Bicyclic bet bromodomain inhibitors and uses thereof

Abstract

The present invention relates to bicyclic BET bromodomain inhibitors and uses thereof. In particular, to compounds that bind to and otherwise modulate the activity of bromodomain-containing proteins, to methods of making these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds to treat a variety of conditions and disorders.

Description

TECHNICAL FIELD

[0001] The present invention relates to compounds that inhibit bromodomain-containing proteins from binding acetylated proteins, to methods of making these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds to treat various medical conditions, diseases, or disorders. BACKGROUND

[0002] Epigenetic chromatin reprogramming is a central mechanism for regulating gene expression. Pharmacological modulation of epigenetic changes represents a new modality for therapeutic intervention in cancer and inflammation. Emerging evidence suggests that such epigenetic modulation can also provide therapeutic means for the treatment of obesity and metabolic, cardiovascular, neurodegenerative, psychiatric, and infectious diseases.

[0003] Eukaryotic genomes are organized into basic packing units called nucleosomes, which comprise a double-stranded DNA helix of approximately 147 base pairs wrapped around a histone octamer, which in turn is composed of two subunits of each of the H2A, H2B, H3, and H4 proteins. Nucleosomes are further packaged into chromatin structures, which can exist in a relatively loose euchromatin state or in a tightly packed heterochromatin structure. The transition from heterochromatin to euchromatin enables genes to be transcribed, although not all genes in the euchromatin structure are transcribed. This transition from heterochromatin to euchromatin is controlled by post-translational modifications of the histone proteins, including acetylation of lysine residues in the H3 / H4 proteins. Histone acetylation is catalyzed by histone acetyltransferases (HATs), resulting in an open euchromatin structure that allows transcription of genes, including tumor suppressor genes. Conversely, histone deacetylation leads to repression of such genes, and this activity is catalyzed by histone deacetylases (HDACs). Inhibition of histone deacetylases is a modality for cancer therapy, and one histone deacetylase inhibitor, vorinostat (Zolinza®) has proven to be an effective drug for cutaneous T-cell lymphoma in humans.

[0004] Histone acetylation is also regulated by Bromodomain-containing proteins. Bromodomains are approximately 110 amino acid long, evolutionarily conserved four alpha-helix bundles that bind to acetylated lysine residues of acetylated proteins. These domains are found in many chromatin-associated proteins, including HATs. Bromodomains were first identified as a novel structural motif in the brahma protein, a regulator of homeotic genes in Drosophila, but are also found in proteins in humans and yeast, as single copies or tandemly repeated domains, and are thought to confer specificity to 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 can be involved in the etiology of cancer, inflammation, obesity, metabolic disease, cardiovascular disease, neurodegenerative disease, psychiatric disease, and infectious disease (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 can provide a novel paradigm for pharmacological intervention in such diseases.

[0005] Among the approximately 50 Bromodomain-containing proteins encoded by the human genome, the BET proteins represent a small family of proteins that includes BRD2, BRD3, BRD4, and BRDT. BET proteins contain two tandem Bromodomains followed by an extra-terminal (ET) domain for protein-protein interactions 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 act by opening chromatin structure and / or by facilitating transcription initiation (Front. Biosci. 2001 Aug 1;6:D1008-18).

[0006] Previously, inhibition of BRD4 either by BRD4-specific RNAi or by the small molecule BET inhibitor (JQ1) was shown to induce suppression of the MYC oncogene (Nature 2011 Aug 3;478(7370):524-8). This indirect suppression of MYC gene expression as a secondary effect of BRD4 inhibition includes a core mechanism by which BET inhibitors exert their effects.

[0007] Inhibition of BET proteins by suppression of MYC gene (Nature 2010 Dec 23;468(7327): 1067-73; Cell. 2011 Sep 16; 146(6):904-1; Proc. Nat. l Acad. Sci. U S A. 2011 Oct 4; 108(40): 16669-74) and MYCN gene (Cancer Discov. 2013 Mar: 3(3) 308-23) expression was shown to be an effective intervention model in rodent models of human NUT-midline carcinoma, multiple myeloma, Burkitt's lymphoma and acute myeloid leukemia. MYC and homologous genes are some of the most overexpressed genes in human cancers; however, to date, no pharmaceutical compound has directly antagonized the activity of the proteins encoded by MYC and homologous genes, in part due to the lack of an effective drug binding site. Thus, there is a need for methods of indirectly inhibiting the expression of MYC and homologous genes by inhibiting the bromodomain of BET proteins that provide an effective treatment model for a variety of diseases, disorders or medical conditions including various cancers. SUMMARY

[0008] The present invention includes compounds that bind to bromodomain-containing proteins and, in turn, modulate the binding of acetylated proteins to bromodomain-containing proteins. In one aspect, the present invention provides a compound of Formula I,

[0009]

[0010] wherein each of R1, R2, R3, R4, L1, X, Y and Z is as defined and described in embodiments herein, and pharmaceutically acceptable salts, solvates, polymorphs, isomers and prodrugs thereof. DETAILED DESCRIPTION

[0011] According to one aspect of the present invention is a compound having the structure of Formula I, including pharmaceutically acceptable salts, polymorphs and isomers thereof:

[0012]

[0013] wherein:

[0014] X is CH or N;

[0015] Z is CH or N; provided that when X is CH, Z is not also CH;

[0016] Y is selected from the group consisting of hydrogen (H), Cl, C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, OR5, NR6R7, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , C 6-10 aryl, and 5-10 membered heteroaryl, wherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl include one or more nitrogen (N), oxygen (O), or sulfur (S) atoms; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl can each be optionally substituted with one or more R8;

[0017] L1is -(CR9R 10 ) n -, C(O), or S(O)2;

[0018] n is 0, 1, 2, or 3;

[0019] R1is selected from the group consisting of C 6-10 aryl, and 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl includes one or more N, O, or S atoms; wherein each of the C 6-10 aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more R8;

[0020] R2is H, C 1-6 alkyl, -C(O)R 11 , -CH2C(O)OR 11 , -C(O)NR 11 R 12 , S(O)2NR 11 R 12 , or -C(O)OR 11 , wherein the C 1-6 alkyl is optionally substituted with one or more R8;

[0021] or, optionally, R1and R2together with the included nitrogen atom and L1may form a 4, 5, 6, or 7 membered heterocyclic or heteroaryl ring system, wherein the heterocyclic or heteroaryl ring system can include one or more additional N, O, or S atoms; and wherein the heterocyclic or heteroaryl ring system can be optionally substituted with one or more R8;

[0022] R3and R4are independently selected from H, C 1-6 alkyl, -OR 11 halogen, -CN, -CF3, -NO2, -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)2R 12 , -NR 11 C(O)NR 12 R 13 , S(O)2NR 11 R 12 , C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, wherein each of said 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl comprises one or more N, O, or S atoms; wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, or 4-10 membered heterocycloalkyl is optionally substituted with one or more R8;

[0023] R5is C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein each of said C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R8;

[0024] R6and R7are each occurrence independently selected from H, C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, wherein said 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl comprises one or more N, O, or S atoms; wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10each of cycloalkyl and 4-10 membered heterocycloalkyl can be optionally substituted with one or more R8;

[0025] or, optionally, R6and R7together with the included nitrogen can form a 4, 5, 6, or 7 membered heterocyclic or heteroaryl ring system, wherein the heterocyclic or heteroaryl ring system is a monocyclic or bicyclic ring optionally having an additional one to four heteroatoms selected from N, O, and S; wherein the heterocyclic or heteroaryl ring system can be optionally substituted with one or more R8;

[0026] R8is, at each occurrence, independently selected from H, OH, SH, halogen, -CN, -CF3, -NO2, -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)2R 12 , -NR 11 C(O)NR 12 R 13 , -(CH2) m -R 16 , -(CH2) q -R 17 , -S(O)R 11 , -S(O)2R 11 , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, wherein the 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 ;

[0027] m is 1, 2, 3, or 4;

[0028] q is 2, 3, or 4;

[0029] R9and R 10 are, at each occurrence, independently selected from H or C 1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more R8;

[0030] or optionally, R9and R 10 together with the included carbon can form a 3-, 4-, 5-, or 6- membered carbocyclic ring system;

[0031] R 11 , R 12 , and R 13 is independently, at each occurrence, selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein each of said C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more R 14 ;

[0032] or optionally, R 11 and R 12 or R 12 and R 13 together with the included nitrogen can form a 4-, 5-, 6-, or 7- membered heterocyclic or heteroaryl ring system, wherein said heterocyclic or heteroaryl ring system is a monocyclic or bicyclic ring that is optionally having an additional one to four heteroatoms selected from N, O, and S; wherein said heterocyclic or heteroaryl ring system can be optionally substituted with one or more R8;

[0033] R 14 is independently, at each occurrence, selected from H, OH, OR 18 , SH, SR 18 , halogen, CN, CF3, NO2, C(O)R 18 , C(O)OR 18 , OC(O)NR 18 R 19 , C(O)NR 18 R 19 , NR 18 R 19 , NR 18 C(O)R 19 , NR 18 C(O)OR 19 , NR 18 S(O)2R 19 , NR 18 C(O)NR 19 R 20 , S(O)R 18 , S(O)2R 18 , C 1-6 alkyl, C3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be coupled with one or more R groups. 15 replace;

[0034] R 15 Each time it appears, it is independently selected from 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;

[0035] Each R 16 Independently -CO2H or -C(O)NR6R7;

[0036] Each R 17 Independently -OH or -NR6R7; and

[0037] Each R 18 R 19 and R 20 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl compounds.

[0038] In some implementation schemes:

[0039] X is CH or N;

[0040] Z is CH or N; the condition is that when X is CH, Z is not also CH.

[0041] Y is selected from hydrogen (H), Cl, alkyl, cycloalkyl, heterocycloalkyl, OR5, NR6R7, aryl and heteroaryl, wherein the heterocycloalkyl and heteroaryl include one or more nitrogen (N), oxygen (O) or sulfur (S) atoms; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may each be optionally substituted with one or more R8 atoms;

[0042] L1 is –(CR9R) 10 ) n - C(O) or S(O)2;

[0043] n is 0, 1, 2, or 3;

[0044] R1is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl comprises one or more N, O, or S atoms; wherein each of the aryl and heteroaryl can be optionally substituted with one or more R8;

[0045] R2is H, alkyl, -C(O)R 11 , -CH2C(O)OR 11 , -C(O)NR 11 R 12 , S(O)2NR 11 R 12 , or -C(O)OR 11 , wherein the alkyl is optionally substituted with one or more R8;

[0046] Optionally, R1and R2together with the included nitrogen atom and L1may form a 4-, 5-, 6-, or 7-membered heterocyclic ring system, wherein the heterocyclic ring system can include one or more additional N, O, or S atoms; and wherein the heterocyclic ring system can be optionally substituted with one or more R8;

[0047] R3and R4are each occurrence independently selected from the group consisting of H, alkyl, -OR 11 , halogen, -CN, -CF3, -NO2, -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)2R 12 , -NR 11 C(O)NR 12 R 13 , S(O)2NR 11 R 12 , aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein each of the heterocycloalkyl and heteroaryl comprises one or more N, O, or S atoms; wherein each of the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R8;

[0048] R5is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R8;

[0049] R6and R7are each occurrence independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the heterocycloalkyl or heteroaryl comprises one or more N, O, or S atoms; wherein each of the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl can be optionally substituted with one or more R8;

[0050] Optionally, R6and R7together with the included nitrogen can form a 4-, 5-, 6-, or 7-membered heterocyclic ring system, wherein the heterocyclic ring system is a monocyclic or bicyclic ring optionally having one to four additional heteroatoms selected from N, O, and S; wherein the cyclic ring system can be optionally substituted with one or more R8;

[0051] R8is each occurrence independently selected from the group consisting of H, OH, SH, halogen, -CN, -CF3, -NO2, -OR 11 , -SR 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)2R 12 , -NR 11 C(O)NR 12 R 13 , -(CH2) m -R 16 , -(CH2) q -R 17 , alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein each of the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R 14 ;

[0052] m is 1, 2, 3, or 4;

[0053] q is 2, 3, or 4;

[0054] R9and R 10 are each occurrence independently selected from H or alkyl, wherein the alkyl can be optionally substituted with one or more R8;

[0055] Optionally, R9and R 10 together with the included carbon can form a 3-, 4-, 5-, or 6-membered carbocyclic ring system;

[0056] R 11R 12 R 13 each occurrence is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be optionally substituted with one or more R 14 ;

[0057] optionally, R 11 and R 12 or R 12 and R 13 together with the included nitrogen can form a 4-, 5-, 6-, or 7-membered heterocyclic ring system, wherein said heterocyclic ring system is a monocyclic or bicyclic ring optionally having one to four additional heteroatoms selected from N, O, and S; wherein said cyclic ring system can be optionally substituted with one or more R 14 ;

[0058] R 14 each occurrence is independently selected from H, OH, OR 18 , SH, SR 18 , halogen, CN, CF3, NO2, C(O)R 18 , C(O)OR 18 , OC(O)NR 18 R 19 , C(O)NR 18 R 19 , NR 18 R 19 , NR 18 C(O)R 19 , NR 18 C(O)OR 19 , NR 18 S(O)2R 19 , NR 18 C(O)NR 19 R 20 , S(O)R 18 , S(O)2R 18 , alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be further substituted with one or more R 15 ;

[0059] R 15 each occurrence is independently selected from H, -CH3, -CH2CH3, n-propyl, i-propyl, -OCH3, halogen, -CN, -CF3, -NH2, -N(CH3)2, -CO2H, -C(O)NH2, -C(O)NH(CH3), and -C(O)N(CH3)2;

[0060] each R 16independently -CO2H or -C(O)NR6R7;

[0061] each R 17 independently -OH or -NR6R7; and

[0062] each R 18 , R 19 and R 20 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0063] In some embodiments:

[0064] X is CH or N;

[0065] Z is CH or N, provided that when X is CH, Z is not also CH;

[0066] Y is selected from the group consisting of hydrogen (H), Cl, alkyl, cycloalkyl, heterocycloalkyl, OR5, NR6R7, aryl, and heteroaryl, wherein the heterocycloalkyl and heteroaryl include one or more nitrogen (N), oxygen (O), or sulfur (S) atoms; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can each be optionally substituted with one or more R8;

[0067] L1is -(CR9R 10 ) n -, C(O), or S(O)2;

[0068] n is 0, 1, 2, or 3;

[0069] R1is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl includes one or more N, O, or S atoms; wherein each of the aryl and heteroaryl can be optionally substituted with one or more R8;

[0070] R2is H, alkyl, -C(O)R 11 , -CH2C(O)OR 11 , -C(O)NR 11 R 12 , S(O)2NR 11 R 12 , or -C(O)OR 11 , wherein the alkyl is optionally substituted with one or more R8;

[0071] Optionally, R1and R2together with the included nitrogen atom and L1may form a 4-, 5-, 6-, or 7-membered heterocyclic ring system, wherein the heterocyclic ring system can include one or more additional N, O, or S atoms; and wherein the heterocyclic ring system can be optionally substituted with one or more R8;

[0072] R3and R4are each independently selected at each occurrence from the group consisting of H, alkyl, -OR11 halo, -CN, -CF3, -NO2, -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)2R 12 , -NR 11 C(O)NR 12 R 13 , S(O)2NR 11 R 12 , aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein each of said heterocycloalkyl and heteroaryl comprises one or more N, O, or S atoms; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R8;

[0073] R5is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R8;

[0074] R6and R7are each occurrence independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said heterocycloalkyl or heteroaryl comprises one or more N, O, or S atoms; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl can be optionally substituted with one or more R8;

[0075] Optionally, R6and R7together with the included nitrogen can form a 4-, 5-, 6-, or 7-membered heterocyclic ring system, wherein said heterocyclic ring system is a monocyclic or bicyclic ring optionally having one to four additional heteroatoms selected from N, O, and S; wherein said ring system can be optionally substituted with one or more R8;

[0076] R8is each occurrence independently selected from the group consisting of H, OH, SH, halo, -CN, -CF3, -NO2, -OR 11 , -SR 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)2R 12 -NR 11 C(O)NR 12 R 13 -(CH2) m -R 16 -(CH2) q -R 17 alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein each of the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R 14 ;

[0077] m is 1, 2, 3, or 4;

[0078] q is 2, 3, or 4;

[0079] R9and R 10 are each, at each occurrence, independently selected from H or alkyl, wherein the alkyl can be optionally substituted with one or more R8;

[0080] Optionally, R9and R 10 together with the included carbon can form a 3-, 4-, 5-, or 6-membered carbocyclic ring system;

[0081] R 11 , R 12 , and R 13 are each, at each occurrence, independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be optionally substituted with one or more R 14 ;

[0082] Optionally, R 11 and R 12 or R 12 and R 13 together with the included atoms can form a 4-, 5-, 6-, or 7-membered heterocyclic ring system, wherein the heterocyclic ring system is a monocyclic or bicyclic ring optionally having one to four additional heteroatoms selected from N, O, and S; wherein the ring system can be optionally substituted with one or more R8;

[0083] R 14 is each, at each occurrence, independently selected from H, OH, OR 11 , SH, SR 11 , halogen, CN, CF3, NO2, C(O)OR 11 , OC(O)NR 11 R12 , 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)2R 12 , NR 11 C(O)NR 12 R 13 , alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally further substituted by one or more R 15 ;

[0084] R 15 is independently, at each occurrence, selected from H, -CH3, -CH2CH3, n-propyl, i-propyl, -OCH3, halogen, -CN, -CF3, -NH2, -N(CH3)2, -CO2H, -C(O)NH2, -C(O)NH(CH3), and -C(O)N(CH3)2;

[0085] R 16 is -CO2H or -C(O)NR6R7; and

[0086] R 17 is -OH or -NR6R7.

[0087] In some embodiments, R8is, at each occurrence, independently selected from H, OH, SH, halogen, -CN, -CF3, -NO2, -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)2R 12 , -NR 11 C(O)NR 12 R 13 , -(CH2) m -R 16-(CH2) q -R 17 -S(O)R 11 -S(O)2R 11 C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups are each optionally divided by one or more R 14 replace;

[0088] The condition is that when R8 is attached to a nitrogen atom (e.g., R1, R2, or the nitrogen atom of a heterocyclic alkyl group formed by R1 and R2 together with the included nitrogen atom and L1), R8 is selected from R 21 , where R 21 It 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)2R 11 Wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl and phenyl are each optionally divided by one or more R 14 replace.

[0089] In some implementation schemes, R 21 C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, and phenyl are each optionally selected by 1, 2, or 3 independently chosen R 14 replace.

[0090] In some implementation schemes, R 21 It 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)2R 11 Wherein C 1-6 Alkyl groups may be optionally replaced by NR 11 R 12 replace.

[0091] 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)2R 11 , wherein said C 1-6 alkyl is optionally substituted with NR 11 R 12 .

[0092] In some embodiments, R 21 is C(O)CH3, S(O)2CH3, CH2CH2N(CH3)2, or C(O)NH(cyclopropyl).

[0093] In some embodiments, R 21 is C(O)CH3or S(O)2CH3.

[0094] In some embodiments, R8is, at each occurrence, independently selected from H, OH, SH, halogen, -CN, -CF3, -NO2, -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)2R 12 , -NR 11 C(O)NR 12 R 13 , -(CH2) m -R 16 , -(CH2) q -R 17 , -S(O)R 11 , -S(O)2R 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, C3-10 Cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with one or more R 14 substituents;

[0095] provided that when R8is attached to a carbon atom (e.g., R1, R2, or a carbon atom of a heterocycloalkyl group formed by R1and R2together with the included nitrogen atom and L1), R8is selected from R 8a wherein R 8a is C 1-6 alkyl, C 3-6 ycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said C 1-6 alkyl, phenyl, and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0096] In some embodiments, R 8a is benzyl, phenyl, or 5-6 membered heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0097] In some embodiments, R 8a is phenyl or 5-6 membered heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0098] In some embodiments, R 8a is phenyl or thienyl, wherein said phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl; and said thienyl is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, Me, Et, cycropropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl.

[0099] In some embodiments, the compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, L1is -(CH2)-, -(CH(CH3))-, -(C(CH3)2)-, -CH(CH2OH)-, or

[0101] In some embodiments, L1is -(CH2)-, -(CH(CH3))-, -(C(CH3)2)-, or

[0102] In some embodiments, L1is -(CH2)- or -(CH(CH3))-

[0103] In some embodiments, L1is -(CH2)-.

[0104] In some embodiments, R1is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R8.

[0105] In some embodiments, R1is C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10 aryl or 5-10 membered heteroaryl optionally substituted with one, two, three, or four independently selected R8.

[0106] In some embodiments, R1is aryl or heteroaryl, wherein the aryl or heteroaryl can each be optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3.

[0107] In some embodiments, R1is C 6-10 aryl or 5-6 membered heteroaryl, wherein the C 6-10 aryl or 5-10 membered heteroaryl optionally substituted with one, two, three, or four independently selected R8.

[0108] In some embodiments, R1is phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl can each be optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3.

[0109] In some embodiments, R1is phenyl, thienyl, or pyridyl, wherein the phenyl, thienyl, or pyridyl can each be optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3.

[0110] In some embodiments, R1is phenyl optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3.

[0111] In some embodiments, L1R1is CH2-phenyl, wherein the phenyl is optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3.

[0112] In some embodiments, L1R1is CH2-pyridyl, wherein the pyridyl is optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3.

[0113] In some embodiments, L1R1is CH2-thiophenyl, wherein the thiophenyl is optionally substituted with one or two substituents selected from F, Cl, Br, and CH3.

[0114] In some embodiments, L1R1is CH2-CH2-phenyl, wherein the phenyl is optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3.

[0115] In some embodiments, L1R1is -1,1-cyclopropyl-phenyl, wherein the phenyl is optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3.

[0116] In some embodiments, R2is H, CH3, or cyclopropyl.

[0117] In some embodiments, R2is H or CH3.

[0118] In some embodiments, R2is H.

[0119] In some embodiments, R1and R2together with the included nitrogen atom and L1form a 4-6 membered heterocycloalkyl having one or two heteroatoms independently selected from nitrogen and oxygen, wherein the heterocycloalkyl is optionally substituted with one or two independently selected R8groups.

[0120] In some embodiments, R1and R2together with the included nitrogen atom and L1form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring, wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring is optionally substituted with one or two independently selected R8groups.

[0121] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0122]

[0123]

[0124] wherein R 21 is C 1-6 1-6 alkyl, C 3-6 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)2R 11 , wherein the C 1-6 1-6 alkyl, C 3-6each optionally substituted with 1, 2, or 3 independently selected R 14 substituted.

[0125] 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)2R 11 , wherein said C 1-6 alkyl is optionally substituted with NR 11 R 12 substituted.

[0126] In some embodiments, R 21 is C(O)CH3, S(O)2CH3, CH2CH2N(CH3)2, or C(O)NH(cyclopropyl).

[0127] In some embodiments, R 21 is C(O)CH3or S(O)2CH3.

[0128] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0129]

[0130] 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)2R 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 substituted.

[0131] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0132]

[0133] wherein R 21 is C 1-6 alkyl, C3-6 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)2R 11 wherein said C 1-6 alkyl, C 3-6 ycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0134] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0135]

[0136] wherein R 21 is C 1-6 alkyl, C 3-6 ycloalkyl, 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)2R 11 wherein said C 1-6 alkyl, C 3-6 ycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0137] In some embodiments, R 21 is C 1-6 alkyl, C 3-6 ycloalkyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 or -S(O)2R 11 wherein said C 1-6 alkyl can be optionally substituted with NR 11 R 12 substituents.

[0138] In some embodiments, R 21 is C(O)CH3, S(O)2CH3, CH2CH2N(CH3)2, or C(O)NH(cyclopropyl).

[0139] In some embodiments, R 21is C(O)CH3or S(O)2CH3.

[0140] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0141]

[0142] wherein R8is phenyl; and

[0143] 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)2R 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 .

[0144] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0145]

[0146] wherein R8is phenyl; and

[0147] 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)2R 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 .

[0148] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0149]

[0150] wherein R8is phenyl; and

[0151] 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)2R 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 .

[0152] 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)2R 11 , wherein said C 1-6 alkyl can be optionally substituted with NR 11 R 12 .

[0153] In some embodiments, R 21 is C(O)CH3, S(O)2CH3, CH2CH2N(CH3)2, or C(O)NH(cyclopropyl).

[0154] In some embodiments, R 21 is C(O)CH3or S(O)2CH3.

[0155] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0156]

[0157] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0158]

[0159] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0160]

[0161]

[0162] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0163]

[0164] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0165]

[0166] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0167]

[0168] In some embodiments, R3and R4are each occurrence independently selected from aryl and heteroaryl, wherein the aryl and heteroaryl can each be optionally substituted with one or more R8.

[0169] In some embodiments, R3and R4are each independently selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 6-10 aryl and 5-10 membered heteroaryl can each be optionally substituted with one or more R8.

[0170] In some embodiments, R3and R4are each independently selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 6-10 aryl and 5-10 membered heteroaryl can each be optionally substituted with one or more R8.

[0171] In some embodiments, R3and R4are each independently selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl can each be optionally substituted with 1, 2, 3, or 4 independently selected R8.

[0172] In some embodiments, R3is isoxazolyl, pyrazolyl, 2-oxopyridinyl, 2- hydroxypyridinyl, each of which is optionally substituted with one or two methyl groups.

[0173] In some embodiments, R3and R4are each independently selected from H,

[0174] In some embodiments, R3is selected from and R4is H.

[0175] In some embodiments, X is CH.

[0176] In some embodiments, X is N.

[0177] In some embodiments, Z is CH.

[0178] In some embodiments, Z is N.

[0179] In some embodiments, X is CH and Z is N.

[0180] In some embodiments, X and Z are both N.

[0181] In some embodiments, X is N; and Z is CH.

[0182] In some embodiments, Y is selected from NR6R7, -C(O)R 11 , -C(O)NR 11 R 12 , heterocycloalkyl, and heteroaryl, wherein the heterocycloalkyl and heteroaryl are optionally substituted with one or more R8.

[0183] In some embodiments, Y is selected from NR6R7, -C(O)R 11 , -C(O)NR 11 R 12 , 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2, 3, or 4 independently selected R8.

[0184] In some embodiments, Y is NR6R7.

[0185] In some embodiments, Y is -C(O)R 11 .

[0186] In some embodiments, Y is -C(O)NR 11 R 12 .

[0187] In some embodiments, Y is 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl can be optionally substituted with one or more R8.

[0188] In some embodiments, Y is 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl can be optionally substituted with 1 or 2 R8independently selected from C 1-6 alkyl, 5-6 membered heterocycloalkyl, phenyl, OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R12 S(O)2R 11 The R8 group is substituted, wherein the C 1-6 Alkyl, 5-6 membered heterocyclic alkyl, and phenyl groups are each optionally selected by one or two independently chosen R groups. 14 Group substitution;

[0189] OR 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 11 R 12 S(O)2R 11 Each R in 11 Independently selected from H and C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups may be optionally represented by one or two independently selected R groups. 14 replace;

[0190] -C(O)NR 11 R 12 Each R 12 Independently selected from H and C 1-6 Alkyl; and

[0191] With R8 or R 11 Each R connected 14 Independently selected from halogens, C 1-6 Alkyl, phenyl, 5-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, OR 18 NR 18 R 19 C(O)R 18 C(O)NR 18 R 19 and S(O)2R 18 The phenyl, 5-6 membered heterocyclic alkyl and 5-6 membered heteroaryl groups may optionally be substituted with one or two methyl groups.

[0192] In some embodiments, Y is a 4-6 membered heterocyclic alkyl group, wherein the 4-6 membered heterocyclic alkyl group may optionally be selected independently by one or two C14 groups. 1-3 Alkyl, 5-6 membered heterocyclic alkyl, phenyl, -C(O)R 11 -C(O)NHR 11 The R8 group of S(O)2CH3 is substituted, wherein the C 1-6 Alkyl, 5-6 membered heterocyclic alkyl, and phenyl groups are each optionally selected by one or two independently chosen R groups. 14 replace.

[0193] wherein -C(O)R 11 and -C(O)NHR 11 each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl groups can be optionally substituted with 1 or 2 independently selected R 14 groups; and

[0194] wherein each R 11 attached to R8or R 14 is independently selected from chloro, methyl, OH, N(CH3)2, C(O)CH3, C(O)NH2, C(O)NHCH3, 1-methyl-lH-imidazolyl, 1,3-dimethyl-lH-pyrazolyl, and 1-methylazetidinyl.

[0195] In some embodiments, Y is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl can be optionally substituted with one or more R8.

[0196] In some embodiments, Y is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl can be optionally substituted with 1 or 2 independently selected R8groups selected from 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)2R 11 , wherein the C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl groups are each optionally substituted with 1 or 2 independently selected R 14 groups;

[0197] OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , S(O)2R 11 each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6Cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl can be optionally substituted with 1 or 2 independently selected R 14 substituted;

[0198] -C(O)NR 11 R 12 each R 12 is independently selected from H and C 1-6 alkyl; and

[0199] each R 11 attached to R8or R 14 is independently selected from 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)2R 18 , wherein said phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl can be optionally substituted with 1 or 2 methyl groups.

[0200] In some embodiments, Y is 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl can be optionally substituted with one or more R8groups independently selected from C 1-3 alkyl, 5-6 membered heterocycloalkyl, phenyl, -C(O)R 11 , -C(O)NHR 11 , S(O)2CH3, wherein said C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 substituted;

[0201] wherein each R 11 in -C(O)R 11 and -C(O)NHR 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl can be optionally substituted with 1 or 2 independently selected R 14 substituted; and

[0202] wherein each R 11 attached to R8or R 14independently selected from chloro, methyl, OH, N(CH3)2, C(O)CH3, C(O)NH2, C(O)NHCH3, 1 -methyl- 1 H-imidazolyl, 1,3-dimethyl- 1 H-pyrazolyl, and 1 -methylazetidinyl.

[0203] In some embodiments, Y is H, chloro, methyl, methoxy, NHR7, -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]decane-2- one, and 4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl, wherein the 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]decane-2-one, 4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl can be optionally substituted with 1 or 2 R8groups independently selected from C 1-3 alkyl, 5-6 membered heterocycloalkyl, phenyl, -C(O)R 11 , -C(O)NHR 11 , and S(O)2CH3, wherein the C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 ;

[0204] wherein each R 11 in -C(O)R 11 and -C(O)NHR 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with 1 or 2 independently selected R 14 ; and

[0205] wherein each R 11 attached to R8or R 14It is independently selected from chlorinated, methyl, OH, N(CH3)2, C(O)CH3, C(O)NH2, C(O)NHCH3, 1-methyl-1H-imidazolyl, 1,3-dimethyl-1H-pyrazolyl and 1-methylazacyclobutane.

[0206] In some implementations, Y is H, -C(O)R 11 -C(O)NHR 11 Piperazinyl, pyrazolyl, piperidinyl, or thiopheneyl, wherein the pipeazinyl, pyrazolyl, piperidinyl, or thiopheneyl group may optionally be selected independently by one or two of C14 groups. 1-3 Alkyl, 5-6 membered heterocyclic alkyl, phenyl, -C(O)R 11 -C(O)NHR 11 And the independently selected R8 group substitution of S(O)2CH3, wherein the C 1-6 Alkyl, 5-6 membered heterocyclic alkyl, and phenyl groups are each optionally selected by one or two independently chosen R groups. 14 replace;

[0207] Where -C(O)R 11 and -C(O)NHR 11 Each R in 11 Independently selected from H and C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups may be optionally represented by one or two independently selected R groups. 14 Replace; and

[0208] Among them, R8 or R 11 Each R connected 14 It is independently selected from chlorinated, methyl, OH, N(CH3)2, C(O)CH3, C(O)NH2, C(O)NHCH3, 1-methyl-1H-imidazolyl, 1,3-dimethyl-1H-pyrazolyl and 1-methylazacyclobutane.

[0209] In some implementation schemes, Y is selected from:

[0210]

[0211]

[0212] In some embodiments, the present invention provides compounds of formula I, wherein:

[0213] X is CH or N;

[0214] Z is CH or N, provided that when X is CH, Z is not also CH;

[0215] Y is selected from heterocycloalkyl, heteroaryl, or NR6R7, wherein the heterocycloalkyl or heteroaryl is optionally substituted with one or more R8;

[0216] L1is -CH2- or -CH(CH3)-;

[0217] R1is aryl or heteroaryl, wherein the aryl or heteroaryl can each be optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3;

[0218] R2is H or CH3;

[0219] R3and R4are each occurrence independently selected from H, aryl, or heteroaryl, wherein the aryl or heteroaryl can each be optionally substituted with one or more R8.

[0220] In some embodiments, the present application provides a compound of Formula I, wherein:

[0221] X is CH or N;

[0222] Z is CH or N, provided that when X is CH, Z is not also CH;

[0223] Y is -C(O)NR 11 R 12 , 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or NR6R7, wherein the 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R8;

[0224] L1is -CH2- or -CH(CH3)-;

[0225] R1is phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl can each be optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3;

[0226] R2is H or CH3;

[0227] R3is 5-6 membered heteroaryl substituted with 1 or 2 methyl groups; and

[0228] R4is H.

[0229] In some embodiments, the present application provides a compound of Formula I, wherein:

[0230] X is CH or N;

[0231] Z is CH or N, provided that when X is CH, Z is not CH;

[0232] Y is -C(O)NR 11 R 12 or heterocycloalkyl or heteroaryl selected from the group consisting of:

[0233]

[0234] wherein:

[0235] n is 1 or 2;

[0236] p is 0, 1 or 2;

[0237] R8is H, C1-C6alkyl or -(CH2) m -R 16 or -(CH2) q -R 17 ;

[0238] m is 1, 2, 3 or 4;

[0239] q is 2, 3 or 4;

[0240] R 16 is -CO2H or -C(O)NR6R7; and

[0241] R 17 is OH or NR6R7.

[0242] In some embodiments, the present application provides a compound of Formula I, wherein:

[0243] X is CH or N;

[0244] Z is CH or N, provided that when X is CH, Z is not CH;

[0245] Y is heterocycloalkyl or heteroaryl selected from the group consisting of:

[0246]

[0247] wherein:

[0248] n is 1 or 2;

[0249] p is 0, 1 or 2;

[0250] R8is H, C1-C6alkyl or -(CH2) m -R 16 or -(CH2) q -R 17 ;

[0251] m is 1, 2, 3 or 4;

[0252] q is 2, 3 or 4;

[0253] R 16-CO2H or -C(O)NR6R7; and

[0254] R 17 is OH or NR6R7.

[0255] In some embodiments, the present application provides a compound of Formula I, wherein:

[0256] X is CH or N;

[0257] Z is CH or N, provided that when X is CH, Z is not also CH;

[0258] L1is -CH2- or -CH(CH3)-;

[0259] Y is -C(O)NR 11 R 12 or a heterocycloalkyl or heteroaryl group selected from:

[0260]

[0261] wherein:

[0262] n is 1 or 2;

[0263] p is 0, 1 or 2;

[0264] R8is H, C1-C6 alkyl or -(CH2) m -R 16 or -(CH2) q -R 17 ;

[0265] m is 1, 2, 3 or 4;

[0266] q is 2, 3 or 4;

[0267] R 16 -CO2H or -C(O)NR6R7;

[0268] R 17 is OH or NR6R7.

[0269] R1is C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10 aryl or 5-10 membered heteroaryl can each be optionally substituted with one or two substituents selected from F, Cl, Br, CH3and -OCH3;

[0270] R2is H or CH3; and

[0271] R3and R4are each occurrence independently selected from H, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10Aryl or 5-10 membered heteroaryl can each be optionally substituted with one or more R8.

[0272] In some embodiments, the present application provides a compound of Formula I, wherein:

[0273] X is CH or N;

[0274] Z is CH or N, provided that when X is CH, Z is not also CH;

[0275] L1is -CH2- or -CH(CH3)-;

[0276] Y is a heterocycloalkyl or heteroaryl selected from:

[0277]

[0278] wherein:

[0279] n is 1 or 2;

[0280] p is 0, 1 or 2;

[0281] R8is H, C1-C6 alkyl or -(CH2) m -R 16 or -(CH2) q -R 17 ;

[0282] m is 1, 2, 3 or 4;

[0283] q is 2, 3 or 4;

[0284] R 16 is -CO2H or -C(O)NR6R7;

[0285] R 17 is OH or NR6R7.

[0286] R1is aryl or heteroaryl, wherein the aryl or heteroaryl can each be optionally substituted with one or two substituents selected from F, Cl, Br, CH3and -OCH3;

[0287] R2is H or CH3; and

[0288] R3and R4are independently at each occurrence selected from H, aryl or heteroaryl, wherein the aryl or heteroaryl can each be optionally substituted with one or more R8.

[0289] In some embodiments, the present application provides a compound of Formula I, wherein:

[0290] X is N;

[0291] Z is N;

[0292] L1is -CH2- or -CH(CH3)-;

[0293] Y is -C(O)NR 11 R 12 or a heterocycloalkyl or heteroaryl group selected from:

[0294]

[0295] wherein:

[0296] n is 1 or 2;

[0297] p is 0, 1 or 2;

[0298] R8is H, C1-C6 alkyl, -(CH2) m -R 16 or -(CH2) q -R 17 ;

[0299] m is 1, 2, 3 or 4;

[0300] q is 2, 3 or 4;

[0301] R 16 is -CO2H or -C(O)NR6R7;

[0302] R 17 is OH or NR6R7;

[0303] R1is C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10 aryl or 5-10 membered heteroaryl can each be optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3;

[0304] R2is H or CH3; and

[0305] R3and R4are independently at each occurrence selected from H, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10 aryl or 5-10 membered heteroaryl can each be optionally substituted with one or more R8.

[0306] In some embodiments, the present application provides a compound of Formula I, wherein:

[0307] X is N;

[0308] Z is N;

[0309] L1is -CH2- or -CH(CH3)-;

[0310] Y is a heterocycloalkyl or heteroaryl group selected from:

[0311]

[0312] wherein:

[0313] n is 1 or 2;

[0314] p is 0, 1, or 2;

[0315] R8is H, C1-C6alkyl, -(CH2) m -R 16 or -(CH2) q -R 17 ;

[0316] m is 1, 2, 3, or 4;

[0317] q is 2, 3, or 4;

[0318] R 16 is -CO2H or -C(O)NR6R7;

[0319] R 17 is OH or NR6R7;

[0320] R1is aryl or heteroaryl, wherein the aryl or heteroaryl can each be optionally substituted with one or two substituents selected from F, Cl, Br, CH3, and -OCH3;

[0321] R2is H or CH3; and

[0322] R3and R4are each occurrence independently selected from H, aryl, or heteroaryl, wherein the aryl or heteroaryl can each be optionally substituted with one or more R8.

[0323] In some embodiments:

[0324] X is CH or N;

[0325] Z is CH or N; provided that when X is CH, Z is not also CH;

[0326] Y is selected from H, Cl, C 1-6 alkyl, OR5, NR6R7, -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 the C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0327] R1and R2together with the included nitrogen atom and L1form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 or 2 independently selected R8;

[0328] R3is selected from H, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0329] R4is selected from H and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0330] R5is selected from C 1-6 alkyl and phenyl, wherein the phenyl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0331] each R6is independently selected from H and C 1-6 alkyl;

[0332] each R7is independently selected from H, C 1-6 alkyl and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl and 4-10 membered heterocycloalkyl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0333] each R8is independently selected from 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)2R 11 , wherein the C 1-6 alkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R 14 ;

[0334] each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R 14 ;

[0335] each R 12 is independently selected from H and C 1-6 alkyl;

[0336] each R 14 is independently selected from H, halo, 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)2R 18 , C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl, wherein the C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl groups can be optionally substituted with 1, 2, 3, or 5 independently selected R 15 substituents;

[0337] each R 15 is independently selected from -CH3, halo, and CN;

[0338] each R 18 is independently selected from H and C 1-6 alkyl; and

[0339] each R 19 is independently selected from H and C 1-6 alkyl.

[0340] In some embodiments:

[0341] X is CH or N;

[0342] Z is CH or N; provided that when X is CH, Z is not also CH;

[0343] Y is selected from H, Cl, C 1-6 alkyl, NR6R7, -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 the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups can be optionally substituted with one or more R8;

[0344] R1and R2, together with the included nitrogen atom and L1, form a 4, 5, 6, or 7 membered heterocycloalkyl group optionally substituted with one or more R8;

[0345] R3is selected from H, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0346] R4is H;

[0347] each R6is independently selected from H and C 1-6 alkyl;

[0348] each R7is independently selected C 1-6 alkyl, each of which can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0349] each R8is independently selected from 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)2R 11 , and S(O)2R 1-6 alkyl, 4-10 membered heterocycloalkyl, phenyl, each optionally substituted with 1, 2, 3, or 4 independently selected R 14 ;

[0350] each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl can be optionally substituted with one or more R 14 ;

[0351] each R 12 is independently selected from H and C 1-6 alkyl;

[0352] each R 14 is independently selected from 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)2R 18 , wherein the phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl can be optionally substituted with one or more R 15substituted;

[0353] each R 15 is CH3or CN;

[0354] each R 18 is independently selected from H and C 1-6 alkyl; and

[0355] each R 19 is independently selected from H and C 1-6 alkyl.

[0356] In some embodiments:

[0357] X is CH or N;

[0358] Z is CH or N; provided that when X is CH, Z is not also CH;

[0359] Y is selected from H, Cl, NR6R7, -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 can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0360] R1and R2, together with the included nitrogen atom and L1, form a 4, 5, 6, or 7 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0361] R3is selected from H, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0362] R4is H;

[0363] each R6is independently selected from H and C 1-6 alkyl;

[0364] each R7is independently selected C 1-6 alkyl, each of which can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0365] each R8is independently selected from 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)2R 11 , wherein said C1-6 alkyl, 4-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 14 substituents;

[0366] each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 independently selected R 14 substituents;

[0367] each R 12 is independently selected from H and C 1-6 alkyl;

[0368] each R 14 is independently selected from 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)2R 18 wherein the phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 independently selected R 15 substituents;

[0369] each R 15 is CH3or CN;

[0370] each R 18 is independently selected from H and C 1-6 alkyl; and

[0371] each R 19 is independently selected from H and C 1-6 alkyl.

[0372] In some embodiments:

[0373] X is CH or N;

[0374] Z is CH or N; provided that when X is CH, Z is not also CH;

[0375] Y is selected from H, NR6R7, -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 can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0376] R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0377]

[0378] R3is selected from H, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0379] R4is H;

[0380] each R6is independently selected from H and C 1-6 alkyl;

[0381] each R7is an independently selected C 1-6 alkyl, each of which can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0382] each R8is independently selected from 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)2R 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 ;

[0383] each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R 14 ;

[0384] each R 12 is independently selected from H and C 1-6 alkyl;

[0385] each R 14 is independently selected from halogen, C 1-6alkyl, 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)2R 18 , wherein said phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 independently selected R 15 ;

[0386] each R 15 is CH3or CN;

[0387] each R 18 is independently selected from H and C 1-6 alkyl;

[0388] each R 19 is independently selected from H and C 1-6 alkyl; and

[0389] 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)2R 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 .

[0390] In some embodiments:

[0391] X is CH or N;

[0392] Z is CH or N; provided that when X is CH, Z is not also CH;

[0393] Y is selected from H, NR6R7, -C(O)R 11 , -C(O)NR 11 R 12 , 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein said heterocycloalkyl and heteroaryl are optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0394] R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0395]

[0396] R3is selected from H, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0397] R4is H;

[0398] each R6is independently selected from H and C 1-6 alkyl;

[0399] each R7is an independently selected C 1-6 alkyl, each of which can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0400] each R8is independently selected from 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)2R 11 , wherein the C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 14 ;

[0401] each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R 14 ;

[0402] each R 12 is independently selected from H and C 1-6 alkyl;

[0403] each R 14 is independently selected from 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)2R 18wherein said phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R 15 substituted;

[0404] each R 15 is CH3or CN;

[0405] each R 18 is independently selected from H and C 1-6 alkyl;

[0406] each R 19 is independently selected from H and C 1-6 alkyl; and

[0407] R 21 is selected from C(O)CH3, S(O)2CH3, CH2CH2N(CH3)2, and C(O)NH(cyclopropyl).

[0408] In some embodiments:

[0409] X is CH or N;

[0410] Z is CH or N; provided that when X is CH, Z is not also CH;

[0411] Y is selected from H, NR6R7, -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 can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0412] R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0413]

[0414]

[0415] R3is selected from H, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0416] R4is H;

[0417] each R6is independently selected from H and C 1-6 alkyl;

[0418] each R7is an independently selected C 1-6 alkyl, each of which can be optionally substituted with 1, 2, 3, or 4 independently selected R8;

[0419] each R8is independently selected from 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)2R 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 substituents;

[0420] each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R 14 substituents;

[0421] each R 12 is independently selected from H and C 1-6 alkyl;

[0422] each R 14 is independently selected from 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)2R 18 wherein said phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl can be optionally substituted with 1, 2, 3, or 4 independently selected R 15 substituents;

[0423] each R 15 is CH3or CN;

[0424] each R 18 is independently selected from H and C 1-6 alkyl; and

[0425] each R 19 is independently selected from H and C 1-6 alkyl.

[0426] In some embodiments:

[0427] X is CH or N;

[0428] Z is CH or N; provided that when X is CH, Z is not also CH;

[0429] Y is selected from H, NHR7, -C(O)R 11 , -C(O)NHR 11 , piperazinyl, pyrazolyl, piperidinyl, and thienyl, wherein the piperazinyl, pyrazolyl, piperidinyl, and thienyl can be optionally substituted with 1 or 2 independently selected R8;

[0430] R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0431]

[0432] R3is isoxazolyl, pyrazolyl, 2-oxopyridinyl, 2-hydroxypyridinyl, each of which is optionally substituted with one or two methyl groups;

[0433] R4is H;

[0434] each R6is independently selected from H and C 1-6 alkyl;

[0435] each R7is an independently selected C 1-6 alkyl, each of which can be optionally substituted with 1 or 2 independently selected R8;

[0436] each R8is independently selected from 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)2R 11 , wherein the C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 ;

[0437] each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl can be optionally substituted with 1 or 2 independently selected R 14 ;

[0438] each R12 independently selected from H and C 1-6 alkyl;

[0439] each R 14 is independently selected from 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)2R 18 , wherein said phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted with 1 or 2 independently selected R 15 ;

[0440] each R 15 is CH3or CN;

[0441] each R 18 is independently selected from H and C 1-6 alkyl; and

[0442] each R 19 is independently selected from H and C 1-6 alkyl.

[0443] In some embodiments:

[0444] X is CH or N;

[0445] Z is CH or N; provided that when X is CH, Z is not also CH;

[0446] Y is selected from H, NHR7, -C(O)R 11 , -C(O)NHR 11 , piperazinyl, pyrazolyl, piperidinyl and thienyl, wherein said piperazinyl, pyrazolyl, piperidinyl and thienyl are optionally substituted with 1 or 2 independently selected R8;

[0447] R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0448]

[0449] R3is isoxazolyl, pyrazolyl, 2-oxopyridinyl, 2-hydroxypyridinyl, each of which is optionally substituted with one or two methyl groups;

[0450] R4is H;

[0451] each R6is independently selected from H and C 1-3 alkyl;

[0452] each R7is an independently selected C 1-3 alkyl, each of which can be optionally substituted with 1 or 2 independently selected R8;

[0453] each R8is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, -C(O)R 11 , -C(O)NHR 11 , S(O)2CH3, wherein the C 1-6 alkyl, 5-6 membered heterocycloalkyl, and phenyl are each optionally substituted with 1 or 2 independently selected R 14 ;

[0454] each R 11 is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl can be optionally substituted with 1 or 2 independently selected R 14 ;

[0455] each R 14 is independently selected from chloro, methyl, OH, N(CH3)2, C(O)CH3, C(O)NH2, C(O)NHCH3, 1-methyl-lH-imidazolyl, 1,3-dimethyl-lH-pyrazolyl, and 1-methylazetidinyl.

[0456] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0457]

[0458] In some embodiments, R1and R2together with the included nitrogen atom and L1form a heterocycloalkyl selected from:

[0459]

[0460] In some embodiments, the present application provides a compound of Formula I, wherein R3and R4are independently selected for each occurrence from:

[0461]

[0462] In some embodiments, the compound is a compound of Formula II:

[0463]

[0464] or a pharmaceutically acceptable salt thereof.

[0465] In some embodiments, R3is

[0466] In some embodiments, the compound is a compound of Formula III:

[0467]

[0468]

[0469] or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 4, and Q is CH or N.

[0470] In some embodiments, R3is

[0471] In some embodiments, p is an integer from 0 to 2.

[0472] In some embodiments, p is 0.

[0473] In some embodiments, p is 1.

[0474] In some embodiments, p is 2.

[0475] In some embodiments, the compound is a compound of Formula IV:

[0476]

[0477] 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)2R 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 .

[0478] 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 12or -S(O)2R 11 wherein the C 1-6 alkyl is optionally substituted with NR 11 R 12 substituted.

[0479] In some embodiments, R 21 is C(O)CH3, S(O)2CH3, CH2CH2N(CH3)2, or C(O)NH(cyclopropyl).

[0480] In some embodiments, R 21 is C(O)CH3or S(O)2CH3.

[0481] In some embodiments, R3is

[0482] In some embodiments, the compound is a compound of Formula V:

[0483]

[0484] 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)2R 11 wherein the 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

[0485] R 8a is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-6 alkyl, phenyl, and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 .

[0486] In some embodiments, R 8a is benzyl, phenyl, or 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 .

[0487] In some embodiments, R 8aIt is a phenyl or a 5-6-membered heteroaryl group, wherein the phenyl and heteroaryl groups may optionally be selected by one, two or three independently chosen R groups. 14 replace.

[0488] In some implementation schemes, R 8a It is a phenyl or thiophene group, wherein the phenyl group may optionally be composed of one, two, or three independently selected from F, Cl, Br, Me, Et, cyclopropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 Alkyl groups and -NHC(O)-C 1-4 The alkenyl group is substituted; and the thiophene group may optionally be replaced by one or two independent groups selected from F, Cl, Br, Me, Et, cyclopropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 Alkyl groups and -NHC(O)-C 1-4 Alkenyl substituent substitution.

[0489] In some implementation schemes, R 21 It 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)2R 11 Wherein C 1-6 Alkyl groups may be optionally replaced by NR 11 R 12 replace.

[0490] In some implementation schemes, R 21 It is C(O)CH3, S(O)2CH3, CH2CH2N(CH3)2 or C(O)NH (cyclopropyl).

[0491] In some implementation schemes, R 21 It is C(O)CH3 or S(O)2CH3.

[0492] In some implementations, R3 is

[0493] In some embodiments, the compound of formula V or a pharmaceutically acceptable salt thereof is a compound of formula Va:

[0494]

[0495] Or its pharmaceutically acceptable salt.

[0496] In some embodiments, the compound of formula V or a pharmaceutically acceptable salt thereof is a compound of formula Vb:

[0497]

[0498] or a pharmaceutically acceptable salt thereof.

[0499] In some embodiments, the compound is a compound of Formula VI:

[0500]

[0501] or a pharmaceutically acceptable salt thereof, wherein R 8a is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said C 1-6 alkyl, phenyl, and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0502] In some embodiments, R 8a is benzyl, phenyl, or 5-6 membered heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0503] In some embodiments, R 8a is phenyl or 5-6 membered heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0504] In some embodiments, R 8a is phenyl or thienyl, wherein said phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, Br, Me, Et, cyclopropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl; and said thienyl is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, Me, Et, cyclopropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl.

[0505] In some embodiments, R3is

[0506] In some embodiments, the compound of Formula VI, or a pharmaceutically acceptable salt thereof, is a compound of Formula Via:

[0507]

[0508] or a pharmaceutically acceptable salt thereof,

[0509] In some embodiments, the compound of Formula VI, or a pharmaceutically acceptable salt thereof, is a compound of Formula VIb:

[0510]

[0511] or a pharmaceutically acceptable salt thereof,

[0512] In some embodiments, the compound is a compound of Formula VII:

[0513]

[0514] or a pharmaceutically acceptable salt thereof.

[0515] In some embodiments, the R8group attached to the piperidinyl ring formed by R1and R2together with the included nitrogen atom and L1is R 8a wherein R 8a is phenyl or 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0516] In some embodiments, R 8a is phenyl or thienyl, wherein the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, Br, Me, Et, cyclopropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl; and the thienyl is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, Me, Et, cyclopropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl.

[0517] In some embodiments, R3is

[0518] In some embodiments, the compound is a compound of Formula VIII:

[0519]

[0520] or a pharmaceutically acceptable salt thereof, wherein R 8a is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R 14 substituents.

[0521] In some embodiments, R 8a is phenyl or thienyl, wherein the phenyl can be optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, Br, Me, Et, cyclopropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl; and the thienyl can be optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, Me, Et, cyclopropyl, OMe, OEt, CF3, CN, NH2, -NHC(O)-C 1-4 alkyl, and -NHC(O)-C 1-4 alkenyl.

[0522] In some embodiments, R3is

[0523] In some embodiments, the compound of Formula VIII, or a pharmaceutically acceptable salt thereof, is a compound of Formula VIIIa:

[0524]

[0525] or a pharmaceutically acceptable salt thereof,

[0526] In some embodiments, the compound of Formula VIII, or a pharmaceutically acceptable salt thereof, is a compound of Formula VIIIb:

[0527]

[0528] or a pharmaceutically acceptable salt thereof,

[0529] In some embodiments, the compound is selected from:

[0530] 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4- amine;

[0531] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine;

[0532] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinoline-4-amine;

[0533] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinoline-4-amine;

[0534] N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-methylquinazoline-2,4- diamine;

[0535] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-amine;

[0536] N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine;

[0537] N-(3-Chlorobenzyl)-6-(3,5-Dimethylisoxazol-4-yl)-2-methoxyquinazoline-4-amine;

[0538] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinazoline-4-amine;

[0539] N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-morpholinoethyl)quinazoline-2,4-diamine;

[0540] N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-(4-methylpiperazin-1-yl)ethyl)quinazoline-2,4-diamine;

[0541] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine;

[0542] 3-((4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)amino)prop-1-ol;

[0543] N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinoline-4-amine;

[0544] 6-Bromo-N-(3-chlorobenzyl)-2-(3,5-dimethylisoxazol-4-yl)quinoline-4-amine;

[0545] N-(3-chlorobenzyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine;

[0546] (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(cyclopropyl)methyl ketone;

[0547] (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methyl ketone;

[0548] 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4- amine;

[0549] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1- yl)ethanol;

[0550] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-isopentylpiperazin-1-yl)quinazolin-4- amine;

[0551] N4-(3-chlorobenzyl)-N2-(2-(dimethylamino)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-N2- methylquinazoline-2,4-diamine;

[0552] (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-4- yl)methanol;

[0553] (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-3- yl)methanol;

[0554] (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-2- yl)methanol;

[0555] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-4-amine

[0556] N-(3-chlorobenzyl)-4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-2-amine;

[0557] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-morpholinoethyl)-1H-pyrazol-4- yl)quinazolin-4-amine;

[0558] (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1- yl)(pyridin-4-yl)methanone;

[0559] 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-4- yl)ethanol;

[0560] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(l,2,3,6-tetrahydropyridin-4- yl)quinazolin-4-amine;

[0561] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine;

[0562] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)- 1,4-diazepan- 1 -yl)ethanol;

[0563] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine;

[0564] (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin- 1 -yl)(pyridin-3-yl)methanone;

[0565] 1 -(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin- 1 -yl)-2-hydroxyethanone;

[0566] 1 -(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin- 1 -yl)-2-(dimethylamino)ethanone;

[0567] 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine;

[0568] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-7-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine;

[0569] 2-(4-(4-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin- 1 -yl)ethanol;

[0570] N-(3-chlorobenzyl)-2-(4-((dimethylamino)methyl)piperidin-l-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine;

[0571] 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-4-yl)ethanol;

[0572] N-(3-chlorobenzyl)-3-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-7-(3,5-dimethylisoxazol-4- yl)isoquinolin-1 -amine;

[0573] 2-(4-(1-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)piperazin-1- yl)ethanol;

[0574] 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1- yl)propan-2-ol;

[0575] (R)-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1- yl)propan-2-ol;

[0576] (S)-1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1- yl)propan-2-ol;

[0577] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1- yl)ethanol;

[0578] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)quinazolin-4- amine;

[0579] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1- yl)acetamide;

[0580] 2-(4-(4-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1- yl)acetamide;

[0581] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)- N,N-dimethylacetamide;

[0582] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin- 1 -yl)-N-methylacetamide;

[0583] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin- 1 -yl)acetamide;

[0584] 2-amino-1 -(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-1 -yl)ethanone;

[0585] 1 -(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1 H- pyrazol-1 -yl)-2-methylpropan-2-ol;

[0586] 3-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1 H- pyrazol-1 -yl)propanenitrile;

[0587] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1 -(2-methoxyethyl)-1 H-pyrazol-4- yl)quinazolin-4-amine;

[0588] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1 H- pyrazol-1 -yl)acetonitrile;

[0589] N-(3-chlorobenzyl)-2-(1 -(2-(dimethylamino)ethyl)-1 H-pyrazol-4-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine;

[0590] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1 -(oxetan-3-yl)-1 H-pyrazol-4- yl)quinazolin-4-amine;

[0591] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1 H- pyrazol-1 -yl)-2-methylpropan-1 -ol;

[0592] (5-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)pyridin-2- yl)methanol;

[0593] (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)quinolin-4-amine;

[0594] N-(3-chlorobenzyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(2- (dimethylamino)ethyl)piperazin-1-yl)quinolin-4-amine;

[0595] 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinolin-6-yl)-1- methylpyridin-2(1H)-one;

[0596] 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinolin-6-yl)pyridin-2- ol;

[0597] 2,6-bis(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinolin-4-amine;

[0598] N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinolin-4-amine;

[0599] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2- ylmethyl)quinolin-4-amine;

[0600] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(2- methoxybenzyl)quinolin-4-amine;

[0601] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(3- methoxybenzyl)quinolin-4-amine;

[0602] N-(2-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-4-amine;

[0603] N-(3-bromobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-4-amine;

[0604] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(2- fluorobenzyl)quinolin-4-amine;

[0605] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- fluoropyridin-3-yl)methyl)quinazolin-4-amine;

[0606] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-4-amine;

[0607] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((4- methylpyridin-3-yl)methyl)quinazolin-4-amine;

[0608] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- fluoropyridin-3-yl)methyl)quinazolin-4-amine;

[0609] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-4-amine;

[0610] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-4-amine;

[0611] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- fluoropyridin-3-yl)methyl)quinazolin-4-amine;

[0612] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- fluoropyridin-3-yl)methyl)quinazolin-4-amine;

[0613] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-4-amine;

[0614] 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-3- fluoropyridin-2-ol;

[0615] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((4- methylthiophen-2-yl)methyl)quinazolin-4-amine;

[0616] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- methylthiophen-2-yl)methyl)quinazolin-4-amine;

[0617] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-(thiophen- 2-yl)ethyl)quinazolin-4-amine;

[0618] N-(1-(3-chlorophenyl)ethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine;

[0619] 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6- yl)-3-methylpyridin-2-ol;

[0620] N-benzyl-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl) quinazolin-4-amine;

[0621] N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3-methylisoxazol-4- yl)quinazolin-4-amine;

[0622] N-((5-chlorothiophen-2-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine;

[0623] N-(4-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol- 4-yl)quinazolin-4-amine;

[0624] 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6- yl)pyridin-2-ol;

[0625] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)-N-methylacetamide;

[0626] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)-N,N-dimethylacetamide;

[0627] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(4- fluorobenzyl)quinazolin-4-amine;

[0628] 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one;

[0629] 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2- yl)-1H-pyrazol-1-yl)acetamide;

[0630] 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;

[0631] 5-(4-((3-chlorobenzyl)amino)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin- 6-yl)-1-methylpyridin-2(1H)-one;

[0632] 3-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2- yl)-1H-pyrazol-1-yl)propanenitrile;

[0633] 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;

[0634] 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyacetyl)piperazin-1-yl)quinazolin-6-yl)-1- methylpyridin-2(1H)-one;

[0635] 5-(2-(4-(2-aminoacetyl)piperazin-1-yl)-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1- methylpyridin-2(1H)-one;

[0636] 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2- yl)piperazin-1-yl)acetamide;

[0637] 2-(4-(4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide;

[0638] 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;

[0639] (S)-5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxypropyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one;

[0640] 2-chloro-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine;

[0641] 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one;

[0642] 5-(4-((3-chlorobenzyl)amino)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one;

[0643] 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylpyridin-3-yl)methyl)quinazolin-4-amine;

[0644] 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one;

[0645] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)acetamide;

[0646] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N-methylacetamide;

[0647] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide;

[0648] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2- yl)piperazin-1-yl)ethanol;

[0649] 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinolin-6-yl)-1- methylpyridin-2(1H)-one;

[0650] 5-(4-((3-chlorobenzyl)amino)-2-(4-(1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)quinolin- 6-yl)-1-methylpyridin-2(1H)-one;

[0651] 5-(4-((3-chlorobenzyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)quinolin-6-yl)-1- methylpyridin-2(1H)-one;

[0652] 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinolin- 6-yl)-1-methylpyridin-2(1H)-one;

[0653] 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)quinolin- 6-yl)-1-methylpyridin-2(1H)-one;

[0654] 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinolin-6-yl)-1- methylpyridin-2(1H)-one;

[0655] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinolin- 2-yl)piperazin-1-yl)acetamide;

[0656] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinolin- 2-yl)piperazin-1-yl)-N-methylacetamide;

[0657] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinolin- 2-yl)piperazin-1-yl)-N,N-dimethylacetamide;

[0658] N-((5-chloropyridin-3-yl)methyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6- (3,5-dimethylisoxazol-4-yl)quinolin-4-amine;

[0659] 2-amino-1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinolin-2-yl)piperazin-1-yl)ethanone;

[0660] 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2- yl)piperazin-1-yl)-2-hydroxyethanone; and

[0661] 5-(2-(4-(2-aminoacetyl)piperazin-1-yl)-4-(((5-chloropyridin-3-yl)methyl)amino)quinolin- 6-yl)-1-methylpyridin-2(1H)-one;

[0662] 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)quinolin-6- yl)-1-methylpyridin-2(1H)-one;

[0663] 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxy-2-methylpropyl)piperazin-1- yl)quinolin-6-yl)-1-methylpyridin-2(1H)-one;

[0664] 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2- yl)piperazin-1-yl)-2-methylpropan-2-ol;

[0665] 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)piperazin-1- yl)-2-methylpropan-2-ol;

[0666] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2- yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol;

[0667] 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;

[0668] 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;

[0669] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)-N-methylacetamide;

[0670] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)acetamide;

[0671] 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-6-yl)-1- methylpyridin-2(1H)-one;

[0672] 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)ethanol;

[0673] 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;

[0674] 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;

[0675] 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;

[0676] 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;

[0677] 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;

[0678] 2-(4-(4-((4-chlorophenyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)ethanol;

[0679] 6-bromo-2-chloro-N-(4-chlorophenyl)quinazolin-4-amine;

[0680] N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1- yl)quinazolin-4-amine;

[0681] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperidin-1-yl)quinazolin-4- amine;

[0682] N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperidin-1- yl)quinazolin-4-amine;

[0683] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4- amine;

[0684] 1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-4-methylpiperidine-4- carbonitrile;

[0685] 1-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-4- methylpiperidine-4-carbonitrile;

[0686] N-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine;

[0687] 5-(4-((4-chlorophenyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one;

[0688] N-(4-chlorophenethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-4-amine;

[0689] 2-(4-(4-(3-benzylazetidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)-N,N- dimethylethanamine;

[0690] N-(4-chlorophenyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine;

[0691] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxylic acid;

[0692] 2-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)ethanol;

[0693] (4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)(4-(2- (dimethylamino)ethyl)piperazin-1-yl)methanone;

[0694] 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H-pyrazol-1- yl)acetic acid;

[0695] N4-(3-chlorobenzyl)-N2-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2,4-diamine;

[0696] N-(4-chlorobenzyl)-4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinoline-2- carboxamide;

[0697] N-(3-chlorobenzyl)-2-(4-chlorophenoxy)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine;

[0698] N-(1-(3-chlorophenyl)cyclopropyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine;

[0699] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4-ylmethyl)quinoline-2- carboxamide;

[0700] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)quinoline-2- carboxamide;

[0701] (S)-2-((2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4- yl)amino)-2-phenylethanol;

[0702] 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpyrrolidin-l-yl)quinazolin-2-yl)piperazin-l-yl)-N,N-dimethylethanamine;

[0703] 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpiperidin-l-yl)quinazolin-2-yl)piperazin-l-yl)-N,N-dimethylethanamine;

[0704] 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-l-yl)-N,N-dimethylethanamine;

[0705] N-((lH-imidazol-2-yl)methyl)-4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide;

[0706] N2-((lH-imidazol-2-yl)methyl)-N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-2,4-diamine;

[0707] 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylazetidin-l-yl)quinazolin-2-yl)piperazin-l-yl)-N,N-dimethylethanamine;

[0708] N-(l-(3-chlorophenyl)cyclopropyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-l-yl)quinazolin-4-amine;

[0709] 2-(4-(4-((l-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-lH-pyrazol-l-yl)-N-methylacetamide;

[0710] l-(4-(4-((l-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol;

[0711] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((l-methyl-lH-imidazol-5-yl)methyl)quinazoline-2-carboxamide;

[0712] l-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-l-yl)ethanone;

[0713] 1-(4-(4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)acetone;

[0714] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)quinazolin-2-carboxamide;

[0715] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylpyridin-3-yl)methyl)quinazolin-2-carboxamide;

[0716] 4-((3-chlorobenzyl)amino)-N-((4-chloropyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-carboxamide;

[0717] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)quinazolin-2-carboxamide;

[0718] 4-((3-chlorobenzyl)amino)-N-((1,5-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-carboxamide;

[0719] 4-((3-chlorobenzyl)amino)-N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-carboxamide;

[0720] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-fluoropyridin-3-yl)methyl)quinazolin-2-carboxamide;

[0721] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylpyridin-3-yl)methyl)quinazolin-2-carboxamide;

[0722] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)quinazolin-2-carboxamide;

[0723] 1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-1-yl)acetone;

[0724] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2- methylthiazol-4-yl)methyl)quinazoline-2-carboxamide;

[0725] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((6- methylpyridin-3-yl)methyl)quinazoline-2-carboxamide;

[0726] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1- methylazetidin-3-yl)quinazoline-2-carboxamide;

[0727] N-(1-acetylpiperidin-4-yl)-4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazoline-2-carboxamide;

[0728] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1- methylazetidin-3-yl)methyl)quinazoline-2-carboxamide;

[0729] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-carboxamide;

[0730] 4-((3-chlorobenzyl)amino)-N-((2-chloropyridin-4-yl)methyl)-6-(3,5- dimethylisoxazol-4-yl)quinazoline-2-carboxamide;

[0731] 4-((3-chlorobenzyl)amino)-N-((6-chloropyridin-3-yl)methyl)-6-(3,5- dimethylisoxazol-4-yl)quinazoline-2-carboxamide;

[0732] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1- dioxotetrahydro-2H-thiopyran-4-yl)quinazoline-2-carboxamide;

[0733] 4-((3-chlorobenzyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5- dimethylisoxazol-4-yl)quinazoline-2-carboxamide;

[0734] 4-(((5-chloropyridin-3-yl)methyl)amino)-N-((2-chloropyridin-4-yl)methyl)-6-(3,5- dimethylisoxazol-4-yl)quinazoline-2-carboxamide;

[0735] 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4- ylmethyl)quinazoline-2-carboxamide;

[0736] 4-((3-chlorobenzyl)amino)-N-((3-chloropyridin-4-yl)methyl)-6-(3,5-dimethylisoxazol-4- yl)quinazoline-2-carboxamide;

[0737] 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1- methylpiperidin-4-yl)quinazoline-2-carboxamide;

[0738] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)quinazolin-4-amine;

[0739] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-N-(1- methylpiperidin-4-yl)quinazoline-2-carboxamide;

[0740] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2-methylthiazol-5- yl)methyl)quinazoline-2-carboxamide;

[0741] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methylthiazol-2- yl)methyl)quinazoline-2-carboxamide;

[0742] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylthiazol-2- yl)methyl)quinazoline-2-carboxamide;

[0743] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((3-fluoropyridin-4- yl)methyl)quinazoline-2-carboxamide;

[0744] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((5-methyloxazol-2- yl)methyl)quinazoline-2-carboxamide;

[0745] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((3-methylpyridin-4- yl)methyl)quinazoline-2-carboxamide;

[0746] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methylpyridin-4- yl)quinazoline-2-carboxamide;

[0747] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(6-methylpyridin-3- yl)quinazoline-2-carboxamide;

[0748] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(4-methylpyridin-3- yl)quinazoline-2-carboxamide;

[0749] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(5-fluoropyridin-3- yl)quinazoline-2-carboxamide;

[0750] 4-((3-chlorobenzyl)amino)-N-(6-chloropyridin-3-yl)-6-(3,5-dimethylisoxazol-4- yl)quinazoline-2-carboxamide;

[0751] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(3-fluoropyridin-4- yl)quinazoline-2-carboxamide;

[0752] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(2,6-dimethylpyridin-4- yl)quinazoline-2-carboxamide;

[0753] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methyl-1H-pyrazol-4- yl)quinazoline-2-carboxamide;

[0754] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4- yl)quinazoline-2-carboxamide;

[0755] 4-((3-chlorobenzyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(1- methylpiperidin-4-yl)quinoline-2-carboxamide;

[0756] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4- yl)quinoline-2-carboxamide;

[0757] 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro- 2H-pyran-4-yl)quinazoline-2-carboxamide;

[0758] 4-((3-chlorobenzyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5- dimethylisoxazol-4-yl)quinoline-2-carboxamide;

[0759] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3- yl)methyl)quinoline-2-carboxamide;

[0760] 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl- 1H-imidazol-5-yl)methyl)quinoline-2-carboxamide;

[0761] 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3- yl)methyl)quinoline-2-carboxamide;

[0762] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3- yl)quinoline-2-carboxamide;

[0763] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H- thiopyran-4-yl)quinoline-2-carboxamide;

[0764] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4- yl)quinoline-2-carboxamide;

[0765] 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3- yl)quinoline-2-carboxamide;

[0766] 4-(((5-chloropyridin-3-yl)methyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5- dimethylisoxazol-4-yl)quinoline-2-carboxamide;

[0767] 4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H- thiopyran-4-yl)quinoline-2-carboxamide;

[0768] 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1- methylazetidin-3-yl)methyl)quinazoline-2-carboxamide;

[0769] 4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)thiomorpholine 1,1-dioxide;

[0770] 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1- methylazetidin-3-yl)quinazoline-2-carboxamide;

[0771] 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)thiomorpholine 1,1-dioxide;

[0772] 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-N,N- dimethylpiperazine-1-carboxamide;

[0773] 4-((1-(3-chlorophenyl)cyclopropyl)amino)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6- (3,5-dimethylisoxazol-4-yl)quinazoline-2-carboxamide;

[0774] 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1- dioxotetrahydro-2H-thiopyran-4-yl)quinazoline-2-carboxamide;

[0775] 4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro- 2H-pyran-4-yl)quinazoline-2-carboxamide;

[0776] 4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)-N,N-dimethylpiperazine-1-carboxamide;

[0777] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2-methylpyridin-4- yl)methyl)quinazoline-2-carboxamide;

[0778] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((trans)-4- hydroxycyclohexyl)quinazoline-2-carboxamide;

[0779] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-imidazol-2- yl)methyl)quinazoline-2-carboxamide;

[0780] 4-((3-chlorobenzyl)amino)-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline- 2-carboxamide;

[0781] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((trans)-3-hydroxycyclobutyl)quinazoline- 2-carboxamide;

[0782] 1-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4- yl)piperidine-4-carboxylic acid;

[0783] 1-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinazolin-4-yl)piperidine- 4-carboxylic acid;

[0784] 4-((3-chlorobenzyl)amino)-N-((3,3-difluorocyclobutyl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline- 2-carboxamide;

[0785] 4-((3-chlorobenzyl)amino)-N-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4- yl)quinazoline-2-carboxamide;

[0786] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((4-methylthiazol-5-yl)methyl)quinazoline- 2-carboxamide;

[0787] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((3,5-dimethylisoxazol-4-yl)methyl)quinazoline- 2-carboxamide;

[0788] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((2,4-dimethylthiazol-5-yl)methyl)quinazoline- 2-carboxamide;

[0789] 1-(6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)piperidine-4-carboxylic acid;

[0790] (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylprop-2-ol;

[0791] (R)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)-2-methylprop-2-ol;

[0792] 4-(6-(3,5-dimethylisoxazo-4-yl)quinazolin-4-yl)-3-phenylmorpholine;

[0793] (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolino-2-yl)piperazin-1-yl)-N,N-dimethylethylamine;

[0794] (R)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin-1-yl)-N,N-dimethylethylamine;

[0795] 1-(2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-N-methylpiperidine-4-carboxamide;

[0796] (R)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)quinazolin-4-yl)-3-phenylmorpholine;

[0797] (S)-4-(6-(3,5-dimethylisoxazo-4-yl)-2-(4-(methanesulfonyl)piperazin-1-yl)quinazolin-4-yl)-3-phenylmorpholine;

[0798] 1-(6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-N-methylpiperidine-4-carboxamide;

[0799] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-sulfur dioxide heterocyclic butane-3-yl)quinazolin-2-carboxamide;

[0800] (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazole-1-yl)-N-methylacetamide;

[0801] 6-(3,5-dimethylisoxazol-4-yl)-N-((trans)-4-hydroxycyclohexyl)-4-((S)-3- phenylmorpholino)quinoline-2-carboxamide;

[0802] 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-((trans)-4- hydroxycyclohexyl)quinoline-2-carboxamide;

[0803] (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4- (3-phenylmorpholino)quinoline-2-carboxamide;

[0804] (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinolin-2-yl)(1- methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone;

[0805] (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylazetidin-3-yl)-4-(3- phenylmorpholino)quinoline-2-carboxamide;

[0806] 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)quinoline-4-amine;

[0807] (S)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methyl-1H-imidazol-5-yl)methyl)-4-(3- phenylmorpholino)quinoline-2-carboxamide;

[0808] (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)-4-(3- phenylmorpholino)quinoline-2-carboxamide;

[0809] (S)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-4-(3- phenylmorpholino)quinoline-2-carboxamide;

[0810] (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridin-5-yl)quinolin-4-yl)-3-phenylmorpholine;

[0811] (S)-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylazetidin-3-yl)methyl)-4-(3- phenylmorpholino)quinoline-2-carboxamide;

[0812] (4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2- yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone;

[0813] (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinolin-2-yl)(1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone;

[0814] (4-((1-(3-chlorophenyl)cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2- yl)(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone;

[0815] (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;

[0816] (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;

[0817] (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl)quinolin-4-yl)-3-phenylmorpholine;

[0818] N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl)quinolin-4-amine;

[0819] (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpiperazin-1-yl)quinolin-2-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol;

[0820] (S)-5-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(3-phenylmorpholino)quinolin- 6-yl)-1-methylpyridin-2(1H)-one;

[0821] (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-l-yl)quinazolin-4-yl)-3- phenylmorpholine;

[0822] (S)-l-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin- 1-yl)ethan-l-one;

[0823] (S)-l-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin- 1-yl)-2-methylpropan-2-ol;

[0824] (S)-l-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-N- methylpiperidine-4-carboxamide;

[0825] (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-lH- pyrazol-l-yl)acetamide;

[0826] (S)-l-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-N- methylpiperidine-4-carboxamide;

[0827] (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-N- ethylpiperazine-l-carboxamide;

[0828] (S)-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin- 1-yl)(l-methyl-lH-pyrazol-4-yl)methanone;

[0829] (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-lH- pyrazol-l-yl)-N,N-dimethylacetamide;

[0830] (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(l-((methylsulfonyl)methyl)-lH-pyrazol-4-yl) quinazolin-4-yl)-3-phenylmorpholine;

[0831] (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin- 1-yl)-N,N-dimethylacetamide;

[0832] (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H- pyrazol-1-yl)-2-methylpropan-1-ol;

[0833] (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin- 1-yl)-2-hydroxyethan-1-one;

[0834] (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H- pyrazol-1-yl)ethan-1-ol;

[0835] (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)piperazin- 1-yl)acetamide;

[0836] (S)-1-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-((S)-3-phenylmorpholino)quinazolin-2-yl)piperazin- 1-yl)propan-2-ol;

[0837] (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;

[0838] (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;

[0839] (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;

[0840] 1-(4-(4-((3-chlorobenzyl)(cyclopropyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)- 1H-pyrazol-1-yl)-2-methylpropan-2-ol;

[0841] (S)-7-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-7- azaspiro[3.5]nonan-2-ol;

[0842] (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinolin-2-yl)- 1,8-diazaspiro[4.5]dec-2-one;

[0843] (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidothietan-3-yl)-4-(3- phenylmorpholino)quinoline-2-carboxamide;

[0844] (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinolin-2-yl)(2- hydroxy-7-azaspiro[3.5]non-7-yl)methanone;

[0845] (S)-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinolin-2-yl)(1- methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;

[0846] (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-methyl-1,4,5,7-tetrahydro-6H- pyrazolo[3,4-c]pyridin-6-yl)quinolin-4-yl)-3-phenylmorpholine;

[0847] (S)-tert-buty\ 4-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinolin- 2-yl)-1 H-pyrazol-1 -yl)piperidine-1 -carboxylate;

[0848] (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinolin-2-yl)-2- methyl-2,8-diazaspiro[4.5]dec-1-one;

[0849] (S)-(5-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinolin-2-yl)pyridin- 2-yl)methanol;

[0850] (S)-N-cyclopropyl-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxy-2- methylpropyl)-1 H-pyrazol-4-yl)quinolin-4-yl)-3-phenylpiperazine-1 -carboxamide;

[0851] (S)-(5-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinolin-2-yl)thiophen- 2-yl)methanol;

[0852] (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;

[0853] (S)-4-(2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)- 3-phenylmorpholine;

[0854] (S)-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)thiophen-2- yl)methanol;

[0855] (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;

[0856] (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;

[0857] (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-2,8- diazaspiro[4.5]decan-1-one;

[0858] (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1-methyl- 1,8-diazaspiro[4.5]decan-2-one;

[0859] (S)-N-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-4-(3- phenylmorpholino)quinoline-2-carboxamide;

[0860] 1-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)quinazolin- 4-yl)-N-methylpiperidine-4-carboxamide;

[0861] (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)quinazolin- 4-yl)-3-phenylmorpholine;

[0862] (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-2-(l-methyl-lH-pyrazol-4-yl)quinazolin-4-yl)-3- phenylmorpholine;

[0863] (S)-3-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-lH- pyrazol-l-yl)propanenitrile;

[0864] (S)-8-(4-(4-acetyl-2-phenylpiperazin-l-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-l- methyl-l,8-diazaspiro[4.5]decane-2-one;

[0865] (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(4-(methylsulfonyl)-2-phenylpiperazin-l-yl)quinazolin- 2-yl)-l-methyl-l,8-diazaspiro[4.5]decane-2-one;

[0866] (S)-5-(2-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)-4-(2-phenylpiperazin-l-yl)quinazolin- 6-yl)-l-methylpyridin-2(lH)-one;

[0867] l-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-morpholinoquinazolin-2-yl)-lH-pyrazol-l-yl)-2- methylpropan-2-ol;

[0868] (S)-5-(4-(4-acetyl-2-phenylpiperazin-l-yl)-2-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4- yl)quinazolin-6-yl)-l-methylpyridin-2(lH)-one;

[0869] or a pharmaceutically acceptable salt thereof.

[0870] In some embodiments, the compound is selected from the compounds 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 trifluoroacetate salt.

[0871] Certain compounds described herein contain one or more chiral centers (e.g., including the compounds of the species of the Examples, unless the chemical name otherwise dictates), or can otherwise be capable of existing as multiple stereoisomers. The scope of the present disclosure includes mixtures of stereoisomers and pure or substantially pure enantiomeric or enantiomeric and / or diastereomeric mixtures. In some embodiments, the compounds provided herein exist as (S)-enantiomers. In some embodiments, the compounds provided herein exist as (R)-enantiomers. Also within the scope of the present disclosure are individual stereoisomers of the compounds represented by Formula I, as well as any mixture of full or partial racemates thereof. The present disclosure also includes individual stereoisomers of the compounds represented by the above formula, as mixtures with their isomers in which one or more chiral centers are inverted.

[0872] In some embodiments, the compounds of the present application are provided as pharmaceutically acceptable salts, which include nontoxic salts of the compounds herein listed. 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, mucate, propionate, succinate, lactate, glycolate, malate, tartarate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with amino acids, such as aspartate and glutamate; alkali metal salts, such as sodium and potassium; alkaline earth metal salts, such as magnesium and calcium; ammonium salts; organic base salts, such as trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, and N,N'-dibenzylethylenediamine salts; and salts with basic amino acids, such as lysine salts and arginine salts.

[0873] The salts provided can in some cases be hydrates or solvates. The present application includes salts or solvates of the compounds described herein, including combinations thereof, such as solvates of salts. The compounds of the present disclosure can exist in solvated (e.g., hydrated or ethanol complexed), as well as unsolvated forms, and the present application encompasses all such forms. The salts of the present disclosure can be pharmaceutically acceptable salts.

[0874] Compounds as provided herein, or pharmaceutically acceptable salts thereof, can crystallize in more than one form, a property known as polymorphism, and such polymorphic forms (“polymorphs”) are within the scope of the present disclosure. Polymorphism can generally occur as a result of changes in response to temperature, pressure, or both. Polymorphism can also result from changes during the crystallization process. Polymorphs can be distinguished by various physical properties known in the art, such as by x-ray diffraction patterns, solubility, and melting point.

[0875] While it is possible that, for use in therapy, a compound of the present disclosure can be administered as the raw chemical, it is preferable to present the compound as a pharmaceutical composition or formulation. Accordingly, provided are pharmaceutical compositions comprising one or more compounds of Formula I and / or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0876] A further embodiment of the present application provides a method of making a pharmaceutical composition comprising admixing one or more compounds of Formula I and / or pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0877] In some embodiments, provided are compounds that bind to acetylated proteins and otherwise modulate the binding of acetylated proteins to bromodomain-containing proteins. Such compounds include at least one compound selected from Formula I as provided herein. Exemplary compounds include, but are not limited to, those compounds previously listed by name.

[0878] In some embodiments, provided are compounds for use in treating or preventing a disease or condition mediated by inhibiting the binding of a bromodomain-containing protein to an acetylated protein. In some embodiments, provided are compounds for use in treating a disease or condition mediated by inhibiting the binding of a bromodomain-containing protein to an acetylated protein.

[0879] In some embodiments, provided are compounds for use in treating or preventing a disease or condition mediated by inhibiting the binding of an acetylated protein to a bromodomain-containing protein. In some embodiments, provided are compounds for use in treating a disease or condition mediated by inhibiting the binding of an acetylated protein to a bromodomain-containing protein.

[0880] In some embodiments, provided are methods of treating or preventing a disease comprising the step of administering a compound as provided herein to inhibit the activity of a bromodomain-containing protein.

[0881] In some embodiments, provided are methods of treating or preventing a disease comprising the step of administering a compound as provided herein to inhibit the activity of a bromodomain-containing protein by inhibiting binding to an acetylated protein. In some embodiments, the method is a method of treating a disease comprising the step of administering a compound as provided herein to inhibit the activity of a bromodomain-containing protein by inhibiting binding to an acetylated protein.

[0882] In some embodiments, the use of a compound, or salt thereof, for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease or condition mediated by inhibition of a bromodomain-containing protein by inhibition of binding to acetylated proteins is provided. In some embodiments, the use of a compound, or salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a disease or condition mediated by inhibition of a bromodomain-containing protein by inhibition of binding to acetylated proteins is provided. In some embodiments, the acetylated proteins are acetylated histones.

[0883] In some embodiments, the acetylated proteins are acetylated histones involved in the regulation or dysregulation of gene expression.

[0884] The compounds of the present application, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof can be used to treat or prevent a variety of conditions or disorders. In some embodiments, the compounds of the present application, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof can be used to treat a variety of conditions or disorders.

[0885] In some embodiments, the disease or condition prevented or treated 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 tumor, 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 treated 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 tumor, Merkel cell carcinoma, prostate cancer, ovarian cancer, chordoma, osteoarthritis, rheumatoid arthritis (e.g., juvenile rheumatoid arthritis), Alzheimer's disease, and HIV infection.

[0886] In some embodiments, the disease or condition prevented or treated includes human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myelogenous leukemia, NPM1c-mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumor, 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 treated includes human NUT midline carcinoma, multiple myeloma, Burkitt's lymphoma, myelogenous leukemia, NPM1c-mutant leukemia, T-cell lymphoblastic leukemia, hepatocellular carcinoma, glioblastoma, neuroblastoma, sarcoma, breast cancer, colorectal cancer, lung cancer, pancreatic cancer, neuroendocrine tumor, Merkel cell carcinoma, prostate cancer, osteoarthritis, rheumatoid arthritis (e.g., juvenile rheumatoid arthritis), Alzheimer's disease, and HIV infection.

[0887] In some embodiments, the disease or condition prevented or treated includes Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, and acute lymphocytic leukemia. In some embodiments, the disease to be treated is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, and acute lymphocytic leukemia.

[0888] In some embodiments, methods of treating or preventing a disease or condition mediated by a bromodomain-containing protein are provided, comprising the step of administering a compound as provided herein. In some embodiments, methods of treating a disease or condition mediated by a bromodomain-containing protein are provided, comprising the step of administering a compound as provided herein. Any of the methods or uses provided herein can include administering to a subject a therapeutically effective amount of a compound as provided herein, including salts or polymorphs thereof, or a pharmaceutical composition including such a compound, salt, or polymorph.

[0889] The manner in which the compounds listed herein, or pharmaceutical compositions thereof, can be administered can vary. In some embodiments, the compounds can be administered orally. Preferred pharmaceutical compositions can 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 tablets and capsules. Pharmaceutical compositions can also be administered via injection, i.e., intravenous, intramuscular, subcutaneous, intraperitoneal, intraarterial, intrathecal, and intracerebroventricular administration. Intravenous administration is the preferred method of injection. Carriers suitable for injection are well known to those skilled in the art and include 5% dextrose solution, saline, and phosphate-buffered saline.

[0890] Other modes of administration of the pharmaceutical compositions can also be used, for example, rectal administration. Formulations suitable for rectal administration such as suppositories are well known to those skilled in the art. The compounds can also be administered by inhalation, for example, in an aerosol form; topically, for example, in a lotion; transdermally, for example, using a transdermal patch of the type e.g., available from Novartis and Alza Corporation; by powder injection; or by buccal, sublingual, or intranasal absorption. The pharmaceutical compositions can be formulated in unit dosage or multiple or subunit dosage formulations.

[0891] The pharmaceutical compositions described herein can be administered intermittently or on a progressive, continuous, constant, or controlled release basis. The pharmaceutical compositions can be administered to a warm-blooded animal, for example, a mammal, such as a human. Moreover, the time of administration of the pharmaceutical compositions during the day and the number of times per day that the pharmaceutical compositions are administered can vary.

[0892] The compounds as provided herein are also useful in the preparation of a medicament for the treatment or prevention of a disease or condition characterized by a bromodomain-containing protein binding to acetylated proteins and altering normal gene expression. In some embodiments, the compounds as provided herein are useful in the preparation of a medicament for the treatment of a disease or condition characterized by a bromodomain-containing protein binding to acetylated proteins and altering normal gene expression. Also provided are methods of treating, preventing, delaying the onset of, or slowing the progression of a disorder mediated by acetylated proteins involved in the regulation or dysregulation of gene expression in a mammal in need of such treatment. The methods involve administering to the subject a therapeutically effective amount of a compound as provided herein, including salts thereof or pharmaceutical compositions including such compounds.

[0893] In some embodiments, the methods of treating, preventing, delaying the onset of, or slowing the progression of a disorder mediated by acetylated proteins involved in the regulation or dysregulation of gene expression in a mammal in need of such treatment include administering at least one compound as provided herein, including but not limited to a compound provided according to Formula I.

[0894] The compounds alone or in pharmaceutical compositions as provided herein can be used to treat a variety of disorders and conditions, and thus can be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prevention of these disorders or conditions. Accordingly, in some embodiments, the present disclosure includes administering a compound of the present disclosure in combination with other therapeutic compounds. Such combinations of pharmaceutically active agents can be administered together or separately, and when administered separately, administration can occur simultaneously or sequentially in any order. The amounts of the compounds or agents, and the relative timings of administration, will be selected by a medical practitioner in order to achieve the desired therapeutic effect. The combination of administering a compound of the present disclosure with other therapeutic agents can be by simultaneous administration of: (1) a single pharmaceutical composition including two or more compounds; or (2) separate pharmaceutical compositions including one of the compounds in each composition. Alternatively, the combination can be administered separately in a sequential manner, where one therapeutic agent is administered first and the second therapeutic agent is administered second. Such sequential administration can be in close proximity in time or at a remote time.

[0895] In some embodiments, the present disclosure includes combination therapies, including administering to a subject a therapeutically or prophylactically effective amount of a compound of the present disclosure and one or more other therapies, including chemotherapy, radiation therapy, gene therapy, or immunotherapy.

[0896] The compounds of the present disclosure are useful for mediating the prevention or treatment of various conditions or disorders mediated by the inhibition of bromodomain-containing proteins binding to acetylated proteins. In some embodiments, the compounds of the present disclosure are useful for mediating the treatment of various conditions or disorders mediated by the inhibition of bromodomain-containing proteins binding to acetylated proteins. The compounds and pharmaceutical compositions thereof are particularly useful for treating or preventing various types of cancer, inflammation, obesity, metabolic diseases, cardiovascular diseases, neurodegenerative diseases, psychiatric diseases, and infectious diseases. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for treating various types of cancer, inflammation, obesity, metabolic diseases, cardiovascular diseases, neurodegenerative diseases, psychiatric diseases, and infectious diseases.

[0897] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for treating or preventing systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cell activation and proliferation, lipid metabolism, fibrosis, and viral infection. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for treating systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cell activation and proliferation, lipid metabolism, fibrosis, and viral infection.

[0898] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for treating or preventing a variety of chronic autoimmune and inflammatory conditions, such as Graves ophthalmopathy, Graves disease, Guillain-Barre 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 airway disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin disease, 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 pharmaceutical compositions thereof are particularly useful for treating a variety of chronic autoimmune and inflammatory conditions listed herein. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for treating or preventing a number 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, Takayasu’s arteritis, Kawasaki disease, Kimura’s disease, vasculitis with organ involvement, and acute rejection of transplanted organs. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for treating a number of acute inflammatory conditions listed herein.

[0899] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for treating or preventing diseases or conditions involving an inflammatory response to infection by bacteria, viruses, fungi, parasites, or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxemia, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postoperative syndrome, sarcoidosis, Herxheimer reaction, 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 pharmaceutical compositions thereof are particularly useful for treating a disease or condition involving an inflammatory response to infection by bacteria, viruses, fungi, parasites, or their toxins listed herein.

[0900] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of conditions associated with ischemia-reperfusion injury, such as myocardial infarction; cerebrovascular ischemia (stroke); acute coronary syndrome; renal reperfusion injury; organ transplantation; coronary artery bypass graft; cardiopulmonary bypass surgery; pulmonary, renal, hepatic, gastrointestinal, or peripheral limb embolism. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment of conditions associated with ischemia-reperfusion injury listed herein.

[0901] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of disorders of lipid metabolism, such as hypercholesterolemia, atherosclerosis, and Alzheimer's disease, via modulation of APO-A1. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment of disorders of lipid metabolism listed herein via modulation of APO-A1.

[0902] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of fibrotic conditions, such as idiopathic pulmonary fibrosis, renal fibrosis, post-surgical stenosis, keloid formation, scleroderma, myocardial fibrosis, cystic fibrosis lung inflammation, and liver fibrosis. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of fibrotic conditions, such as idiopathic pulmonary fibrosis, renal fibrosis, post-surgical stenosis, keloid formation, scleroderma, and myocardial fibrosis. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for 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 pharmaceutical compositions thereof are particularly useful for the treatment of fibrotic conditions listed herein.

[0903] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of Rubinstein-Taybi syndrome. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment of Rubinstein-Taybi syndrome.

[0904] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of a disease selected from juvenile rheumatoid arthritis, cystic fibrosis lung inflammation, idiopathic pulmonary fibrosis, liver fibrosis, Guillain-Barre syndrome, and Rubinstein-Taybi syndrome. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment of a disease selected from juvenile rheumatoid arthritis, cystic fibrosis lung inflammation, idiopathic pulmonary fibrosis, liver fibrosis, Guillain-Barre syndrome, and Rubinstein-Taybi syndrome.

[0905] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of viral infections such as herpes viruses, human papilloma virus, adenovirus, and pox viruses and other DNA viruses. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment of viral infections listed herein.

[0906] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of diseases associated with systemic inflammatory response syndrome, including sepsis, burns, pancreatitis, severe trauma, hemorrhage, and ischemia. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment of diseases associated with systemic inflammatory response syndrome listed herein.

[0907] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of SIRS, the onset of shock, multiple organ dysfunction syndrome, the onset of acute lung injury, ARDS, acute kidney injury, acute liver injury, acute cardiac injury, and acute gastrointestinal injury, and death. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment of SIRS, the onset of shock, and multiple organ dysfunction syndrome.

[0908] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment or prevention of sepsis, sepsis syndrome, septic shock and endotoxemia, acute or chronic pancreatitis, herpes simplex infection and reactivation, cold sores, shingles infection and reactivation, chickenpox, shingles, human papilloma virus, cervical tumors, adenovirus infection (including acute respiratory disease), poxvirus infection (such as cowpox and smallpox and African swine fever virus), and for the treatment of human papilloma virus infection of skin or cervical epithelial cells. In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for the treatment of sepsis, sepsis syndrome, septic shock and endotoxemia, acute or chronic pancreatitis, herpes simplex infection and reactivation, cold sores, shingles infection and reactivation, chickenpox, shingles, human papilloma virus, cervical tumors, adenovirus infection (including acute respiratory disease), poxvirus infection (such as cowpox and smallpox and African swine fever virus), and for the treatment of human papilloma virus infection of skin or cervical epithelial cells.

[0909] In some embodiments, the compounds and pharmaceutical compositions thereof are particularly useful for treating or preventing various forms of cancer, leukemia and lymphoma, including acute myeloid leukemia, NPM1c-mutant leukemia, Burkitt's lymphoma, multiple myeloma, T-cell lymphoblastic leukemia, and other hematological cancers involving translocations of the 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 pharmaceutical compositions thereof are particularly useful for treating various forms of cancer, leukemia and lymphoma, including acute myeloid leukemia, NPM1c-mutant leukemia, Burkitt's lymphoma, multiple myeloma, T-cell lymphoblastic leukemia, and other hematological cancers involving translocations of the 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 tumor, 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 tumor, Merkel cell carcinoma, prostate cancer, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, and HIV infection.

[0910] It is contemplated, and thus within the scope of the application, that any of the above features can be combined with any of the other above features.

[0911] It is also contemplated and thus within the scope of the application that negative provisos can be added to exclude any compound or delete any feature.

[0912] Definitions

[0913] The following definitions are meant to clarify, but not limit, the terms defined if not specifically defined herein. If a particular term used herein is not specifically defined, it should not be considered to be undefined. Rather, the term is to be taken in its generally accepted context.

[0914] As used throughout this specification, the preferred number of atoms (such as carbon atoms) will be indicated by, for example, the phrase "C x- C y "alkyl" means, unless otherwise indicated, an alkyl group as defined herein containing the indicated number of carbon atoms. Similar terminology will also apply to other preferred terms and ranges. Thus, for example, C 1-6 "alkyl" means, unless otherwise indicated, an alkyl group as defined herein containing the indicated number of carbon atoms. Similar terminology will also apply to other preferred terms and ranges. Thus, for example, C 1-4 , C 1-3 and the like.

[0915] As used herein, the term "alkyl" refers to a straight-chain or branched-chain hydrocarbon, which can 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, t-butyl, isopentyl, and n-pentyl. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0916] As used herein, the term "alkene" refers to an unsaturated hydrocarbon comprising one or more carbon-carbon double bonds. The term "lower alkene" refers to an alkene comprising five to twenty carbon atoms (such as two to ten carbon atoms), while the term "higher alkene" refers to an alkene comprising more than twenty carbon atoms (such as twenty-one to one hundred carbon atoms). The term "substituted alkene" refers to an alkene having one or more of its hydrogen atoms replaced by one or more substituents (such as halogen). In some embodiments, an alkene group contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0917] As used herein, the term "alkyne" refers to an unsaturated hydrocarbon comprising one or more carbon-carbon triple bonds. The term "lower alkyne" refers to an alkyne comprising five to twenty carbon atoms (such as two to ten carbon atoms), while the term "higher alkyne" refers to an alkyne comprising more than twenty carbon atoms (such as twenty-one to one hundred carbon atoms). The term "substituted alkyne" refers to an alkyne having one or more of its hydrogen atoms replaced by one or more substituents (such as halogen). In some embodiments, an alkyne moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0918] As used herein, the term "cycloalkyl" refers to a fully saturated, optionally substituted monocyclic, bicyclic, spirocyclic, or bridged hydrocarbon ring, wherein multiple degrees of substitution are allowed. Preferably, the ring is a three- to twelve-membered ring, more preferably a five- to six-membered ring. Exemplary "cycloalkyl" groups as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The ring-forming carbon atoms of a cycloalkyl group can optionally be substituted with oxo or sulfido (e.g., C(O) or C(S)). In some embodiments, the cycloalkyl group is a C 3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl group is a C 3-10 monocyclic cycloalkyl.

[0919] As used herein, the term "alkoxy" refers to the group -OR a where R a is an "alkyl" group as defined herein. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0920] As used herein, the term "heterocycloalkyl" or "heterocycle" or "heterocyclyl" refers to an optionally substituted monocyclic or polycyclic ring system, optionally containing one or more degrees of unsaturation, and also containing one or more heteroatoms, which can optionally be substituted, wherein multiple degrees of substitution are allowed. Exemplary heteroatoms include nitrogen, oxygen, or sulfur atoms, including N-oxides, S-oxides, and dioxides. Preferably, the ring is a three- to twelve-membered ring, preferably a five- or six-membered ring, and is either fully saturated or has one or more degrees of unsaturation. Such rings can optionally be fused to one or more separate heterocyclic or cycloalkyl rings. Examples of "heterocycle" 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. In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic ring system that can 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.

[0921] As used herein, the term "aryl" refers to a single benzene ring or a fused benzene ring system that can be optionally substituted, wherein multiple degrees of substitution are allowed. Examples of "aryl" groups used include, but are not limited to, phenyl, benzyl, 2-naphthyl, 1-naphthyl, anthracene, and phenanthrene. Preferably, the aryl ring has five to ten members. The term "aryl" also includes fused benzene ring systems, i.e., where a cyclic hydrocarbon or heterocycle (e.g., a cyclohexane or dioxane ring) or heteroaryl (e.g., pyridine) is fused to an aromatic ring (aryl, such as a benzene ring). In some embodiments, the aryl group has 6 to 10 carbon atoms.

[0922] As used herein, the term "heteroaryl" refers to a monocyclic five- to seven- membered aromatic ring, a fused bicyclic aromatic ring system comprising two such aromatic rings, which can be optionally substituted, with multiple degrees of substitution being allowed, or to a fused bicyclic ring system, i.e., where a cycloalkyl or heterocyclic ring (e.g., a cyclohexane or dioxane ring) is fused to a heteroaryl ring. Preferably, the heteroaryl ring contains five to ten members. These heteroaryl rings contain one or more nitrogen, sulfur, and / or oxygen atoms. In certain embodiments, the heteroaryl ring contains one to three nitrogens, one to three oxygens, or one or two sulfur atoms. N-oxides, sulfoxides, 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. In some embodiments, the heteroaryl is a monocyclic 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.

[0923] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0924] 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 chain "haloalkyl" groups as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl independently substituted with one or more halogens, e.g., fluoro, chloro, bromo, and iodo. The term "haloalkyl" is to be interpreted to include substituents such as perfluoroalkyl groups, e.g., -CF3. In some embodiments, the haloalkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0925] As used herein, the term "mercapto" refers to the -SH group.

[0926] As used herein, the term "thioalkoxy" refers to the group -SR a where R a is an "alkyl" group as defined herein. In some embodiments, the thioalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0927] As used herein, the term "carboxamido" refers to -NH-C(O)-W, where W is hydrogen or an unsubstituted or substituted alkyl, alkene, alkyne, cycloalkyl, aryl, or heterocyclyl group.

[0928] As used herein, the term "amine" has its ordinary meaning and includes primary (e.g., -NH2), secondary (e.g., -NHR), and tertiary amines (e.g., -NRR).

[0929] 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 a cycloalkyl or heterocycle.

[0930] As used herein, the term "sulfonamido" refers to the group -SO2NR'R" wherein R' and R" are as defined in the definition of "amido."

[0931] As used herein, an "optionally substituted" group can be substituted or unsubstituted. Substituents (or substituting groups) can include, but are not limited to, one or more substituents independently selected from the following groups or a specified subset thereof: lower (C1-C6) alkyl, lower alkenyl, lower alkynyl, lower aryl, heteroaryl, alicyclo, heterocyclo, arylalkyl, heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino, dialkylamino, diarylalkylamino, alkylthio, arylthio, heteroarylthio, oxo, oxa, carbonyl (-C(O)), carboxylate (-C(O)OR), carboxamido (-C(O)NH2), carboxyl, acyloxy, -H, halo, -CN, -NO2, -N3, -SH, -OH, -C(O)CH3, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridyl, thiophene, furanyl, indole, indazole, ester, amide, phosphonate, phosphonic acid, phosphate, phosphoramidate, sulfonate, sulfone, sulfate, sulfonamide, carbamate, urea, thiourea, and thioamide, thioalkyl. An optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level therebetween (e.g., -CH2CF3). In some embodiments, a group can be optionally substituted with 1, 2, 3, 4, or 5 independently selected groups (e.g., aryl and heteroaryl of R1may be optionally substituted with 1, 2, 3, 4, or 5 independently selected R8groups). In some embodiments, a group can be optionally substituted with 1, 2, 3 independently selected groups (e.g., aryl and heteroaryl of R1may be optionally substituted with 1, 2, or 3 independently selected R8groups). In some embodiments, a group can be optionally substituted with 1 or 2 independently selected groups (e.g., aryl and heteroaryl of R1may be optionally substituted with 1 or 2 independently selected R8groups). In some embodiments, a group can be optionally substituted with 1 group (e.g., aryl and heteroaryl of R1may be optionally substituted with 1 R8group).

[0932] As used herein, the term "pharmaceutically acceptable" means a carrier, diluent, excipient, or salt form of the compounds of the disclosure that is compatible with the other ingredients of the formulation of the pharmaceutical composition.

[0933] As used herein, the term "pharmaceutical composition" refers to a compound of the disclosure optionally admixed with one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical compositions preferably exhibit a certain degree of stability to environmental conditions so as to make them suitable for production and commercialization purposes.

[0934] As used herein, the terms "effective amount", "therapeutic amount" and "effective dose" refer to the amount of a compound of the disclosure that is sufficient to result in the desired pharmacological or therapeutic effect, leading to the effective prevention or treatment of a disorder. The treatment of a disorder can be manifested as a delay or prevention of the onset or progression of the disorder and of the symptoms associated with the disorder. The treatment of a disorder can also be manifested as a reduction or elimination of symptoms, reversal of the progression of the disorder and any other contribution to the patient's health. The effective dose can vary depending on factors such as the patient's condition, the severity of the symptoms of the disorder and the manner of administration of the pharmaceutical composition.

[0935] The term "prodrug" as used herein is intended to encompass a class of analogs of the compounds of the present invention in which a metabolically labile moiety is attached to the compound of the invention via an available NH, C(O)H, COOH, C(O)NH2, OH or SH functional group. The prodrug forming moiety is removed by a metabolic process and the active compound with a free NH, C(O)H, COOH, C(O)NH2, OH or SH group is released in vivo. Prodrugs can be used to modulate the pharmacokinetic properties of a compound, such as solubility and / or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration and clearance. The design and preparation of various forms of prodrugs are known to those skilled in the art and described, for example, in:

[0936] a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Chapter 31 (Academic Press, 1996).

[0937] b) Design of Prodrugs, H. Bundgaard, ed. (Elsevier, 1985); 33.

[0938] c) A Textbook of Drug Design and Development, edited by P. Krogsgaard-Larson and H. Bundgaard, Chapter 5, pp. 113-191 (Harwood Academic Publishers, 1991); and

[0939] d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).

[0940] The descriptions of prodrugs in the references cited are incorporated herein by reference.

[0941] General methods of making compounds

[0942] The present application also provides processes for synthesizing the compounds of the present disclosure. The present application further provides processes for synthesizing compounds useful as intermediates in the preparation of the compounds of the present disclosure. The compounds can be prepared according to the methods described below using starting materials and reagents that are readily available. Variations of the methods described can be used by one of ordinary skill in the art without departing from the scope of the present application. Those skilled in the art of organic synthesis will appreciate that there are many methods of preparing the compounds of the present disclosure. Exemplary synthetic methods are set forth herein, including methods involving specific selected compounds identified in Table 2.

[0943] 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 can vary depending on the particular reactants or solvent used, but once these are selected, they can be determined by ordinary optimization procedures.

[0944] Those skilled in the art of organic synthesis will appreciate that susceptible moieties such as C(O)OH, C(O) and C(O)H, NH, C(O)NH2, OH, and SH moieties can be protected and deprotected if necessary. Protecting groups for C(O)OH moieties include, but are not limited to, allyl, benzoylmethyl, benzyl, benzyloxymethyl, t-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-dioxanyl ketal, diethyl ketal, dimethyl ketal, 1,3-dithianyl ketal, O-methyl oxime, O-phenyl oxime, and the like. Protecting groups for NH moieties include, but are not limited to, acetyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc), 3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoryl, formyl, methanesulfonyl, p-methoxybenzyloxycarbonyl, phenylacetyl, phthalyl, succinyl, trichloroethoxycarbonyl, triethylsilyl, trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl, p-toluenesulfonyl, and the like.

[0945] Protecting groups for OH and SH moieties include, but are not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, t-butyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 3,4-dimethoxybenzyl, 3,4-dimethoxybenzyloxycarbonyl, 1,1-dimethyl-2-propenyl, diphenylmethyl, methanesulfonyl, methoxyacetyl, 4-methoxybenzyloxycarbonyl, p-methoxybenzyl, methoxycarbonyl, methyl, p-toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloroethyl, triethylsilyl, trifluoroacetyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-trimethylsilyl ethyl, triphenylmethyl, 2-(triphenylphosphoryl)ethoxycarbonyl, and the like.

[0946] A discussion of protecting groups is given in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons, New York (1999).

[0947] Examples

[0948] General Synthetic Schemes

[0949] The invention will now be further described with reference to the following exemplary embodiments, wherein, unless otherwise stated, (i) all air- or moisture-sensitive reactions are carried out in dried glassware under positive nitrogen pressure; (ii) chemical reagents and anhydrous solvents are 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, i.e., in the range of 18–25°C; (iv) organic solutions are dried with anhydrous sodium sulfate or magnesium sulfate, unless otherwise stated; evaporation of organic solvents is carried out using a rotary evaporator under reduced pressure; (v) column chromatography means silica gel rapid chromatography; thin-layer chromatography (TLC) is performed on silica gel plates; (vi) generally, the reaction process is tracked by TLC or liquid chromatography / mass spectrometry (LC / MS), and the reaction times given are for illustrative purposes only; (vii) Phenomenex Luna is used on a Waters semi-preparative HPLC. Preparative purification was performed using a C18 (5 μm, 30 x 75 mm) column at a flow rate of 45 mL / min, with a mobile phase consisting of acetonitrile and water (each containing 0.1% trifluoroacetic acid); a 10% to 50% acetonitrile gradient was used during purification over 8 minutes; fraction collection was initiated by UV detection (220 nm); (viii) Analytical 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 equivalent gradient, 4% to 100% acetonitrile (0.05% trifluoroacetic acid) in water over 3 minutes, with a run time of 4.5 minutes and a flow rate of 0.8 mL / min; Phenomenex Luna was used at 50 °C. C18 column (3 μm, 3 x 75 mm); Method 2: Flow rate of 1 mL / min over 8 minutes, with a 7-minute gradient of 4% to 100% acetonitrile (containing 0.05% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid).025% trifluoroacetic acid) were analyzed on an Agilent 1260; using a Phenomenex Luna C18 column (3 microns, 3 x 75 mm) at 50 °C; purity determinations were made using an Agilent diode array detector for both Method 1 and Method 2; mass determinations were made using an Agilent 6130 mass spectrometer in positive mode electrospray ionization; all analogs tested had greater than 95% purity based on both analytical methods; (ix) high resolution mass spectra were recorded on an Agilent 6210 time-of-flight LC / MS system; (x) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and / or mass spectral data; (xi) when NMR data is given, it is in the form of delta values for major diagnostic protons given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, and was obtained on a Varian 400 (100) and 600 MHz spectrometer 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 structure of the compound described herein, the structure controls; (xiv) solvent ratios are given in volume:volume (v / v); (xv) the yields given are only illustrative and are not necessarily the yields that would be obtained by diligent process development; preparations were repeated if more material was needed.

[0950] Representative synthetic schemes

[0951] Scheme 1

[0952]

[0953] Compounds of Formula I, wherein Y is NR6R7, aryl or heteroaryl, can be prepared according to Scheme 1. Dichloride 1 can be reacted with amine R1-L1-NH-R2 in an ethanolic solution to give intermediate compound 2. 2 can be coupled with a boronic acid or boronic ester in the presence of a palladium catalyst to give compound 3. Treatment of 3 with an amine R6R7NH in an ethanolic solution will give an amine of Formula I, wherein Y is NR6R7, while 3 can be coupled with an aryl or heteroaryl boronic acid or boronic ester in the presence of a palladium catalyst to give a compound of Formula I, wherein Y is aryl or heteroaryl.

[0954] Scheme 2

[0955]

[0956] In an alternative, compounds of Formula I wherein X and Z are N and Y is NR6R7 can be prepared according to Scheme 2. Dichloride 1 can be reacted with potassium t-butoxide to give t-butyl ether 4. 4 can be coupled with a boronic acid or boronate ester in the presence of a palladium catalyst to give compound 5. Treatment of 5 with an amine in an ethanolic solution followed by deprotection in the presence of trifluoroacetic acid gives amine 6, which can be coupled with an amine R1-L1-NH-R2 in the presence of a suitable activating agent such as PyBrOP to give a compound of Formula I.

[0957] Compounds of the application prepared according to Scheme 1 or Scheme 2 are given in Table 1 and further details of their preparation are provided in the following synthetic procedures.

[0958] Table 1

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022] Detailed synthesis procedure

[1023] Example 1. 2-Chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4- amine .

[1024] Step 1: 6-Bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine.

[1025] 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 Et3N (0.209 ml, 1.5 mmol). The mixture was stirred at room temperature for 1 h. The mixture was poured into EtOAc / H2O (5 mL / 5 mL). The aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was triturated with hexanes 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.

[1026] Step 2: 2-Chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4- amine.

[1027] 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), PdCl2(dppf) (65.9 mg, 0.09 mmol) and K2CO3(311 mg, 2.250 mmol). The air was removed and refilled with N2(2-3 times). Then a mixture of 1,4-dioxane (3 ml) and water (1 ml) was added and stirred at 95 °C (preheated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was triturated with 50% CH2Cl2 / hexanes to give 48 mg of pure solid product. The filtrate was concentrated and purified by silica gel chromatography using 20-40% EtOAc / hexanes as eluent, then the product was triturated with 5% CH2Cl2 / hexanes to give 170 mg of pure solid product. A total of 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-d6) 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.

[1028] Example 2. N-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[1029] Step 1: 6-Bromo-N-(3-chlorobenzyl)quinazolin-4-amine.

[1030] 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 Et3N (0.21 ml, 1.5 mmol). The mixture was stirred at room temperature for 3 h. The mixture was poured into EtOAc / H2O (5 mL / 5 mL). The aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was triturated with hexanes 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.

[1031] Step 2: N-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[1032] 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), PdCl2(dppf) (14.6 mg, 0.02 mmol) and K2CO3(83 mg, 0.6 mmol). The air was removed and refilled with N2(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 (preheated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 20-40% EtOAc / hexanes as 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.

[1033] Example 3. N-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinoline-4-amine.

[1034] Step 1: 6-Bromo-N-(3-chlorobenzyl)quinoline-4-amine.

[1035] Into 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 / H2O (30 mL / 30 mL). The organic layer was washed with H2O (30 mL), dried (Na2SO4), and filtered. After removal of the solvent, the product was triturated with 2% CH2Cl2 / hexanes, then dried to give 6-bromo-N-(3-chlorobenzyl)quinolin-4-amine (238 mg, 0.685 mmol, 68.5% yield). MS (M+H) + = 349.

[1036] Step 2: N-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinoline-4-amine.

[1037] Into a 2-necked 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), PdCl2(dppf) (18.29 mg, 0.025 mmol), and K2CO3(138 mg, 1.0 mmol). The air was removed and refilled with N2(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 (preheated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 0-5% MeOH / EtOAc as eluent to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine (88.5 mg, 0.243 mmol, 97% yield). 1H 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.

[1038] Example 4. N-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinoline-4- amine.

[1039] Step 1: 6-Bromo-N-(3-chlorobenzyl)-2-methylquinoline-4-amine.

[1040] A microwave tube was charged with 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 / H2O (30 mL / 30 mL). The organic layer was washed with H2O (30 mL), dried (Na2SO4), and filtered. After removal of the solvent, the product was triturated with 2% CH2Cl2 / hexanes, 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.

[1041] Step 2: N-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinoline-4- amine.

[1042] A 2-neck flask was charged with 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), PdCl2(dppf) (18.29 mg, 0.025 mmol) and K2CO3(138 mg, 1.0 mmol). The air was removed and refilled with N2(2-3 times). A mixture of 1,4-dioxane (1.5 ml) and water (0.5 ml) was then added and stirred at 95 °C (preheated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 0-5% MeOH / EtOAc as 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.

[1043] Example 5. N4-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-methylquinazoline- 2,4-diamine. Example 6. N-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin- 1-yl)quinazolin-4-amine.

[1044] 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 methylamine (1.0 ml, 2.0 mmol) (2M in THF). The tube was sealed and heated at 75 °C for 16 h. After cooling to room temperature, the mixture was concentrated and the residue was re-dissolved in DMSO, filtered through a filter and purified 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.

[1045] Example 7. N4-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(1-methylpiperidin- 4-yl)quinazoline-2,4-diamine. Example 8. N-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methoxyquinazolin-4- amine.

[1046] 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 room temperature, the mixture was concentrated and the residue was re-dissolved in DMSO, filtered through a filter and purified to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4- amine, 2 TFA (23.1 mg, 0.033 mmol, 39.3% yield). 1 H NMR (400 MHz, DMSO-d6) 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.

[1047] 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.

[1048] 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 room temperature, the mixture was concentrated and the residue was re-dissolved in DMSO, filtered through a filter and purified to give N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine, 2 TFA (17 mg, 0.024 mmol, 28.4% yield). MS (M+H) + = 477.

[1049] Step 2: N-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methylquinazolin-4- amine.

[1050] 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, ~ 6.5 M). The tube was sealed and heated at 75 °C for 3 h. After cooling to room temperature, the mixture was concentrated, then H2O (6 mL) was added. The white solid was collected, triturated with water (2 mL x 2) and hexanes (2 mL), 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.

[1051] Example 10. N4-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-morpholinoethyl) quinazoline-2,4-diamine.

[1052] Example 11. N4-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-(4-methylpiperazin- 1-yl)ethyl)quinazoline-2,4-diamine.

[1053] 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) was added 1,4-dioxane (4 ml) under N2, then triethylamine (253 mg, 2.5 mmol) was added. The mixture was stirred at room temperature for 1 h and (3-chlorophenyl)methanamine (142 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 24 h. To the mixture was added H2O (5 mL), and the aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 20-40% EtOAc / hexanes as eluent to give 6-bromo-N-(3-chlorobenzyl)-2-methylquinazolin-4-amine (66 mg, 0.182 mmol, 36.4% yield). MS (M+H) + = 364.

[1054] Example 12. N-(3-Chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine.

[1055] A 2-necked flask was charged with 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), PdCl2(dppf) (12.11 mg, 0.017 mmol) and K2CO3(68.6 mg, 0.496 mmol). Air was removed and refilled with N2(2-3 times). A mixture of 1,4-dioxane (1 ml) and water (0.3 ml) was then added and stirred at 95 °C (preheated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic layer was dried (Na2SO4) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 35-60% EtOAc / hexanes as 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.

[1056] ​ ​

[1057] 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-morpholinoethylamine (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 room temperature, the mixture was filtered through a filter and purified to give N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-morpholinoethyl)quinazoline-2,4-diamine, 2 TFA (23.1 mg, 0.032 mmol, 32.0% yield). 1H NMR (400 MHz, DMSO-d6) 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). (includes 2 salt NH); MS (M+H) + = 493.

[1058] ​ ​

[1059] To a mixture of 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazoline-4- amine (Example 1, 39.9 mg, 0.1 mmol) and 2-(4-methylpiperazin-l-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 room temperature, the mixture was filtered through a filter and purified to give N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-(4- methylpiperazin-l-yl)ethyl)quinazoline-2,4-diamine, 2 TFA (28.6 mg, 0.039 mmol, 39.0% yield). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 2 salt NH); MS (M+H) + = 506.

[1060] ​ ​

[1061] 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-l-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 room temperature, the mixture was filtered through a filter and purified to give N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-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-d6) 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). (includes 2 salt NH); MS (M+H) + = 520.

[1062] Example 13. 3-((4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)amino)propan-1-ol. Example 14. N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinolin-4-amine.

[1063] The title compound was prepared according to a procedure analogous to that described in Example 12 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-l-ol (75 mg, 1.0 mmol). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 438.

[1064] Example 15. 6-bromo-N-(3-chlorobenzyl)-2-(3,5-dimethylisoxazol-4-yl)quinolin-4- amine.

[1065] To a mixture of 4,4'-(4-chloroquinolin-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 under microwave irradiation at 160 °C for 1 h. The mixture was then filtered through a filter and purified 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.

[1066] Example 16. N-(3-chlorobenzyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinolin-4-amine.

[1067] 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 (1 ml). The tube was sealed and heated under microwave irradiation at 160 °C for 1 h. The mixture was then filtered through a filter and purified 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.

[1068] Example 17. (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-1-yl)(cyclopropyl)methanone. 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.

[1069] The title compound was prepared according to a procedure analogous to that described in Example 12 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-l-yl)propan-l-amine (42.8 mg, 0.25 mmol). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 2 salt NH); MS (M+H) + = 534.

[1070] Example 19. 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin- 4-amine. Example 20. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-1-yl)ethanol.

[1071] The title compound was prepared according to a procedure analogous to that described in Example 12 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-l-yl)methanone, HC1 (47.7 mg, 0.25 mmol) and Hunig's base (0.044 ml, 0.250 mmol). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 517.

[1072] Example 21. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-isopentylpiperazin-1-yl)quinazolin- 4-amine. Example 22. N4-(3-chlorobenzyl)-N2-(2-(dimethylamino)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-N2- methylquinazoline-2,4-diamine.

[1073] The title compound was prepared according to a procedure analogous to that described in Example 12 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-lH-pyrazol-4-yl)(piperazin-l- yl)methanone, HC1 (57.7 mg, 0.25 mmol) and Hunig's base (0.044 ml, 0.25 mmol). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 557.

[1074] Example 23. (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin- 4-yl)methanol. NExample 24. (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin- 3-yl)methanol. Example 25. (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin- 2-yl)methanol.

[1075] 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-l-yl)ethanamine (39.3 mg, 0.25 mmol) according to a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) 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). (includes 2 salt NH); MS (M+H) + = 505.

[1076] Example 26. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinolin-4-amine. Example 27. N-(3-chlorobenzyl)-4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinolin-2-amine.

[1077] 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-l-yl)ethanol (32.5 mg, 0.25 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 493.

[1078] Example 28. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-morpholinoethyl)-1H- pyrazol-4-yl)quinazolin-4-amine. N ​ ​

[1079] 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- isopenty lpiperazine (39.1 mg, 0.25 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 519.

[1080] ​ ​

[1081] 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 a procedure analogous to that described in Example 12. MS (M+H) + = 465.

[1082] ​ ​

[1083] 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 a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 478.

[1084] ​ ​

[1085] 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 a procedure analogous to that described in Example 12. 1H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 478.

[1086] ​ ​

[1087] The title compound was prepared according to a procedure analogous to that described in Example 12 from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4- amine (Example 1, 19.96 mg, 0.05 mmol) and piperidin-2-ylmethanol (28.8 mg, 0.250 mmol). MS (M+H) + = 478.

[1088] ​ ​

[1089] 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-l-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 room temperature, the mixture was filtered through a filter and purified to give N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4- amine, 2 TFA (21.6 mg, 0.029 mmol, 19.27% yield). 1H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 519.

[1090] ​ ​

[1091] 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-l-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 room temperature, the mixture was filtered through a filter and purified to give N-(3-chlorobenzyl)-4-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5- dimethylisoxazol-4-yl)quinolin-2-amine, 2 TFA (22.8 mg, 0.031 mmol, 20.34% yield). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 519.

[1092] ​ ​

[1093] A 2-neck flask was charged with 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethyl)morpholine (61.4 mg, 0.2 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.00 μmol), and K2CO3(69.1 mg, 0.5 mmol). Air was removed and refilled with N2(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 (preheated) for 1 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was dissolved in DMF, filtered through a filter and purified to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(l-(2-morpholinoethyl)-lH-pyrazol-4-yl)quinazolin-4-amine, 2TFA (15.2 mg, 0.02 mmol, 19.69% yield). 1 HNMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 544.

[1094] Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine. Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine.

[1095] The title compound was prepared according to a procedure analogous to that described in Example 12 from 2-chloro-N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 19.96 mg, 0.05 mmol), piperazin-l-yl(pyridin-4-yl)methanone, 2HCI (66.0 mg, 0.25 mmol), and Hunig's base (0.175 ml, 1.0 mmol). 1H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 554.

[1096] Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine. Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine.

[1097] The title compound was prepared according to a procedure analogous to that described in Example 12 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). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 492.

[1098] Step 1: N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-2-yl)piperidin- 1 -yl)ethanamine Step 2: N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-2-yl)piperidin- 1 -yl)ethanamine

[1099] Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine. Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine.

[1100] A 2-necked flask was charged with 2-chloro-N-(3-chlorobenzyl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine (Example 1, 399 mg, 1 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester (464 mg, 1.5 mmol), PdCl2(dppf)-CH2Cl2adduct (82 mg, 0.1 mmol) and K2CO3(622 mg, 4.5 mmol). Air was removed and refilled with N2(2-3 times). Then a mixture of 1,4-dioxane (6 ml) and water (3 ml) was added and stirred at 95 °C (preheated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 20-40-50% EtOAc / hexanes as eluent to give 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-5,6- dihydropyridine-l(2H)-carboxylic acid tert-butyl ester (403 mg, 0.738 mmol, 73.8% yield). MS (M+H) + = 546.

[1101] Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine. Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine.

[1102] To a solution of 4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin- 2-yl)-5,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester (403 mg, 0.738 mmol) in 1,4- dioxane (2 ml) was added HCl (4 M in dioxane, 2 mL). The mixture was stirred at room temperature for 2 h. Then, hexanes (20 mL) was added and the solvent was carefully removed (3 times). The solid was then dried under vacuum to give N-(3-chlorobenzyl)-6-(3,5- dimethylisoxazol-4-yl)-2-(l,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine, 2HCl (390 mg, 0.752 mmol, 102% crude yield). This material was used in the next step without further purification. 25 mg was purified to give N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(l,2,3,6- tetrahydropyridin-4-yl)quinazolin-4-amine, 2TFA (as TFA salt) for screening. 1H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 446.

[1103] Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine. Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine.

[1104] The title compound was prepared according to a procedure analogous to that described in Example 12 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). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 534.

[1105] Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine. Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine.

[1106] The title compound was prepared according to a procedure analogous to that described in Example 12 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). 1H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 507.

[1107] Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine. Example 29. N-(3-chlorobenzyl)-2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-l-yl)ethanamine.

[1108] 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 a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) 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). (includes 2 salt NH); MS (M+H) + = 519.

[1109] ​ ​

[1110] 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 a procedure analogous to that described in Example 12. 1H NMR (400 MHz, DMSO-d6) 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). Includes 1 salt NH); MS (M+H) + = 554.

[1111] ​ ​

[1112] The title compound was prepared according to a procedure analogous to that described in Example 12 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). 1 H NMR (400 MHz, DMSO-d6) 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). Includes 1 salt NH); MS (M+H) + = 507.

[1113] ​ ​

[1114] The title compound was prepared according to a procedure analogous to that described in Example 12 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). 1H NMR (400 MHz, DMSO-d6) 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). (includes 2 salt NH); MS (M+H) + = 534.

[1115] ​

[1116] Into a 2-necked 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-l,3,2-dioxaborolan-2-yl)isoxazole (223 mg, 1.000 mmol), PdCl2(dppf)-CH2Cl2 adduct (82 mg, 0.1 mmol) and K2CO3(415 mg, 3.0 mmol). The air was removed and refilled with N2(2-3 times). Then a mixture of 1,4-dioxane (3 ml) and water (1.5 ml) was added and stirred at 95 °C (preheated) for 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 25-60% EtOAc / hexanes as eluent to give 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-4- amine (370 mg, 0.927 mmol, 93% yield). HPLC purification of 25 mg of material gave the TFA salt for screening. MS (M+H) + = 399.

[1117] ​ ​

[1118] The title compound was prepared according to a procedure analogous to that described in Example 12 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-l-yl)ethanamine (39.3 mg, 0.25 mmol). MS (M+H) + = 520.

[1119] ​​

[1120] 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-l- yl)ethanol (32.5 mg, 0.250 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 493.

[1121] ​ ​

[1122] 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-l-(piperidin-4-yl)methanamine (35.6 mg, 0.25 mmol) according to a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) 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). (includes 2 salt NH); MS (M+H) + = 505.

[1123] Example 42. 2-(l-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)-lH-pyrazol-4-yl)ethanol. Example 43. N-(3-chlorobenzyl)-3-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-7-(3,5- dimethylisoxazol-4-yl)isoquinolin-l -amine.

[1124] 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-(lH-pyrazol-4-yl)ethanol (28.0 mg, 0.250 mmol) and K2CO3(34.6 mg, 0.25 mmol) was added DMF (volume: 1 ml). The tube was sealed and heated under microwave irradiation at 150 °C for 1.5 h. After cooling to room temperature, the mixture was filtered through a filter and purified to give 2-(l-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-lH-pyrazol-4- yl)ethanol, 2 TFA (0.6 mg, 0.854 μmol, 1.707 % yield). MS (M+H) + = 475.

[1125] Example 44. 2-(4-(l-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-3- yl)piperazin-l-yl)ethanol. Example 45. l-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-l-yl)propan-2-ol.

[1126] To a mixture of 3-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)isoquinlin-1-amine (0.02 g, 0.05 mmol) and N,N-dimethyl-2-(piperazin-l-yl)ethanamine (0.157 g, 1.0 mmol) was added DMF (1 ml). The tube was sealed and heated under microwave irradiation at 200 °C for 2 h. After cooling to room temperature, the mixture was filtered through a filter and purified to give N-(3-chlorobenzyl)-3-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-1- amine, 2 TFA. MS (M+H) + = 519.

[1127] Example 46. (R)-l-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-l-yl)propan-2-ol. Example 47. (S)-l-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-l-yl)propan-2-ol.

[1128] To a mixture of 3-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)isoquinlin-1-amine (0.02 g, 0.05 mmol) and 2-(piperazin-l-yl)ethanol (0.13 g, 1.0 mmol) was added DMF (1 ml). The tube was sealed and heated under microwave irradiation at 200 °C for 2 h. After cooling to room temperature, the mixture was filtered through a filter and purified to give 2-(4-(l-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)piperazin-l-yl)ethanol, 2 TFA. MS (M+H) + = 492.

[1129] Example 48. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)-lH-pyrazol-l-yl)ethanol. Example 49. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(l-methyl-lH-pyrazol-4- yl)quinazolin-4-amine.

[1130] 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- (piperidin-4-yl)ethanol (36.1 mg, 0.25 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 507.

[1131] Example 50. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)-lH-pyrazol-l-yl)acetamide. Example 51. 2-(4-(4-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)-lH-pyrazol-l-yl)acetamide.

[1132] 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 a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) 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.

[1133] Example 52. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-l-yl)-N,N-dimethylacetamide. Example 53. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-l-yl)-N-methylacetamide.

[1134] 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 a procedure analogous to that described in Example 12. MS (M+H) + = 507.

[1135] Example 54. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-l-yl)acetamide. Example 55. 2-amino-l-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin- 2-yl)piperazin-l-yl)ethanone.

[1136] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethanol (23.81 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol) and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 28. 1 H NMR (400 MHz, DMSO-d6) 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.

[1137] Example 56. l-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-l-yl)ethanone. ​

[1138] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (20.81 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol) and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) + = 445.

[1139] ​ ​

[1140] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)acetamide (25.1 mg, 0.100 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol), and K2CO3(34.6 mg, 0.250 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) + = 488.

[1141] ​ ​

[1142] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)acetamide (25.1 mg, 0.100 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol), and K2CO3(34.6 mg, 0.250 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) 1 H NMR (400 MHz, DMSO-d6) 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.

[1143] ​ ​

[1144] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)acetamide (25.1 mg, 0.100 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol), and K2CO3(34.6 mg, 0.250 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) 1H NMR (400 MHz, DMSO-d6) 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.

[1145] ​ ​

[1146] The title compound was prepared according to a procedure analogous to that described in Example 12 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-l-yl)acetamide, HC1 (48.4 mg, 0.25 mmol) and Hunig's base (0.175 ml, 1.0 mmol). 1 H NMR (400 MHz, DMSO-d6) 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) + = 520.

[1147] ​ ​

[1148] The title compound was prepared according to a procedure analogous to that described in Example 12 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-l-yl)acetamide, HC1 (44.9 mg, 0.25 mmol) and Hunig's base (0.175 ml, 1.0 mmol). 1H NMR (400 MHz, DMSO-d6) 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.

[1149] ​ ​

[1150] The title compound was prepared according to a procedure analogous to that described in Example 12 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, HC1 (44.9 mg, 0.25 mmol) and Hunig's base (0.175 ml, 1.0 mmol). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 2 salt NH); MS (M+H) + = 506.

[1151] ​ 1H-pyrazole-1-yl)-2-methylprop-2-ol.

[1152] The title compound was prepared according to a procedure analogous to that described in Example 28 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), PdCl2(dppf)- CH2Cl2adduct (8.17 mg, 10.0 μmol) and K2CO3(41.5 mg, 0.30 mmol). MS (M+H) + = 503.

[1153] Example 57. 3-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- 1H-pyrazole-1-yl)propionitrile.

[1154] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propanenitrile (24.71 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol), and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 28. MS (M + H) + = 484.

[1155] Example 58. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-methoxyethyl)- 1H-pyrazol-4-yl)quinazolin-4-amine.

[1156] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (25.2 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol), and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 28. 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M + H) + = 489.

[1157] Example 59. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- 1H-pyrazole-1-yl)acetonitrile.

[1158] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)acetonitrile (23.31 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol) and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) + = 470.

[1159] Example 60. N-(3-chlorobenzyl)-2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-6-(3,5- (dimethylisoxazol-4-yl)quinazolin-4-amine.

[1160] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethanamine (0.027 g, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol) and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 28. 1 H NMR (400 MHz, DMSO-d6) 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.

[1161] Example 61. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(oxecyclobutane-3-) 1H-pyrazole-4-yl)quinazolin-4-amine.

[1162] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan-l- ol (53.2 mg, 0.20 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol) and K2CO3(83 mg, 0.60 mmol) according to a procedure analogous to that described in Example 28. MS (M + H) + = 487.

[1163] Example 62. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- 1H-pyrazole-1-yl)-2-methylprop-1-ol.

[1164] 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan-l- ol (53.2 mg, 0.20 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol) and K2CO3(83 mg, 0.60 mmol) according to a procedure analogous to that described in Example 28. MS (M + H) 1 H NMR (400 MHz, DMSO-d6) 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.

[1165] Example 63. (5-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl) Pyridin-2-yl)methanol.

[1166] 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), PdCl2(dppf)- CH2Cl2adduct (8.17 mg, 10.0 μmol), and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 28. 1 H NMR (400 MHz, DMSO-d6) 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.

[1167] Example 64. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(1H-pyrazole- 4-yl)quinazolin-4-amine.

[1168] Step 1: 6-Bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4- amine.

[1169] 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-l- yl)ethanamine (314 mg, 1.995 mmol) followed by Hunig's base (0.348 ml, 1.995 mmol). The tube was sealed and heated at 90 °C for 5 h. After cooling to room temperature, the mixture was poured into EtOAc / H2O (50 mL / 50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was dried under vacuum to give 6-bromo-N-(3-chlorobenzyl)-2-(4-(2- (dimethylamino)ethyl)piperazin-l-yl)quinazolin-4-amine (760 mg, 1.508 mmol, 101% yield) which was used in the next step without further purification. MS (M+H) + = 505.

[1170] Step 2: N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(1H-pyrazole-4-) (By) quinazolin-4-amine.

[1171] 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), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole-1 - carboxylic acid tert-butyl ester (0.029 g, 0.10 mmol), PdCl2(dppf)-CH2Cl2 adduct (4.08 mg, 5.0 μmol), and K2CO3(0.041 g, 0.30 mmol). The air was removed and refilled with N2(2-3 times). A mixture of 1,4-dioxane (1 ml) and water (0.5 ml) was then added and stirred at 95 °C (preheated) for 1 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was filtered through a PL-Thio-resin, eluted with EtOAc, dried, dissolved in DMF, and purified with basic conditions to give N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(1 H-pyrazol-4-yl)quinazolin-4-amine, 2TFA. 1 H NMR (400 MHz, DMSO-d6) 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). (Includes 1 salt NH.); MS (M+H) + = 491.

[1172] Example 65. N-(3-chlorobenzyl)-6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(2-(dimethylamino) 1-(ethyl)piperazine-1-yl)quinazolin-4-amine.

[1173] A 2-neck flask was charged with 6-bromo-N-(3-chlorobenzyl)-2-(4-(2- (dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), 3,5- dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole-1 - carboxylate (32.2 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (4.08 mg, 5.0 μmol), and K2CO3(41.5 mg, 0.30 mmol). Air was removed and refilled with N2(2-3 times). A mixture of 1,4-dioxane (1 ml) and water (0.5 ml) was then added and stirred at 95 °C (preheated) overnight. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was filtered through a PL-Thio-resin, eluted with EtOAc, and dried. TFA (0.5 mL) was then added and stirred for 10 minutes to help complete the deprotection. The mixture was then concentrated to remove most of the TFA, dissolved in DMF, and purified with basic conditions to give N-(3-chlorobenzyl)-6-(3,5-dimethyl-1 H-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-d6) 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.

[1174] Example 66. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinoline (Zoxolin-6-yl)-1-methylpyridin-2(1H)-one.

[1175] 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(1 H)-one (23.51 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2 adduct (4.08 mg, 5.0 μmol) and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 65. 1 H NMR (400 MHz, DMSO-d6) 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). (Includes 1 salt NH.); MS (M+H) + = 532.

[1176] Example 67. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinoline (Zazoline-6-yl)pyridine-2-ol.

[1177] 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(1 H)-one (23.51 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2 adduct (4.08 mg, 5.0 μmol) and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 65. 1¹H NMR (400MHz, DMSO-d⁶) 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, 2.8Hz, ¹H), 7.82 (s, ¹H), 7.64 (s, ¹H), 7.48 (s, ¹H), 7.41–7.28 (m, ³H), 6.50 (d, J = 9.6Hz, ¹H), 4.81 (d, J = 5.6Hz, ²H), 3.81 (s, ⁴H), 3.22 (s, ²H), 2.79 (s, ⁶H), 2.68–2.60 (m, ²H), 2.55 (s, ⁴H). (Includes one NH₃ salt.) MS (M+H) + =518.

[1178] Example 68. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazole-4-yl) (By) quinazolin-4-ol.

[1179] Step 1: 6-bromo-4-(tert-butoxy)-2-chloroquinazoline.

[1180] KOtBu (13.75 ml, 13.75 mmol) (in 1 M THF) was added to a partial suspension of 6-bromo-2,4-dichloroquinazoline (3.47 g, 12.5 mmol) in THF (12 ml) at 0 °C. The mixture was stirred at 0 °C for 1.5 h. The mixture was then poured into H2O / NH4Cl. 水溶液 Extracted with EtOAc (50 mL x 2) in 25 mL solutions. The combined organic layers were dried (Na₂SO₄) and filtered. After removing the 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 substance was used in the next step without further purification.

[1181] Step 2: 4-(4-(tert-butoxy)-2-chloroquinazolin-6-yl)-3,5-dimethylisoxazole.

[1182] Into a 2-necked flask was placed 6-bromo-4-(tert-butoxy)-2-chloroquinazoline (1515 mg, 4.8 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (1178 mg, 5.28 mmol), PdCl2(dppf)-CH2Cl2 adduct (392 mg, 0.48 mmol) and K2CO3(2189 mg, 15.84 mmol). The air was removed and refilled with N2(2-3 times). Then a mixture of 1,4-dioxane (12 ml) and water (6 ml) was added and stirred at 95 °C (preheated) for 1.5 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 3). The combined organics were dried (Na2SO4) and filtered. After removal of the solvent, the product was dried under vacuum 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)quinazolin-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).

[1183] Step 3: 2-(4-(4-(tert-butoxy)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin- 1-yl)-N,N-dimethylethanamine. Step 4: 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin- 4-ol, 2HCl.

[1184] 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-l-yl)ethanamine (464 mg, 2.95 mmol) followed by Hunig's base (0.703 ml, 4.02 mmol). The tube was sealed and heated at 90 °C for 5 h. After cooling to room temperature, the mixture was concentrated to remove most of the EtOH, then poured into EtOAc / H2O / Na2CO3(aq) (50 mL / 30 mL / 20 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was purified by silica gel chromatography using 0-10-20% MeOH / EtOAc as eluent to give 2-(4-(4-(tert-butoxy)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-l-yl)-N,N-dimethylethanamine (1030 mg, 2.276 mmol, 85% yield). 1 HNMR (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.

[1185] 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, HC1.

[1186] To a solution of 2-(4-(4-(tert-butoxy)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-l-yl)-N,N-dimethylethanamine (1240 mg, 2.74 mmol) in CH2Cl2(6 ml) was added HCl (4 M in dioxane, 12 mL). The suspension was stirred vigorously at room temperature for 5 h. To the mixture was added hexanes (40 mL). The solid was filtered and washed with hexanes (5 mL x 3). The product was then transferred to a vial (hygroscopic) and dried under vacuum to give 2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCl as an off-white solid. This material was used without further purification in the next step. MS (M+H) + = 397.

[1187] Step 2: 2,6-Bis(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine.

[1188] Example 70. N-(3-Chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine.

[1189] To a solution of 4,4'-(4-(tert-butoxy)quinazoline-2,6-diyl)bis(3,5- dimethylisoxazole) (500 mg, 1.274 mmol) in CH2Cl2(2 ml) was added HC1 (4 M in dioxane, 6 mL). The suspension was stirred at room temperature for 3 h. To the mixture was added hexanes (20 mL). The solid was filtered and washed with hexanes (3 mL x 3). The product was then transferred to a vial and dried under vacuum to give 2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, HC1 (395 mg, 1.060 mmol, 83% yield) as an off-white solid. MS (M+H) + = 337.

[1190] Example 71. 2-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine.

[1191] To a suspension of 2,6-bis(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, HC1 (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 Et3N (0.139 ml, 1.0 mmol). The mixture was stirred at room temperature for 2 h, 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 through a filter and purified to give 2,6-bis(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine, 2 TFA (14.1 mg, 0.021 mmol, 21.38% yield). MS (M+H) + = 432.

[1192] Example 72. 2-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)-N-(2-methoxybenzyl)quinazolin-4-amine.

[1193] To a suspension of 2,6-bis(3,5-dimethylisoxazol-4-yl)quinolin-4-ol, HCI (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 Et3N (0.139 ml, 1.0 mmol). The mixture was stirred at room temperature for 2 h, 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 through a filter and purified to give N-(3-chlorobenzyl)-2,6-bis(3,5-dimethylisoxazol-4-yl)quinolin-4-amine, 2 TFA (15.4 mg, 0.022 mmol, 22.38% yield). MS (M+H) + = 460.

[1194] Example 73. 2-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)-N-(3-methoxybenzyl)quinazolin-4-amine. Example 74. N-(2-Chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine.

[1195] To a suspension of 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinolin-4-ol, 2 HCI (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 Et3N (0.139 ml, 1.0 mmol). The mixture was stirred at room temperature for 2 h, 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 purified to give 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(thiophen-2-ylmethyl)quinolin-4-amine, 2 TFA (11.6 mg, 0.016 mmol, 32.2% yield). MS (M+H) + = 492.

[1196] Example 75. N-(3-Bromobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine. Example 76. 2-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)-N-(2-fluorobenzyl)quinazolin-4-amine.

[1197] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin- 1 -yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-ol, 2HCI (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-l-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol), and (2-methoxyphenyl)methanamine (13.72 mg, 0.10 mmol) according to a procedure analogous to that described in Example 71. MS (M+H) + = 516.

[1198] Example 77. 2-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)-N-(3-fluorobenzyl)quinazolin-4-amine. Example 78. N-(3-Chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(5- methylisoxazol-4-yl)quinazolin-4-amine.

[1199] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin- 1 -yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-ol, 2HCI (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-l-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol), and (3-methoxyphenyl)methanamine (13.72 mg, 0.10 mmol) according to a procedure analogous to that 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). (includes 1 salt NH); MS (M+H) + = 516.

[1200] Example 79. 2-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)-N-(furan-2-ylmethyl)quinazolin-4-amine ​

[1201] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin- 1 -yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-ol, 2HCI (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-l-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol), and (2-chlorophenyl)methanamine (14.16 mg, 0.10 mmol) according to a procedure analogous to that described in Example 71. MS (M+H) + = 520.

[1202] ​ ​

[1203] The title compound was prepared in accordance with the procedure described in Example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-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). MS (M+H) + = 566.

[1204] ​ ​

[1205] The title compound was prepared in accordance with the procedure described in Example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-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). MS (M+H) + = 504.

[1206] ​ ​

[1207] The title compound was prepared in accordance with the procedure described in Example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-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). MS (M+H) + = 504.

[1208] ​ ​

[1209] The title compound was prepared according to a procedure analogous to that described in Example 65 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), PdCl2(dppf)-CH2Cl2 adduct (4.08 mg, 5.0 μmol) and K2CO3(41.5 mg, 0.30 mmol). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 506.

[1210] ​ ​

[1211] The title compound was prepared according to a procedure analogous to that described in Example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-4-ol, 2HCI (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). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 476.

[1212] Example 80. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)-N-(pyridin-3-ylmethyl)quinazolin-4-amine.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.

[1213] The title compound was prepared in analogy to the procedure described in example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-4-ol, 2HCI (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). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 487.

[1214] Example 82. N-((4-chloropyridin-2-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1- yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine. 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.

[1215] The title compound was prepared in analogy to the procedure described in example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-4-ol, 2HCI (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). MS (M+H) + = 521.

[1216] 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. Example 85. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)-N-methylquinazolin-4-amine.

[1217] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin- 1 -yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-ol, 2HCI (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-l-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol), and (4- chloropyridin-2-yl)methanamine (14.26 mg, 0.10 mmol) overnight according to a procedure analogous to that described in Example 71. MS (M + H) + = 521.

[1218] Example 86. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin- 6-yl)-3-fluoropyridin-2-ol. 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.

[1219] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin- 1 -yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-ol, 2HCI (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-l-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol), and (5-fluoropyridin-3-yl)methanamine (12.61 mg, 0.10 mmol) overnight according to a procedure analogous to that described in Example 71. MS (M + H) + = 505.

[1220] 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. 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.

[1221] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin- 1 -yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-ol, 2HCI (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-l-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol), and (4-methylpyridin-3-yl)methanamine (12.22 mg, 0.10 mmol) overnight according to a procedure analogous to that described in Example 71. 1 H NMR (400 MHz, DMSO-d6) 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). (Includes 1 salt NH.); MS (M + H) + = 501.

[1222] Example 90. N-(1-(3-chlorophenyl)ethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6- (3,5-dimethylisoxazol-4-yl)quinazolin-4-amine. Example 91. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin- 6-yl)-3-methylpyridin-2-ol.

[1223] The title compound was prepared according to a procedure analogous to that described in Example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-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). MS (M + H) + = 534.

[1224] Example 92. N-benzyl-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-4-amine. ​

[1225] The title compound was prepared according to a procedure analogous to that described in Example 65 from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinolin-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), PdCl2(dppf)-CH2Cl2adduct (4.08 mg, 5.0 μmol), and K2CO3 (41.5 mg, 0.30 mmol). MS (M + H) + = 536.

[1226] ​ ​

[1227] The title compound was prepared according to a procedure analogous to that described in Example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-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). MS (M + H) + = 506.

[1228] ​ ​

[1229] The title compound was prepared in accordance with the procedure described in Example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-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). MS (M + H) + = 506.

[1230] ​ ​

[1231] The title compound was prepared in accordance with the procedure described in Example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-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)ethylamine (12.72 mg, 0.10 mmol). MS (M + H) + = 506.

[1232] ​ ​

[1233] The title compound was prepared in accordance with the procedure described in Example 71 from 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)quinolin-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) ethylamine (15.56 mg, 0.10 mmol). MS (M + H) + = 534.

[1234] ​ ​

[1235] The title compound was prepared according to a procedure analogous to that described in Example 65 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), PdCl2(dppf)- CH2Cl2adduct (4.08 mg, 5.0 μmol) and K2CO3(41.5 mg, 0.30 mmol). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 532.

[1236] ​ ​

[1237] The title compound was prepared according to a procedure analogous to that described in Example 71 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), bromotriisopropylphosphonium hexafluorophosphate (46.6 mg, 0.10 mmol) and phenylmethanamine (10.72 mg, 0.10 mmol) overnight. MS (M+H) + = 486.

[1238] Example 93. N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3- methylisoxazol-4-yl)quinazolin-4-amine. 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.

[1239] 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-l,3,2-dioxaborolan-2-yl)isoxazole (20.90 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (4.08 mg, 5.0 μmol), and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 65. 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 506.

[1240] 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. Example 95. N-(4-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine.

[1241] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin- 1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCI (Example 68, 23.47 mg, 0.05 mmol), bromotriisopropylphosphonium hexafluorophosphate (46.6 mg, 0.10 mmol), and (5-chlorothiophen-2-yl)methanamine, HCI (18.41 mg, 0.10 mmol) according to a procedure analogous to that described in Example 71. MS (M+H) + = 526.

[1242] Example 96. 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin- 6-yl)pyridin-2-ol. Example 97. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)-N-methylacetamide.

[1243] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin- 1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-ol, 2HCI (Example 68, 23.47 mg, 0.05 mmol), bromotriisopropylphosphonium hexafluorophosphate (46.6 mg, 0.10 mmol), and (4-chlorophenyl)methanamine (0.014 g, 0.10 mmol) according to a procedure analogous to that described in Example 71. MS (M+H) + = 520.

[1244] Example 97. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)-N-methylacetamide. Example 97. 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-1-yl)-N-methylacetamide.

[1245] The title compound was prepared according to a procedure analogous to that described in Example 65 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-l,3,2-dioxaborolan-2- yl)pyridin-2-ol (22.11 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (4.08 mg, 5.0 μmol) and K2CO3(41.5 mg, 0.30 mmol). 1 H NMR (400 MHz, DMSO-d6) 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). (includes 1 salt NH); MS (M+H) + = 518.

[1246] Example 99. 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(4- fluorobenzyl)quinazolin-4-amine. Example 100. 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[1247] The title compound was prepared according to a procedure analogous to that described in Example 28 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-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)acetamide (26.5 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2adduct (8.17 mg, 10.0 μmol) and K2CO3(41.5 mg, 0.30 mmol). 1H NMR (400 MHz, DMSO-d6) 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.

[1248] 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. 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.

[1249] The title compound was prepared according to a procedure analogous to that described in Example 28 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-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)acetamide (27.9 mg, 0.100 mmol), PdCl2(dppf)- CH2Cl2adduct (8.17 mg, 10.0 μmol) and K2CO3(41.5 mg, 0.30 mmol). 1 H NMR (400 MHz, DMSO-d6) 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.

[1250] 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. 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.

[1251] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-ol, 2HCl (Example 68, 23.47 mg, 0.05 mmol), bromotri(pyrrolidin-l-yl)phosphonium hexafluorophosphate (46.6 mg, 0.10 mmol), and (4-fluorophenyl)methanamine (12.51 mg, 0.10 mmol) according to a procedure analogous to that described in Example 71. MS (M+H) + = 504.

[1252] 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. Example 106. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyacetyl)piperazin-1-yl)quinazolin-6-yl)-1- methylpyridin-2(1H)-one.

[1253] Into a 2-necked flask was placed 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4- amine (766 mg, 2 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2(lH)-one (517 mg, 2.200 mmol), PdCl2(dppf)-CH2Cl2adduct (163 mg, 0.20 mmol), and K2CO3(912 mg, 6.6 mmol). The air was removed and replaced with N2(2-3 times). Then a mixture of 1,4-dioxane (6 mL) and water (3 mL) was added and stirred at 95 °C (preheated) for 2 h. After cooling to room temperature, H2O (20 mL) was added and the solid was filtered, washed with H2O (3 mL x 2), and then dried. The dried solid was placed in 5% EtOAc in hexanes (30 mL), stirred vigorously for 30 min, and then filtered to give 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)-l-methylpyridin- 2(lH)-one (741 mg, 1.441 mmol, 72.1% crude yield) as a yellow solid. The material of about 80% purity was used without further purification. Purification of 20 mg of the crude material was performed for screening. MS (M+H) + = 411.

[1254] ​ ​

[1255] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Example 100, 0.039 g, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -yl)ethanol (0.038 g, 0.150 mmol), PdCl2(dppf)- CH2Cl2adduct (12 mg, 15 μmol) and K2CO3(62 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) + = 500

[1256] ​ ​

[1257] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Example 100, 0.039 g, 0.075 mmol), N-methyl-2-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -yl)acetamide (39.8 mg, 0.15 mmol), PdCl2(dppf)- CH2Cl2adduct (12 mg, 15 μmol) and K2CO3(62 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) + = 514.

[1258] ​ ​

[1259] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Example 100, 0.039 g, 0.075 mmol), 2-methyl- 1 -(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -yl)propan-2-ol (39.9 mg, 0.150 mmol), PdCl2(dppf)-CH2Cl2adduct (12 mg, 15 μmol) and K2CO3(62 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) + = 515.

[1260] ​ ​

[1261] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Example 100, 0.039 g, 0.075 mmol), 3-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -yl)propan- 1 -ol (39.9 mg, 0.150 mmol), PdCl2(dppf)-CH2Cl2adduct (12 mg, 15 μmol) and K2CO3(62 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) + = 496.

[1262] ​ ​

[1263] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Example 100, 0.039 g, 0.075 mmol), 3-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -yl)propan- 1 -ol (39.9 mg, 0.150 mmol), PdCl2(dppf)-CH2Cl2adduct (12 mg, 15 μmol) and K2CO3(62 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) + = 515.

[1264] ​ 6-yl)-1 -methylpyridin-2(1 H)-one.

[1265] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-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 a procedure analogous to that described in Example 12. MS (M+H) + = 519.

[1266] Example 107. 5-(2-(4-(2-aminoacetyl)piperazin-1 -yl)-4-((3-chlorobenzyl)amino)quinolin- 6-yl)-1 -methylpyridin-2(1 H)-one.

[1267] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Example 100, 38.6 mg, 0.075 mmol), 2-amino- 1 -(piperidin- 1 - yl)ethanone, 2HCl (0.081 g, 0.375 mmol) and Hunig's base (0.131 ml, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 518.

[1268] Example 108. 2-(4-(4-((3-chlorobenzyl)amino)-6-(1 -methyl-6-oxo-1,6-dihydropyridin- 3-yl)quinolin-2-yl)piperazin-1 -yl)acetamide.

[1269] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-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 a procedure analogous to that described in Example 12. MS (M+H) + = 518.

[1270] Example 109. 2-(4-(4-((3-chlorobenzyl)amino)-6-(1 -methyl-6-oxo-1,6-dihydropyridin- 3-yl)quinolin-2-yl)piperazin-1 -yl)-N-methylacetamide.

[1271] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-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 a procedure analogous to that described in Example 12. MS (M+H) + = 532.

[1272] Example 110. 2-(4-(4-((3-chlorobenzyl)amino)-6-(1 -methyl-6-oxo-1,6-dihydropyridin- 3-yl)quinolin-2-yl)piperazin-1 -yl)-N,N-dimethylacetamide.

[1273] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-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 a procedure analogous to that described in Example 12. MS (M+H) + = 546.

[1274] Example 111. (S)-5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxypropyl)piperazin-1 -yl)quinolin-6-yl)-1 -methylpyridin-2(1 H)-one.

[1275] The title compound was prepared from 5-(2-chloro-4-((3- chlorobenzyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1 H)-one (Example 100, 38.6 mg, 0.075 mmol), (S)-1 -(piperazin-1 -yl)propan-2-ol, HC1 (0.068 g, 0.375 mmol) and Hunig's base (0.131 ml, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 519.

[1276] Example 112. 2-chloro-4-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quin N Example 113. 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinolin-6-yl)-1 -methylpy Example 114. 5-(4-((3-chlorobenzyl)amino)-2-(1 -(2-hydroxyethyl)-1 H-pyrazol-4-yl)quinolin-

[1277] 6-yl)-1 -methylpyridin-2(1 H)-one.

[1278] 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) followed by Et3N (1.463 ml, 10.50 mmol) at room temperature. The mixture was stirred at 0 °C for 15 min, then warmed to room temperature for 1.5 h (determined by TLC to be complete). The mixture was poured into EtOAc / H2O (50 mL / 50 mL). The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product and some EtOAc (5-10 mL) were sonicated, then hexanes (200 mL) were added slowly. The solid was filtered and triturated with hexanes, then dried to give 6-bromo-2-chloro-N-((5-chloropyridin-3-yl)methyl)quinazolin-4-amine as a solid (2.31 g, 6.01 mmol, 86% yield).

[1279] Example 115. 2-(4-(2-(dimethylamino)ethyl)piperazin-1 -yl)-6-(3,5-dimethylisoxazol-4-yl)-N- ((5-methylpyridin-3-yl)methyl)quinolin-4-amine.

[1280] A 2-neck flask was charged with 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), PdCl2(dppf)-CH2Cl2 adduct (0.204 g, 0.25 mmol) and K2CO3(1.140 g, 8.25 mmol). The air was removed and refilled with N2(2-3 times). Then a mixture of 1,4-dioxane (9 ml) and water (4.5 ml) was added and stirred at 95 °C (preheated) for 1.5 h. After cooling to room temperature, the organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layer was dried (Na2SO4) and filtered. The product was triturated with 10% EtOAc / hexanes 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 containing some impurities was used without further purification. 40 mg of the material was purified for screening. MS (M+H) + = 400.

[1281] Example 116. 4-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1 -yl) quinolin-6-yl)-1 -methylpyridin-2(1 H)-one.

[1282] A 2-neck flask was charged with 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), PdCl2(dppf)-CH2Cl2 adduct (0.245 g, 0.300 mmol) and K2CO3(1.368 g, 9.90 mmol). The air was removed and refilled with N2(2-3 times). Then a mixture of 1,4-dioxane (10 ml) and water (5 ml) was added and stirred at 95 °C (preheated) for 1.5 h. After cooling to room temperature, H2O (20 mL) was added and the solid was filtered, washed with H2O (5 mL x 2) and then dried. Then the product was triturated with 10% EtOAc / hexanes 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 containing some impurities was used without further purification. 40 mg of the material was purified for screening. MS (M+H) + = 412.

[1283] Example 117. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl) quinolin-2-yl)piperazin-1 -yl)acetamide.

[1284] The title compound was prepared from 5-(2-chloro-4-((3- chlorobenzyl)amino)quinazolin-6-yl)-l-methylpyridin-2(lH)-one (Example 100, 0.039 g, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)ethanol (35.7 mg, 0.150 mmol), PdCl2(dppf)-CH2Cl2 adduct (12 mg, 15 μmol), and K2CO3(62 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. MS (M+H) + = 487.

[1285] Example 118. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl) quinolin-2-yl)piperazin-1 -yl)-N-methylacetamide.

[1286] The title compound was prepared from 2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-ol, 2HCl (Example 68, 46.9 mg, 0.1 mmol), bromotri(pyrrolidin-l-yl)phosphonium hexafluorophosphate (93 mg, 0.2 mmol), and (5-methylpyridin-3-yl)methanamine (24.43 mg, 0.20 mmol) according to a procedure analogous to that described in Example 71. MS (M+H) + = 501.

[1287] ​ ​

[1288] The title compound was prepared from 6-bromo-N-(3-chlorobenzyl)-2-(4-(2- (dimethylamino)ethyl)piperazin-l-yl)quinolin-4-amine (25.2 mg, 0.05 mmol), l-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (0.024 g, 0.10 mmol), PdCl2(dppf)-CH2Cl2 adduct (4.08 mg, 5.0 μmol), and K2CO3(41.5 mg, 0.30 mmol) according to a procedure analogous to that described in Example 65. MS (M+H) + = 532.

[1289] ​ ​

[1290] 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-(piperidin-l-yl)acetamide, HC1 (67.4 mg, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 507.

[1291] ​ ​ N ​

[1292] 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-l-yl)acetamide, HC1 (72.6 mg, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 521.

[1293] Example 119. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide. Example 120. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinolin-2-yl)piperazin-1-yl)ethanol. N , N Example 121. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinolin-6- yl)-1-methylpyridin-2(1H)-one.

[1294] 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-l-yl)acetamide (64.2 mg, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 535.

[1295] Example 122. 5-(4-((3-chlorobenzyl)amino)-2-(4-(1-methyl-1H-pyrazole-4-carbonyl)piperazin-1- yl)quinolin-6-yl)-1-methylpyridin-2(1H)-one. Example 123. 5-(4-((3-chlorobenzyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)quinolin- 6-yl)-1-methylpyridin-2(1H)-one.

[1296] 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-(piperidin-l-yl)ethanol (48.8 mg, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H)+ = 494.

[1297] Example 124. 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1- yl)quinolin-6-yl)-1-methylpyridin-2(1H)-one. Example 125. 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(3-(dimethylamino)propyl)piperazin-1- yl)quinolin-6-yl)-1-methylpyridin-2(1H)-one.

[1298] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridazin- 3(2H)-one (Example 1 1, 40.0 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 a procedure analogous to that described in Example 12. MS (M+H) + = 505.

[1299] Example 126. 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxyethyl)piperazin-1-yl)quinolin-6- yl)-1-methylpyridin-2(1H)-one. Example 127. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)quinolin-2-yl)piperazin-1-yl)acetamide.

[1300] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridazin- 3(2H)-one (Example 1 1, 40.0 mg, 0.075 mmol), (1 -methyl- 1 H-pyrazol-4-yl)(piperazin- 1 -yl)methanone, HC1 (87 mg, 0.375 mmol) and Hunig's base (0.131 ml, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 569.

[1301] Example 128. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)quinolin-2-yl)piperazin-1-yl)-N-methylacetamide. Example 129. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)quinolin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide.

[1302] The title compound was prepared from 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1 -methylpyridazin- 3(2H)-one (Example 1 1, 40.0 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 a procedure analogous to that described in Example 12. MS (M+H) + = 546.

[1303] Example 130. N-((5-chloropyridin-3-yl)methyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinolin-4-amine. Example 131. 2-amino-1-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinolin-2-yl)piperazin-1-yl)ethanone.

[1304] 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-l-yl)ethylamine (0.059 g, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 533.

[1305] ​ ​

[1306] 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-l-yl)propan-l -amine (0.064 g, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 547.

[1307] ​ ​

[1308] 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-l-yl)ethanol (0.049 g, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 506.

[1309] ​ ​

[1310] 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-l-yl)acetamide, HCI (0.067 g, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 519.

[1311] ​ ​

[1312] 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-l-yl)acetamide, HC1 (0.073 g, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 533.

[1313] ​ ​

[1314] 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-l-yl)acetamide (0.064 g, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 547.

[1315] ​ ​

[1316] 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-l-yl)propan-l -amine (64.2 mg, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 535.

[1317] ​ Oxazol-4-yl)quinazolin-2-yl)piperazin-l-yl)ethanone.

[1318] 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-(piperidin-4-yl)ethanone, 2HCl (0.081 g, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 507.

[1319] Example 132. l-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-2-yl)piperazin-l-yl)-2-hydroxyethanone. Example 133. 5-(2-(4-(2-aminoacetyl)piperazin-l-yl)-4-(((5-chloropyridin-3-yl)methyl) amino)quinazolin-6-yl)-l-methylpyridin-2(lH)-one.

[1320] 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 a procedure analogous to that described in Example 12. MS (M+H) + = 508.

[1321] Example 133. 5-(2-(4-(2-aminoacetyl)piperazin-l-yl)-4-(((5-chloropyridin-3-yl)methyl) amino)quinazolin-6-yl)-l-methylpyridin-2(lH)-one. Example 134. 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-hydroxy-2-methylpropyl)piperazin-l- yl)quinazolin-6-yl)-l-methylpyridin-2(lH)-one, 2TFA.

[1322] 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-(piperidin-4-yl)ethanone, 2HCl (81 mg, 0.375 mmol) and Hunig's base (0.131 mL, 0.75 mmol) according to a procedure analogous to that described in Example 12. MS (M+H) + = 519.

[1323] Example 135. 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(4-(2-hydroxy-2-methylpropyl) piperazin-l-yl)quinazolin-6-yl)-l-methylpyridin-2(lH)-one, 2TFA. Example 136. l-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-2-yl)piperazin-l-yl)-2-methylpropan-2-ol, 2TFA.

[1324] 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 a procedure analogous to that described in Example 12. 1H NMR (400MHz, DMSO-d6) δ9.30(s,1H),8.40(s,1H),8.20(d,J=2.6Hz,1H),8.01(s,1H),7.91(dd,J=9.5,2.7Hz,1H),7.57–7.49(m ,3H),7.41–7.28(m,2H),6.55(d,J=9.4Hz,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.

[1325] Example 137. l-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2- yl)piperazin-l-yl)-2-methylpropan-2-ol, 2TFA. Example 138. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-2-yl)-lH-pyrazol-l-yl)-2-methylpropan-l-ol, 2TFA.

[1326] 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)prop-2-ol, 2HCl (52.0 mg, 0.225 mmol) according to a procedure similar to that described in Example 12. 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.62(d,J=1.8Hz,1H),8.53(d,J=2.3Hz,1H),8.37(s,1H),8.20(d,J=2.7Hz,1H),8.06–7.93(m,2H),7.9 0(dd,J=9.5,2.8Hz,1H),7.57(s,1H),6.55(d,J=9.5Hz,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.

[1327] Example 139. l-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-2-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol, 2TFA. Example 140. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-2-yl)-lH-pyrazol-l-yl)-N,N-dimethylacetamide, 2TFA.

[1328] 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)prop-2-ol, 2HCl (52.0 mg, 0.225 mmol) according to a procedure similar to that described in Example 12. 1H NMR (400 MHz, DMSO-d6) 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.

[1329] Example 141. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-2-yl)-lH-pyrazol-l-yl)-N-methylacetamide, 2TFA. Example 142. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4- yl)quinazolin-2-yl)-lH-pyrazol-l-yl)acetamide, 2TFA.

[1330] 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 a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) 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.

[1331] Example 143. 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(l-(2-hydroxyethyl)-lH-pyrazol- ​

[1332] 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 a procedure analogous to that described in Example 12. 1H NMR (400 MHz, DMSO-d6) 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.

[1333] ​ ​

[1334] The title compound was prepared according to a procedure analogous to that described in Example 28 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-l-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan-2-ol (39.9 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol). 1 H NMR (400 MHz, DMSO-d6) 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.

[1335] ​ ​

[1336] 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-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)acetamide (41.9 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. 1 H NMR (400 MHz, DMSO-d6) 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.

[1337] ​ ​

[1338] 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-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)acetamide (39.8 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1 H), 8.72 (s, 1 H), 8.68 (d, J = 1.9 Hz, 1 H), 8.53 (d, J = 2.3 Hz, 1 H), 8.33 (s, 2 H), 8.19 (s, 1 H), 8.04 (t, J = 2.1 Hz, 1 H), 7.98 (s, 1 H), 7.87 (d, J = 8.3 Hz, 1 H), 5.05 (s, 2 H), 4.92 (s, 2 H), 2.63 (d, J = 4.6 Hz, 3 H), 2.46 (s, 3 H), 2.28 (s, 3 H); MS (M+H) + = 503.

[1339] ​ ​ H ​

[1340] The title compound was prepared according to a procedure analogous to that described in Example 28 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)- 1 H-pyrazol- 1 -yl)acetamide (37.7 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1 H), 8.72 (s, 1 H), 8.68 (d, J = 1.8 Hz, 1 H), 8.53 (d, J = 2.4 Hz, 1 H), 8.33 (s, 2 H), 8.04 (t, J = 2.1 Hz, 1 H), 7.98 (s, 1 H), 7.88 (d, J = 8.5 Hz, 1 H), 7.68 (s, 1 H), 7.35 (s, 1 H), 5.06 (d, J = 5.6 Hz, 2 H), 4.92 (s, 2 H), 2.46 (s, 3 H), 2.28 (s, 3 H); MS (M+H) + = 489.

[1341] ​ 4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA.

[1342] The title compound was prepared according to a procedure analogous to that described in Example 28 from 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2( 1 H)-one (Example 113, 30.9 mg, 0.075 mmol), 2-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethanol (35.7 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol). 1 HNMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.70 (d, J = 1.8 Hz, 2H), 8.54 (d, J = 2.4 Hz, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 8.18 (s, 1H), 8.06 (t, J = 2.1 Hz, 1H), 7.95 (dd, J = 9.5, 2.8 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 6.58 (d, J = 9.5 Hz, 1H), 5.05 (br s, 3H), 4.26 (t, J = 5.3 Hz, 2H), 3.77 (t, J = 5.4 Hz, 2H), 3.53 (s, 3H); MS (M+H) + = 488.

[1343] Example 144. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazole-4-) 2-(2-yl)-1H-pyrazole-1-yl)ethanol, 2TFA.

[1344] The title compound was prepared according to a procedure analogous to that described in Example 28 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-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)ethanol (35.7 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol). 1 ​H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1 H), 8.72 (s, 1 H), 8.69 (d, J = 1.8 Hz, 1 H), 8.53 (d, J = 2.3 Hz, 1 H), 8.36 (s, 1 H), 8.34 - 8.27 (m, 1 H), 8.05 (t, J = 2.1 Hz, 1 H), 7.99 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 8.6 Hz, 1 H), 5.06 (d, J = 5.3 Hz, 2 H), 4.27 (t, J = 5.3 Hz, 2 H), 3.78 (t, J = 5.3 Hz, 2 H), 2.45 (s, 3 H), 2.28 (s, 3 H). (OH not shown); MS (M+H) + = 476.

[1345] Example 145. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-) Dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazole-1-yl)acetamide, 2TFA.

[1346] The title compound was prepared according to a procedure analogous to that described in Example 28 from 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)- 1 -methylpyridin-2(1 H)-one (Example 113, 30.9 mg, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 -yl)acetamide (37.7 mg, 0.15 mmol), PdCI2(dppf)-CH2CI2 adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1 H), 8.72 (s, 1 H), 8.69 (d, J = 1.8 Hz, 1 H), 8.53 (d, J = 2.3 Hz, 1 H), 8.36 (s, 1 H), 8.34 - 8.27 (m, 1 H), 8.05 (t, J = 2.1 Hz, 1 H), 7.99 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 8.6 Hz, 1 H), 5.06 (d, J = 5.3 Hz, 2 H), 4.27 (t, J = 5.3 Hz, 2 H), 3.78 (t, J = 5.3 Hz, 2 H), 2.45 (s, 3 H), 2.28 (s, 3 H). (OH not shown); MS (M+H) + = 501.

[1347] Example 146. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-) (dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazole-1-yl)-N,N-dimethylacetamide,2TFA.

[1348] The title compound was prepared from 5-(2-chloro-4-(((5-chloropyridin-3- yl)methyl)amino)quinolin-6-yl)-1-methylpyridin-2(1 H)-one (Example 113, 30.9 mg, 0.075 mmol), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- pyrazol-1 -yl)acetamide (41.9 mg, 0.15 mmol), PdCI2(dppf)-CH2CI2 adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1 H), 8.70 (d, J = 1.9 Hz, 1 H), 8.65 (s, 1 H), 8.57 - 8.50 (m, 2H), 8.33 (d, J = 9.7 Hz, 1 H), 8.30 (d, J = 2.7 Hz, 1 H), 8.20 (d, J = 8.8 Hz, 1 H), 8.06 (t, J = 2.2 Hz, 1 H), 7.95 (dd, J = 9.5, 2.8 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 6.59 (d, J = 9.5 Hz, 1 H), 5.28 (s, 2H), 5.07 (d, J = 5.8 Hz, 2H), 3.53 (s, 3H), 3.04 (s, 3H), 2.85 (s, 3H); MS (M+H) + = 529.

[1349] Example 147. 2-(4-(4-(((5-chloropyridin-3-yl)methyl)amino)-6-(1-methyl-6-oxo-1,6-) dihydropyridin-3-yl)quinazolin-2-yl)-1H-pyrazole-1-yl)- N -Methylacetamide, 2TFA.

[1350] The title compound was prepared from 5-(2-chloro-4-(((5-chloropyridin-3- yl)methyl)amino)quinolin-6-yl)-1-methylpyridin-2(1 H)-one (Example 113, 30.9 mg, 0.075 mmol), N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- pyrazol-1 -yl)acetamide (39.8 mg, 0.15 mmol), PdCI2(dppf)-CH2CI2 adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.70(d,J=1.8Hz,2H),8.54(d,J=2.4Hz ,1H),8.51(s,1H),8.29(d,J=2.7Hz,2H),8.14(d,J=30.2Hz,2H),8.08–8.02(m ,1H),7.95(dd,J=9.5,2.8Hz,1H),7.80(d,J=8.7Hz,1H),6.58(d,J=9.5Hz,1H ),5.06(s,2H),4.91(s,2H),3.53(s,3H),2.62(dd,J=4.5,2.8Hz,3H); MS(M+H) + =515.

[1351] Example 148. 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, 2TFA.

[1352] The title compound was prepared according to a procedure similar to that described in Example 28 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), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazol-1-yl)prop-2-ol (39.9 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (12.25 mg, 0.015 mmol), and K2CO3 (62.2 mg, 0.45 mmol). 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.70(d,J=1.9Hz,1H),8.65(s,1H),8.54(d, J=2.4Hz,1H),8.52(s,1H),8.32(s,1H),8.29(d,J=2.7Hz,1H),8.18(s,1H),8.06( t,J=2.1Hz,1H),7.95(dd,J=9.5,2.8Hz,1H),7.80(d,J=8.7Hz,1H),6.58(d,J=9.5 Hz,1H),5.05(s,2H),4.83(s,1H),4.13(s,2H),3.53(s,3H),1.09(s,6H); MS(M+H) + =516.

[1353] Example 149. 5-(4-(((5-chloropyridin-3-yl)methyl)amino)-2-(1-(1-hydroxy-2-methylprop-2-) 2TFA)-1H-pyrazol-4-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one.

[1354] The title compound was prepared from 5-(2-chloro-4-(((5-chloropyridin-3- yl)methyl)amino)quinazolin-6-yl)-1-methylpyridin-2(1 H)-one (Example 113, 30.9 mg, 0.075 mmol), 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- pyrazol-1 -yl)propan-1 -ol (39.9 mg, 0.15 mmol), PdCI2(dppf)-CH2CI2 adduct (12.25 mg, 0.015 mmol) and K2CO3(62.2 mg, 0.45 mmol) according to a procedure analogous to that described in Example 28. 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.67 (s, 1H), 8.53 (d, J = 2.4 Hz, 2H), 8.34 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 8.19 (s, 1H), 8.07 (t, J = 2.2 Hz, 1H), 7.95 (dd, J = 9.5, 2.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 9.5 Hz, 1H), 5.05 (s, 3H), 3.62 (s, 2H), 3.53 (s, 3H), 1.53 (s, 6H); MS (M+H) + = 516.

[1355] Examples 150-151. 2-(4-(4-((4-chlorophenyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazole (-2-yl)-1H-pyrazol-1-yl)ethanol, 2TFA (Example 150) and 6-bromo-2-chloro-N-(4-chlorophenyl)quinazolin-4-amine (Example 151).

[1356] Step 1: 6-bromo-2-chloro-N-(4-chlorophenyl)quinazolin-4-amine.

[1357] To a mixture of 6-bromo-2,4-dichloroquinazoline (1.112 g, 4 mmol) and 4- chloroaniline (0.765 g, 6.0 mmol) in THF (10 ml) was added slowly potassium tert- butoxide (5.0 mL, 5.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was poured into EtOAc / H2O (50 mL / 50 mL). The organic layer was dried over Na2SO4and filtered. After removal of the solvent, the product was triturated with 10% CH2Cl2 / hexanes, then dried to give 1.25 g of crude product which was used without further purification. The filtrate was concentrated and purified by silica gel chromatography using 0-20% EtOAc / hexanes as eluent to give another 100 mg of crude product. A total of ~1.35 g of crude 6-bromo-2-chloro-N-(4-chlorophenyl)quinazolin-4- amine (1.35 g, 2.93 mmol, 73.2% yield) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 8.9, 2.1 Hz, 1H), 7.85 - 7.76 (m, 2H), 7.65 (d, J = 8.9 Hz, 1H), 7.55 - 7.44 (m, 2H); MS (M+H) + = 369.

[1358] Step 2: 6-Bromo-2-chloro- N -(4-chlorophenyl)quinazolin-4-amine (Example 151).

[1359] In a 2-neck flask was placed 6-bromo-2-chloro-N-(4-chlorophenyl)quinazolin-4- amine (738 mg, 2 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)isoxazole (491 mg, 2.2 mmol), PdCl2(dppf)-CH2Cl2 adduct (163 mg, 0.2 mmol) and K2CO3 (912 mg, 6.6 mmol). Air was removed and refilled with N2 (2-3 times). Then a mixture of 1,4-dioxane (7 ml) and water (3.5 ml) was added and stirred at 95 °C (preheated) for 1.5 h. After cooling to room temperature, the organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The product was triturated with 70% EtOAc / hexanes and dried to give 280 mg of crude product which was used without further purification. The filtrate was concentrated and purified by silica gel chromatography eluting with 10-20% EtOAc / CH2Cl2 to give another 165 mg of crude product. A total of 445 mg of 2-chloro-N-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4- amine (1.16 mmol, 57.8% yield) was obtained. 20 mg was purified to give a TFA salt for screening. MS (M+H) + = 386.

[1360] Step 3: 2-(4-(4-((4-chlorophenyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)- 1H-pyrazole-1-yl)ethanol, 2TFA.

[1361] The title compound was prepared from 2-chloro-N-(4-chlorophenyl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine (48.2 mg, 0.1 mmol), 2-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethanol (47.6 mg, 0.20 mmol), PdCl2(dppf)-CH2Cl2adduct (16.33 mg, 0.02 mmol) and K2CO3(83 mg, 0.60 mmol) according to a procedure analogous to that described in Example 28. 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8.18 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.6 Hz, 3H), 7.60 - 7.52 (m, 2H), 4.26 (t, J = 5.4 Hz, 2H), 3.77 (t, J = 5.4 Hz, 2H), 2.47 (s, 3H), 2.29 (s, 3H). (OH not shown); MS (M+H) + = 461.

[1362] Example 152. N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methyl) (2TFA) sulfonyl)piperazin-1-yl)quinazolin-4-amine

[1363] 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, 61.6 mg, 0.1 mmol) and l-(methylsulfonyl)piperazine (49.3 mg, 0.30 mmol) according to a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 10.09 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.82 - 7.71 (m, 2H), 4.83 (s, 2H), 3.92 (s, 4H), 3.19 (s, 4H), 2.87 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H). (includes 1 salt NH); MS (M+H) + = 529.

[1364] Example 153. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazine) (Pyridine-1-yl)quinazolin-4-amine, 2TFA.

[1365] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3- yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine (Example 112, 61.6 mg, 0.1 mmol) and 4-(methylsulfonyl)piperidine (49.0 mg, 0.30 mmol) according to a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 10.06 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 4.83 (d, J = 5.4 Hz, 2H), 4.63 (s, 1H), 3.44 (m, 2H), 3.16 (m, 2H), 2.91 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 2.10 (m, 2H), 1.58 (s, 2H). (includes one salt NH); MS (M+H) + = 527.

[1366] Example 154. N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperidin-l-yl)quinazolin-4-amine, 2TFA. Example 154. N-((5-chloropyridin-3-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperidin-l-yl)quinazolin-4-amine, 2TFA.

[1367] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3- yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine (Example 112, 61.6 mg, 0.1 mmol) and 4-(methylsulfonyl)piperidine (49.0 mg, 0.30 mmol) according to a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 10.06 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 4.83 (d, J = 5.4 Hz, 2H), 4.63 (s, 1H), 3.44 (m, 2H), 3.16 (m, 2H), 2.91 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 2.10 (m, 2H), 1.58 (s, 2H). (includes one salt NH); MS (M+H) + = 528.

[1368] Example 155. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-l-yl)quinazolin-4-amine, 2TFA. Example 155. N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-(methylsulfonyl)piperazin-l-yl)quinazolin-4-amine, 2TFA.

[1369] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3- yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine (Example 112, 61.6 mg, 0.1 mmol) and 4-methylpiperidine-4-carbonitrile, HC1 (48.2 mg, 0.30 mmol) according to a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 10.11 (s, 1H), 8.22 (s, 1H), 7.82 - 7.72 (m, 2H), 7.48 (s, 1H), 7.41 - 7.27 (m, 3H), 4.79 (s, 2H), 3.92 (s, 4H), 3.19 (s, 4H), 2.87 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H). (includes one salt NH); MS (M+H) + = 528.

[1370] Example 156. l-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-4-methylpiperidine-4-carbonitrile, 2TFA. Example 156. l-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-4-methylpiperidine-4-carbonitrile, 2TFA.

[1371] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3- yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine (Example 112, 61.6 mg, 0.1 mmol) and 4-methylpiperidine-4-carbonitrile, HC1 (48.2 mg, 0.30 mmol) according to a procedure analogous to that described in Example 12. 1 H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 10.11 (s, 1H), 8.22 (s, 1H), 7.82 - 7.72 (m, 2H), 7.48 (s, 1H), 7.41 - 7.27 (m, 3H), 4.79 (s, 2H), 3.92 (s, 4H), 3.19 (s, 4H), 2.87 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H). (includes one salt NH); MS (M+H) + = 487.

[1372] Example 158. N-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA. Step 1. 6-Bromo-N-(4-chlorophenyl)quinazolin-4-amine

[1373] The title compound was prepared from 2-chloro-N-((5-chloropyridin-3- yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine (Example 112, 61.6 mg, 0.1 mmol) and 4-methylpiperidine-4-carbonitrile, HC1 (48.2 mg, 0.30 mmol) according to a procedure analogous to that described in Example 12.1 H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 10.08 (s, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.20 (s, 1H), 7.97 (t, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 4.84 (d, J = 5.6 Hz, 2H), 4.48 (s, 2H), 3.28 (s, 2H), 2.42 (s, 3H), 2.24 (s, 3H), 1.97 (d, J = 13.7 Hz, 2H), 1.56 (s, 2H), 1.34 (s, 3H). (includes one salt NH); MS (M+H) + = 488.

[1374] N-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA.

[1375] Example 159. 5-(4-((4-chlorophenyl)amino)quinazolin-6-yl)-l-methylpyridin-2(lH)-one, TFA.

[1376] 6-Bromo-N-(4-chlorophenyl)quinazolin-4-amine was prepared from 6-bromo-2,4- dichloroquinazoline and (3-chlorophenyl)methanamine according to a procedure analogous to that described in Example 1, Step 1.

[1377] Step 2. Example 160. N-(4-chlorophenethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-amine, 2TFA.

[1378] The title compound was prepared from 6-bromo-N-(4-chlorophenyl)quinazolin-4- amine (50.2 mg, 0.15 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)isoxazole (66.9 mg, 0.30 mmol), PdCl2(dppf)-CH2Cl2adduct (12.25 mg, 0.015 mmol) and K2CO3(124 mg, 0.90 mm...

Claims

1. A compound selected from the group consisting of: 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-l-yl)quinazolin-4- amine; N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-(l-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-methoxyquinazolin-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-l-yl)ethyl) quinazoline-2,4-diamine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-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-(4-(3-(dimethylamino)propyl)piperazin-l-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-l- yl)(cyclopropyl)methanone; (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-l- yl)(l-methyl-lH-pyrazol-4-yl)methanone; 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)quinazolin-4- amine; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperazin-l- yl)ethanol; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(4-isopentylpiperazin-l-yl)quinazolin- 4-amine; N4-(3-chlorobenzyl)-N2-(2-(dimethylamino)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-N2- methylquinazoline-2,4-diamine; (l-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)piperidin-4- yl)methanol; or a pharmaceutically acceptable salt thereof. (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)piperidin-3-yl)methanol; (1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)piperidin-3-yl)methanol; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)quinolin-4-amine; (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)piperazin-1-yl)(pyridin-4-yl)methanone; 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)piperidin-4-yl)ethanol; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-amine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)-1,4-diazepan-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-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)quinolin-4-amine; (4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)piperazin-1-yl)(pyridin-3-yl)methanone; 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)piperazin-1-yl)-2-hydroxyethanone; 1-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethanone; 2-chloro-N-(3-chlorobenzyl)-7-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine; 2-(4-(4-((3-chlorobenzyl)amino)-7-(3,5-dimethylisoxazol-4-yl)quinolin-2-yl)piperazin-1-yl)ethanol; N-(3-chlorobenzyl)-2-(4-((dimethylamino)methyl)piperidin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine; 2-(1-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-1H- pyrazol-4-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)-7-(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-(l-(2-(dimethylamino)ethyl)-lH-pyrazol-4-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-2-(l-(oxetan-3-yl)-lH-pyrazol-4- yl)quinazolin-4-amine; 2-(4-(4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-2-yl)-lH- pyrazol-l-yl)-2-methylpropan-l-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-l-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-amine; N-(3-chlorobenzyl)-6-(3,5-dimethyl-lH-pyrazol-4-yl)-2-(4-(2- (dimethylamino)ethyl)piperazin-l-yl)quinazolin-4-amine; 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)quinazolin- 6-yl)-l-methylpyridin-2(lH)-one; 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-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-l-yl)-6-(3,5-dimethylisoxazol-4-yl)-N- (thiophen-2-ylmethyl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(2- methoxybenzyl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(3- methoxybenzyl)quinazolin-4-amine; N-(2-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine; N-(3-bromobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-l-yl)-6-(3,5- dimethylisoxazol-4-yl)quinazolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-l-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-((5- fluoropyridin-3-yl)methyl)quinolin-4-amine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(5-methylisoxazol-4- yl)quinolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- fluoropyridin-3-yl)methyl)quinolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- fluoropyridin-3-yl)methyl)quinolin-4-amine; N-((5-chloropyridin-3-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinolin-4-amine; N-((4-chloropyridin-2-yl)methyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- fluoropyridin-3-yl)methyl)quinolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- fluoropyridin-3-yl)methyl)quinolin-4-amine; N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4- yl)-N-methylquinolin-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-((5- fluoropyridin-3-yl)methyl)quinolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-((5- fluoropyridin-3-yl)methyl)quinolin-4-amine; 2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-(thiophen-2- yl)ethyl)quinolin-4-amine; N-(1-(3-chlorophenyl)ethyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5- dimethylisoxazol-4-yl)quinolin-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.

2. A compound selected from the group consisting of: 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; 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)quinoline-2-carboxamide; N-(3-chlorobenzyl)-2-(4-chlorophenoxy)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine; N-(1-(3-chlorophenyl)cyclopropyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-4-amine; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4-ylmethyl)quinoline-2-carboxamide; 4-((3-chlorobenzyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)quinoline-2-carboxamide; (S)-2-((2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)quinolin-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)quinoline-2- carboxamide; N2-((1H-imidazol-2-yl)methyl)-N4-(3-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)quinoline-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-(((5-chloropyridin-3-yl)methyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H- pyran-4-yl)quinazoline-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-methyl-1H- imidazol-5-yl)methyl)quinazoline-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-methyl-1H- imidazol-5-yl)methyl)quinazoline-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-methyl-1H- imidazol-5-yl)methyl)quinazoline-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-methyl-1H- imidazol-5-yl)methyl)quinazoline-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-methyl-1H- imidazol-5-yl)methyl)quinazoline-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-methyl-1H- imidazol-5-yl)methyl)quinazoline-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-methyl-1H- imidazol-5-yl)methyl)quinazoline-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-((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; (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-dioxothietan-3-yl)quinoline- 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) quinoline-2-carboxamide; (S)-6-(3,5-dimethylisoxazol-4-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(3- phenylmorpholino)quinoline-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)quinoline- 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)quinolin-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; (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)-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; (S)-4-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester; (S)-8-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-2-methyl-2,8-diazaspiro[4.5]dec-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-phenylpiperazin-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)quinoline-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.

3. The compound (S)-N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-4-(3- phenylmorpholino)quinoline-2-carboxamide.

4. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition, wherein the treatment is mediated by inhibition of binding of a bromodomain-containing protein to acetylated proteins.

6. The use of claim 5, wherein the acetylated proteins are acetylated histones.

7. The use of claim 6, wherein the acetylated proteins are acetylated histones involved in the regulation or deregulation of gene expression.

8. The use of claim 5, 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 tumor, Merkel cell carcinoma, prostate cancer, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, and HIV infection.

9. The use of claim 5, wherein the disease or condition is a fibrotic condition.

10. The use of claim 9, wherein the fibrotic condition is idiopathic pulmonary fibrosis, renal fibrosis, or myocardial fibrosis.

11. The use of claim 10, wherein the fibrotic condition is idiopathic pulmonary fibrosis.

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