinazolin-4-amine (1.152 g, 3 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.776 g, 3.30 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.245 g, 0.300 mmol), and K 2 CO 3 (1.368 g, 9.90 mmol). The air was removed and re-filled with N 2 (2-3 times). Then added a mixture of 1,4-dioxane (10 ml) and water (5 ml) was added and stirred at 95 °C (pre-heated) for 1.5 h. After cooling to rt, H 2 O (20 mL) was added and the solid was filtered, washed with H 2 O (5 mL x 2), and then dried. Then, the product was triturated with 10% EtOAc / hexane and dried to give crude 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (1.52 g, 2.77 mmol, 92 % yield). The crude material contained some impurity was used without further purification. 40 mg of material was submitted for purification for screening. MS (M+H) +< =412.Example 114. 5-(4-((3-chlorobenzyl)amino)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0355] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 0.039 g, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (35.7 mg, 0.150 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12 mg, 15 µmol), and K 2 CO 3 (62 mg, 0.45 mmol) according to similar procedure described in Example 28. MS (M+H) +< = 487.Example 115. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylpyridin-3-yl)methyl)quinazolin-4-amine.

[0356] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl (Example 68, 46.9 mg, 0.1 mmol), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (93 mg, 0.2 mmol) and (5-methylpyridin-3-yl)methanamine (24.43 mg, 0.20 mmol) according to similar procedure described in Example 71. MS (M+H) +< = 501.Example 116. 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0357] The title compound was prepared from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), 1-methyl-4-

[0358] (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.024 g, 0.10 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (4.08 mg, 5.0 µmol), and K 2 CO 3 (41.5 mg, 0.30 mmol) according to similar procedure described in Example 65. MS (M+H) +< = 532.Example 117. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)acetamide.

[0359] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-(piperazin-1-yl)acetamide, HCl (67.4 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 507.Example 118. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide.

[0360] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), N-methyl-2-(piperazin-1-yl)acetamide, HCl (72.6 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 521.Example 119. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide.

[0361] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), N,N-dimethyl-2-(piperazin-1-yl)acetamide (64.2 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 535.Example 120. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanol.

[0362] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-(piperazin-1-yl)ethanol (48.8 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 494.Example 121. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0363] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 38.6 mg, 0.075 mmol), 2-(piperazin-1-yl)ethanol (48.8 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 505.Example 122. 5-(4-((3-chlorobenzyl)amino)-2-(4-(1-methyl-1H-pyrazole,4-carbonyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0364] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 38.6 mg, 0.075 mmol), (1-methyl-1H-pyrazol-4-yl)(piperazin-1-yl)methanone, HCl (87 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 569.Example 123. 5-(4-((3-chlorobenzyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0365] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 38.6 mg, 0.075 mmol), N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine (0.064 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 546.Example 124.5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0366] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), N,N-dimethyl-2-(piperazin-1-yl)ethanamine (0.059 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 533.Example 125. 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0367] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine (0.064 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 547.Example 126. 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0368] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-(piperazin-1-yl)ethanol (0.049 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 506.Example 127. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)acetamide.

[0369] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-(piperazin-1-yl)acetamide, HCl (0.067 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 519.Example 128. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)auinazolin-2-yl)piperazin-1-yl)-N-methylacetamide.

[0370] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), N-methyl-2-(piperazin-1-yl)acetamide, HCl (0.073 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 533.Example 129. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide.

[0371] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), N,N-dimethyl-2-(piperazin-1-yl)acetamide (0.064 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 547.Example 130. N-((5-chloropyridin-3-yl)methyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yi)-6-(3,5-di methylisoxazol-4-yl)quinazolin-4-amine.

[0372] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine (64.2 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 535.Example 131. 2-amino-1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)ethanone.

[0373] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-amino-1-(piperazin-1-yl)ethanone, 2HCl (0.081 g, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 507.Example 132. 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-hydroxyethanone.

[0374] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-hydroxy-1-(piperazin-1-yl)ethanone (54.1 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 508.Example 133. 5-(2-(4-(2-aminoacetyl)piperazin-1-yl),4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[0375] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-amino-1-(piperazin-1-yl)ethanone, 2HCl (81 mg, 0.375 mmol), and Hunig's base (0.131 ml, 0.75 mmol) according to similar procedure described in Example 12. MS (M+H) +< = 519.Example 134. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA.

[0376] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 100, 30.8 mg, 0.075 mmol) and 2-methyl-1-(piperazin-1-yl)propan-2-ol, 2HCl (52.0 mg, 0.225 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.30 (s, 1H), 8.40 (s, 1H), 8.20 (d, J = 2.6 Hz, 1H), 8.01 (s, 1H), 7.91 (dd, J = 9.5, 2.7 Hz, 1H), 7.57 - 7.49 (m, 3H), 7.41 - 7.28 (m, 2H), 6.55 (d, J = 9.4 Hz, 1H), 5.28 (s, 1H), 4.81 (s, 2H), 4.68 - 2.78 (m, 10H), 3.51 (s, 3H), 1.24 (s, 6H); MS (M+H) +< = 533.Example 135. 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA.

[0377] The title compound was prepared from 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (Example 113, 30.9 mg, 0.075 mmol) and 2-methyl-1-(piperazin-1-yl)propan-2-ol, 2HCl (52.0 mg, 0.225 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.27 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J = 2.7 Hz, 1H), 8.06 - 7.93 (m, 2H), 7.90 (dd, J = 9.5, 2.8 Hz, 1H), 7.57 (s, 1H), 6.55 (d, J = 9.5 Hz, 1H), 5.28 (s, 1H), 4.84 (s, 2H), 4.66 - 2.85 (m, 10H), 3.51 (s, 3H), 1.24 (s, 6H); MS (M+H) +< = 534.Example 136. 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol, 2TFA.

[0378] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 30.0 mg, 0.075 mmol) and 2-methyl-1-(piperazin-1-yl)propan-2-ol, 2HCl (52.0 mg, 0.225 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.27 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.16 (s, 1H), 7.95 (t, J = 2.2 Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 5.27 (s, 1H), 4.82 (d, J = 5.6 Hz, 2H), 4.70 - 2.82 (m, 10H), 2.42 (s, 3H), 2.25 (s, 3H), 1.24 (s, 6H); MS (M+H) +< = 522.Example 137. 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol, 2TFA.

[0379] The title compound was prepared from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 0.03 g, 0.075 mmol) and 2-methyl-1-(piperazin-1-yl)propan-2-ol, 2HCl (0.052 g, 0.225 mmol) according to similar procedure described in Example 12. 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.36 (s, 1H), 8.19 (s, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.41 - 7.22 (m, 3H), 5.26 (s, 1H), 4.79 (d, J = 5.6 Hz, 2H), 4.67 - 2.76 (m, 10H), 2.42 (s, 3H), 2.25 (s, 3H), 1.24 (s, 6H); MS (M+H) +< = 521.Example 138. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol, 2TFA.

[0380] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (39.9 mg, 0.15 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12.25 mg, 0.015 mmol), and K 2 CO 3 (62.2 mg, 0.45 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.69 (d, J = 1.9 Hz, 2H), 8.53 (d, J = 2.4 Hz, 1H), 8.34 (s, 2H), 8.05 (t, J = 2.2 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 5.05 (d, J = 5.5 Hz, 2H), 3.62 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H), 1.53 (s, 6H). (OH not shown); MS (M+H) +< = 504.Example 139. 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, 2TFA.

[0381] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (39.9 mg, 0.15 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12.25 mg, 0.015 mmol), and K 2 CO 3 (62.2 mg, 0.45 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.69-8.68 (m, 2H), 8.53 (d, J = 2.4 Hz, 1H), 8.33 (s, 2H), 8.04 (t, J = 2.1 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 5.04 (s, 2H), 4.13 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H), 1.10 (s, 6H). (OH not shown); MS (M+H) +< = 504.Example 140. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide, 2TFA.

[0382] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (41.9 mg, 0.15 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12.25 mg, 0.015 mmol), and K 2 CO 3 (62.2 mg, 0.45 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.65 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.33 (s, 2H), 8.04 (t, J = 2.1 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 5.27 (s, 2H), 5.06 (s, 2H), 3.04 (s, 3H), 2.85 (s, 3H), 2.46 (s, 3H), 2.28 (s, 3H); MS (M+H) +< = 517.Example 141. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)-N-methylacetamide, 2TFA.

[0383] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (39.8 mg, 0.15 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12.25 mg, 0.015 mmol), and K 2 CO 3 (62.2 mg, 0.45 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 8.72 (s, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.33 (s, 2H), 8.19 (s, 1H), 8.04 (t, J = 2.1 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 5.05 (s, 2H), 4.92 (s, 2H), 2.63 (d, J = 4.6 Hz, 3H), 2.46 (s, 3H), 2.28 (s, 3H); MS (M+H) +< = 503.Example 142. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1-yl)acetamide, 2TFA.

[0384] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 112, 46.2 mg, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (37.7 mg, 0.15 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12.25 mg, 0.015 mmol), and K 2 CO 3 (62.2 mg, 0.45 mmol) according to similar procedure described in Example 28. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.72 (s, 1H), 8.68 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.33 (s, 2H), 8.04 (t, J = 2.1 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.35 (s, 1H), 5.06 (d, J = 5.6 Hz, 2H), 4.92 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H); MS (M+H) +< = 489.Example 143. 5-(4-(((5-chloropyridin-3-yl)methyl)ami...

Claims

1. A compound of Formula I, including pharmaceutically acceptable salts, and polymorphs, thereof: wherein: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of hydrogen (H), Cl, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, OR5, NR6R7, -C(O)R11, -C(O)OR11, -C(O)NR11R12, C6-10 aryl and 5-10 membered heteroaryl, wherein said 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl include one or more nitrogen (N), oxygen (O) or sulfur (S) atoms; wherein said C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl may each optionally be substituted by one or more R8; R1 and R2, together with the included nitrogen atom and L1, form a heterocycloalkyl group selected from the group consisting of: and wherein R21 is C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R11, -C(O)OR11, -C(O)NR11R12, or -S(O)2R11, wherein said C1-6 alkyl, Cs_ 6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R14; R3 is selected from the group consisting of C1-6 alkyl, -OR11, halogen, -CN, -CF3, -NO2, - C(O)OR11, -OC(O)NR11R12, -C(O)NR11R12, -NR11R12, -NR11C(O)R12, -NR11C(O)OR12,-NR11S(O)2R12, -NR11C(O)NR12R13, S(O)2NR11R12, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein each of said 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl include one or more N, O or S atoms; wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl or 4-10 membered heterocycloalkyl are each optionally substituted with one or more R8; R4 is H; R5 is C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, wherein each of said C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl is optionally substituted with one or more R8; R6 and R7 are independently selected for each occurrence from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein said 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl include one or more N, O or S atoms; wherein each of said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl may optionally be substituted with one or more R8; or optionally, R6 and R7, together with the included nitrogen, may form a 4-, 5-, 6- or 7-membered heterocyclic or heteroaryl ring system, wherein said heterocyclic or heteroaryl ring system is a mono- or bicyclic ring optionally having an additional from one to four heteroatoms selected from N, O and S; wherein said heterocyclic or heteroaryl ring system may optionally be substituted with one or more R8; R8 is selected independently for each occurrence from the group consisting of H, OH, SH, halogen, -CN, -CF3, -NO2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -OC(O)NR11R12, - C(O)NR11R12, -NR11R12, -NR11C(O)R12,- NR11C(O)OR12, -NR11S(O)2R12, -NR11C(O)NR12R13, - (CH2)m-R16, -(CH2)q-R17, -S(O)R11, -S(O)2R11, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with one or more R14; m is 1, 2, 3 or 4; q is 2, 3 or 4; R11, R12, and R13 are independently chosen for each occurrence from the group consisting of H, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, wherein each of said C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl may optionally be substituted with one or more R14; or optionally, R11 and R12, or R12 and R13, together with the included nitrogen, may form a 4-, 5-, 6- or 7-membered heterocyclic or heteroaryl ring system, wherein said heterocyclic or heteroaryl ring system is a mono- or bicyclic ring optionally having an additional from one to four heteroatoms selected from N, O and S; wherein said heterocyclic or heteroaryl ring system may optionally be substituted with one or more R8; R14 is selected independently for each occurrence from the group consisting of H, OH, OR18, SH, SR18, halogen, CN, CF3, NO2, C(O)R18, C(O)OR18, OC(O)NR18R19, C(O)NR18R19, NR18R19, NR18C(O)R19, NR18C(O)OR19, NR18S(O)2R19, NR18C(O)NR19R20,S(O)R18, S(O)2R18, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl, wherein said C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl groups may be optionally substituted with one or more of R15; R15 is selected independently for each occurrence from the group consisting of H, -CH3, - CH2CH3, n-propyl, isopropyl, -OCH3, halogen, -CN, -CF3, -NH2, -N(CH3)2, -CO2H, -C(O)NH2, - C(O)NH(CH3), and -C(O)N(CH3)2; each R16 is independently-CO2H or -C(O)NR6R7; each R17 is independently -OH or -NR6R7; and each R18, R19, and R20 are independently selected for each occurrence from the group consisting of H, C1-6 alkyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl and 5-10 membered heteroaryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8 is selected independently for each occurrence from the group consisting of H, OH, SH, halogen, - CN, -CF3, -NO2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -OC(O)NR11R12, -C(O)NR11R12, -NR11R12, - NR11C(O)R12,- NR11C(O)OR12, -NR11S(O)2R12, -NR11C(O)NR12R13, -(CH2)m-R16, -(CH2)q-R17, - S(O)R11, -S(O)2R11, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with one or more R14; provided that when R8 is attached to a nitrogen atom R8 is selected from R21, wherein R21 is C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R11, -C(O)OR11, -C(O)NR11R12, or -S(O)2R11, wherein said C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with one or more R14.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the included nitrogen atom and L1, form a heterocycloalkyl group selected from the group consisting of:

4. The compound of any of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X and Z are each N.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not CH; Y is -C(O)NR11R12 or a heterocycloalkyl or heteroaryl selected from: wherein: n is 1 or 2; p is 0, 1 or 2; R8 is H, C1-C6 alkyl, or-(CH2)m-R16 or-(CH2)q-R17; m is 1, 2, 3 or 4; q is 2, 3 or 4; R16 is -CO2H or -C(O)NR6R7; and R17 is OH or NR6R7.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, NR6R7, -C(O)R11, -C(O)NR11R12, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said 4-10 membered heterocycloalkyl and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R8; R1 and R2, together with the included nitrogen atom and L1, form a heterocycloalkyl group selected from the group consisting of: and R3 is selected from the group consisting of 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R8; R4 is H; each R6 is independently selected from the group consisting of H and C1-6 alkyl; each R7 is an independently selected C1-6 alkyl group, each of which may optionally be substituted by 1, 2, 3, or 4 independently selected R8; each R8 is independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, OR11, -C(O)R11, -C(O)OR11, -C(O)NR11R12, S(O)2R11, wherein said C1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, or 4 independently selected R14; each R11 is independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C1-6 alkyl, Cs_ 6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R14; each R12 is independently selected from the group consisting of H and C1-6 alkyl; each R14 is independently selected from the group consisting of halogen, C1-6 alkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, OR18, NR18R19, C(O)R18, C(O)NR18R19, and S(O)2R18, wherein said phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R15; each R15 is CH3 or CN; each R18 is independently selected from the group consisting of H and C1-6 alkyl; and each R19 is independently selected from the group consisting of H and C1-6 alkyl; and R21 is C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R11, -C(O)OR11, -C(O)NR11R12, or -S(O)2R11, wherein said C1-6 alkyl, Cs_ 6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R14.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; Z is CH or N; with the proviso that when X is CH, Z is not also CH; Y is selected from the group consisting of H, NR6R7, -C(O)R11, -C(O)NR11R12, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said heterocycloalkyl and heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R8; R1 and R2, together with the included nitrogen atom and L1, form a heterocycloalkyl group selected from the group consisting of: and R3 is selected from the group consisting of 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said heterocycloalkyl and heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R8; R4 is H; each R6 is independently selected from the group consisting of H and C1-6 alkyl; each R7 is an independently selected C1-6 alkyl group, each of which may optionally be substituted by 1, 2, 3, or 4 independently selected R8; each R8 is independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, OR11, -C(O)R11, -C(O)OR11, -C(O)NR11R12, S(O)2R11, wherein said C1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, or 4 independently selected R14; each R11 is independently selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocyloalkyl, 5-6 membered heteroaryl, wherein said C1-6 alkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R14; each R12 is independently selected from the group consisting of H and C1-6 alkyl; each R14 is independently selected from the group consisting of halogen, C1-6 alkyl, phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, OR18, NR18R19, C(O)R18, C(O)NR18R19, and S(O)2R18, wherein said phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl may optionally be substituted with 1, 2, 3, or 4 independently selected R15; each R15 is CH3 or CN; each R18 is independently selected from the group consisting of H and C1-6 alkyl; each R19 is independently selected from the group consisting of H and C1-6 alkyl; and R21 is C1-6 alkyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -C(O)R11, -C(O)OR11, -C(O)NR11R12, or -S(O)2R11, wherein said C1-6 alkyl, Cs_ 6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R14.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of and R4 is H.

9. The compound of claim 1 or 2, wherein the compound is a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein R8a is C1-6 alkyl, C3-6 cycloalkyl, phenyl, or a 5-6 membered heteroaryl, wherein said phenyl and heteroaryl may optionally be substituted by 1, 2, or 3 independently selected R14.

10. The compound of claim 9, wherein R8a is phenyl, wherein said phenyl may optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, Me, Et, cyclopropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C1-4alkyl, and -NHC(O)-C1-4alkenyl.

11. A pharmaceutical composition comprising a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment or prevention of a disease or condition mediated by inhibiting bromodomain-containing proteins comprising the step of administering a compound of any of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

13. The compound, or a pharmaceutically acceptable salt thereof, for use of claim 12, wherein the compound or the pharmaceutically acceptable salt thereof inhibits the activity of bromodomain-containing proteins by inhibiting binding to acetylated proteins; optionally wherein the acetylated protein is an acetylated histone involved in the regulation or dysregulation of gene expression.

14. The compound, or a pharmaceutically acceptable salt thereof, for use of claim 12, wherein the disease or condition is selected from the group consisting of cancer, systemic or tissue inflammation, and inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, and viral infections; or wherein the disease or condition is selected from the group consisting of human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myeloid leukemia, NPM1c mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, ovarian cancer, chordoma, neuroendocrine tumors, Merkel cell carcinoma, prostate cancer, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, and HIV infection.

15. The compound, or a pharmaceutically acceptable salt thereof, for use of claim 12, wherein the disease or condition is a fibrotic condition; optionally wherein the fibrotic condition is idiopathic pulmonary fibrosis, renal fibrosis, postoperative stricture, keloid formation, scleroderma, cardiac fibrosis, cystic fibrosis, lung inflammation, or liver fibrosis; optionally wherein the fibrotic condition is idiopathic pulmonary fibrosis.