Kinase inhibitors

Abstract

Disclosed is a class of kinase inhibitors of formula (I) or formula (II). Related pharmaceutical compositions and methods of using the kinase inhibitors are also disclosed.

Description

KINASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of U.S. Provisional Patent Application No.63 / 527,274, filed July 17, 2023, which is incorporated by reference in its entirety herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under project number Z01ZIABC011744 by the National Institutes of Health, National Cancer Institute, project number Z01ZIABC011471 by the National Institutes of Health, National Cancer Institute, and project number Z01ZIABC011854 by the Cancer Moonshot NCI Program for Natural Product Discovery. The Government has certain rights in this invention. BACKGROUND OF THE INVENTION Mammals have enzymes called kinases that are associated with cell functions such as cell signaling, metabolism, and division. Some kinases have been found to be more active in certain types of cancers. Blocking the kinases associated with cancer growth may provide therapeutic advantages to those suffering from cancer. Given that cancer is currently a major health concern and that there is a lack of effective treatments against all cancers, there is an urgent need to identify new kinase inhibitors to treat cancers. There is also an urgent need to identify kinase inhibitors associated with non-cancer pathologies (e.g., infections) in order to treat conditions and disorders associated with non-cancer pathologies. The Molecular Targets Program of the United States’ National Cancer Institute (NCI) completed a screen of ~150,000 pre-fractionated natural products from the NCI Program for Natural Product Discovery (NPNPD) (Thornburg et al., ACS Chem. Biol., 13: 2484-2497 (2018)). A class of active compounds identified were isolated from the marine organism Aplidium sp. These compounds, named Aplithianines A & B, were shown to potently inhibit both (1) oncogenic gene fusion DNAJB1-PRKACA (PKADJ) and (2) wild type protein kinase A (PKA) at nanomolar concentrations. Aplithianine A was shown to potently and selectively inhibit a broad range of kinases, not just PKADJ or PKA, broadening its potential utility. Further kinetic analysis showed that Aplithianine A was a competitiveinhibitor of kinases, competing with ATP for binding to PKA. Additional structural studies showed that aplithianine A bound to the catalytic pocket in PKADJ where ATP normally binds, further proving the competitive mechanism of inhibition and providing structural insights for further synthetic modification of this compound class.

[0005] The aplithianine structural class is a group of potent kinase inhibitors with broad potential applicability to numerous kinases of importance, e.g., for cancer chemotherapy. For example, gene fusions (a genetic lesion ligating two normally non-adjacent portions of the genome next to one another) were one of the earliest recognized biomarkers of cancer. Approximately 20% of all solid malignancies have at least one identifiable gene fusion. The experience with the BCR-ABL1 kinase inhibitor imatmib (Savage, et al.. Ai Engl. J. Med.. 346(9): 683-93 (2002)), and a continuing emphasis on precision medicine suggests that focusing on gene fusion associated pharmaceutical development could produce disease specific medicines. One such fusion is the recently identified PKADJ oncogenic gene fusion associated with fibrolamellar hepatocellular carcinoma (FL-HCC) (Honeyman. et al., Science. 343: 1010-14 (2014) and Kastenhuber, et al., PAMS USA, 1 14: 13076-84 (2017)). Among liver cancers, FL-HCC is unusually tragic in that its patient population is young (<35 years of age) and lacks any successful disease specific chemotherapeutic regime, with a 5 year survival rate of only approximately 34% (Riggle, et al., Pediatr. Blood Cancer, 63: 1 163-7 (2016)). The biological understanding of FL-HCC improved in 2014 when for the first time it was shown that all FL-HCC patients carried an in-frame intrachromosomal gene fusion between the first exon of the gene encoding the Heat Shock Protein 40 (HSP40) family member DNAJB1 and the second exon of the gene for the adenosine 3',5’-monophosphate (cAMP)--dependent PKA catalytic subunit alpha, PRKACA (Honeyman. et al.. Science, 343: 1010-14 (2014)). 'rhe DNAJB1 -PRKACA gene fusion produces an enzymatically active chimeric protein DNAJ. Studies have demonstrated that PKA activity was required for tumor formation. Equivalent expression of PKAca or expression of a kinase-dead version of the oncogenic fusion protein is not sufficient for transformation and the tumorigenicity of PKAJ is dependent on its kinase activity’ (Kastenhuber, et al.. ENAS USA. 114: 13076-84 (2017)). ^0006] DNAJ fusion complexes may present novel small molecule binding sites which can be exploited for the treatment of FL-HCC (Tomasmi, et al., Scientific Reports, 8: 720 (2018); Cheung, et al., PEAS USA, 112: 1374-7S? (2015); and Averill, et al., J. Cell Biochem., 120: 13783-91 (2019)).{0007] Thus, there remains a need to develop novel small molecules that can act as both inhibitors and activators of PKAJ. There also exists a need for methods of treatment using such inhibitors and activators of PKAJ.[00081 The invention provides such small molecules that can act as both inhibitors and activators of PKAJ and methods. These, and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.BRIEF SUMMARY OF THE INVENTION

[0009] In some aspects, the invention provides compounds of formula (I):wherein X’, X2, X3, xzzzzr, R!, and A are defined herein, or a pharmaceutically acceptable salt thereof.

[0010] In some aspects, the invention provides compounds of formula (II):wherein X], X2, X3, R'. and E are defined herein, or a pharmaceutically acceptable salt thereof.

[0011] The invention also provides pharmaceutical compositions comprising compounds of formula (I) or formula (11).

[0012] The invention further provides methods of inhibiting kinase activity in a subject, methods of suppressing the immune system in a subject, methods of preventing organ rejection in a subject, methods of treating cancer in a subject, methods of treating diabetic neuropathic pain in a subject, methods of treating malaria in a subject, and / or methods of treating an infection associated with a protozoa in a subject comprising administering to the subject compounds or pharmaceutical compositions of aspects of the present invention.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0013] FIG. 1 is a graph showing the normalized % JPKAca Activity curve for compound Compound GS.

[0014] FIG. 2 is a graph showing the normalized % JPKAca Activity curve for compound Compound JV.

[0015] FIG. 3 is a graph showing the normalized % JPKAca Activity curve for compound Compound JN.

[0016] FIG. 4 is a graph showing the normalized % JPKAca Activity curve for compound Compound JB.

[0017] FIG. 5 is a graph showing the normalized % JPKAca Activity curve for compound Compound IX.FIG.6 is a graph showing the normalized % JPKAcĮ Activity curve for compound Compound IW. FIG.7 is a graph showing the normalized % JPKAcĮ Activity curve for compound Compound GX. FIG.8 is a graph showing the IC50value reproducibility across three separate trial runs for select compounds of Example 12. FIG.9 shows the NCI-60 human tumor cell line screen results for Compound BO. FIG.10 shows the NCI-60 human tumor cell line screen results for Compound BJ. DETAILED DESCRIPTION OF THE INVENTION In some aspects, the invention provides a compound of formula (I)wherein is a single or double bond,X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3 alkyl;R3is an aryl; R4is C1-C3 alkyl; A is –NR5((CHR7)mR6); R5, R6, and R7are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, - (C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, C3-C8 cycloalkyl, C3-C8heterocycloalkyl, C8-C10bicycloalkyl, C4-C10biheterocycloalkyl, aryl, heteroaryl, or R5 and R6 combine to form a C3-C8 heterocycloalkyl, C4-C10 biheterocycloalkyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6 alkyl), -(C1-C3 alkyl)-C(O)OH, -(C1-C3 alkyl)-C(O)O-(C1-C6 alkyl), - (C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1- C6 alkyl), -(C1-C3 alkyl)-NH-C(O)OH, -(C1-C3 alkyl)-NH-C(O)O-(C1-C6 alkyl), -(C1-C3 alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)- C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6 alkyl)-(C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)-heterocycloalkyl, - (C1-C6alkyl)-heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl-(C1-C6 alkyl), halo, nitro, hydroxy, amino, C1-C6 alkl ino, di-C1-C6 alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6 alkyl), -C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, spiro C3- C8 cycloalkyl, fused C3-C8 heterocycloalkyl, spiro C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, provided that R5 and R6 are not both hydrogen; and m is 0 or 1; or a pharmaceutically acceptable salt thereof. In some aspects, the invention provides a compound of formula (I)whereinis a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl; R4is C1-C3alkyl; A is –NR5((CHR7)mR6); R5, R6, and R7are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)- NH2, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, or R5and R6combine to form a C3-C8 heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, - (C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, provided that R5and R6are not both hydrogen; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.In some aspects, the invention provides a compound of formula (I) O X3Awherein a is a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3 alkyl; R3is an aryl; R4is C1-C3 alkyl; A is –NR5R6; and R5 and R6 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)- NH2, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, or R5 and R6 combine to form a C3-C8 heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, - (C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof, provided that R5 and R6 are not both hydrogen; or a pharmaceutically acceptable salt thereof.In an aspect of the invention, the compound of formula (I) is of formula (Ia): O S A or a pharmaceutically accepta. In an aspect of the invention, the compound of formula (I) is of formula (Ib): O Aor a pharmaceutically acceptable salt thereof. In an aspect of the invention, the compound of formula (I) is of formula (Ic):O S A or a pharmaceutically accepta. In an aspect of the invention, the compound of formula (I) is of formula (Id): O Aor a pharmaceutically acceptable salt thereof. In an aspect of the invention, the compound of formula (I) is of formula (Ie):O S A or a pharmaceutically accepta. In an aspect of the invention, the compound of formula (I) is of formula (In): O Aor a pharmaceutically acceptable salt thereof. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A is a nitrogen bound C3-C8heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C1- C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH- C(O)O-(C1-C6 alkyl), -NH-C(O)-(C1-C6 alkyl), -(C1-C3 alkyl)-NH-C(O)OH, -(C1-C3 alkyl)- NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, - (C1-C6 alkyl)-NH2, -(C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)-(C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)- heterocycloalkyl, -(C1-C6 alkyl)-C(O)-heterocycloalkyl-(C1-C6 alkyl), halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH- heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8 cycloalkyl, spiro C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, spiro C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A is a nitrogen bound C3-C8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3- C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, - CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A comprises a nitrogen bound C3-C8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), - (C1-C3 alkyl)-C(O)OH, -(C1-C3 alkyl)-C(O)O-(C1-C6 alkyl), -(C1-C3 alkyl)-C(O)-(C1-C6 alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3 alkyl)-NH-C(O)O-(C1-C6 alkyl), -(C1-C3 alkyl)-NH-C(O)-(C1-C6 alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-C(O)O-(C1-C6 alkyl), -(C1-C6 alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-heterocycloalkyl, -(C1-C6 alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6 alkyl), -C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, spiro C3-C8cycloalkyl, fused C3- C8 heterocycloalkyl, spiro C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A comprises a C3-C8heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)- COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl- amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, - (C1-C3alkyl)-CN, carbonyl, and a combination thereof. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A comprises at least one nitrogen atom (e.g., at least two nitrogen atoms or at least three nitrogen atoms). In certain embodiments, A contains exactly 1 nitrogen atom. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A comprises at least two nitrogen atoms. In certain embodiments, A contains exactly 2 nitrogen atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A comprises at least 3 (e.g., 3-10, 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6-12, or 7-12) carbon atoms. In certain embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A comprises at least five (e.g., 5-10, 6-10, 7-10, 5-12, 6-12, or 7- 12) carbon atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A contains only carbon, nitrogen, and hydrogen atoms, e.g., does not contain an oxygen atom. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A contains only carbon, nitrogen, oxygen, and hydrogen atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A contains only carbon, nitrogen, sulfur, and hydrogen atoms.In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A fulfills the following requirements: (i) A comprises a C3-C8heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents, (ii) A comprises at least two nitrogen atoms, (iii) A comprises at least five (e.g., 5-10, 6-10, 7-10, 5-12, 6-12, or 7-12) carbon atoms, and (iv) A contains only carbon, nitrogen, and hydrogen atoms, e.g., does not contain an oxygen atom. In some embodiments (i.e., any of the aspects described herein) of the compound a of formula (I), is a single bond. diments (i.e., any of the aspects described herein) of the compounda of formula (I), is a double bond. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), m is 0. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), R1is H. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), R7is H. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), m is 1 and R7is H. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), X1and X2are not both N. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), X1and X2are each independently CH or CR4. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), X1and X2are each independently CH. In an aspect of the invention, the compound of formula (I) is of formula (If):O NH2S R8, wherein X1and X2are each independently CH, CR4, or N; R1is H or –NR2R3; R2is H or C1-C3 alkyl; R3is an aryl; R4is C1-C3 alkyl; R8is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, - (C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di- C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof; and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. In an aspect of the invention, the compound of formula (I) is of formula (Ig):O S NH2, wherein X1and X2are each independently CH, CR4, or N; R1is H or –NR2R3; R2is H or C1-C3 alkyl; R3is an aryl; R4is C1-C3 alkyl; R8is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, - (C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di- C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof; and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. In an aspect of the invention, the compound of formula (I) is of formula (Ih):O S H R8, wherein X1and X2are each independently CH, CR4, or N; R1is H or –NR2R3; R2is H or C1-C3 alkyl; R3is an aryl; R4is C1-C3 alkyl; R8is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, - (C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di- C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof; and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. In an aspect of the invention, the compound of formula (I) is of formula (Ij):O R8, wherein X1and X2are each independently CH, CR4, or N; R1is H or –NR2R3; R2is H or C1-C3 alkyl; R3is an aryl; R4is C1-C3 alkyl; R8is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, - (C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di- C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof; and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. In some embodiments, R8 is hydrogen. In an aspect of the invention, the compound of formula (I) is of formula (Ik):R8O H2, wherein X1and X2are each independently CH, CR4, or N; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl; R4is C1-C3alkyl; R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, - (C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di- C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof; and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. In an aspect of the invention, the compound of formula (I) is of formula (Im):, wherein X1and X2are each independently CH, CR4, or N; R1is H or –NR2R3; R2is H or C1-C3 alkyl; R3is an aryl; R4is C1-C3 alkyl; R8is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, - (C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di- C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof; and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.In some embodiments, the compound of formula (I) is:H N O absOor a phIn some embodiments (i.e., any of the aspects described herein), the compound of formula (I) is not one or more of the following compounds:61 O O S N S N N H H altIn some aspect, the invention provides a compound of formula (II)(II) wherein is a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl; R4is C1-C3 alkyl; and E is C3-C8 heterocycloalkyl, C8-C10 bicycloalkyl, C4-C10 biheterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C1-C6 alkoxy, -C(O)OH, -C(O)O-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1- C6 alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6 alkyl), -NH-C(O)-(C1-C6 alkyl), -(C1-C3 alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-NH2, -(C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-heterocycloalkyl, -(C1-C6 alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6 alkyl), -C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, spiro C3-C8cycloalkyl, fused C3- C8 heterocycloalkyl, spiro C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof,or a pharmaceutically acceptable salt thereof. In some aspects, the invention provides a compound of formula (II) X3E R1wherein a is a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl; R4is C1-C3alkyl; and E is C3-C8 heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)- NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof. In some aspects, the invention provides a compound of formula (II)X3E R1wherein a is a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl; R4is C1-C3alkyl; and E is a carbon bound C3-C8 heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3- C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, - CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof. In an aspect of the invention, the compound of formula (II) is of formula (IIa):S E R1or a pharmaceutically acceptable salt thereof. In an aspect of the invention, the compound of formula (II) is of formula (IIb): S E R1 or a pharmaceutically acceptabIn an aspect of the invention, the compound of formula (II) is of formula (IIc): S E R1or a pharmaceutically acceptable salt thereof. In an aspect of the invention, the compound of formula (II) is of formula (IId): S E R1 or a pharmaceutically acceptabIn an aspect of the invention, the compound of formula (II) is of formula (IIe): S E R1 or a pharmaceutically acceptablIn an aspect of the invention, the compound of formula (II) is of formula (IIf):S E R1or a pharmaceutically acceptable salt thereof. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (II), E is selected from: HNNN HN O S HN NH O S NH NH N N , , O ,each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6 alkoxy, -C(O)OH, -C(O)O-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6 alkyl), -NH-C(O)-(C1-C6 alkyl), -(C1-C3 alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-NH2, -(C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-heterocycloalkyl, -(C1-C6 alkyl)-C(O)-heterocycloalkyl- (C1-C6 alkyl), halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, spiro C3-C8 cycloalkyl, fused C3- C8heterocycloalkyl, spiro C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (II), E is selected from: HNNN HN O S HN NH O S NH NH N , ,each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)- OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), E comprises at least one nitrogen atom (e.g., at least two nitrogen atoms or atleast three nitrogen atoms). In certain embodiments, E contains exactly 1 nitrogen atom. In other embodiments, E contains exactly 2 nitrogen atoms. In some embodiments, E contains exactly 3 nitrogen atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), E comprises at least 3 (e.g., 3-10, 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6-12, or 7-12) carbon atoms. In certain embodiments (i.e., any of the aspects described herein) of the compound of formula (II), E comprises at least 4 (e.g., 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6- 12, or 7-12) carbon atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (II), E contains only carbon, nitrogen, and hydrogen atoms, e.g., does not contain an oxygen atom. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), E contains only carbon, nitrogen, oxygen, and hydrogen atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), E contains only carbon, nitrogen, sulfur, and hydrogen atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (II), E fulfills the following requirements: (i) E comprises at least one nitrogen atom (e.g., at least two nitrogen atoms), and (ii) E comprises at least 3 (e.g., 3-10, 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6-12, or 7-12) carbon atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (II), E fulfills the following requirements: (i) E comprises at least one nitrogen atom (e.g., at least two nitrogen atoms), (ii) E comprises at least 4 (e.g., 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6-12, or 7-12) carbon atoms, and (iii) E contains only carbon, nitrogen, and hydrogen atoms, e.g., does not contain an oxygen atom. In some embodiments (i.e., any of the aspects described herein) of the compound a of formula (II), is a single bond. In some embodiments (i.e., any of the aspects described herein) of the compound a of formula (II), is a double bond. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (II), R1is H.In some embodiments (i.e., any of the aspects described herein) of the compound of formula (II), X1and X2are not both N. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (II), X1and X2are each independently CH or CR4. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (II), X1and X2are each independently CH. In some embodiments, the compound of formula (II) is:NH2N S Sor a pharmIn some embodiments (i.e., any of the aspects described herein), the compound of formula (II) is not one or more of the following compounds:H3C Br H3C N H3C N O N N S N N S , orAny of the compounds of formula (I) and formula (II) can exist as any suitable stereoisomer thereof. For example, the invention provides enantiomers and diastereomers of any of the compounds disclosed herein. Alternatively, any of the compounds of formula (I) and formula (II) can exist as a racemic mixture and / or a mixture of diastereomers. In any of the aspects of the compounds of formula (I) and formula (II), the term “alkyl” implies a straight-chain or branched alkyl substituent containing from, for example, from about 1 to about 6 carbon atoms, e.g., from about 1 to about 4 carbon atoms. Examples of alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, isopentyl, n-hexyl, and the like. This definition also applies wherever “alkyl” occurs as part of a group, such as, e.g., in C3-C6cycloalkylalkyl, hydroxyalkyl, haloalkyl (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl), cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, arylcarbonylalkyl (-(alkyl)C(O)aryl), arylalkyl, etc. The alkyl can be substituted or unsubstituted, as described herein. Even in instances in which the alkyl is an alkylene chain (e.g., -(CH2)n-), the alkyl group can be substituted or unsubstituted. In any of the aspects of the compounds of formula (I) and formula (II), the term “alkenyl,” as used herein, means a linear alkenyl substituent containing from, for example, about 2 to about 6 carbon atoms (branched alkenyls are about 3 to about 6 carbon atoms), e.g., from about 3 to about 5 carbon atoms (branched alkenyls are about 3 to about 6 carbonatoms). In accordance with an aspect of the invention, the alkenyl group is a C2-C4alkenyl. Examples of alkenyl group include ethenyl, allyl, 2-propenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, and the like. The alkenyl can be substituted or unsubstituted, as described herein. In any of the aspects of the compounds of formula (I) and formula (II), the term “cycloalkyl,” as used herein, means a cyclic alkyl moiety containing from, for example, 3 to 6 carbon atoms or from 5 to 6 carbon atoms. Examples of such moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl may contain a carbonyl such that there is an exocylclic (=O) group. The cycloalkyl can be substituted or unsubstituted, as described herein. The cycloalkyl may also be fused to a neighboring substituent (e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl), i.e, sharing two atoms and a bond with a neighboring substituent. In any of the aspects of the compounds of formula (I) and formula (II),, the term “aryl” refers to a mono, bi, or tricyclic carbocyclic ring system having one, two, or three aromatic rings, for example, phenyl, naphthyl, anthracenyl, or biphenyl. The term “aryl” refers to an unsubstituted or substituted aromatic carbocyclic moiety, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like. An aryl moiety generally contains from, for example, 6 to 30 carbon atoms, from 6 to 18 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 10 carbon atoms. It is understood that the term aryl includes carbocyclic moieties that are planar and comprise 4n+2 π electrons, according to Hückel’s Rule, wherein n = 1, 2, or 3. This definition also applies wherever “aryl” occurs as part of a group, such as, e.g., in haloaryl (e.g., monohaloaryl, dihaloaryl, and trihaloaryl), arylalkyl, etc. The aryl can be substituted or unsubstituted, as described herein. The aryl may also be fused to a neighboring substituent (e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl), i.e,. sharing two atoms and a bond with a neighboring substituent. In any of the aspects of the compounds of formula (I) and formula (II), the term “heteroaryl” refers to aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S, or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groupsmay contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl. The heteroaryl can be substituted or unsubstituted, as described herein. The heteroaryl may also be fused to a neighboring substituent (e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl), i.e,. sharing two atoms and a bond with a neighboring substituent. In any of the aspects of the compounds of formula (I) and formula (II), the term “heterocycloalkyl” means a stable, saturated, or partially unsaturated monocyclic, bicyclic, and spiro ring system containing 3 to 7 ring members of carbon atoms and other atoms selected from nitrogen, sulfur, and / or oxygen. In an aspect, a heterocycloalkyl is a 5, 6, or 7- membered monocyclic ring and contains one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl may be attached to the parent structure through a carbon atom or through any heteroatom of the heterocycloalkyl that results in a stable structure. Alternatively, or additionally, the heterocycloalkyl may contain a carbonyl such that there is an exocylclic (=O) group. In other words, as used herein when referring to a substituent, the term “carbonyl” refers to a (=O) group. Examples of such heterocycloalkyl rings are isoxazolyl, thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyranyl, piperidyl, oxazolyl, and morpholinyl. The heterocycloalkyl can be substituted or unsubstituted, as described herein. In any of the aspects of the compounds of formula (I) and formula (II), the term “C8-C10 bicycloalkyl” refers to an aryl group fused to a cycloalkyl group, as described herein. In any of the aspects of the compounds of formula (I) and formula (II), the term “C4-C10 biheterocycloalkyl” refers to an aryl group fused to a heterocycloalkyl group, a heteroaryl group fused to a heterocycloalkyl group, or a heteroaryl group fused to a cycloalkyl group, as described herein. In any of the aspects of the compounds of formula (I) and formula (II), the term “fused” means that the indicated ring system shares a bond with the ring system to which it is attached.In any of the aspects of the compounds of formula (I) and formula (II), the term “spiro” means that the indicated ring system shares an atom with the ring system to which it is attached. In any of the aspects of the compounds of formula (I) and formula (II), the term “hydroxy” refers to the group –OH. In any of the aspects of the compounds of formula (I) and formula (II), the term “cyano” refers to the group –CN, whereas the term “thiocyano” refers to -SCN. In any of the aspects of the compounds of formula (I) and formula (II), the terms “alkoxy” and “cycloalkyloxy” embrace linear or branched alkyl and cycloalkyl groups, respectively, that are attached to a divalent oxygen. The alkyl and cycloalkyl groups are the same as described herein. In any of the aspects of the compounds of formula (I) and formula (II), the term “halo” refers to a halogen selected from fluorine, chlorine, bromine, and iodine. In any of the aspects of the compounds of formula (I) and formula (II), the term “carboxylato” refers to the group -C(O)OH. In any of the aspects of the compounds of formula (I) and formula (II), the term “amino” refers to the group –NH2. The term “alkylamino” refers to –NHR, whereas the term “dialkylamino” refers to –NRR’. R and R' are the same or different and each is a substituted or unsubstituted alkyl group, as described herein. In any of the aspects of the compounds of formula (I) and formula (II), the term “amido” refers to the group -C(O)NRR’, which R and R’ are the same or different and each is hydrogen or a substituted or unsubstituted alkyl group, as described herein. In any of the aspects of the compounds of formula (I) and formula (II), the term “phosphonato” refers to the group -P(O)(OR)2, which R is hydrogen or a substituted or unsubstituted alkyl group, as described herein.

[0100] In any of the aspects of the compounds of formula (I) and formula (II), the term “amino acid” refers to any amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In some embodiments, when used as a substituent, the amino acid is alanine or glycine. In certain embodiments, when used as a substituent, the amino acid is nitrogen bound. In any of the aspects of the compounds of formula (I) and formula (II), the term “amino acid methyl ester” refers to any amino acid described herein that has been converted to the methyl ester.

[0101] In any of the aspects of the compounds of formula (I) and formula (II), any substituent that is not hydrogen (e.g., C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl) can be an optionally substituted moiety. The substituted moiety typically comprises at least one substituent (e.g., 1, 2, 3, 4, 5, 6, etc.) in any suitable position (e.g., 1-, 2-, 3-, 4-, 5-, or 6-position, etc.). When an aryl group is substituted with a substituent, e.g., halo, amino, alkyl, OH, alkoxy, and others, the aromatic ring hydrogen is replaced with the substituent and this can take place in any of the available hydrogens, e.g., 2, 3, 4, 5, and / or 6-position wherein the 1-position is the point of attachment of the aryl group in the compound of the present invention. Suitable substituents include, e.g., halo, alkyl, alkenyl, hydroxy, nitro, cyano, amino, alkylamino, alkoxy, aryloxy, aralkoxy, carboxyl, carboxyalkyl, carboxyalkyloxy, amido, alkylamido, haloalkylamido, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, fused aryl, fused heteroaryl, fused heterocycloalkyl, and fused cycloalkyl, each of which is described herein. In some instances, the substituent is at least one alkyl, halo, and / or haloalkyl (e.g., 1 or 2).

[0102] In any of the aspects of the compounds of formula (I) and formula (II), whenever a range of the number of atoms in a structure is indicated (e.g., a C1-12, C1-8, C1-6, C1-4, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1- 8 carbon atoms (e.g., C1-C8), 1-6 carbon atoms (e.g., C1-C6), 1-4 carbon atoms (e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl, cycloalkyl, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, and / or 8 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, etc., as appropriate).

[0103] In any of the aspects of the compounds of formula (I) and formula (II), the phrase “salt” or “pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. For example, an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid), an organic acid (e.g., oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, or benzylsulfonic acid), an inorganic base (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or ammonium hydroxide), an organic base(e.g., methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, or cinchonine), or an amino acid (e.g., lysine, arginine, or alanine) can be used. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p.1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For example, they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium of salt. In an aspect, the salt is a trifluoroacetate salt. Pharmaceutical Compositions

[0104] An aspect of the invention provides pharmaceutical compositions comprising a compound of the present invention. The pharmaceutical compositions contain a pharmaceutically acceptable carrier. For example, the pharmaceutical composition of the present invention can comprise a compound of formula (I) and / or a compound of formula (II), or a pharmaceutically acceptable salt thereof.

[0105] In an aspect, the compound has a purity of at least about 85% (e.g., at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%).

[0106] The pharmaceutical composition can comprise a compound of the present invention (e.g., a compound of formula (I) and / or a compound of formula (II)) in combination with one or more other pharmaceutically active agents or drugs, such as a chemotherapeutic agent, e.g., a topoisomerase I inhibitor, asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.

[0107] Preferably, the carrier is a pharmaceutically acceptable carrier. With respect to pharmaceutical compositions, the carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the active compound(s), and by the route of administration. The pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, and diluents, are well-known to those skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active agent(s) and one which has no detrimental side effects or toxicity under the conditions of use.

[0108] The choice of carrier will be determined in part by the particular compounds, as well as by the particular method used to administer the compounds. Accordingly, there are a variety of suitable formulations of the pharmaceutical composition of the invention. The compounds, a pharmaceutically acceptable salt thereof, can be administered in any suitable manner (e.g., orally, intravenously, intramuscularly, intrathecally, subcutaneously, sublingually, buccally, rectally, vaginally, by ocular route, by otic route, nasally, by inhalation, by nebulization, topically, systemically, transdermally, or a combination thereof). In an embodiment, the pharmaceutical composition of the invention is administered orally.

[0109] The following formulations for administration are exemplary and are in no way limiting. More than one route can be used to administer the compounds, and in certain instances, a particular route can provide a more immediate and more effective response than another route.

[0110] Formulations suitable for administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compounds can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol or hexadecyl alcohol, a glycol, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol, ketals such as 2,2-dimethyl-1,3-dioxolane- 4-methanol, ethers, poly(ethyleneglycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin,carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0111] Oils, which can be used in formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

[0112] Suitable soaps for use in formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-β-aminopropionates, and 2-alkyl- imidazoline quaternary ammonium salts, and (e) mixtures thereof.

[0113] The formulations will typically contain from about 0.5% to about 25% by weight of the compounds in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. The requirements for effective pharmaceutical carriers for compositions are well-known to those of ordinary skill in the art (see, e.g., Lloyd et al. (eds.), Remington: The Science and Practice of Pharmacy, 22nd Ed., Pharmaceutical Press (2012)).

[0114] It will be appreciated by one of skill in the art that, in addition to the above- described pharmaceutical compositions, the compounds of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.

[0115] For purposes of the invention, the amount or dose of the compounds administered should be sufficient to effect a desired response, e.g., a therapeutic or prophylactic response, in the mammal over a reasonable time frame. For example, the dose of the compounds should be sufficient to inhibit growth of a target cell or treat or prevent cancer in a period of from about 2 hours or longer, e.g., 12 to 24 or more hours, from the time of administration. In certain aspects, the time period could be even longer. The dose will be determined by the efficacy of the particular compounds and the condition of the mammal (e.g., human), as well as the body weight of the mammal (e.g., human) to be treated.

[0116] Many assays for determining an administered dose are known in the art. An administered dose may be determined in vitro (e.g., cell cultures) or in vivo (e.g., animal studies). For example, an administered dose may be determined by determining the IC50(the dose that achieves a half-maximal inhibition of symptoms), LD50 (the dose lethal to 50% of the population), the ED50(the dose therapeutically effective in 50% of the population), and the therapeutic index in cell culture and / or animal studies. The therapeutic index is the ratio of LD50to ED50(i.e., LD50 / ED50).

[0117] The dose of the compounds also will be determined by the existence, nature, and extent of any adverse side effects that might accompany the administration of a particular compound. Typically, the attending physician will decide the dosage of the compounds with which to treat each individual patient, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, compounds to be administered, route of administration, and the severity of the condition being treated. By way of example and not intending to limit the invention, the dose of the compounds can be about 0.001 to about 1000 mg / kg body weight of the subject being treated / day, from about 0.01 to about 10 mg / kg body weight / day, about 0.01 mg to about 1 mg / kg body weight / day, from about 1 to about to about 1000 mg / kg body weight / day, from about 5 to about 500 mg / kg body weight / day, from about 10 to about 250 mg / kg body weight / day, about 25 to about 150 mg / kg body weight / day, or about 10 mg / kg body weight / day.

[0118] In an aspect, the concentration of the compounds in the pharmaceutical composition is at least 0.05 mg / ml (e.g., at least about 0.1 mg / ml, at least about 0.2 mg / ml, at least about 0.5 mg / ml, or at least about 1 mg / ml). This concentration is greater than thenaturally occurring concentration of the compounds in their natural environment (e.g., in a sea sponge). Methods of Use

[0119] In an aspect, the invention provides methods of inhibiting kinase activity in a subject, the method comprising administering to the subject a compound or pharmaceutical composition of the invention. As used herein, “inhibiting” does not necessarily mean 100% reduction in activity, but can mean about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% reduction in activity.

[0120] In some aspects of the invention, the kinase is a PKA, a PKG, a PKC, a STK, a CLK, a DYRK, or LATS.

[0121] In some aspects of the invention, the kinase is PKA, PKA / DNAJ, cAMP-PKA, PKG1a, PKG1b, PKG2, PfPKG, PKC-^, PKC-nu, PKC-d, PKC-eta, PKC-g, STK39, CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, LATS1, or LATS2. In some aspects of the invention, the kinase is PKA, PKA / DNAJ, PKG1a, PKG1b, PKG2, PKC-^, PKC-nu, PKC-d, PKC-eta, PKC-g, STK39, CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, LATS1, or LATS2.

[0122] In some aspects of the invention, the kinase is PKA, PKA / DNAJ, or cAMP-PKA.

[0123] In some aspects of the invention, the kinase is protein kinase A (PKA). In an aspect, PKA is inhibited resulting in therapeutic benefits to the subject. In an aspect, PKA is inhibited resulting in treatment of a cancer. In an aspect, PKA is inhibited resulting in treatment of liver cancer, for example, hepatocellular carcinoma (HCC) and fibrolamellar hepatocellular carcinoma. In an aspect, PKA is inhibited resulting in treatment of diabetic neuropathic pain (Ma, et al., Neuroscience Letters, 750: 135763 (2021)).

[0124] In some aspects of the invention, the kinase is PKA / DNAJ. In an aspect, PKA / DNAJ is inhibited resulting in therapeutic benefits to the subject. In an aspect, PKA / DNAJ is inhibited resulting in treatment of a cancer. In an aspect, PKA / DNAJ is inhibited resulting in treatment of liver cancer, for example, hepatocellular carcinoma (HCC) and fibrolamellar hepatocellular carcinoma. In an aspect, PKA / DNAJ is inhibited resulting in treatment of diabetic neuropathic pain.

[0125] In some aspects of the invention, the kinase is cyclic adenosine monophosphate- protein kinase A (cAMP-PKA). In an aspect, cAMP-PKA is inhibited resulting intherapeutic benefits to the subject. In an aspect, cAMP-PKA is inhibited resulting in treatment of a cancer. In an aspect, cAMP-PKA is inhibited resulting in treatment of liver cancer, for example, hepatocellular carcinoma (HCC) and fibrolamellar hepatocellular carcinoma. In an aspect, cAMP-PKA is inhibited resulting in treatment of diabetic neuropathic pain.

[0126] In some aspects of the invention, the kinase inhibited by compounds of aspects of the invention is a protein kinase G (PKG). In an aspect, a PKG is inhibited resulting in therapeutic benefits to the subject. In an aspect, a PKG is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer (Wu, et al., Molecular Medicine Reports, 14: 1849-1856 (2016); Islam, et al., Carcinogenesis, 43(6): 584–593 (2022)). In an aspect, a PKG is inhibited resulting in treatment and / or prevention of an infection, for example, a parasite infection, for example, malaria (i.e., infection caused by a Plasmodium) (Eck, et al., ChemBioChem, 23(7): 1-8 (2022)).

[0127] In some aspects of the invention, the kinase is PKG1a, PKG1b, PKG2, or PfPKG.

[0128] In some aspects of the invention, the kinase is PKG1a. In an aspect, PKG1a is inhibited resulting in therapeutic benefits to the subject. In an aspect, PKG1a is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, PKG1a is inhibited resulting in treatment and / or prevention of an infection, for example, malaria.

[0129] In some aspects of the invention, the kinase is PKG1b. In an aspect, PKG1b is inhibited resulting in therapeutic benefits to the subject. In an aspect, PKG1b is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, PKG1b is inhibited resulting in treatment and / or prevention of an infection, for example, malaria.

[0130] In some aspects of the invention, the kinase is PKG2. In an aspect, PKG2 is inhibited resulting in therapeutic benefits to the subject. In an aspect, PKG2 is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, PKG2 is inhibited resulting in treatment and / or prevention of an infection, for example, malaria.

[0131] In some aspects of the invention, the kinase is PfPKG. In an aspect, PfPKG is inhibited resulting in therapeutic benefits to the subject. In an aspect, PfPKG is inhibited resulting in treatment and / or prevention of an infection, for example, malaria.

[0132] In some aspects of the invention, the kinase is a protein kinase C (PKC).

[0133] In some aspects of the invention, a PKC is inhibited resulting in therapeutic benefits to the subject. In an aspect, a PKC is inhibited resulting in treatment of a cancer.

[0134] In some aspects of the invention, the kinase is PKC-^, PKC-nu, PKC-d, PKC-eta, or PKC-g. In an aspect of the invention, the kinase is PKC-^. In an aspect of the invention, the kinase is PKC-nu. In an aspect of the invention, the kinase is PKC-d. In an aspect of the invention, the kinase is PKC-eta. In an aspect of the invention, the kinase is PKC-g.

[0135] In some aspects of the invention, the kinase is a serine / threonine kinase (STK). In an aspect, a STK is inhibited resulting in therapeutic benefits to the subject. In an aspect, a STK is inhibited resulting in treatment of a cancer, for example, breast cancer.

[0136] In some aspects of the invention, the kinase is STK39. In an aspect, STK39 is inhibited resulting in therapeutic benefits to the subject. In an aspect, STK39 is inhibited resulting in treatment of a cancer, for example, breast cancer.

[0137] In some aspects of the invention, the kinase inhibited by compounds of aspects of the invention is a dual-specificity tyrosine-regulated kinase (DYRK). In an aspect, a DYRK is inhibited resulting in therapeutic benefits to the subject. In an aspect, a DYRK is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer (Boni, et al., Cancers, 12: 1-26 (2020); Henderson, et al., J. Med. Chem., 64: 11709í11728 (2021)). In an aspect, a DYRK is inhibited resulting in treatment and / or prevention of an infection, for example, an infection caused by a protozoa (Loaëc, et al., Mar. Drugs, 15(316): 1-15 (2017)) or parasite (e.g., Trypanosoma brucei; Cayla, et al., eLife, 1-34 (2020)).

[0138] In some aspects of the invention, the kinase is DYRK1A, DYRK1B, DYRK2, DYRK3, or DYRK4.

[0139] In some aspects of the invention, the kinase is DYRK1A. In an aspect, DYRK1A is inhibited resulting in therapeutic benefits to the subject. In an aspect, DYRK1A is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, DYRK1A is inhibited resulting in treatment and / or prevention of an infection, for example, an infection caused by a protozoa or parasite.

[0140] In some aspects of the invention, the kinase is DYRK1B. In an aspect, DYRK1B is inhibited resulting in therapeutic benefits to the subject. In an aspect, DYRK1B is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, DYRK1B is inhibited resulting in treatment and / or prevention of an infection, for example, an infection caused by a protozoa or parasite.

[0141] In some aspects of the invention, the kinase is DYRK2. In an aspect, DYRK2 is inhibited resulting in therapeutic benefits to the subject. In an aspect, DYRK2 is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, DYRK2 is inhibited resulting in treatment and / or prevention of an infection, for example, an infection caused by a protozoa or parasite.

[0142] In some aspects of the invention, the kinase is DYRK3. In an aspect, DYRK3 is inhibited resulting in therapeutic benefits to the subject. In an aspect, DYRK3 is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, DYRK3 is inhibited resulting in treatment and / or prevention of an infection, for example, an infection caused by a protozoa or parasite.

[0143] In some aspects of the invention, the kinase is DYRK4. In an aspect, DYRK4 is inhibited resulting in therapeutic benefits to the subject. In an aspect, DYRK4 is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, DYRK4 is inhibited resulting in treatment and / or prevention of an infection, for example, an infection caused by a protozoa or parasite.

[0144] In some aspects of the invention, the kinase inhibited by compounds of aspects of the invention is a Cdc2-like kinase (CLK). In an aspect, a CLK is inhibited resulting in therapeutic benefits to the subject. In an aspect, a CLK is inhibited resulting in treatment of cancer. In an aspect, a CLK is inhibited resulting in treatment of gastric cancer (Tam, et al., Cancer Letters, 473: 186–197 (2020)), pancreatic cancer (Chen, et al., J. Hematol. Oncol., 14: 60 (2021)), prostate cancer (Uzor, et al., Scientific Reports, 11: 7963 (2021)), breast cancer (e.g., triple negative breast cancer) (Riggs, et al., J. Med. Chem., 60: 8989-9002 (2017); Yoshida, et al., Cancer Res, 75(7): 1515-1526 (2015)), lung cancer (e.g., non-small cell) (Liu, et al., JBUON, 26(1): 58-64 (2021)), and / or gliomas (Park, et al., Am. J. Cancer Res., 10(11): 3765-3783 (2020)). In an aspect, a CLK is inhibited resulting in treatment or prevention of memory impairments and neurotoxicityinduced by oligomeric Aȕ25–35 peptide administration (Naert, et al., European Neuropsychopharmacology, 2170–2182 (2015); Tam, et al., Cancer Letters, 473: 186–197 (2020); Moyano, et al., Int. J. Mol. Sci., 21: 7549 (2020); and Qin, et al., J. Med. Chem., 64: 13191í13211 (2021)). In an aspect, a CLK is inhibited resulting in treatment or prevention of arthritis, e.g., osteoarthritis (e.g., knee osteoarthritis) (Sun, et al., J. Med. Chem., 67: 6, 4603–4623 (2024)). In an aspect, a CLK is inhibited resulting in treatment or prevention of arthritis, e.g., osteoarthritis (e.g., knee osteoarthritis).

[0145] In some aspects of the invention, the compounds of aspects of the invention modulate RNA splicing. It has been reported that CLK inhibition may function as a pre- mRNA splicing modulation-based anti-cancer strategy, e.g., for MYC-driven cancers (Iwai, et al., EMBO Molecular Medicine, 10: e8289 (2018); Duncan, et al., Experimental Cell Research, 241: 300–308 (1998)). Accordingly, in an aspect, a CLK is inhibited resulting in therapeutic mRNA splicing modulation.

[0146] In some aspects of the invention, the kinase is CLK1, CLK2, CLK3, or CLK4.

[0147] In some aspects of the invention, CLK1 is inhibited resulting in therapeutic benefits to the subject. In an aspect, CLK1 is inhibited resulting in treatment of a cancer, for example, gastric cancer. In an aspect, CLK1 is inhibited resulting in prevention of memory impairments and neurotoxicity induced by oligomeric Aȕ25–35 peptide administration.

[0148] In some aspects of the invention, CLK2 is inhibited resulting in therapeutic benefits to the subject. In an aspect, CLK2 is inhibited resulting in treatment of a cancer, for example, gastric cancer. In an aspect, CLK2 is inhibited resulting in prevention of memory impairments and neurotoxicity induced by oligomeric Aȕ25–35 peptide administration.

[0149] In some aspects of the invention, CLK3 is inhibited resulting in therapeutic benefits to the subject. In an aspect, CLK3 is inhibited resulting in treatment of a cancer, for example, gastric cancer. In an aspect, CLK3 is inhibited resulting in prevention of memory impairments and neurotoxicity induced by oligomeric Aȕ25–35 peptide administration.

[0150] In some aspects of the invention, CLK4 is inhibited resulting in therapeutic benefits to the subject. In an aspect, CLK4 is inhibited resulting in treatment of a cancer, for example, gastric cancer. In an aspect, CLK4 is inhibited resulting in prevention of memory impairments and neurotoxicity induced by oligomeric Aȕ25–35 peptide administration.

[0151] In some aspects of the invention, the kinase inhibited by compounds of aspects of the invention is a LATS (Large Tumor Suppressor Kinase). In an aspect, a LATS is inhibited resulting in therapeutic benefits to the subject. In an aspect, a LATS is inhibited resulting in treatment of a cancer.

[0152] In some aspects of the invention, the kinase inhibited by compounds of aspects of the invention is LATS1 (Large Tumor Suppressor Kinase 1). In an aspect, LATS1 is inhibited resulting in therapeutic benefits to the subject. In an aspect, a LATS1 is inhibited resulting in treatment of a cancer.

[0153] In some aspects of the invention, the kinase inhibited by compounds of aspects of the invention is LATS2 (Large Tumor Suppressor Kinase 2). In an aspect, LATS2 isinhibited resulting in therapeutic benefits to the subject. In an aspect, a LATS2 is inhibited resulting in treatment of a cancer.

[0154] In some aspects, the invention provides methods of suppressing the immune system in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0155] In some aspects, the invention provides methods preventing organ rejection in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0156] In some aspects, the invention provides methods of treating diabetic neuropathic pain in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0157] In some aspects, the invention provides methods of treating malaria in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0158] In some aspects, the invention provides methods of treating an infection associated with a protozoa in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0159] In some aspects, the invention provides methods of treating a neurodegenerative disease, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention. In an aspect, the invention provides methods of treating Down syndrome, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention. In an aspect, the invention provides methods of treating Alzheimer's disease, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0160] In some aspects, the invention provides methods of treating cardiac disease, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention. In anaspect, the invention provides methods of treating heart failure, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0161] In some aspects, the invention provides methods of treating Cushing’s syndrome, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0162] In some aspects, the invention provides methods of treating McCune-Albright Syndrome, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0163] In some aspects, the invention provides methods of treating Carney complex, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.

[0164] An aspect of the invention provides compounds and pharmaceutically compositions for use in treating or preventing cancer. Without being bound by a particular theory or mechanism, it is believed that the compounds inhibit kinases.

[0165] The terms “treat” and “prevent” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment or prevention. Rather, there are varying degrees of treatment or prevention of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the methods of an aspect of the invention can provide any amount of any level of treatment or prevention of cancer in a mammal. Furthermore, the treatment or prevention provided by the method of an aspect of the invention can include treatment or prevention of one or more conditions or symptoms of the disease, e.g., cancer, being treated or prevented. Also, for purposes herein, “prevention” can encompass delaying the onset of the disease, or a symptom or condition thereof.

[0166] With respect to the methods of aspects of the invention, the cancer can be any cancer, including any of adrenal gland cancer, sarcomas (e.g., synovial sarcoma, osteogenic sarcoma, leiomyosarcoma uteri, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, and teratoma), lymphomas (e.g., small lymphocytic lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma), hepatocellular carcinoma, glioma, head cancers (e.g., squamous cell carcinoma), neck cancers (e.g., squamous cell carcinoma), acute lymphocytic cancer, leukemias (e.g., hairy cell leukemia, myeloid leukemia (acute and chronic), lymphatic leukemia (acute and chronic),prolymphocytic leukemia (PLL), myelomonocytic leukemia (acute and chronic), and lymphocytic leukemia (acute and chronic)), bone cancer (osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumors), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, and retinoblastoma), fallopian tube cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, and fibrosarcoma), myeloproliferative disorders (e.g., chronic myeloid cancer), colon cancers (e.g., colon carcinoma), esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), cervical cancer (cervical carcinoma and pre-invasive cervical dysplasia), gastric cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, larynx cancer, liver cancers (e.g., hepatocellular carcinoma, fibrolamellar carcinoma (FLC), fibrolamellar hepatocellular carcinoma (FL-HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma), lung cancers (e.g., bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma), malignant mesothelioma, skin cancer (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, nevi, dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids), multiple myeloma, nasopharynx cancer, ovarian cancer (e.g., ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid carcinoma, and clear cell adenocarcinoma), granulosa-theca cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, and malignant teratoma), pancreatic cancer (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and VIPoma), peritoneum, omentum, mesentery cancer, pharynx cancer, prostate cancer (e.g., adenocarcinoma and sarcoma), rectal cancer, kidney cancer (e.g., adenocarcinoma, Wilms tumor (nephroblastoma), and renal cell carcinoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), soft tissue cancer, stomachcancer (e.g., carcinoma, lymphoma, and leiomyosarcoma), testicular cancer (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, Leydig cell tumor, fibroma, fibroadenoma, adenomatoid tumors, and lipoma), cancer of the uterus (e.g., endometrial carcinoma), thyroid cancer, and urothelial cancers (e.g., squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, ureter cancer, and urinary bladder cancer). In an aspect of the invention, the cancer is hepatocellular carcinoma. In an aspect of the invention, the cancer is fibrolamellar carcinoma (FLC). In an aspect of the invention, the cancer is fibrolamellar hepatocellular carcinoma (FL-HCC). In an aspect of the invention, the cancer is liver cancer. In an aspect of the invention, the cancer is breast cancer (e.g., triple negative breast cancer). In an aspect of the invention, the cancer is gastric cancer. In an aspect of the invention, the cancer is colon cancer. In an aspect of the invention, the cancer is prostate canceer. In an aspect of the invention, the cancer in pancreatic cancer. In an aspect of the invention, the cancer is a glioma.

[0167] In certain aspects of the invention, the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, can be co-administered with an anti-cancer agent (e.g., a chemotherapeutic agent) and / or radiation therapy. In an aspect, the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, are administered in an amount that is effective to sensitize the cancer cells to one or more therapeutic regimens (e.g., chemotherapy or radiation therapy). The terms “co-administered” or “co-administration” refer to simultaneous or sequential administration. The compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, can be administered before, concurrently with, or after administration of another anti-cancer agent (e.g., a chemotherapeutic agent).

[0168] One or more than one, e.g., two, three, or more anti-cancer agents can be administered. In this regard, the present invention is directed a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, and at least one anti- cancer agent (e.g., chemotherapeutic agent).

[0169] Examples of anti-cancer agents include platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin,dactinomycin), taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, pemetrexed, thioguanine, floxuridine, capecitabine, and methotrexate), nucleoside analogues (e.g., fludarabine, clofarabine, cladribine, pentostatin, nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine), proteosome inhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vincristine, vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, sunitinib), monoclonal antibodies (e.g., rituximab, cetuximab, panitumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab), nitrosoureas (e.g., carmustine, fotemustine, and lomustine), enzymes (e.g., L- Asparaginase), biological agents (e.g., interferons and interleukins), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide, lenalidomide), steroids (e.g., prednisone, dexamethasone, and prednisolone), hormonal agents (e.g., tamoxifen, raloxifene, leuprolide, bicalutamide, granisetron, flutamide), aromatase inhibitors (e.g., letrozole and anastrozole), arsenic trioxide, tretinoin, nonselective cyclooxygenase inhibitors (e.g., nonsteroidal anti- inflammatory agents, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin), selective cyclooxygenase-2 (COX- 2) inhibitors, cellular immunotherapy (e.g., chimeric antigen receptor T cell therapy, tumor- infiltrating lymphocyte therapy), or any combination thereof. In some aspects, the anti- cancer agent is cisplatin, cytarabine, methotrexate, doxorubicin, or a combination thereof.

[0170] In certain aspects of the invention, the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, can be attached to targeting molecules. Such targeting molecules include antibodies (for ADCs) and small molecules that target other regions of kinases to afford more selectivity (i.e., a second molecule that binds the DNAJ domain of the PKADJ fusion protein).

[0171] In certain aspects of the invention, the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, can be attached to an E3 ligase binding molecule to make a proteolysis-targeting chimeras (PROTAC).

[0172] In some embodiments, the subject is a mammal. As used herein, the term “mammal” refers to any mammal, including, but not limited to, mammals of the order Rodentia, including mice and hamsters, mammals of the order Logomorpha, including rabbits, mammals from the order Carnivora, including Felines (cats) and Canines (dogs), mammals from the order Artiodactyla, including Bovines (cows) and Swines (pigs),mammals from the order Perssodactyla, including Equines (horses), mammals of the order Primates, Ceboids, or Simoids (monkeys), and mammals of the order Anthropoids (humans and apes). An especially preferred mammal is the human. Examples of Non-Limiting Aspects of the Disclosure

[0173] Aspects, including embodiments, of the present subject matter described herein may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure numbered 1-38 are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below:

[0174] (1) A compound of formula (I) whereinis a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl;R4is C1-C3alkyl; A is –NR5((CHR7)mR6); R5, R6, and R7are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)- NH2, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C8-C10bicycloalkyl, C4-C10biheterocycloalkyl, aryl, heteroaryl, or R5 and R6 combine to form a C3-C8 heterocycloalkyl, C4-C10biheterocycloalkyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C1-C6 alkoxy, -C(O)OH, -C(O)O- (C1-C6alkyl), -C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3 alkyl)-C(O)-(C1-C6 alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6 alkyl), -NH- C(O)-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), - (C1-C3 alkyl)-NH-C(O)-(C1-C6 alkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-O- (C1-C6alkyl), -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6 alkyl), -(C1-C6 alkyl)-(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-NH2, -(C1- C6cycloalkyl)-NH2, -(C1-C6alkyl)-(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6 alkyl)-heterocycloalkyl-(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-heterocycloalkyl, -(C1-C6 alkyl)-C(O)-heterocycloalkyl-(C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6 alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6 alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, spiro C3- C8 cycloalkyl, fused C3-C8 heterocycloalkyl, spiro C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, provided that R5 and R6 are not both hydrogen; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0175] (2) The compound of aspect 1, wherein is a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2;R3is an aryl; R4is C1-C3 alkyl; A is –NR5((CHR7)mR6); R5, R6, and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)- NH2, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, or R5 and R6 combine to form a C3-C8heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, - (C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof, provided that R5 and R6 are not both hydrogen; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0176] (3) The compound of aspect 1 or 2, wherein wherein is a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3 alkyl; R3is an aryl; R4is C1-C3 alkyl; A is –NR5R6; and R5 and R6 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)- NH2, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, or R5 and R6 combine to form a C3-C8heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, - (C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl,C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, provided that R5and R6are not both hydrogen; or a pharmaceutically acceptable salt thereof.

[0177] (4) The compound of any one of aspects 1-3, wherein is a double bond.

[0178] (5) The compound of any one of aspects 1-4, wherei h ompound of formula (I) is of formula (Ia): , or a pharmaceutically accepta

[0179] (6) The compound of aspect 5, wherein A is a nitrogen bound C3-C8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, - (C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

[0180] (7) The compound of any one of aspects 1-6, wherein the compound of formula (I) is of formula (Ib), (Ic), (Id), or (Ie):, or a pharma

[0181] (8) The compound of any one of aspects 1-7, wherein R1is H.

[0182] (9) The compound of any one of aspects 1-8, wherein A comprises a C3-C8heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, - (C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

[0183] (10) The compound of aspect 1, wherein the compound of formula (I) is selected from Compounds EA, EC-ES, and EU-WP or a pharmaceutically acceptable salt thereof.

[0184] (11) A compound of formula (II) whereinis a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl; R4is C1-C3alkyl; and E is C3-C8 heterocycloalkyl, C8-C10 bicycloalkyl, C4-C10 biheterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C1-C6 alkoxy, -C(O)OH, -C(O)O-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), -(C1-C3 alkyl)-C(O)OH, -(C1-C3 alkyl)-C(O)O-(C1-C6 alkyl), -(C1-C3 alkyl)-C(O)-(C1- C6 alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6 alkyl), -NH-C(O)-(C1-C6 alkyl), -(C1-C3 alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-NH2, -(C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-heterocycloalkyl, -(C1-C6 alkyl)-C(O)-heterocycloalkyl-(C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6 alkyl), -C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, spiro C3-C8cycloalkyl, fused C3- C8 heterocycloalkyl, spiro C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, or a pharmaceutically acceptable salt thereof.

[0185] (12) The compound of aspect 11, wherein is a single or double bond, 2 are each independently CH, CR4, or N;X3is S, S=O, or S(=O)2; R1is H or –NR2R3;R3is an aryl; R4is C1-C3alkyl; and E is C3-C8heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)- NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

[0186] (13) The compound of aspect 11 or 12, wherein wherein is a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2;R3is an aryl;R4is C1-C3alkyl; and E is a carbon bound C3-C8 heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3- C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, - CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

[0187] (14) The compound of any one of aspects 11-13, wherein is a double bond.

[0188] (15) The compound of any one of aspects 11-14, wherein the compound of formula (II) is of formula (IIa): , or a pharmaceutically acceptabl

[0189] (16) The compound of any one of aspects 11-15, wherein the compound of formula (II) is of formula (IIb), (IIc), (IId), or (IIe):, ,elected from: , ,,alkyl, C2-C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C1-C6 alkoxy, -C(O)OH, -C(O)O-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), - (C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-C(O)-(C1-C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6 alkyl), -NH-C(O)-(C1-C6 alkyl), -(C1-C3 alkyl)- NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6alkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-OH, - (C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-NH2, -(C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)- (C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)-heterocycloalkyl, -(C1-C6alkyl)-heterocycloalkyl- (C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-heterocycloalkyl, -(C1-C6 alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6 alkyl), -C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, spiro C3-C8cycloalkyl, fused C3- C8 heterocycloalkyl, spiro C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, or a pharmaceutically acceptable salt thereof.

[0191] (18) The compound of any one of aspects 11-17, wherein E is selected from: ,each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)- OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

[0192] (19) The compound of any one of aspects 11-18, wherein R1is H.

[0193] (20) The compound of aspect 11, wherein the compound of formula (II) is selected from Compounds A-Z, AA-AE, AG-DZ, and YA-YV or a pharmaceutically acceptable salt thereof.

[0194] (21) A pharmaceutical composition comprising a compound of any one of aspects 1-20 and a pharmaceutical carrier.

[0195] (22) A method of inhibiting kinase activity in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.

[0196] (23) The method of aspect 22, wherein the kinase is PKA, PKA / DNAJ, cAMP- PKA, PKG1a, PKG1b, PKG2, PfPKG, PKC-^, PKC-nu, PKC-d, PKC-eta, PKC-g, STK39, CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, LATS1, or LATS2.

[0197] (24) The method of aspect 22, wherein the kinase is PKA, PKA / DNAJ, or cAMP- PKA.

[0198] (25) The method of aspect 22, wherein the kinase is PKG1a, PKG1b, PKG2, or PfPKG.

[0199] (26) The method of aspect 22, wherein the kinase is DYRK1A, DYRK1B, DYRK2, DYRK3, or DYRK4.

[0200] (27) The method of aspect 22, wherein the kinase is CLK1, CLK2, CLK3, or CLK4.

[0201] (28) A method of suppressing the immune system in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.

[0202] (29) A method of preventing organ rejection in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.

[0203] (30) A method of treating cancer in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.

[0204] (31) The method of aspect 30, wherein the cancer is fibrolamellar carcinoma (FLC).

[0205] (32) The method of aspect 30, wherein the cancer is fibrolamellar hepatocellular carcinoma (FL-HCC).

[0206] (33) The method of aspect 30, wherein the cancer is gastric cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer, lung cancer, or gliomas.

[0207] (34) A method of modulating mRNA splicing in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.

[0208] (35) A method of treating diabetic neuropathic pain in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.

[0209] (36) A method of treating malaria in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.

[0210] (37) A method of treating an infection associated with a protozoa in a subject, the method comprising administering to the subject a compound of any one of aspects 1-21 or the pharmaceutical composition of aspect 20 to the subject.

[0211] (38) The method of any one of aspects 22-37, wherein the subject is human. EXAMPLES

[0212] All solvents were of LC-MS grade or better.

[0213] NMR data were obtained on a Bruker Avance III NMR spectrometer equipped with a 3 mm cryogenic probe (600 MHz for1H, 150 MHz for13C).

[0214] Specimens of the tunicate Aplidium sp. were collected from a reef in South Africa in September 2000, and kept frozen until extraction. The collection was carried out by the Coral Reef Research Foundation under contract with the Natural Products Branch, U.S.National Cancer Institute. A voucher specimen (voucher ID # 0CDN7423) was deposited at the Smithsonian Institution, Washington, D.C. The animal material (234 g, wet weight) was ground and processed using the standard NCI method (McCloud, Molecules, 15: 4526-4563 (2010)) for marine samples to provide 3.27 g of organic extract (NSC # C020725) and 16.2 g of aqueous extract (NSC # C020724).

[0215] General procedure for Suzuki reaction conditions of Examples 1-4:

[0216] Condition-A: To a stirred solution of bromo derivative (1 mmol) in 1,4-dioxane (30 vol.) and water (10 vol.) was added boronic acid or boronate ester (1.5 mmol) and K2CO3 (4 mmol) and the resulting reaction mixture was purged with argon for 5 min. The catalyst XPhos-PdG3 (0.05 mmol) was added under argon, and the resulting reaction mixture was irradiated by microwave at 120 °C for 1 h. The reaction progress was monitored by UPLC- MS until complete consumption of starting material was observed. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0217] Condition-B: To a stirred solution of bromo derivative (1 mmol) in 1,4-dioxane (30 vol.) and water (10 vol.) was added boronic acid or boronate ester (1.2 mmol) and Na2CO3(3 mmol) and the resulting reaction mixture was purged with argon for 5 min. The catalyst XPhos-PdG3 (0.05 mmol) was added under argon, and the resulting reaction mixture was stirred at 100 °C for 18 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0218] Condition-C: To a stirred solution of bromo derivative (1 mmol) in 1,4-dioxane (30 vol.) and H2O (10 vol.) was added boronic acid or boronate ester (1.5 mmol) and K2CO3 (4 mmol) and the resulting reaction mixture was purged with argon for 5 min. The catalyst XPhos-PdG3 (0.05 mmol) was added under argon, and the resulting reaction mixture was stirred at 110 °C for 18 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0219] General procedure for Boc-deprotection of Examples 1-4:

[0220] Condition-D: To a stirred solution of Boc derivative (1 mmol) in 1,4-dioxane was added 4 M hydrochloric acid in 1,4-dioxane (2 vol.) at 0 °C and the resulting reaction mixture was warmed to room temperature and stirred for 3 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by washing with 10:1 mixture of acetonitrile and CH3OH or a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0221] Condition-E: To a stirred solution of Boc derivative (1 mmol) in trifluoroethanol (5 vol.) was added trimethylsilyl chloride (1 vol.) at 0 °C and the resulting reaction mixture was stirred at room temperature for 18 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0222] General procedure for esterification of Examples 1-4:

[0223] Condition-F: To a stirred solution of an acid derivative (1 mmol) in Methanol (5 vol) was added thionyl chloride (1 vol) at 0 °C and the resulting reaction mixture was stirred at reflux for 4 h. The progress of the reaction was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0224] General procedure for amide reaction conditions of Examples 8-12:

[0225] Condition-A: To a stirred solution of acid derivative (1 mmol) in dimethylformamide (10 vol.), was added diisopropylethylamine (3 mmol) and the requisite amine (1.2 mmol). The resulting reaction mixture was stirred for 5 min. Propylphosphonic anhydride (50% in ethyl acetate) (1 mmol) was added under argon, and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0226] Condition-B: To a stirred solution of acid derivative (1 mmol) in methylene chloride (50 vol.), was added triethylamine (3 mmol) and the requisite amine (1.2 mmol). The resulting reaction mixture was stirred for 5 min. N-(3-Dimethylaminopropyl)-N-ethyl carbodiimide hydrochloride (1.5 mmol) and 1-hydroxybenzotriazole hydrate (1.5 mmol) was added under argon, and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0227] Condition-C: To a stirred solution of acid derivative (1 mmol) in dimethylformamide (10 vol.) was added diisopropylethylamine (3 mmol) and the requisite amine (1.2 mmol). The resulting reaction mixture was stirred for 5 min.1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1.5 mmol) was added under argon, and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0228] Condition-I: To a stirred solution of acid derivative (1 mmol) in methylene chloride (50 vol.), was added triethylamine (3 mmol) and the requisite amine (1.2 mmol). The resulting reaction mixture was stirred for 5 min.1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.5 mmol) was added under argon, and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0229] Condition-J: To a stirred solution of acid derivative (1 mmol) in methylene chloride (50 vol.), was added triethylamine (3 mmol) and the requisite amine (1.2 mmol). The resulting reaction mixture was stirred for 5 min. Propylphosphonic anhydride (50% in ethyl acetate) (1 mmol) was added under argon, and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture wasconcentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.

[0230] General procedure for Boc-deprotection of Examples 8-12:

[0231] Condition-D: To a stirred solution of a Boc protected derivative (1 mmol) in 1,4- dioxane (5 vol.) was added 4 M hydrochloric acid in 1,4-dioxane (2 vol.) at 0 °C and the resulting reaction mixture was warmed to room temperature and stirred for 16 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was lyophilized from a solution of acetonitrile and water to afford the desired target.

[0232] Condition-E: To a stirred solution of a Boc protected derivative (1 mmol) in 1,4- dioxane (5 vol.) was added 4 M hydrochloric acid in 1,4-dioxane (2 vol.) at 0 °C and the resulting reaction mixture was warmed to room temperature and stirred for 2 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was lyophilized from a solution of acetonitrile and water to afford the desired target.

[0233] Condition-F: To a stirred solution of a Boc protected derivative (1 mmol) in trifluoroethanol (5 vol.) was added trimethylsilyl chloride (1 vol.) at 0 °C and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was lyophilized from a solution of acetonitrile and water to afford the desired target.

[0234] General procedure for Benzoyl deprotection of Examples 8-12:

[0235] Condition-G: To a stirred solution of benzoyl protected derivative (1 mmol) in tetrahydrofuran and water (2:1, 10 vol.) was added lithium hydroxide monohydrate (3 mmol) at room temperature and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by mass directed auto purification system using reverse phase chromatography to afford the desired product.

[0236] General procedure for reduction of azide of Examples 8-12:

[0237] Condition-H: To a stirred solution of azide derivative (1 mmol) in tetrahydrofuran and water (2:1, 10 vol.) was added triphenylphosphine (1.50 mmol) at room temperature and the resulting reaction mixture was stirred at 50 °C for 16 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was diluted with water and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired product.

[0238] General procedure for ultra-performance liquid chromatography (UPLC) of Examples 1-4 and 8-12: Table 1. Method-A Column: Acquity UPLC BEH C181.7 micron 2.1*50 mm A ACN TaColumn: Gemini 3uM NX C18110Å 4.6*100mm7.1 0.8 2 98 8 0.8 2 98 TaA:ACN TaCoumn: una Omega C8 .6 mcron . 50 mm TaColumn: Kinetex EVO C181.7 micron 2.1*50 mm2.4 0.5 95 5 3.2 0.5 95 5

[0239] This example provides an exemplary synthesis for Compounds A-U and DO.

[0240] Starting materials Bromo-SEM-Scaffold and Bromo-Scaffold-A were prepared using the synthetic protocol set forth in Scheme 1. Scheme 1: Preparation of Bromo-SEM-Scaffold and Bromo-Scaffold-A of Example 1dihydro-2H-1,4-thiazine-6-carboxylicacid (2): To a stirred solution of ethyl 4-(9-((2- (trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylate (13.5 g, 32.1 mmol) in ethanol:tetrahydrofuran:water (2:2:1, 250 mL) at room temperature was added lithium hydroxide hydrate (2.69 g, 64.2 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction progress was monitored by TLC until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure to obtain crude material which was diluted with water (100 mL) and acidified with 10% aqueous citric acid solution (pH~5). The solid material was collected by filtration and washed with excess cold water. The solid was dried to afford 4-(9-((2- (trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylicacid [10.50 g (crude)] as an off-white solid.1H NMR (400 MHz, DMSO-d6): į 12.60 (br s, 1H), 9.70 (s, 1H), 8.63 (s, 1H), 8.57 (s, 1H), 5.63 (s, 2H), 4.53 (br s, 2H), 3.59 (t, J = 8.40 Hz, 2H), 3.17-3.14 (m, 2H), 0.86 (t, J = 8.00 Hz, 2H), -0.07 (s, 9H); MS (ESI) m / z 394.1 [C16H23N5O3SSi + H]+.

[0242] Preparation of 6-bromo-4-(9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)- 3,4-dihydro-2H-1,4-thiazine (Bromo-SEM-scaffold): To a stirred solution of 4-(9-((2- (trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid(7.70 g, 19.5 mmol) in dry chloroform (100 mL) was added triethylamine (2.33 mL, 19.5 mmol) at 0 °C. The resultant reaction mixture was stirred for 10 min and then N- bromosuccinimide (3.83 g, 21.5 mmol) was added portionwise under argon atmosphere and stirring continued for 1 h under argon. The reaction progress was monitored by TLC until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure to obtain the crude material as a pale-yellow solid. The crude material was purified by flash chromatography using silica gel (230-400 mesh). The desired product was eluted with 20 -25% EtOAc / hexanes, the pure fractions were collected and concentrated under reduced pressure to afford 6-bromo-4-(9-((2- (trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine (6.20 g, 74%) as colorless oil that solidified after standing overnight.1H NMR (400 MHz, CDCl3): į 9.20- 8.60 (m, 1H), 8.47 (s, 1H), 7.99 (s, 1H), 5.60 (s, 2H), 4.73 (br s, 2H), 3.59 (t, J = 8.40 Hz, 2H), 3.27-3.24 (m, 2H), 0.93 (t, J = 8.00 Hz, 2H), -0.04 (s, 9H); MS (ESI) m / z 428.0 [C15H22BrN5OSSi + H]+.

[0243] Preparation of 6-bromo-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine (Bromo- Scaffold-A): To a stirred solution of 6-bromo-4-(9-((2-(trimethylsilyl)ethoxy)methyl)-9H- purin-6-yl)-3,4-dihydro-2H-1,4-thiazine (6.00 g, 14.0 mmol) in trifluoroethanol (40.00 mL) was added trimethylsilyl chloride (9.00 mL) at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 3 h. The mixture was concentrated under reduced pressure to afford 6-bromo-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine [4.50 g (crude HCl salt)] as a yellow solid.1H NMR (400 MHz, DMSO-d6): į 13.59-12.50 (m, 1H), 9.01 (br s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 4.58 (b r s, 2H), 3.36-3.34 (m, 2H); MS (ESI) m / z 298.0 [C9H8BrN5S + H]+.

[0244] Bromo-SEM-Scaffold and Bromo-Scaffold-A were transformed into Compounds A-U, YB, and YE using the general synthetic protocol for Suzuki targets set forth in Scheme 2. eral Synthetic Protocol for Suzuki Targets of Example 1.

[0245] Preparation of 6-(1-methyl-1H-pyrazol-5-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine (Compound A): 6-(1-Methyl-1H-pyrazol-5-yl)-4-(9H- -dihydro-2H-1,4-thiazine was preparedusing a Suzuki reaction with the appropriate boronic acid by following condition-B. Off- white solid. Yield: 15%.1H NMR (400 MHz, DMSO-d6): į 13.38 (br s, 1H), 8.94 (br s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 7.43 (d, J = 1.60 Hz, 1H), 6.30 (d, J = 2.00 Hz, 1H), 4.59 (br s, 2H), 3.91 (s, 3H), 3.35-3.32 (m, 2H); MS (ESI) m / z 300.4 [C13H13N7S + H]+; UPLC Purity: 98.3% (Method-A).

[0246] Preparation of 6-(1-methyl-1H-pyrazol-4-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine (Compound B): 6-(1-Methyl-1H-pyrazol-4-yl)-4-(9Hdihydro-2H-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-B. Off-white solid. Yield: 7%.1H NMR (400 MHz, DMSO-d6): į 13.29 (br s, 1H), 8.89-8.86 (m, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 4.61 (br s, 2H), 3.84 (s, 3H), 3.32 (s, 2H); MS (ESI) m / z 300.3 [C13H13N7S + H]+; UPLC Purity: 98.9% (Method-A).

[0247] Preparation of 4-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-3,5- dimethylisoxazole (Compound C):4-(4-(9H-Purin-6-yl)-3,4-dihydro-2H- yl)-3,5-dimethylisoxazole was preparedusing a Suzuki reaction with the appropriate boronic acid by following condition-B. Off- white solid. Yield: 7%.1H NMR (400 MHz, DMSO-d6): į 13.34 (br s, 1H), 8.72-8.65 (m, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 4.59 (br s, 2H), 3.32 (s, 2H), 2.44 (s, 3H), 2.27 (s, 3H); MS (ESI) m / z 315.3 [C14H14N6OS + H]+; UPLC Purity: 97.9% (Method-A).

[0248] Preparation of 2-(4-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H- pyrazol-1-yl)ethan-1-ol (Compound D): 2-(4-(4-(9H-purin-6-yl)-3,4-dihy)-1H-pyrazol-1-yl)ethan-1-ol was prepared using the Suzuki reaction with the appropriate boronate ester by following condition-A. Off-white solid. Yield: 9%.1H NMR (400 MHz, DMSO-d6): į 13.29 (br s, 1H), 8.95-8.76 (m, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.77 (s, 1H), 7.55 (s, 1H), 4.90 (br s, 1H), 4.61 (br s, 2H), 4.14 (t, J = 5.60 Hz, 2H), 3.73 (t, J = 5.20 Hz, 2H), 3.28-3.26 (m, 2H); MS (ESI) m / z 330.4 [C14H15N7OS + H]+; UPLC Purity: 98.2% (Method-A).

[0249] Preparation of 5-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6- yl)nicotinonitrile (Compound E):5-(4-(9H-Purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)nicotinonitrile was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-B. Off-white solid. Yield: 4%.1H NMR (400 MHz, DMSO-d6): į 13.41 (br s, 1H), 9.36 (s, 1H), 8.99 (d, J = 2.40 Hz, 1H), 8.90 (d, J = 1.60 Hz, 1H), 8.49-8.48 (m, 1H), 8.43-8.42 (m, 1H), 8.27 (t, J = 2.40 Hz, 1H), 4.61 (br s, 2H), 3.36-3.34 (m, 2H); MS (ESI) m / z 322.4 [C15H11N7S + H]+; UPLC Purity: 99.7% (Method-C).

[0250] Preparation of 6-phenyl-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine (Compound F): 6-Phenyl-4-(9H-purin-6-yl)-3,4-dihyd zine was prepared using a Suzukireaction with the appropriate boronic acid by following condition-A. Off-white solid. Yield: 23%.1H NMR (400 MHz, DMSO-d6): į 13.32 (br s, 1H), 9.22 (s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 7.53 (d, J = 7.60 Hz, 2H), 7.41 (t, J = 8.00 Hz, 2H), 7.29 (t, J = 7.20 Hz, 1H), 4.59 (br s, 2H), 3.31-3.29 (m, 2H); MS (ESI) m / z 296.3 [C15H13N5S + H]+; UPLC Purity: 99.3% (Method-A).

[0251] Preparation of 4-(9H-purin-6-yl)-6-(pyridin-3-yl)-3,4-dihydro-2H-1,4-thiazine (Compound G): 4-(9H-Purin-6-yl)-6-(pyridin-3-yl)-3,1,4-thiazine was prepared using the Suzuki reaction with the appropriate boronic acid by following condition-B. Off-white solid. Yield: 2%.1H NMR (400 MHz, DMSO-d6): į 13.33 (br s, 1H), 9.44-9.29 (m, 1H), 8.75 (d, J = 2.00 Hz, 1H), 8.48 (dd, J = 1.60, 4.60 Hz, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 7.88-7.85 (m, 1H), 7.45-7.42 (m, 1H), 4.60 (br s, 2H), 3.35-3.32 (m, 2H); MS (ESI) m / z 297.3 [C14H12N6S + H]+; UPLC Purity: 95.2% (Method-A).

[0252] Preparation of 2-(4-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H- pyrazol-1-yl) acetic acid (Compound H): 2-(4-(4-(9H-Purin-6-yl)-3,4-dihyd )-1H-pyrazol-1-yl)acetic acid wasprepared using a Suzuki reaction with the appropriate boronate ester by following condition- B. Off-white solid. Yield: 3%.1H NMR (400 MHz, DMSO-d6): į 13.45 (br s, 1H), 8.97-8.71 (m, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 7.79 (s, 1H), 7.55 (s, 1H), 4.87 (s, 2H), 4.61 (br s, 2H), 3.29-3.26 (m, 2H); acid (COOH) not observed; MS (ESI) m / z 344.4 [C14H13N7O2S + H]+; UPLC Purity: 99.8% (Method-A).

[0253] Preparation of 6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine•HCl (Compound I): 6-(1-(Piperidin-4-yl)-1H-pyrazol-l)-3,4-dihydro-2H-1,4-thiazine•HCl was prepared using a Suzuki reaction with the appropriate Boc protected boronic acid by following condition-A. The Boc derivative was deprotected using condition-D and the final compound was purified by washing with 10:1 mixture of acetonitrile and methanol. Off- white solid. Yield: 8% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 13.32 (br s, 1H), 8.97-8.70 (m, 3H), 8.38 (s, 1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.62 (s, 1H), 4.62-4.47 (m, 3H), 3.41-3.38 (m, 2H), 3.29-3.26 (m, 2H), 3.05 (br s, 2H), 2.19-2.13 (m, 4H); MS (ESI) m / z 369.4 [C17H21ClN8S + H]+; UPLC Purity: 98.5% (Method-A).

[0254] Preparation of 2-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine•HCl (Compound J):2-(4-(9H-Purin-6-yl)-3,4-dihydro ,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride was prepared by a Suzuki reaction with the appropriate Boc protected boronic acid by following condition-A. The Boc derivative was deprotected using condition-D and the final compound was purified by washing with 10:1 mixture of acetonitrile and CH3OH. Off-white solid. Yield: 10% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 13.42 (br s, 1H), 9.75-9.25 (m, 3H), 8.43 (s, 1H), 8.35 (s, 1H), 6.91 (s, 1H), 4.60-4.52 (m, 2H), 4.16 (br s, 2H), 3.32-3.29 (m, 4H), 3.02 (t, J = 5.60 Hz, 2H); MS (ESI) m / z 357.3 [C16H17ClN6S2 + H]+; UPLC Purity: 99.7% (Method-A).

[0255] Preparation of 4-(9H-purin-6-yl)-6-(1H-pyrazol-3-yl)-3,4-dihydro-2H-1,4- thiazine (Compound K): 4-(9H-Purin-6-yl)-6-(1H-pyrazol-3-yH-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-A. Off-white solid. Yield: 3%.1H NMR (400 MHz, DMSO-d6): į 13.33 (br s, 1H), 12.70 (br s, 1H), 9.43- 9.20 (m, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 7.70 (s, 1H), 6.36 (s, 1H), 4.62 (br s, 2H), 3.25-3.24 (m, 2H); MS (ESI) m / z 286.35 [C12H11N7S + H]+; UPLC Purity: 97.6% (Method-B).

[0256] Preparation of 6-(1H-indazol-6-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4- thiazine (Compound L):6-(1H-Indazol-6-yl)-4-(9H-purin-6-y H-1,4-thiazine was prepared using aSuzuki reaction with the appropriate boronicacid by following condition-A. Off-white solid. Yield: 9%.1H NMR (400 MHz, DMSO-d6): į 13.38 (br s, 1H), 13.04 (s, 1H), 9.46 (s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.78 (d, J = 8.40 Hz, 1H), 7.61 (s, 1H), 7.38 (d, J = 8.80 Hz, 1H), 4.63 (br s, 2H), 3.32 (s, 2H); MS (ESI) m / z 336.3 [C16H13N7S + H]+; UPLC Purity: 95.7% (Method-B).

[0257] Preparation of 5-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-4- methyloxazole (Compound M): 5-(4-(9H-Purin-6-yl)-3,4-dihydro-2H-yl)-4-methyloxazole was prepared using a Suzuki reaction with the appropriate boronate ester and following condition-A. Off-white solid. Yield: 15%.1H NMR (400 MHz, DMSO-d6): į 13.40 (br s, 1H), 9.15 (br s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 4.59 (br s, 2H), 3.33-3.29 (m, 2H), 2.32 (s, 3H); MS (ESI) m / z 301.3 [C13H12N6OS + H]+; UPLC Purity: 97.7% (Method-A).

[0258] Preparation of 5-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2- methyloxazole (Compound N):5-(4-(9H-Purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2-methyloxazole was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-A. Off-white solid. Yield: 3%.1H NMR (400 MHz, DMSO-d6): į 13.37 (br s, 1H), 9.10 (br s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 6.90 (s, 1H), 4.66 (br s, 2H), 3.33-3.30 (m, 2H), 2.44 (s, 3H); MS (ESI) m / z 301.3 [C13H12N6OS + H]+; UPLC Purity: 99.8% (Method-A).

[0259] Preparation of 5-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)oxazole (Compound O): 5-(4-(9H-Purin-6-yl)-3,4-dihydro-2H yl)oxazole was prepared using a Suzukireaction of Bromo-SEM-Scaffold-A with the appropriate boronate ester by following condition-C. The crude compound was deprotected using condition-E and the final compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target. Off-white solid. Yield: 12% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 13.43 (br s, 1H), 9.34 (br s, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 7.06 (s, 1H), 4.62 (br s, 2H), 3.33-3.30 (m, 2H); MS (ESI) m / z 287.2 [C12H10N6OS + H]+; UPLC Purity: 95.3% (Method-A).

[0260] Preparation of 4-(9H-purin-6-yl)-6-(1,2,3,4-tetrahydroisoquinolin-6-yl)-3,4- dihydro-2H-1,4-thiazine (Compound P): 4-(9H-Purin-6-yl)-6-(1,2,3,4-tetrah)-3,4-dihydro-2H-1,4-thiazine was prepared using a Suzuki reaction of Bromo-SEM-Scaffold-A with the appropriate boronate ester by following condition-C. The crude compound was deprotected using condition-E and the final compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target. Off-white solid. Yield: 3% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 9.52 (br s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 7.28 (dd, J = 2.00, 7.80 Hz, 1H), 7.21 (s, 1H), 7.05 (d, J = 8.00 Hz, 1H), 4.60 (br s, 2H), 3.87 (s, 2H), 3.29- 3.27 (m, 2H), 2.98 (t, J = 5.60 Hz, 2H), 2.73 (t, J = 5.60 Hz, 2H), imidazole-NH and cyclic- NH was not observed; MS (ESI) m / z 351.34 [C18H18N6S + H]+; UPLC Purity: 95.9% (Method-A).

[0261] Preparation 7-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine (Compound Q): 7-(4-(9H-Purin-6-yl)-3,4-dihydro-2H )-3,4-dihydro-2H-benzo[b][1,4]oxazinewas prepared using a Suzuki reaction of Bromo-SEM-Scaffold-A with the appropriate boronate ester by following condition-C. The crude compound was deprotected using condition-E and the final compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target. Off-white solid. Yield: 5% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 13.28 (br s, 1H), 8.98 (br s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 6.86 (dd, J = 2.00, 10.40 Hz, 1H), 6.81 (d, J = 2.00 Hz, 1H), 6.57 (d, J = 8.40 Hz, 1H), 5.91 (s, 1H), 4.54 (br s, 2H), 4.13 (t, J = 8.80 Hz, 2H), 3.30-3.28 (m, 2H), 3.25- 3.22 (m, 2H); MS (ESI) m / z 353.2 [C17H16N6OS + H]+; UPLC purity: 96.7% (Method-A).

[0262] Preparation of 4-(9H-purin-6-yl)-6-(1,2,3,4-tetrahydroquinolin-7-yl)-3,4-dihydro- 2H-1,4-thiazine (Compound R): 4-(9H-Purin-6-yl)-6-(1,2,3,4-tetrahy3,4-dihydro-2H-1,4-thiazine was prepared using a Suzuki reaction of Bromo-SEM-Scaffold-A with the appropriate Boc protected boronate ester by following condition-C. The crude compound was deprotectedusing condition-E and the final compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target. Off-white solid. Yield: 10% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 13.31 (br s, 1H), 8.99 ( br s, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 6.83 (d, J = 8.00 Hz, 1H), 6.61 (d, J = 2.00 Hz, 1H), 6.59 (s, 1H), 5.78 (s, 1H), 4.59 (br s, 2H), 3.26-3.23 (m, 2H), 3.19-3.16 (m, 2H), 2.65 (t, J = 12.40 Hz, 2H), 1.82-1.76 (m, 2H); MS (ESI) m / z 351.3 [C18H18N6S + H]+; UPLC purity: 97.4% (Method-A).

[0263] Preparation of 4-(9H-purin-6-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4- dihydro-2H-1,4-thiazine (Compound S): 4-(9H-Purin-6-yl)-6-(1,2,3,4-tetra)-3,4-dihydro-2H-1,4-thiazine was prepared using a Suzuki reaction of Bromo-SEM-Scaffold-A with the appropriate Boc protected boronate ester by following condition-C. The deprotection of SEM and Boc groups was done by using condition-E and the final compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target. Off- white solid. Yield: 11% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 9.07 (br s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 7.27 (dd, J = 2.00, 10.00 Hz, 1H), 7.14 (d, J = 1.60 Hz, 1H), 7.09 (d, J = 8.00 Hz, 1H), 4.59 (br s, 2H), 3.87 (s, 2H), 3.29-3.27 (m, 2H), 2.96 (t, J = 12.00 Hz, 2H), 2.69 (t, J = 11.60 Hz, 2H), imidazole-NH and cyclic-NH was not observed; MS (ESI) m / z 351.3 [C18H18N6S + H]+; UPLC purity: 97.3% (Method-A).

[0264] Preparation of 46-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2H- benzo[b][1,4]oxazin-3(4H)-one (Compound T):6-(4-(9H-Purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one was prepared using a Suzuki reaction of Bromo-SEM-Scaffold-A with the appropriate boronate ester by following condition-C. The crude compound was deprotected using condition-E and the final compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target. Off-white solid. Yield: 6% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 13.34 (s, 1H), 10.77 (s, 1H), 9.03 (br s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 7.10-7.07 (m, 2H), 7.00-6.97 (m, 1H), 4.59 (s, 4H), 3.30-3.28 (m, 2H)); MS (ESI) m / z 367.31 [C17H14N6O2S + H]+; UPLC purity: 97.17% (Method-A).

[0265] Preparation of 7-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-3,4- dihydroisoquinolin-1(2H)-one (Compound U):3,4-dihydroisoquinolin-1(2H)-one was prepared using a Suzuki reaction of Bromo-SEM-Scaffold-A with the appropriate boronate ester by following condition-C. The crude compound was deprotected using condition-E and the final compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target. Off-white solid. Yield: 15% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 13.36 (br s, 1H), 9.16 (br s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 8.10-7.99 (m, 2H), 7.63 (dd, J = 2.40, 10.00 Hz, 1H), 7.35 (d, J = 8.00 Hz, 1H), 4.63 (br s, 2H), 3.41-3.37 (m, 2H), 3.34-3.30 (m, 2H), 2.91 (t, J = 12.80 Hz, 2H); MS (ESI) m / z 365.3 [C18H16N6OS + H]+; UPLC purity: 97.3% (Method-A).

[0266] Preparation of 7-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-3,4- dihydroquinolin-2(1H)-one (Compound DO):7-(4-(9H-Purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-3,4-dihydroquinolin-2(1H)-one was prepared using a Suzuki reaction with the appropriate boronic acid by following Condition-C. The SEM group was deprotected using Condition-E. Off-white solid. Yield: 1%.1H NMR (400 MHz, DMSO-d6): į 13.36 (br s, 1H), 10.15 (s, 1H), 9.03 (br s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.20 ^ 7.18 (m, 1H), 7.09 (dd, J = 1.60, 7.80 Hz, 1H), 7.05 ^ 7.04 (m, 1H), 4.60 (br s, 2H), 3.30 ^ 3.28 (m, 2H), 2.87 (t, J = 7.60 Hz, 2H), 2.46 ^ 2.44 (m, 2H); MS (ESI) m / z 365.3 [C18H16N6OS + H]+; UPLC Purity: 97.5% (Method-A). EXAMPLE 2

[0267] This example provides an exemplary synthesis for Compounds V-AO, DP-DS, DU, DZ, YA, YB, YD-YF, YJ-YO, and YR-YU.

[0268] Starting materials Bromo-SEM-Scaffold and Bromo-Scaffold-B were prepared using the synthetic protocol set forth in Scheme 3. Scheme 3: Preparation of Bromo-SEM-Scaffold and Bromo-Scaffold-B of Example 2pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid (4): To a stirred solution of ethyl 4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxylate (6.00 g, 14.2 mmol) in ethanol:tetrahydrofuran:water (2:2:1, 75 mL) at room temperature was added lithium hydroxide hydrate (1.49 g, 35.7 mmol). The resulting mixture was stirred at 90 °C for 3 h. The reaction progress was monitored by TLC until complete consumption of starting material was observed. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude material which was diluted with water (50 mL) and acidified with 10% aqueous citric acid solution (pH~5). The solid material was collected by filtration and washed with excess cold water. The solid was dried to afford 4-(7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid [5.21 g (crude)] as an off- white solid.1H NMR (400 MHz, DMSO- d6): į 8.79 (s, 1H), 8.49 (s, 1H), 7.66 (d, J = 4.00 Hz, 1H), 6.75 (d, J = 4.00 Hz, 1H), 5.61 (s, 2H), 4.36-4.33 (m, 2H), 3.52 (t, J = 8.00 Hz, 2H),3.15-3.13 (m, 2H), 0.84 (t, J = 8.00 Hz, 2H), -0.081 (s, 9H), acid proton was not observed; MS (ESI) m / z 393.3 [C17H24N4O3SSi + H]+.

[0270] Preparation of 6-bromo-4-(7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3- d] pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Bromo-SEM-scaffold): To a stirred solution of 4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxylic acid (5.20 g, 13.2 mmol) in dry chloroform (100 mL) was added triethylamine (1.80 mL, 13.2 mmol) at 0 °C. The resultant reaction mixture was stirred for 10 min and then N-bromosuccinimide (2.59 g, 14.5 mmol) was added in portionwise under argon atmosphere and stirring was continued for 1 h under argon. The progress of the reaction was monitored by TLC until complete consumption of starting material was observed. The reaction progress concentrated under reduced pressure to obtain crude material as a pale-yellow solid. The obtained crude material was purified by flash chromatography using silica gel (230-400 mesh). The desired product was eluted with 20 -25% EtOAc / hexanes, the pure fractions were collected and concentrated under reduced pressure to afford 6-bromo-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,4-dihydro-2H-1,4-thiazine (4.50 g, 79%) as an off white solid.1H NMR (400 MHz, CDCl3): į 8.44 (s, 1H), 7.80 (s, 1H), 7.21 (d, J =3.60 Hz, 1H), 6.62 (d, J = 4.00 Hz, 1H), 5.61 (s, 2H), 4.44-4.47 (m, 2H), 3.51-3.55 (m, 2H), 3.24-3.26 (m, 2H), 0.89-0.93 (m, 2H), (s, 9H); MS (ESI) m / z 427.0 [C16H23BrN4OSSi + H]+.

[0271] Preparation of 6-bromo-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazine (Bromo-Scaffold-B): To a stirred solution of 6-bromo-4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazine (6.00 g, 14.0 mmol) in trifluoroethanol (40.0 mL) was added trimethylsilyl chloride (9.00 mL) at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. The crude intermediate was dissolved in methanol and added ammonia solution (35% in water) at below 10 °C (while adding ammonia solution solid formation was observed) and stirring was continued at room temperature for 18 h. The reaction progress was monitored by TLC until complete consumption of starting material was observed. The resulting solid reaction mixture was cooled to 0 °C and filtered, and the solid cake was washed with cold methanol and dried to afford 6-bromo-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine [3.60 g (crude)] as a yellow solid.1H NMR (400 MHz, DMSO-d6): į 12.01 (s, 1H), 8.30 (s, 1H),7.98 (s, 1H), 7.37-7.36 (m, 1H), 6.63-6.61 (m, 1H), 4.39-4.36 (m, 2H), 3.33-3.30 (m, 2H); MS (ESI) m / z 297.2 [C10H9BrN4S + H]+.

[0272] Bromo-SEM-Scaffold and Bromo-Scaffold-B were transformed into Compounds V-AO using the general synthetic protocol for Suzuki targets set forth in Scheme 4. Scheme 4: General Synthetic Protocol for Suzuki Targets Of Example 2. [02- yl)-3,4-dihydro-2H-1,4-thiazine (Compound V): 6-(1-Methyl-1H-pyrazol-4-yl)-4-(7H-yrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 17%.1H NMR (400 MHz, DMSO-d6): į 11.93 (s, 1H), 8.28 (s, 1H), 7.82 (d, J = 6.80 Hz, 2H), 7.56 (s, 1H), 7.32 (t, J = 2.80 Hz, 1H), 6.61 (q, J = 2.00 Hz, 1H), 4.37-4.35 (m, 2H), 3.83 (s, 3H), 3.25-3.23 (m, 2H); MS (ESI) m / z 299.3 [C14H14N6S + H]+; UPLC purity: 97.2% (Method-A).

[0274] Preparation of 6-(1-methyl-1H-pyrazol-5-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3,4-dihydro-2H-1,4-thiazine (Compound W): 6-(1-Methyl-1H-pyrazol-5-yl)-4-(7H-p, ]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by followingcondition-C. Off-white solid. Yield: 20%.1H NMR (400 MHz, DMSO-d6): į 12.01 (s, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 7.41 (d, J = 2.00 Hz, 1H), 7.36 (q, J = 2.40 Hz, 1H), 6.63 (q, J = 1.60 Hz, 1H), 6.30 (d, J = 2.00 Hz, 1H), 4.44-4.42 (m, 2H), 3.87 (s, 3H), 3.32 (s, 2H); MS (ESI) m / z 299.3 [C14H14N6S + H]+; UPLC purity: 97.4% (Method-A).

[0275] Preparation of 6-(1H-pyrazol-3-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine (Compound X): 6-(1H-Pyrazol-3-yl)-4-(7H-pyrrolo[2 4-yl)-3,4-dihydro-2H-1,4-thiazine wasprepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 4%.1H NMR (400 MHz, DMSO-d6): į 12.71 (s, 1H), 11.97 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.72 (s, 1H), 7.36 (d, J = 2.80 Hz, 1H), 6.64 (s, 1H), 6.38 (s, 1H), 4.39-4.38 (m, 2H), 3.23-3.21 (m, 2H); MS (ESI) m / z 285.3 [C13H12N6S + H]+; UPLC purity: 99.8% (Method-A).

[0276] Preparation of 4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-3,5-dimethylisoxazole (Compound Y): 4-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-y-2H-1,4-thiazin-6-yl)-3,5- dimethylisoxazole was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C.Off-white solid. Yield: 45%.1H NMR (400 MHz, DMSO-d6): į 11.97 (s, 1H), 8.30 (s, 1H), 7.54 (s, 1H), 7.34 (q, J = 2.40 Hz, 1H), 6.61 (q, J = 1.20 Hz, 1H), 4.43- 4.40 (m, 2H), 3.31-3.26 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H); MS (ESI) m / z 314.3 [C15H15N5OS + H]+; UPLC purity: 99.9% (Method-A).

[0277] Preparation of 6-(1H-indazol-6-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine (Compound Z):6-(1H-Indazol-6-yl)-4-(7H-pyrrolo[2 4-yl)-3,4-dihydro-2H-1,4-thiazine wasprepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 4%.1H NMR (400 MHz, DMSO-d6): į 13.01 (s, 1H), 12.01 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 8.05 (t, J = 1.20 Hz, 1H), 7.76 (d, J = 8.40 Hz, 1H), 7.59 (s, 1H), 7.38-7.36 (m, 1H), 7.33 (dd, J = 1.60, 8.40 Hz, 1H), 6.65 (q, J = 1.60 Hz, 1H), 4.45-4.43 (m, 2H), 3.42-3.27 (m, 2H); MS (ESI) m / z 335.3 [C17H14N6S + H]+; UPLC purity: 96.4% (Method-A).

[0278] Preparation of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)nicotinonitrile (Compound AA): 5-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4H-1,4-thiazin-6-yl)nicotinonitrile was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 21%.1H NMR (400 MHz, DMSO-d6): į 12.06 (s, 1H), 8.96 (d, J = 2.40 Hz, 1H), 8.87 (d, J = 2.00 Hz, 1H), 8.38 (s, 1H), 8.36 (t, J = 2.00 Hz, 1H), 8.25 (s, 1H), 7.41 (dd, J = 2.40 , 3.60 Hz, 1H), 6.70 (dd, J = 1.60 , 3.60 Hz, 1H), 4.45-4.42 (m, 2H), 3.38- 3.33 (m, 2H); MS (ESI) m / z 321.4 [C16H12N6S + H]+; UPLC purity: 99.9% (Method-A).

[0279] Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol (Compound AB):2-(4-(4-(7H-Pyrrolo[2,3-d]pyrimidi -2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 38%.1H NMR (400 MHz, DMSO-d6): į 11.93 (s, 1H), 8.29 (s, 1H), 7.82 (t, J = 0.40 Hz, 2H), 7.60 (d, J = 0.40 Hz, 1H), 7.32 (dd, J = 2.40 , 3.60 Hz, 1H), 6.61 (dd, J = 2.00 , 3.40 Hz, 1H), 4.89 (t, J = 5.20 Hz, 1H), 4.38-4.35 (m, 2H), 4.13 (t, J = 5.60 Hz, 2H), 3.73 (q, J = 5.60 Hz, 2H), 3.26-3.23 (m, 2H); MS (ESI) m / z 329.4 [C15H16N6OS + H]+; UPLC purity: 99.9% (Method-A).

[0280] Preparation of 6-phenyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazine (Compound AC): 6-Phenyl-4-(7H-pyrrolo[2,3-d]pyrimidihydro-2H-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off- white solid. Yield: 28%.1H NMR (400 MHz, DMSO-d6): į 12.00 (s, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.51 (dd, J = 0.80 , 8.20 Hz, 2H), 7.41-7.36 (m, 3H), 7.32-7.26 (m, 1H), 6.64-6.62 (m, 1H), 4.42-4.40 (m, 2H), 3.30-3.27 (m, 2H); MS (ESI) m / z 295.3 [C16H14N4S + H]+; UPLC purity: 97.6% (Method-A).

[0281] Preparation of 6-(pyridin-3-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro- 2H-1,4-thiazine (Compound AD):6-(Pyridin-3-yl)-4-(7H-pyrrolo[2,3-d] l)-3,4-dihydro-2H-1,4-thiazine wasprepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 26%.1H NMR (400 MHz, DMSO-d6): į 12.03 (s, 1H), 8.72-8.70 (m, 1H), 8.47 (dd, J = 1.60, 4.60 Hz, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.89-7.86 (m, 1H), 7.43-7.37 (m, 2H), 6.78-6.62 (m, 1H), 4.44-4.42 (m, 2H), 3.33-3.30 (m, 2H); MS (ESI) m / z 296.3 [C15H13N5S + H]+; UPLC purity: 99.6% (Method-A).

[0282] Preparation of 6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound AE): 6-(1-(Piperidin-4-yl)-1H-pyrazol-4-y[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazine was prepared by a Suzuki reaction with the appropriate Boc protected boronic acid by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by mass directed auto purification system using reverse phase chromatography to afford the desired target. Pale yellow solid. Yield: 6%.1H NMR (400 MHz, DMSO-d6): į 11.93 (s, 1H), 8.28 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.59 (d, J = 0.40 Hz, 1H), 7.32-7.32 (m, 1H), 6.62 (d, J = 3.20 Hz, 1H), 4.37-4.35 (m, 2H), 4.22-4.14 (m, 1H), 3.25-3.23 (m, 2H), 3.04-3.01 (m, 2H), 2.60-2.53 (m, 2H), 1.93-1.90 (m, 2H), 1.83-1.73 (m, 2H) cyclic-NH was not observed; MS (ESI) m / z 368.4 [C18H21N7S + H]+; UPLC purity: 95.3% (Method-A).

[0283] Preparation of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-4-methyloxazole (Compound AG):5-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl) ro-2H-1,4-thiazin-6-yl)-4-methyloxazole was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 20%.1H NMR (400 MHz, DMSO-d6): į 12.05 (br s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.40-7.39 (m, 1H), 6.67-6.66 (m, 1H), 4.43-4.41 (m, 2H), 3.30-3.27 (m, 2H), 2.29 (s, 3H); MS (ESI) m / z 300.3 [C14H13N5OS + H]+; UPLC purity: 99.6% (Method-A).

[0284] Preparation of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Compound AH):6-yl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine was prepared by a Suzuki reaction with the appropriate Boc protected boronic acid by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by mass directed auto purification system using reverse phase chromatography to afford the desired target. Off-white solid. Yield: 6% (Over 2 steps).1H NMR (400 MHz, DMSO-d6): į 12.02 (br s, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.39-7.37 (m, 1H), 6.75 (s, 1H), 6.62 (d, J = 3.20 Hz, 1H), 4.40-4.38 (m, 2H), 3.68 (s, 2H), 3.27-3.25 (m, 2H), 2.94 (t, J = 11.20 Hz, 2H), 2.63 (t, J = 10.80 Hz, 2H) cyclic-NH was not observed; MS (ESI) m / z 356.3 [C17H17N5S2+ H]+; UPLC purity: 99.8% (Method-A).

[0285] Preparation of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1,2,3,4- tetrahydroisoquinolin-6-yl)-3,4-dihydro-2H-1,4-thiazine (Compound AI):4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl ydroisoquinolin-6-yl)-3,4-dihydro-2H- 1,4-thiazine was prepared by a Suzuki reaction with the appropriate Boc protected boronate ester by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by mass directed auto purification system using reverse phase chromatography to afford the desired target. Off-white solid. Yield: 4% (Over 2 steps).1H NMR (400 MHz, DMSO-d6): į 11.98 (br s, 1H), 8.31 (d, J = 6.00 Hz, 1H), 7.99 (s, 1H), 7.35 (d, J = 3.20 Hz, 1H), 7.24 (dd, J = 2.40, 10.00 Hz, 1H), 7.18 (s, 1H), 7.02 (d, J = 8.00 Hz, 1H), 6.60 (d, J = 3.20 Hz, 1H), 4.40-4.38 (m, 2H), 3.84 (s, 2H), 3.27-3.25 (m, 2H), 2.94 (t, J = 11.60 Hz, 2H), 2.71 (t, J = 11.32 Hz, 2H) cyclic-NH was not observed; MS (ESI) m / z 350.3 [C19H19N5S + H]+; UPLC purity: 98.0% (Method-A).

[0286] Preparation of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1,2,3,4- tetrahydroquinolin-7-yl)-3,4-dihydro-2H-1,4-thiazine•HCl (Compound AJ): 4-(7H-Pyrrolo[2,3-d]pyrimidin-4-ydroquinolin-7-yl)-3,4-dihydro-2H-1,4- thiazine hydrochloride was prepared by a Suzuki reaction with the appropriate Boc protected boronate ester by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by washing with 10:1 mixture of acetonitrile and methanol. Off-white solid. Yield: 8% (Over 2 steps).1H NMR (400 MHz, DMSO-d6): į 12.42 (br s, 1H), 8.43 (s, 1H), 7.99 (s, 1H), 7.46-7.45 (m, 1H), 7.34 (d, J = 8.00 Hz, 1H), 7.25 (d, J = 8.00 Hz, 2H), 6.76-6.74 (m, 1H), 4.78 (br s, 2H),4.44-4.42 (m, 2H), 3.34 (t, J = 10.00 Hz, 4H), 2.81 (t, J = 12.40 Hz, 2H), 2.01-1.97 (m, 2H); MS (ESI) m / z 350.3 [C19H20ClN5S + H]+; UPLC purity: 95.8% (Method-E).

[0287] Preparation of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1,2,3,4- tetrahydroisoquinolin-7-yl)-3,4-dihydro-2H-1,4-thiazine (Compound AK):4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl) ydroisoquinolin-7-yl)-3,4-dihydro-2H- 1,4-thiazine was prepared by a Suzuki reaction with the appropriate Boc protected boronate ester by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by mass directed auto purification system using reverse phase chromatography to afford the desired target. Off-white solid. Yield: 6% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 11.98 (br s, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.35 (d, J = 3.20 Hz, 1H), 7.24 (dd, J = 2.40, 10.00 Hz, 1H), 7.13 (s, 1H), 7.07 (d, J = 8.00 Hz, 1H), 6.60 (d, J = 3.60 Hz, 1H), 4.40-4.37 (m, 2H), 3.86 (s, 2H), 3.27-3.25 (m, 2H), 2.94 (t, J = 11.60 Hz, 2H), 2.68 (t, J = 11.20 Hz, 2H); cyclic-NH was not observed; MS (ESI) m / z 350.4 [C19H19N5S + H]+; UPLC purity: 98.6% (Method-A).

[0288] Preparation of 7-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-3,4-dihydroquinolin-2(1H)-one (Compound AL):-thiazin-6-yl)-3,4- dihydroquinolin-2(1H)-one was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 5%.1H NMR (400 MHz, DMSO-d6): į 12.00 (br s, 1H), 10.12 (s, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.37-7.35 (m, 1H), 7.17 (d, J = 8.40 Hz, 1H), 7.07-7.05 (m, 2H), 6.64-6.63 (m, 1H), 4.41-4.39 (m, 2H), 3.28- 3.25 (m, 2H), 2.87 (t, J = 14.80 Hz, 2H), 2.45 (t, J = 8.80 Hz, 2H); MS (ESI) m / z 364.3 [C19H17N5OS + H]+; UPLC purity: 95.8% (Method-A).

[0289] Preparation of 7-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-3,4-dihydroisoquinolin-1(2H)-one (Compound AM):7-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4- 2H-1,4-thiazin-6-yl)-3,4- dihydroisoquinolin-1(2H)-one was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 21%.1H NMR (400 MHz, DMSO-d6): į 12.01 (br s, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 7.99-7.97 (m, 2H), 7.61 (dd, J = 2.40, 10.00 Hz, 1H), 7.38-7.32 (m, 2H), 6.65-6.63 (m, 1H), 4.43-4.41 (m, 2H), 3.40-3.36 (m, 2H), 3.30-3.28 (m, 2H), 2.91 (t, J = 13.20 Hz, 2H); MS (ESI) m / z 364.2 [C19H17N5OS + H]+; UPLC purity: 98.4% (Method-D).

[0290] Preparation of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)aniline (Compound AN): 3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4H-1,4-thiazin-6-yl)aniline was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 29%.1H NMR (400 MHz, DMSO-d6): į 11.98 (br s, 1H), 8.31 (s, 1H), 7.98 (s, 1H), 7.35-7.34 (m, 1H), 7.01 (t, J = 15.60 Hz, 1H), 6.74-6.73 (m, 1H), 6.66-6.62 (m, 2H), 6.48-6.46 (m, 1H), 5.16 (s, 2H), 4.40-4.37 (m, 2H), 3.25-3.23 (m, 2H); MS (ESI) m / z 310.3 [C16H15N5S + H]+; UPLC purity: 98.3% (Method-A).

[0291] Preparation of 6-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-3,4-dihydroisoquinolin-1(2H)-one (Compound AO):6-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-3,4- dihydroisoquinolin-1(2H)-one was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 21%.1H NMR (400 MHz, DMSO-d6): į 12.03 (br s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 7.87 (s, 1H), 7.84 (d, J = 8.00 Hz, 1H), 7.47 (dd, J = 1.60, 8.00 Hz, 1H), 7.41 (s, 1H), 7.41-7.38 (m, 1H), 6.66-6.65 (m, 1H), 4.44-4.41 (m, 2H), 3.40-3.36 (m, 2H), 3.30-3.29 (m, 2H), 2.93 (t, J = 13.20 Hz, 2H); MS (ESI) m / z 364.2 [C19H17N5OS + H]+; UPLC purity: 99.9% (Method-E).

[0292] Preparation (5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)oxazol-2-yl)methanol (Compound DP): (5-(4-(7H-Pyrrolo[2,3-d]pyrimidin-2H-1,4-thiazin-6-yl)oxazol-2- yl)methanol was prepared using a Suzuki reaction with the appropriate boronate ester by following Condition-C. Off-white solid.6.00 mg, Yield: 6%.1H-NMR (400 MHz, DMSO- d6): į 12.06 (br s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 7.41 ^ 7.40 (m, 1H), 6.97 (s, 1H), 6.70 ^ 6.68 (m, 1H), 5.69 (t, J = 6.00 Hz, 1H), 4.50 (d, J = 6.40 Hz, 2H), 4.45 ^ 4.42 (m, 2H), 3.29 ^ 3.26 (m, 2H); MS (ESI) m / z 316.3 [C14H13N5O2S + H]+; UPLC Purity: 96.6% (Method-A).

[0293] Preparation of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)oxazole (Compound DQ): 5-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-y, -2H-1,4-thiazin-6-yl)oxazole was prepared using a Suzuki reaction with the appropriate boronate ester by following Condition- C. Off-white solid.6.50 mg, Yield: 7%.1H NMR (400 MHz, DMSO-d6): į 12.07 (br s, 1H), 8.36 (s, 1H), 8.32 (d, J = 2.00 Hz, 2H), 7.42 ^ 7.40 (m, 1H), 7.06 (s, 1H), 6.69 – 6.67 (m,1H), 4.44 ^ 4.42 (m, 2H), 3.30 ^ 3.27 (m, 2H); MS (ESI) m / z 286.1 [C13H11N5OS + H]+; UPLC Purity: 98.0% (Method-A).

[0294] Preparation of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-2-methyloxazole (Compound DR): -2H-1,4-thiazin-6-yl)-2-methyloxazolewas prepared using a Suzuki reaction with the appropriate boronate ester by following Condition-C. Off-white solid.15.0 mg, Yield: 15%.1H NMR (400 MHz, DMSO-d6): į 12.05 (br s, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 7.41 ^ 7.39 (m, 1H), 6.88 (s, 1H), 6.68 – 6.67 (m, 1H), 4.43 ^ 4.41 (m, 2H), 3.27 – 3.25 (m, 2H), 2.43 (s, 3H); MS (ESI) m / z 300.2 [C14H13N5OS + H]+; UPLC Purity: 96.8% (Method-A).

[0295] Preparation 7-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound DU): 7-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4H-1,4-thiazin-6-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazine was prepared using a Suzuki reaction with the appropriate boc- protected boronate ester by following Condition-C. Off-white solid.35.0 mg, Yield: 45%. The Boc derivative was deprotected using Condition-D. Off-white solid.15.0 mg, Yield: 55%.1H NMR (400 MHz, DMSO-d6): į 11.93 (br s, 1H), 8.28 (s, 1H), 7.79 (s, 1H), 7.33 - 7.31 (m, 1H), 6.84 (dd, J = 2.00 Hz, J = 8.40 Hz, 1H), 6.76 (d, J = 2.00 Hz, 1H), 6.57 - 6.55 (m, 2H), 5.90 (br s, 1H), 4.36 - 4.33 (m, 2H), 4.12 (t, J = 4.40 Hz, 2H), 3.30 – 3.27 (m, 2H), 3.23 – 3.21 (m, 2H): MS (ESI) m / z 352.2 [C18H17N5OS + H]+; UPLC purity: 95.1% (Method- E).

[0296] Preparation of 6-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound YB): 6-(4-(7H-Pyrrolo[2,3-d]pyrimidin- -1,4-thiazin-6-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one was prepared using a Suzuki reaction with the appropriate boronate ester following condition-A. Off-white solid.2.00 mg, Yield: 1.5%.1H-NMR (400 MHz, DMSO-d6): į 12.00 (br s, 1H), 10.74 (s, 1H), 8.32 (s, 1H), 7.95 (s, 1H), 7.36 (t, J = 2.80 Hz, 1H), 7.08 - 7.05 (m, 2H), 6.97 - 6.95 (m, 1H), 6.63 (dd, J = 1.60 Hz, J = 3.40 Hz, 1H), 4.58 (s, 2H), 4.41 - 4.38 (m, 2H), 3.28 - 3.26 (m, 2H); MS (ESI) m / z 366.2 [C18H15N5O2S + H]+; UPLC Purity: 99.3% (Method-A).

[0297] Preparation of 4-(2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1- yl)ethyl)morpholine (Compound YE):1,4-thiazin-6-yl)-1H-pyrazol-1- yl)ethyl)morpholine was prepared using a Suzuki reaction with the appropriate boronate ester following condition-A. Off-white solid, 52.0 mg, Yield: 78%.1H-NMR (400 MHz, DMSO- d6): į 11.94 (br s, 1H), 8.29 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.58 (d, J = 0.40 Hz, 1H), 7.32 (d, J = 3.60 Hz, 1H), 6.61 (d, J = 3.60 Hz, 1H), 4.38 - 4.35 (m, 2H), 4.21 (t, J = 6.80 Hz, 2H), 3.55 (t, J = 4.80 Hz, 4H), 3.26 - 3.23 (m, 2H), 2.70 (t, J = 6.80 Hz, 2H), 2.41 (t, J = 4.40 Hz, 4H); MS (ESI) m / z 398.4 [C19H23N7OS + H]+; UPLC Purity: 97.5% (Method-A).

[0298] Compounds DS and DZ comprising Scaffold-B were prepared by the synthetic protocol set forth in Scheme 5. Scheme 5: Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)acetic acid (Compound DZ) and methyl 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)acetate (Compound DS):epa a on o me y - - - -py o o , - py m n- -y - , - y o- H- 1,4-thiazin-6-yl)-1H-pyrazol-1-yl)acetate (Compound DS): Methyl 2-(4-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)acetate was prepared from 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H- pyrazol-1-yl)acetic acid by following Condition-F. Off-white solid. Yield: 30%.1H NMR (400 MHz, DMSO-d6): į 11.95 (br s, 1H), 8.29 (s, 1H), 7.87 (s, 2H), 7.66 (s, 1H), 7.33 (t, J = 2.80 Hz, 1H), 6.62 (d, J = 1.60 Hz, 1H), 5.08 (s, 2H), 4.39 ^ 4.36 (m, 2H), 3.69 (s, 3H), 3.27 ^ 3.24 (m, 2H); MS (ESI) m / z 357.3 [C16H16N6O2S + H]+; UPLC purity: 90.8% (Method-A).

[0300] Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)acetic acid (Compound DZ): 2-(4-(4-(7H-Pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)acetic acid was prepared using a Suzuki reaction with methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)acetate by following Condition-C. Hydrolysis of the ester was observed during the Suzuki reaction. Off-white solid. Yield: 11%.1H NMR (400 MHz, DMSO-d6): į 11.94 (br s, 1H), 8.29 (s, 1H), 7.83 (d, J = 10.40 Hz, 2H), 7.59 (s, 1H), 7.32 (d, J = 2.00 Hz, 1H), 6.62 (d, J = 3.20 Hz, 1H), 4.81 (s, 2H), 4.38 ^ 4.36 (m, 2H), 3.26 ^ 3.24 (m, 2H) (Acid proton not observed); MS (ESI) m / z 343.4 [C15H14N6O2S + H]+; UPLC purity: 99% (Method-A).

[0301] Compound YA comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 5. Scheme 5: Preparation of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1,3,4-oxadiazole (Compound YA):[ ] repara on o - - - r me y s y e oxy me y - -pyrro o[ , - d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carbohydrazide (2): To a stirred solution of ethyl 4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxylate (1.50 g, 3.57 mmol) in ethanol (30.0 mL) was added hydrazine hydrate (890 mg, 17.9 mmol) at room temperature. The resulting solution was refluxed for 48 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was triturated with methyl tert-butyl ether. The obtained solid was filtered and collected to afford 4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carbohydrazide (1.20 g, crude) as a light brown solid. The crude product was used for the next step without further purification.

[0303] Preparation of 2-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1,3,4-oxadiazole (3): The solution of 4- (7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazine-6-carbohydrazide (0.30 g, 0.73 mmol) in triethyl orthoformate (3.00 mL) was heated to 100 °C for 18 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude was purified by mass triggered preparative HPLC to afford 2-(4- (7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1,3,4-oxadiazole (0.15 g, Yield: 51%) as an off-white solid. MS (ESI) m / z 411 [C18H24N6O2SSi + H]+; UPLC Purity: 97.2% (Method-A).

[0304] Preparation of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1,3,4-oxadiazole (Compound YA): Trimethylsilyl chloride (0.10 mL, 2.00 vol) was added to a stirred solution of 2-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1,3,4-oxadiazole (0.05 g, 0.12 mmol) in trifluoroethanol (2.00 mL) at room temperature. The resulting solution was stirred at same temperature for 3 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure. The obtainedresidue was dissolved in methanol (1.00 mL), and then ammonium hydroxide solution (1.00 mL) was added to the reaction mixture. After stirring at room temperature for 18 h, the solid precipitate was collected and dried under reduced pressure to afford 2-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1,3,4-oxadiazole (21.0 mg, Yield: 96.8%) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): į 12.19 (s, 1H), 9.14 (s, 1H), 8.78 (s, 1H), 8.44 (s, 1H), 7.50 - 7.48 (m, 1H), 6.74 - 6.73 (m, 1H), 4.49 - 4.46 (m, 2H), 3.31 - 3.29 (m, 2H); MS (ESI) m / z 287.2 [C12H10N6OS + H]+; UPLC Purity: 96.8% (Method-A).

[0305] Compound YD comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 6. Scheme 6: Preparation of 6-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride (Compound YD):ro- 2H-1,4-thiazin-6-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (1): tert-Butyl 4-(4-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2H-1,2,3-triazol-2- yl)piperidine-1-carboxylate was prepared using a Suzuki reaction with tert-butyl 4-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (BA-30) following condition-C (95.0 mg, 27%).

[0307] Preparation of 6-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride (Compound YD): 6-(2- (Piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazine hydrochloride was prepared by deprotection of Boc-group using condition-E. Off-white solid.67.0 mg, Yield: 82%,1H NMR (400 MHz, DMSO-d6): į 12.41 (s, 1H), 9.31 - 9.20 (m, 1H), 9.01 - 8.89 (m, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.47 (q, J = 2.80 Hz, 1H), 6.78 (q, J = 2.00 Hz, 1H), 4.92 - 4.85 (m, 1H), 4.45 - 4.43 (m, 2H), 3.39 - 3.36 (m,2H), 3.32 - 3.30 (m, 2H), 3.16 - 3.08 (m, 2H), 2.35 - 2.19 (m, 4H); MS (ESI) m / z 369 [C17H21ClN8S + H]+; UPLC Purity: 99% (Method-A).

[0308] Compound YF comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 7. Scheme 7: Preparation of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)-5-methyl-1,3,4-oxadiazole (Compound YF): [0pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1,3,4-oxadiazole (2): The solution of 4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carbohydrazide (0.35g, 0.86 mmol) in triethyl orthoacetate (3.50 mL) was heated to 100 °C for 18 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The crude material was purified by mass triggered preparative HPLC to afford 2-methyl-5-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1,3,4-oxadiazole (120 mg, Yield: 34%) as an off-white solid. MS (ESI) m / z 431.4 [C19H26N6O2SSi + H]+; UPLC Purity: 95.2% (Method-A).

[0310] Preparation of 2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-5-methyl-1,3,4-oxadiazole (Compound YF): Trimethylsilyl chloride (0.10 mL, 2.00 vol) was added to a stirred solution of 2-methyl-5-(4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)-1,3,4-oxadiazole (0.05 g, 0.11 mmol) in trifluoroethanol (2.00 mL) at room temperature. The resulting solution was stirred at room temperature for 3 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2.00 mL), and then ammonium hydroxide solution (2.00 mL) was added to the reaction mixture. After stirring at room temperature for 18 h, the solid precipitate was collected byfiltration, washed with methyl tert-butyl ether and dried under reduced pressure to afford 2- (4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1,3,4-oxadiazole (17.0 mg, Yield: 47.0%) as an off-white solid.1H NMR (400 MHz, DMSO-d6): į 12.17 (s, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 7.49 - 7.47 (m, 1H), 6.74 - 6.73 (m, 1H), 4.48 - 4.45 (m, 2H), 3.29 - 3.27 (m, 2H), 2.52 (s, 3H); MS (ESI) m / z 301.2 [C13H12N6OS + H]+; UPLC Purity: 99.6% (Method-A).

[0311] Compound YJ comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 8. Scheme 8: Preparation of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-2-(pyridin-3-yl)oxazole (Compound YJ):

[0312] Synthesis of (1H-benzo[d][1,2,3]triazol-1-yl)(4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)methanone (3): To a stirred solution of 1H-benzo[d][1,2,3]triazole (3.00 g, 7.63 mmol) in dichloromethane (30.0 mL) was added thionyl chloride (0.56 mL, 7.6 mmol) at room temperature. After stirring for 30 min at room temperature, 4-(7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid (2.70 g, 22.9 mmol) was added to the reaction mixture and stirred at same temperature for 16 h. The reaction mixture was diluted with water (30.0 mL) and extracted with dichloromethane (2 × 100 mL). The combined organic extracts were washed with water (30.0mL), brine solution (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (1H-benzo[d][1,2,3] triazol-1-yl)(4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)methanone (3.00 g, 81%) as a yellow solid.1H NMR (400 MHz, CDCl3): į 9.72 (s, 1H), 8.66 (s, 1H), 8.35 (d, J = 8.40 Hz, 1H), 8.19 (d, J = 8.00 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.58 - 7.54 (m, 1H), 7.47 (d, J = 3.60 Hz, 1H), 7.15 (d, J = 3.60 Hz, 1H), 5.71 (s, 2H), 4.67 - 4.65 (m, 2H), 3.59 (t, J = 8.40 Hz, 2H), 3.34 - 3.32 (m, 2H), 0.97 (t, J = 8.40 Hz, 2H), 0.002 (s, 9H); MS (ESI) m / z 494.6 [C23H27N7O2SSi + H]+.

[0313] Synthesis of 2-nitro-1-(4-(7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3- d] pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl) ethan-1-one (4): To a stirred solution of nitromethane (0.12 mL, 2.2 mmol) in dimethylsulfoxide (10.0 mL) was added potassium tert- butoxide (497 mg, 4.44 mmol) at 10 °C. After stirring for 10 min, the solution of (1H- benzo[d][1,2,3] triazol-1-yl)(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)methanone (1.00 g, 2.02 mmol) in dimethylsulfoxide (5.00 mL) was added to the reaction mixture slowly at same temperature. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (2 × 100mL). The combined organic extracts were washed with water (50.0 mL), brine solution (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by flash chromatography by using silica gel, eluting with 20% to 25% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to obtain 2-nitro-1-(4-(7-((2-(trimethylsilyl) ethoxy) methyl)-7H- pyrrolo[2,3-d] pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl) ethan-1-one (360 mg, 41%) as a yellow color solid.1H NMR (400 MHz, CDCl3): į 8.96 (s, 1H), 8.64 (s, 1H), 7.42 (d, J = 3.60 Hz, 1H), 6.74 (d, J = 3.60 Hz, 1H), 5.71 (s, 2H), 5.66 (s, 2H), 4.58 - 4.56 (m, 2H), 3.61 - 3.57 (m, 2H), 3.22 - 3.19 (m, 2H), 0.99 - 0.95 (m, 2H), 0.002 (s, 9H); MS (ESI) m / z 436.5 [C18H25N5O4SSi + H]+.

[0314] Synthesis of 2-amino-1-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)ethan-1-one (5): To a stirred solution of 2- nitro-1-(4-(7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazin-6-yl) ethan-1-one (0.36 g, 0.82 mmol) in methanol, tetrahydrofuran, water (1:1:1, 6.00 mL) was added zinc-dust (537 mg, 8.27 mmol)) followed by ammonium chloride (438 mg, 8.27 mmol) at room temperature. The resulting solution was stirred for 16h. The reaction mixture was filtered through celite pad, washed with dichloromethane (2 × 50 mL). The combined layer was washed with water (20.0 mL), brine solution (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get 2-amino-1-(4-(7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)ethan-1-one (90 mg, crude). MS (ESI) m / z 406.5 [C18H27N5O2SSi + H]+. The crude product was used for the next step without purification as a viscous pale-yellow oil.

[0315] Synthesis of N-(2-oxo-2-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)ethyl)nicotinamide (7): To a stirred solution of 2-amino-1-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)ethan-1-one. (90.0 mg, 0.22 mmol) in dichloromethane (4.00 mL) were added triethylamine (0.10 mL, 0.66 mmol), nicotinic acid (32.0 mg, 0.26 mmol) and propane phosphonic acid anhydride (50% solution in ethyl acetate, 0.28 mL, 0.44 mmol) at 0 ºC. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20.0 mL) and extracted with dichloromethane (2 × 50.0 mL). The combined organic extracts were washed with water (20.0 mL), brine solution (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by flash chromatography with silica gel, eluting with 4% to 6% methanol in dichloromethane. The pure fractions were concentrated under reduced pressure to afford N-(2-oxo-2-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)ethyl)nicotinamide (45 mg, 39%) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6): į 9.13-9.08 (m, 2H), 9.05 (s, 1H), 8.81 (t, J = 3.20 Hz, 1H), 8.64 (s, 1H), 8.32 - 8.29 (m, 1H), 7.79 (d, J = 4.00 Hz, 1H), 7.61 (q, J = 4.80 Hz, 1H), 6.97 (d, J = 3.60 Hz, 1H), 5.70 (s, 2H), 4.65 (d, J = 5.60 Hz, 2H), 4.49 - 4.48 (m, 2H), 3.60 (t, J = 8.00 Hz, 2H), 3.24 - 3.23 (m, 2H), 0.92 (t, J = 8.00 Hz, 2H), 0.002 (s, 9H); MS (ESI) m / z 511.6 [C24H30N6O3SSi + H]+.

[0316] Synthesis of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)-2-(pyridin-3-yl)oxazole (Compound YJ): The solution of N-(2-oxo-2-(4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)ethyl)nicotinamide (45.0 mg, 0.09 mmol) in phosphorus oxychloride (0.50 mL) was heated to 110 ºC for 12 h. The reaction mixture was concentrated under reduced pressure to obtain the crude which was dissolved in methanol (0.20 mL). Aqueous ammonium hydroxide solution (0.20 mL) was added at 0 ºC. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The crudecompound was purified by using prep-HPLC purification to afford 5-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2-(pyridin-3-yl)oxazole (4.00 mg, 13%, IN-RVN-F-17) as a yellow solid.1H-NMR (400 MHz, DMSO-d6): į 12.21 (s, 1H), 9.16 (t, J = 0.80 Hz, 1H), 8.70 (q, J = 1.60 Hz, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.33 - 8.30 (m, 1H), 7.61 - 7.57 (m, 1H), 7.45 (d, J = 3.60 Hz, 1H), 7.27 (s, 1H), 6.75 (d, J = 3.20 Hz, 1H), 4.48 - 4.45 (m, 2H), 3.30 (s, 2H); MS (ESI) m / z 363.3 [C18H14N6OS + H]+; UPLC Purity: 99.5% (Method-A).

[0317] Compound YK comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 9. Scheme 9: Preparation of 6-(2-(piperidin-3-yl)-2H-1,2,3-triazol-4-yl)-4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride (Compound YK):

[0318] Preparation of tert-butyl 3-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro- 2H-1,4-thiazin-6-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (1): tert-Butyl 3-(4-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2H-1,2,3-triazol-2- yl)piperidine-1-carboxylate was prepared by a Suzuki reaction with tert-butyl 3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate following condition-C (70.0 mg, 20%).

[0319] Preparation of 6-(2-(piperidin-3-yl)-2H-1,2,3-triazol-4-yl)-4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride (Compound YK): 6-(2- (Piperidin-3-yl)-2H-1,2,3-triazol-4-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazine hydrochloride was prepared by deprotection of Boc-group using condition-E. Off-white solid.20.0 mg, Yield: 33%.1H NMR (400 MHz, DMSO-d6): į 12.21 (s, 1H), 9.36 - 9.10 (m, 2H), 8.40 - 8.32 (m, 2H), 8.06 (s, 1H), 7.44 - 7.42 (m, 1H), 6.73 - 6.71 (m, 1H), 5.05 - 4.87 (m, 1H), 4.83 - 4.41 (m, 2H), 3.65 - 3.62 (m, 1H), 3.46 - 3.34 (m, 1H), 3.30 - 3.25(m, 3H), 3.09 - 2.92 (m, 1H), 2.28 - 2.24 (m, 1H), 2.16 - 2.04 (m, 1H), 1.94 - 1.82 (m, 2H); MS (ESI) m / z 369.32 [C17H21ClN8S + H]+; UPLC Purity: 98.48% (Method-A).

[0320] Compound YL comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 10. Scheme 10: Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-1-morpholinoethan-1-one (Compound YL): borolan-2-yl)-1H-pyrazol-1-yl)ethan-1-one (3): To a stirred solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetic acid (0.80 g , 3.2 mmol) and morpholine (0.33 g, 3.8 mmol) in dichloromethane (50.0 mL) was added triethylamine (0.96 g, 9.5 mmol) followed by propylphosphonic anhydride (50% in ethyl acetate, 1.51 g, 4.75 mmol) at room temperature. The resulting solution was stirred at room temperature for 16 h. The reaction progress was monitored by UPLC-MS. The reaction mixture was diluted with water (50.0 mL) and extracted with dichloromethane (2 × 50.0 mL). The combined organic extracts were washed with water (50.0 mL), brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1-morpholino-2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1-yl) ethan-1-one (0.70 g, crude) as a light brown solid. The crude material was used for the next step without purification.

[0322] Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-1-morpholinoethan-1-one (Compound YL): 2-(4-(4-(7H- Pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)-1- morpholinoethan-1-one was prepared using a Suzuki reaction with 1-morpholino-2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) ethan-1-one following condition-C. Off-white solid, 21.0 mg, Yield: 21%).1H NMR (400 MHz, DMSO-d6): į11.94 (s, 1H), 8.28 (s, 1H), 7.84 (s, 1H), 7.77 (d, J = 0.40 Hz, 1H), 7.61 (d, J = 0.80 Hz, 1H), 7.33 - 7.32 (m, 1H), 6.62 - 6.61 (m, 1H), 5.15 (s, 2H), 4.39 - 4.36 (m, 2H), 3.62 - 3.57 (m, 4H), 3.52 - 3.50 (m, 2H), 3.46 - 3.45 (m, 2H), 3.26 - 3.39 (m, 2H); MS (ESI) m / z 412.3 [C19H21N7O2S + H]+; UPLC Purity: 97.1% (Method-A).

[0323] Compound YM comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 11. Scheme 11: Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one (Compound YM):1H-pyrazol-1-yl)acetyl)piperazine-1-carboxylate (3): To a stirred solution of 2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetic acid (50.0 mg, 0.19 mmol) and tert-butyl piperazine-1-carboxylate (40.0 mg, 0.22 mmol) in dichloromethane (3.00 mL) was added triethylamine (83.0 ^L, 0.57 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 0.18 mL, 0.29 mmol) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was diluted with water (10.0 mL) and extracted with dichloromethane (10.0 mL). The organic extracts were washed with water (10.0 mL) and brine (10.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get tert-butyl 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)acetyl)piperazine-1-carboxylate (75.0 mg, crude) as a light brown solid. The crude material was used for the next step without further purification.

[0325] Preparation of tert-butyl 4-(2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)acetyl)piperazine-1-carboxylate (4): tert-Butyl 4-(2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol- 1-yl)acetyl)piperazine-1-carboxylate was prepared using a Suzuki reaction with tert-butyl 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetyl)piperazine-1- carboxylate following condition-B (23.0 mg, Yield: 44%).

[0326] Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one (Compound YM): 2-(4-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)-1- (piperazin-1-yl)ethan-1-one was prepared by deprotection of Boc group by using condition- E. Off-white solid.8.00 mg, Yield: 44%,1H NMR (400 MHz, DMSO-d6): į 11.95 (s, 1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 7.34 - 7.32 (m, 1H), 6.62 - 6.61 (m, 1H), 5.10 (s, 2H), 4.38 - 4.36 (m, 2H), 3.38 - 3.36 (m, 4H), 3.26 - 3.24 (m, 2H), 2.71 - 2.63 (m, 4H); MS (ESI) m / z 411.3 [C19H22N8OS + H]+; UPLC Purity: 99.2% (Method-A).

[0327] Compound YN comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 12. Scheme 12: Preparation of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-2-(pyrazin-2-yl)oxazole (Compound YN):3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)ethyl)pyrazine-2-carboxamide (3): To a stirred solution of 2-amino-1-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)ethan-1-one (90.0 mg, 0.22 mmol) in dichloromethane (4.00 mL) were added triethylamine (0.10 mL, 0.66 mmol), pyrazine-2- carboxylic acid (30.0 mg, 0.24 mmol) and propane phosphonic acid anhydride (50% solution in ethyl acetate, 0.26 mL, 0.44 mmol) at 0 ºC. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20.0 mL) and extracted with dichloromethane (2 × 50.0 mL). The combined extracts were washed with water (20.0 mL), brine solution (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by flashchromatography with silica gel, eluting with 4% to 6% methanol in dichloromethane. The pure fractions were concentrated under reduced pressure to afford N-(2-oxo-2-(4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)ethyl)pyrazine-2-carboxamide (45 mg, 39%) as a brown solid.1H NMR (400 MHz, DMSO-d6): į 9.21 (d, J = 1.60 Hz, 1H), 9.01 (t, J = 6.00 Hz, 1H), 8.96 (s, 1H), 8.92 (d, J = 2.40 Hz, 1H), 8.80 - 8.79 (m, 1H), 8.58 (s, 1H), 7.72 (d, J = 3.60 Hz, 1H), 6.89 (d, J = 3.60 Hz, 1H), 5.63 (s, 2H), 4.64 (d, J = 5.60 Hz, 2H), 4.42 - 4.40 (m, 2H), 4.40 (t, J = 2.80 Hz, 2H), 3.18 - 3.15 (m, 2H), 0.85 (t, J = 8.00 Hz, 2H), 0.002 (s, 9H). MS (ESI) m / z 512.6 [C23H29N7O3SSi + H]+.

[0329] Synthesis of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)-2-(pyrazin-2-yl)oxazole (Compound YN): The solution of N-(2-oxo-2-(4-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)ethyl)pyrazine-2-carboxamide (45.0 mg, 0.09 mmol) in phosphorus oxychloride (0.50 mL) was heated to 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain the crude which was dissolved in methanol (0.20 mL). Aqueous ammonium hydroxide solution (0.20 mL) was added at 0 ºC. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by using prep-HPLC purification to afford 5-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2-(pyridin-3-yl)oxazole (4.0 mg, 12) as a yellow solid.1H NMR (400 MHz, DMSO-d6): į 12.11 (s, 1H), 9.29 (d, J = 1.60 Hz, 1H), 8.80 - 8.75 (m, 2H), 8.55 (s, 1H), 8.42 (s, 1H), 7.45 (t, J = 2.40 Hz, 1H), 7.37 (s, 1H), 6.74 (q, J = 2.00 Hz, 1H), 4.49 (q, J = 2.80 Hz, 2H), 3.38 (s, 2H). MS (ESI) m / z 364.2 [C17H13N7OS + H]+; UPLC Purity: 98.7% (Method-A).

[0330] Compound YO comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 13. Scheme 13: Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one (Compound YO):dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one (3): To a stirred solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetic acid (0.80 g, 3.17 mmol) and 1-methylpiperazine (0.38 g, 3.80 mmol) in dichloromethane (30.0 mL) was added triethylamine (0.96 g, 9.51 mmol) and propylphosphonic anhydride (3.02 g, 50% in ethyl acetate, 4.75 mmol) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was diluted with water (50.0 mL) and extracted with dichloromethane (2 × 50.0 mL). The combined organic extracts were washed with water (50.0 mL), brine (50.0 mL), dried over sodium sulfate and concentrated under reduced pressure to get 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one (0.60 g, crude) as an off-white solid. The crude product was used for the next step without further purification.

[0332] Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one (Compound YO): 2-(4- (4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)-1- (4-methylpiperazin-1-yl)ethan-1-one was prepared using a Suzuki reaction following condition-B. Off-white solid.48.0 mg, Yield: 34%,1H NMR (400 MHz, DMSO-d6): į 11.94 (s, 1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.76 (d, J = 0.40 Hz, 1H), 7.60 (d, J = 0.40 Hz, 1H), 7.33 - 7.31 (m, 1H), 6.62 - 6.61 (m, 1H), 5.11 (s, 2H), 4.38 - 4.36 (m, 2H), 3.49 - 3.44 (m, 4H), 3.26 - 3.24 (m, 2H), 2.35 - 2.33 (m, 2H), 2.29 - 2.26 (m, 2H), 2.20 (s, 3H); MS (ESI) m / z 425.4 [C20H24N8OS + H]+; UPLC Purity: 97.4% (Method-A).

[0333] Compound YR comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 14.Scheme 14: Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-N-methylethan-1-amine (Compound YR): [1- yl) ethyl methane sulfonate (2): To a stirred solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (0.50 g, 2.1 mmol) and triethylamine (0.63 g, 6.3 mmol) in dichloromethane (10.0 mL) was added methanesulfonyl chloride (0.28 g, 2.5 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was diluted with water (50.0 mL) and extracted with dichloromethane (2 × 50.0 mL). The combined organic extracts were washed with water (50.0 mL), brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get 2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) ethyl methane sulfonate (0.55 g, crude) as an off-white solid. The crude product was used for the next step without further purification.

[0335] Preparation of N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl) ethan-1-amine (3): The sealed tube was charged with 2-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (0.20 g, 0.63 mmol) and methylamine (7% in THF, 20 vol.). The resulting solution was stirred at 80 °C for 16 h. The reaction progress was monitored by thin layer chromatography. The reaction mixture was diluted with water (30.0 mL) and extracted with dichloromethane (2 × 30.0 mL). The combined organic extracts were washed with water (30.0 mL), brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get N-methyl-2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) ethan-1-amine (0.10 g, crude) as a viscous material. The crude product was used for the next step without further purification.

[0336] Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)-N-methylethan-1-amine (Compound YR): 2-(4-(4-(7H- Pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)-N- methylethan-1-amine was prepared by a Suzuki reaction following condition-B. Off-white solid.5.50 mg, Yield: 5%,1H NMR (400 MHz, DMSO-d6): į 11.93 (s, 1H), 8.29 (s, 1H), 7.83 (d, J = 9.20 Hz, 2H), 7.59 (s, 1H), 7.32 (d, J = 2.00 Hz, 1H), 6.62 (d, J = 3.20 Hz, 1H), 4.38 - 4.35 (m, 2H), 4.16 - 4.13 (m, 2H), 3.25 - 3.23 (m, 2H), 2.86 - 2.83 (m, 2H), 2.27 (s, 3H) (NH proton is not observed); MS (ESI) m / z 342.3 [C16H19N7S + H]+; UPLC Purity: 97.4% (Method-A).

[0337] Compound YS comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 15. Scheme 15: Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)ethan-1-amine (Compound YS):

[0338] pyrazol-1- yl)ethan-1-amine (2): The sealed tube was charged with 2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (0.20 g, 0.63 mmol) and ammonia (30% in THF, 10 vol.). The resulting solution was stirred at 80 °C for 16 h. The reaction mixture was cooled, diluted with water (30.0 mL) and extracted with dichloromethane (2 × 30.0 mL). The combined organic extracts were washed with water (30.0 mL), brine (30.0 mL) and dried over sodium sulfate. Concentration under reduced pressure afforded 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan- 1-amine (0.10 g, crude) as a viscous material. The crude product was used for the next step without further purification.

[0339] Preparation of 2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)-1H-pyrazol-1-yl)ethan-1-amine (Compound YS): 2-(4-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)ethan-1-amine was prepared by a Suzuki reaction following condition-B. Off-white solid.15.0 mg, Yield: 14%,1H NMR (400 MHz, DMSO-d6): į 11.94 (s, 1H), 8.30 (s, 1H), 7.84 (d, J = 9.60 Hz, 2H), 7.61 (d, J = 0.80 Hz, 1H), 7.32 (d, J = 2.00 Hz, 1H), 6.62 (d, J = 3.60 Hz, 1H), 4.38 - 4.35 (m, 2H), 4.10 - 4.07 (m, 2H), 3.29 - 3.23 (m, 2H), 2.96 - 2.93 (m, 2H); MS (ESI) m / z 328.2 [C15H17N7S + H]+; UPLC Purity: 99.2% (Method-B).

[0340] Compound YT comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 16. Scheme 16: Preparation of 6-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound YT):

[0341] -2-yl)- 1H-pyrazol-1-yl)ethyl)piperazine (3): A sealed tube was charged with 2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (0.20 g, 0.63 mmol) and 1-methylpiperazine (1.0 mL ). The resulting solution was stirred at 90 °C for 16 h. The reaction mixture was cooled, diluted with water (30.0 mL) and extracted with dichloromethane (2 × 30.0 mL). The combined organic extracts were washed with water (30.0 mL), brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get 1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)ethyl)piperazine (0.18 g, crude) as a light brown solid. The crude product was used for the next step without further purification.

[0342] Preparation of 6-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound YT): 6-(1-(2-(4- Methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine was prepared by a Suzuki reaction following condition-B. Off-whitesolid.21.0 mg, Yield: 15%.1H NMR (400 MHz, DMSO-d6): į 11.95 (s, 1H), 8.29 (s, 1H), 7.84 (d, J = 16.40 Hz, 2H), 7.58 (s, 1H), 7.32 (d, J = 2.40 Hz, 1H), 6.61 (d, J = 3.20 Hz, 1H), 4.38 - 4.36 (m, 2H), 4.21 - 4.18 (m, 2H), 3.26 - 3.23 (m, 2H), 2.70 - 2.67 (m, 2H), 2.42 (br s, 4H), 2.30 (br s, 4H), 2.14 (s, 3H); MS (ESI) m / z 411.4 [C20H26N8S + H]+; UPLC Purity: 99.8% (Method-B).

[0343] Compound YU comprising Scaffold-B was prepared by the synthetic protocol set forth in Scheme 17. Scheme 17: Preparation of 6-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound YU): [1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (3): A sealed tube was charged with 2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (0.30 g, 0.94 mmol), tert-butyl piperazine-1-carboxylate (0.26 g), diisopropylethylamine (0.36 g, 2.8 mmol) and tetrahydrofuran (10 vol.). The resulting solution was stirred at 80 °C for 16 h. The reaction mixture was cooled, diluted with water (50.0 mL) and extracted with dichloromethane (2 × 50.0 mL). The combined organic extracts were washed with water (50.0 mL), brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide tert-butyl 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (0.32 g, crude) as a light brown solid. The crude product was used for the next step without further purification.

[0345] Preparation of tert-butyl 4-(2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (4): tert-Butyl 4-(2-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol- 1-yl)ethyl)piperazine-1-carboxylate was prepared using a Suzuki reaction with the tert-butyl4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)piperazine-1- carboxylate following condition-B (12.0 mg, Yield: 2%).

[0346] Preparation of 6-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound YU): 6-(1-(2-(piperazin-1- yl)ethyl)-1H-pyrazol-4-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine was prepared by deprotection of Boc group using condition-E. Off-white solid.3.5 mg, Yield: 40%.1H NMR (400 MHz, DMSO-d6): į 11.94 (s, 1H), 8.29 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.59 (s, 1H), 7.34 - 7.32 (m, 1H), 6.61 (d, J = 2.80 Hz, 1H), 4.38 - 4.35 (m, 2H), 4.22 - 4.19 (m, 2H), 3.26 - 3.23 (m, 2H), 2.87 - 2.85 (m, 4H), 2.74 - 2.70 (m, 2H), 2.44 - 2.42 (m, 4H); MS (ESI) m / z 397.3 [C19H24N8S + H]+; UPLC Purity: 97.2% (Method-A). EXAMPLE 3

[0347] This example provides an exemplary synthesis for Compounds AP-BI, DN, DT, DV-DY, YG, YH, YI, and YP.

[0348] Starting materials Bromo-SEM-Scaffold and Bromo-Scaffold-C were prepared using the synthetic protocol set forth in Scheme 18. Scheme 18: Preparation of Bromo-SEM-Scaffold and Bromo-Scaffold-C of Example 3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid (6): To a stirred solution of ethyl 4-(5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,4-dihydro-2H-1,4-thiazine-6-carboxylate (13.5 g, 31.1 mmol) in ethanol:water (2:1, 150 mL) at room temperature was added potassium hydroxide (3.50 g, 62.2 mmol). The resulting mixture was stirred at 95 °C for 3 h. The progress of the reaction was monitored by TLC until complete consumption of starting material was observed. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude compound was diluted with water (100 mL) and acidified with 10% aqueous citric acid solution (pH~5). The solid material was collected by filtration and washed with excess cold water. The solid was dried to afford 4-(5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylicacid [11.50 g (crude)] as a yellow solid.1HNMR (400 MHz, DMSO- d6): į 12.51 (s, 1H), 8.56 (s, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 5.63 (s, 2H), 4.27-4.24 (m, 2H), 3.58 (t, J = 8.00 Hz, 2H), 3.27-3.25 (m, 2H), 2.42 (s, 3H), 0.91 (t, J = 8.00 Hz, 2H), - 0.005 (s, 9H); MS (ESI) m / z 407.1 [C18H26N4O3SSi + H]+.

[0350] Preparation of 6-bromo-4-(5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Bromo-SEM-scaffold): To a stirred solution of 4-(5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylicacid (11.5 g, 28.3 mmol) in dry chloroform (400 mL) was added triethylamine (4.83 mL, 56.6 mmol) at 0 °C. The resultant reaction mixture was stirred for 10 min and then N-bromosuccinimide (5.05 g, 28.3 mmol) was added portionwise under argon atmosphere and stirring was continued for 1 h under argon. The reaction progress monitored by TLC until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure to obtain crude material as a pale-yellow solid. The obtained crude material was purified by flash chromatography using silica gel (230-400 mesh). The desired product was eluted with 15-20% EtOAc / hexanes, the pure fractions were collected and concentrated under reduced pressure to afford 6-bromo-4-(5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (9.40 g, 76%) as a pale-yellow solid.1H NMR (400 MHz, CDCl3): į 8.42 (s, 1H), 7.17 (s, 1H), 7.01 (d, J = 0.80 Hz, 1H), 5.55 (s, 2H), 4.33-4.31 (m, 2H), 3.54-3.50 (m, 2H), 3.30-3.27 (m, 2H), 2.41 (d, J = 1.20 Hz, 3H), 0.94- 0.90 (m, 2H), -0.045 (s, 9H); MS (ESI) m / z 441.0 [C17H25BrN4OSSi + H]+.

[0351] Preparation of 6-bromo-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine (Bromo-Scaffold-C): To a stirred solution of 6-bromo-4-(5-methyl- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazine (9.00 g, 20.4 mmol) in trifluoroethanol (60.0 mL) was added trimethylsilyl chloride (10.0 mL) at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. The obtained intermediate was dissolved in methanol (30.00 mL), added ammonia solution (50.0 mL, 35% in water) at below 10 °C (while adding ammonia solution solid formation was observed) and stirring was continued further at room temperature for 18 h. The reaction progress monitored by TLC until complete consumption of starting material was observed. The resulting solid reaction mixture was cooled to 0 °C and filtered, and the solid cake was washed with cold methanol and dried to afford 6-bromo-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine [5.50 g (crude)] as an off white solid.1H NMR (400 MHz, DMSO-d6): į 11.77 (s, 1H), 8.30 (s, 1H), 7.27 (s, 1H), 7.19 (d, J = 1.20 Hz, 1H), 4.19-4.17 (m, 2H), 3.33-3.31 (m, 2H), 2.34 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 311.0 [C11H11BrN4S + H]+.

[0352] Bromo-SEM-Scaffold and Bromo-Scaffold-C were transformed into Compounds AP-BI, YG, and YH using the general synthetic protocol for Suzuki targets set forth in Scheme 19. Scheme 19: General Synthetic Protocol for Suzuki Targets Of Example 3.

[0353] Preparation of 5-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)nicotinonitrile (Compound AP): 5-(4-(5-Methyl-7H-pyrrolo[2,3-d] pydihydro-2H-1,4-thiazin-6- yl)nicotinonitrile was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 32%.1H NMR (400 MHz, DMSO-d6): į 11.83 (s, 1H), 8.93 (d, J = 2.40 Hz, 1H), 8.81 (d, J =2.00 Hz, 1H), 8.41-8.38 (m, 2H), 7.73 (s, 1H), 7.22 (d, J = 0.80 Hz, 1H), 4.26-4.23 (m, 2H), 3.36-3.33 (m, 2H), 2.19 (d, J = 0.40 Hz, 3H); MS (ESI) m / z 335.2 [C17H14N6S + H]+; UPLC purity: 96.9% (Method-D).

[0354] Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-phenyl-3,4- dihydro-2H-1,4-thiazine (Compound AQ):4-(5-Methyl-7H-pyrrolo[2,3-d]pyrimid nyl-3,4-dihydro-2H-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 13%.1H NMR (400 MHz, DMSO-d6): į 11.75 (s, 1H), 8.32 (s, 1H), 7.47 (dd, J = 1.20, 8.40 Hz, 2H), 7.42 (s, 1H), 7.34 (t, J = 8.00 Hz, 2H), 7.24 (t, J = 4.40 Hz, 1H), 7.23-7.21 (m, 1H), 4.23-4.20 (m, 2H), 3.36-3.33 (m, 2H), 2.20 (d, J = 1.20 Hz, 3H); MS (ESI) m / z 309.2 [C17H16N4S + H]+; UPLC purity: 95.6%. (Method-D).

[0355] Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(pyridin-3-yl)- 3,4-dihydro-2H-1,4-thiazine (Compound AR): 4-(5-Methyl-7H-pyrrolo[2,3-d] pyrimiridin-3-yl)-3,4-dihydro-2H-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 16%.1H NMR (400 MHz, DMSO-d6): į 11.78 (s, 1H), 8.69 (t, J = 0.40 Hz, 1H), 8.42 (dd, J = 1.60, 4.80 Hz, 1H), 8.31 (s, 1H), 7.87-7.84 (m, 1H), 7.51 (s, 1H), 7.37-7.34 (m, 1H), 7.18 (s, 1H), 4.25-4.22 (m, 2H), 3.36-3.33 (m, 2H), 2.19 (d, J = 0.40 Hz, 3H); MS (ESI) m / z 310.2 [C16H15N5S + H]+; UPLC purity: 95.0%. (Method-D).

[0356] Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1-(piperidin-4- yl)-1H-pyrazol-4-yl)-3,4-dihydro-2H-1,4-thiazine•HCl (Compound AS):4-(5-Methyl-7H-pyrrolo[2,3-d]pyri eridin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride was prepared by a Suzuki reaction with the appropriate Boc protected boronic acid by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by washing with 10:1 mixture of acetonitrile and CH3OH. Off-white solid. Yield: 8% (Over 2 steps).1H NMR (400 MHz, DMSO-d6): į 12.36 (br s, 1H), 9.21-9.18 (m, 1H), 8.99-8.97 (m, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.70 (s, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 4.52-4.44 (m, 1H), 4.22-4.20 (m, 2H), 3.37- 3.34 (m, 4H), 3.10-2.93 (m, 2H), 2.27 (d, J = 0.80 Hz, 3H), 2.19-2.15 (m, 4H); MS (ESI) m / z 382.3 [C19H24ClN7S + H]+; UPLC purity: 97.7% (Method-D).

[0357] Preparation of 6-(1-methyl-1H-pyrazol-5-yl)-4-(5-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound AT):pyrimidin-4-yl)-3,4-dihydro- 2H-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 20%.1H NMR (400 MHz, DMSO-d6): į 11.76 (s, 1H), 8.32 (s, 1H), 7.39 (d, J = 1.60 Hz, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 6.24 (d, J = 1.60 Hz, 1H), 4.25-4.22 (m, 2H), 3.83 (s, 3H), 3.36-3.33 (m, 2H), 2.26 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 313.2 [C15H16N6S + H]+; UPLC purity: 95.3% (Method-D).

[0358] Preparation of 3,5-dimethyl-4-(4-(5-methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)- 3,4-dihydro-2H-1,4-thiazin-6-yl) isoxazole (Compound AU):3,5-Dimethyl-4-(4-(5-methyl-7H-pyrr idin-4-yl)-3,4-dihydro-2H-1,4-thiazin- 6-yl)isoxazole was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 27%.1H NMR (400 MHz, DMSO-d6): į 11.71 (s, 1H), 8.30 (s, 1H), 7.14 (d, J = 1.20 Hz, 1H), 6.87 (s, 1H), 4.23-4.21 (m, 2H), 3.36- 3.33 (m, 2H), 2.36 (s, 3H), 2.25 (d, J = 1.20 Hz, 3H), 2.20 (s, 3H); MS (ESI) m / z 328.2 [C16H17N5OS + H]+; UPLC purity: 95.9% (Method-D).

[0359] Preparation of 6-(1H-indazol-6-yl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3,4-dihydro-2H-1,4-thiazine (Compound AV): HNN6-(1H-Indazol-6-yl)-4-(5-methyl-7Hmidin-4-yl)-3,4-dihydro-2H-1,4- thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 22%.1H NMR (400 MHz, DMSO-d6): į 12.97 (s, 1H), 11.76 (s, 1H), 8.33 (s, 1H), 8.02 (t, J = 2.40 Hz, 1H), 7.69 (d, J = 8.40 Hz, 1H), 7.54 (d, J = 6.40 Hz, 2H), 7.30 (dd, J = 1.60, 8.80 Hz, 1H), 7.17 (t, J = 2.00 Hz, 1H), 4.25-4.23 (m, 2H), 3.35-3.33 (m, 2H), 2.21 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 349.2 [C18H16N6S + H]+; UPLC purity: 95.3% (Method-D).

[0360] Preparation of 3-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)aniline (Compound AW):3-(4-(5-Methyl-7H-pyrrolo[2,3-d]py ihydro-2H-1,4-thiazin-6-yl)aniline was prepared using a Suzuki reactionwith the appropriate boronic acid by following condition-C. Off-white solid. Yield: 22%.1H NMR (400 MHz, DMSO-d6): į 11.73 (s, 1H), 8.30 (s, 1H), 7.29 (s, 1H), 7.15 (d, J = 1.20 Hz, 1H), 6.96 (t, J = 7.60 Hz, 1H), 6.69-6.62 (m, 1H), 6.60 (d, J = 0.80 Hz, 1H), 6.44 (dd, J = 1.60, 8.00 Hz, 1H), 5.08 (s, 2H), 4.19-4.17 (m, 2H), 3.28-3.26 (m, 2H), 2.22 (d, J = 0.40 Hz, 3H); MS (ESI) m / z 324.2 [C17H17N5S + H]+; UPLC purity: 98.6% (Method-E).

[0361] Preparation of 7-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)-3,4-dihydroisoquinolin-1(2H)-one (Compound AX):1,4-thiazin-6-yl)-3,4- dihydroisoquinolin-1(2H)-one was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 37%.1H NMR (400 MHz, DMSO-d6): į 11.76 (s, 1H), 8.33 (s, 1H), 7.95 (s, 1H), 7.92 (d, J = 2.00 Hz, 1H), 7.59 (dd, J = 2.40, 8.00 Hz, 1H), 7.46 (s, 1H), 7.27 (d, J = 8.00 Hz, 1H), 7.17-7.18 (m, 1H), 4.21-4.23 (m, 2H), 3.35-3.39 (m, 2H), 3.26-3.28 (m, 2H), 2.89 (t, J = 6.40 Hz, 2H), 2.21 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 378.3 [C20H19N5OS + H]+; UPLC purity: 96.7% (Method-A).

[0362] Preparation of 6-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)-3,4-dihydroisoquinolin-1(2H)-one (Compound AY):6-(4-(5-Methyl-7H-pyrrolo[2,3-d]p hydro-2H-1,4-thiazin-6-yl)-3,4- dihydroisoquinolin-1(2H)-one wasprepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 9%.1H NMR (400 MHz, DMSO-d6): į 11.79 (s, 1H), 8.35 (s, 1H), 7.85-7.80 (m, 1H), 7.78 (d, J = 8.00 Hz, 1H), 7.57 (s, 1H), 7.44 (dd, J = 2.06, 8.00 Hz, 1H), 7.39 (d, J = 1.60 Hz, 1H), 7.19 (d, J = 1.20 Hz, 1H), 4.24-4.21 (m, 2H), 3.38-3.35 (m, 2H), 3.30-3.28 (m, 2H), 2.89 (t, J = 12.80 Hz, 2H), 2.21 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 378.2 [C20H19N5OS + H]+; UPLC purity: 97.3% (Method-E).

[0363] Preparation of 2-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine•HCl (Compound AZ):n-6-yl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine hydrochloride was prepared by a Suzuki reaction with the appropriate Boc protected boronate ester by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by washing with 10:1 mixture of acetonitrile and CH3OH. Off-white solid. Yield: 7% (Over 2 steps).1H NMR (400 MHz, DMSO-d6): į 12.04 (s, 1H), 9.37 (br s, 2H), 8.39 (s, 1H), 7.31 (s, 1H), 7.26 (d, J = 1.20 Hz, 1H), 6.89 (s, 1H), 4.25-4.23 (m, 2H), 4.17-4.09 (m, 2H), 3.40-3.38 (m, 2H), 3.35-3.32 (m, 2H), 2.99 (t, J = 11.60 Hz, 2H), 2.28 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 370.2 [C18H20ClN5S2+ H]+; UPLC purity: 95.7% (Method-D).

[0364] Preparation of 7-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)-3,4-dihydroquinolin-2(1H)-one (Compound BA):7-(4-(5-Methyl-7H-pyrrolo[2,3-d]p hydro-2H-1,4-thiazin-6-yl)-3,4- dihydroquinolin-2(1H)-one was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 11%.1H NMR (400 MHz, DMSO-d6): į 11.76 (s, 1H), 10.03 (s, 1H), 8.31 (s, 1H), 7.33 (s, 1H), 7.19-7.15 (m, 2H), 7.02 (dd, J = 2.00, 7.80 Hz, 1H), 6.98 (d, J = 2.00 Hz, 1H), 4.21-4.19 (m, 2H), 3.30-3.28 (m, 2H), 2.85 (t, J =8.00 Hz, 2H), 2.44 (q, J =7.20 Hz, 2H), 2.22 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 378.3 [C20H19N5OS + H]+; UPLC purity: 97.4% (Method-A).

[0365] Preparation of 2-(4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro- 2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol (Compound BB): 2-(4-(4-(5-Methyl-7H-pyrrolo[2,3-d4-dihydro-2H-1,4-thiazin-6-yl)-1H- pyrazol-1-yl)ethan-1-ol was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 23%.1H NMR (400 MHz, DMSO- d6): į 11.68 (s, 1H), 8.27 (s, 1H), 7.76 (s, 1H), 7.57 (d, J = 0.40 Hz, 1H), 7.21 (s, 1H), 7.14 (d, J = 1.20 Hz, 1H), 4.88 (t, J = 5.20 Hz, 1H), 4.19-4.16 (m, 2H), 4.10 (t, J = 5.60 Hz, 2H), 3.72 (q, J = 5.60 Hz, 2H), 3.29-3.26 (m, 2H), 2.26 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 343.2 [C16H18N6OS + H]+; UPLC purity: 97.0% (Method-E).

[0366] Preparation of 6-(1-methyl-1H-imidazol-5-yl)-4-(5-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound BC):6-(1-Methyl-1H-imidazol-5-yl)-4-(5-m olo[2,3-d]pyrimidin-4-yl)-3,4-dihydro- 2H-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 21%.1H NMR (400 MHz, DMSO-d6): į 11.74 (s, 1H), 8.30 (s, 1H), 7.61 (s, 1H), 7.16 (d, J = 0.80 Hz, 1H), 7.01 (s, 1H), 6.87 (d, J = 1.20 Hz, 1H), 4.23-4.20 (m, 2H), 3.62 (s, 3H), 3.34-3.32 (m, 2H), 2.27 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 313.2 [C15H16N6S + H]+; UPLC purity: 96.5% (Method-E).

[0367] Preparation of 4-methyl-5-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazin-6-yl)oxazole (Compound BD): 4-Methyl-5-(4-(5-methyl-7H-pyrrolo[2n-4-yl)-3,4-dihydro-2H-1,4-thiazin-6- yl)oxazole was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 15%.1H NMR (400 MHz, DMSO-d6): į 11.81 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.37 (s, 1H), 7.21-7.20 (m, 1H), 4.24-4.21 (m, 2H), 3.31-3.29 (m, 2H), 2.30 (d, J = 0.80 Hz, 3H), 2.25 (s, 3H); MS (ESI) m / z 314.2 [C15H15N5OS + H]+; UPLC purity: 97.7% (Method-E).

[0368] Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1,2,3,4- tetrahydroquinolin-7-yl)-3,4-dihydro-2H-1,4-thiazine. HCl (Compound BE):4-(5-Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1,2,3,4-tetrahydroquinolin-7-yl)-3,4- dihydro-2H-1,4-thiazine hydrochloride was prepared by a Suzuki reaction with the appropriate Boc protected boronate ester by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by washing with 10:1 mixture of acetonitrile and CH3OH. Off-white solid. Yield: 5% (over 2 steps).1H NMR (400 MHz, DMSO-d6): į 12.22 (s, 1H), 8.43 (s, 1H), 7.40 (s, 1H), 7.34-7.29 (m, 2H), 7.21-7.19 (m, 2H), 5.86 (br s, 2H), 4.24-4.22 (m, 2H), 3.37-3.32 (m, 4H), 2.79 (t, J = 6.40 Hz, 2H), 2.22 (d, J = 0.80 Hz, 3H), 1.98-1.91 (m, 2H); MS (ESI) m / z 364.3 [C20H22ClN5S + H]+; UPLC purity: 99.8% (Method-E).

[0369] Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1,2,3,4- tetrahydroisoquinolin-7-yl)-3,4-dihydro-2H-1,4-thiazine•HCl (Compound BF): lin-7-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride was prepared by a Suzuki reaction with the appropriate Boc protected boronate ester by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by washing with 10:1 mixture of acetonitrile and CH3OH. Off-white solid. Yield: 8% (Over 2 steps).1H NMR (400 MHz, DMSO-d6): į 12.09 (br s, 1H), 9.37 (br s, 2H), 8.40 (s, 1H), 7.41-7.39 (m, 2H), 7.35 (s, 1H), 7.27-7.24 (m, 2H), 4.25-4.20 (m, 4H), 3.33-3.35 (m, 4H), 3.00 (t, J = 12.00 Hz, 2H), 2.19 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 364.3 [C20H22ClN5S + H]+; UPLC purity: 97.2% (Method-A).

[0370] Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1,2,3,4- tetrahydroisoquinolin-6-yl)-3,4-dihydro-2H-1,4-thiazine•HCl (Compound BG):4-(5-Methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-6-(1,2,3,4-tetrahydroisoquinolin-6-yl)-3,4- dihydro-2H-1,4-thiazine hydrochloride was prepared by a Suzuki reaction with the appropriate Boc protected boronate ester by following condition-C. The Boc derivative was deprotected using condition-D and the final compound was purified by washing with 10:1 mixture of acetonitrile and CH3OH. Off-white solid. Yield: 9% (Over 2 steps).1H NMR (400 MHz, DMSO-d6): į 12.01 (s, 1H), 9.29 (br s, 2H), 8.38 (s, 1H), 7.42 (s, 1H), 7.38 (dd, J = 2.00, 8.20 Hz, 1H), 7.34 (s, 1H), 7.24-7.18 (m, 2H), 4.25-4.20 (m, 4H), 3.37-3.32 (m, 4H), 3.01 (t, J = 6.40 Hz, 2H), 2.19 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 364.3 [C20H22ClN5S + H]+; UPLC purity: 96.1% (Method-A).

[0371] Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1H-pyrazol-3- yl)-3,4-dihydro-2H-1,4-thiazine (Compound BH): -pyrazol-3-yl)-3,4-dihydro-2H-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronic acid by following condition-C. Off-white solid. Yield: 3%.1H NMR (400 MHz, DMSO-d6): į 12.63 (s, 1H), 11.71 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.16 (s, 1H), 6.35 (s, 1H), 4.20-4.18 (m, 2H), 3.28-3.25 (m, 2H), 2.29 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 299.3 [C14H14N6S + H]+; UPLC purity: 95.2% (Method-A).

[0372] Preparation of 6-(1-methyl-1H-pyrazol-4-yl)-4-(5-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound BI): 6-(1-Methyl-1H-pyrazol-4-yl)-4-(5-mo[2,3-d]pyrimidin-4-yl)-3,4-dihydro- 2H-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronate ester by following condition-C. Off-white solid. Yield: 21%.1H NMR (400 MHz, DMSO-d6): į11.68 (s, 1H), 8.27 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 0.80 Hz, 1H), 7.19 (s, 1H), 7.14-7.13 (m, 1H), 4.18-4.16 (m, 2H), 3.80 (s, 3H), 3.29-3.26 (m, 2H), 2.24 (d, J = 1.20 Hz, 3H); MS (ESI) m / z 313.2 [C15H16N6S + H]+; UPLC purity: 99.2% (Method-E).

[0373] Preparation 7-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound DN):7-(4-(5-Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazine was prepared using a Suzuki reaction with an appropriate boc-protected boronate ester by following Condition-C. Off-white solid.40.0 mg, Yield: 27%. The Boc derivative was deprotected using Condition-D. Off-white solid.8.0 mg, Yield: 26%.1H NMR (400 MHz, DMSO-d6): į 11.67 (br s, 1H), 8.26 (s, 1H), 7.14 (s, 1H), 7.13 ^ 7.12 (m, 1H), 6.79 (dd, J = 2.00, 8.40 Hz, 1H), 6.72 (d, J = 2.00 Hz, 1H), 6.51 (d, J = 8.40 Hz, 1H), 5.83 (br s, 1H), 4.16 ^ 4.14 (m, 2H), 4.10 (t, J = 4.00 Hz, 2H), 3.26 – 3.23 (m, 4H), 2.20 (s, 3H); MS (ESI) m / z 366.2 [C19H19N5OS + H]+; UPLC purity: 99.1% (Method-A).

[0374] Preparation of (5-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)oxazol-2-yl)methanol (Compound DT): (5-(4-(5-Methyl-7H-pyrrolo[2,3-d]pyri,4-dihydro-2H-1,4-thiazin-6-yl)oxazol-2- yl)methanol was prepared using a Suzuki reaction with the appropriate boronic acid by following Condition-C. Off-white solid. Yield: 11%.1H NMR (400 MHz, DMSO-d6): į11.83 (br s, 1H), 8.35 (s, 1H), 7.56 (s, 1H), 7.25 (s, 1H), 6.94 (s, 1H), 5.63 (t, J = 6.40 Hz, 1H), 4.46 (d, J = 6.40 Hz, 2H), 4.26-4.23 (m, 2H), 3.31-3.30 (m, 2H), 2.32 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 330.3 [C15H15N5O2S + H]+; UPLC purity: 98.1% (Method-A).

[0375] Preparation of 5-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)oxazole (Compound DV): 5-(4-(5-Methyl-7H-pyrrolo[2,3-d]pyrim 4-dihydro-2H-1,4-thiazin-6-yl)oxazolewas prepared using a Suzuki reaction with the appropriate boronic acid by following Condition-C. Off-white solid. Yield: 20%.1H NMR (400 MHz, DMSO-d6): į 11.84 (br s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.57 (s, 1H), 7.23 (d, J = 0.80 Hz, 1H), 7.03-0.00 (m, 1H), 4.26-4.24 (m, 2H), 3.33-3.30 (m, 2H), 2.31 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 300.2 [C14H13N5OS + H]+; UPLC purity: 99.2%. (Method-D).

[0376] Preparation of 2-methyl-5-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazin-6-yl)oxazole (Compound DX):n-4-yl)-3,4-dihydro-2H-1,4-thiazin-6- yl)oxazole was prepared using a Suzuki reaction with the appropriate boronic acid by following Condition-C. Off-white solid. Yield: 23%.1H NMR (400 MHz, DMSO-d6): į 11.82 (br s, 1H), 8.34 (s, 1H), 7.49 (s, 1H), 7.23 (d,= 1.20 Hz, 1H), 6.85 (s, 1H), 4.24-4.22 (m, 2H), 3.31-3.27 (m, 2H), 2.39 (s, 3H), 2.32 (d, J = 0.80 Hz, 3H); MS (ESI) m / z 314.2 [C15H15N5OS + H]+; UPLC purity: 99.5%. (Method-D).

[0377] Preparation of 6-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H- 1,4-thiazin-6-yl)indolin-2-one (Compound YG):6-(4-(5-Methyl-7H-pyrrolo[2,3-d] hydro-2H-1,4-thiazin-6-yl)indolin-2-one was prepared using a Suzuki reaction with the appropriate boronate ester following condition-C. Off-white solid.8.00 mg, Yield: 7%.1H NMR (400 MHz, DMSO-d6): į 11.75 (br s, 1H), 10.32 (s, 1H), 8.32 (s, 1H), 7.37 (s, 1H), 7.17 - 7.15 (m, 2H), 7.05 (dd, J = 1.60, J = 8.00 Hz, 1H), 6.91 (d, J = 1.20 Hz, 1H), 4.22 - 4.19 (m, 2H), 3.46 (s, 2H), 3.31 - 3.29 (m, 2H), 2.21 (s, 3H); MS (ESI) m / z 364.3 [C19H17N5OS + H]+; UPLC Purity: 99.6% (Method-A).

[0378] Preparation of 4-(2-(4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)ethyl)morpholine (Compound YH):azin-6-yl)-1H- pyrazol-1-yl)ethyl) morpholine was prepared using a Suzuki reaction with the appropriate boronate ester following condition-B. Off-white solid.54 mg, Yield: 40%.1H NMR (400 MHz, DMSO-d6): į 11.68 (br s, 1H), 8.27 (s, 1H), 7.82 (d, J = 0.80 Hz, 1H), 7.55 (d, J = 0.80 Hz, 1H), 7.20 (s, 1H), 7.14 (dd, J = 0.80 Hz, J =2.20 Hz, 1H), 4.20 - 4.17 (m, 4H), 3.53 (t, J = 4.80 Hz, 4H), 3.29 - 3.26 (m, 2H), 2.67 (t, J = 2.40 Hz, 2H), 2.38 (t, J = 4.40 Hz, 4H), 2.24 (s, 3H); MS (ESI) m / z 412.4 [C20H25N7OS + H]+; UPLC Purity: 95.3% (Method-A).

[0379] Compounds DW and DY comprising Scaffold-C were prepared by the synthetic protocol set forth in Scheme 20. Scheme 20: Preparation of 2-(4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro- 2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)acetic acid (Compound DW) and methyl 2-(4-(4-(5- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1- yl)acetate (Compound DY):ro- -pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)acetic acid was prepared using a Suzuki reaction with methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate by following Condition-C. Hydrolysis of the ester was observed during the Suzuki reaction. Off-white solid. Yield: 5%.1H NMR (400 MHz, DMSO-d6): į 11.68 (br s, 1H), 8.27 (s, 1H), 7.71 (s, 1H), 7.54 (s, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 4.68 (s, 2H), 4.19 ^ 4.17 (m, 2H), 3.29 ^ 3.27 (m, 2H), 2.26 (d, J = 0.80 Hz, 3H) (Acid proton not observed); MS (ESI) m / z 357.3 [C16H16N6O2S + H]+; UPLC purity: 97.6% (Method-A).

[0381] Preparation of methyl 2-(4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)acetate (Compound DY): Methyl 2-(4-(4-(5- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1- yl)acetate was prepared from 2-(4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazin-6-yl)-1H-pyrazol-1-yl)acetic acid by following Condition-F. Off- white solid. Yield: 46%.1H NMR (400 MHz, DMSO-d6): į 11.69 (br s, 1H), 8.28 (s, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 5.05 (s, 2H), 4.19 ^ 4.17 (m, 2H), 3.68 (s, 3H), 3.30 ^ 3.27 (m, 2H), 2.26 (s, 3H); MS (ESI) m / z 371.2 [C17H18N6O2S + H]+; UPLC purity: 97.1% (Method-A).

[0382] Compound YI comprising Scaffold-C was prepared by the synthetic protocol set forth in Scheme 20. Scheme 20: Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(2-(piperidin-4- yl)-2H-1,2,3-triazol-4-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride (Compound YI):4-dihydro-2H-1,4-thiazin-6-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (1): tert-Butyl 4- (4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2H- 1,2,3-triazol-2-yl)piperidine-1-carboxylate was prepared using a Suzuki reaction with tert- butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1- carboxylate (BA-30) using condition-C (48.0 mg, 13%).

[0384] Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(2-(piperidin-4- yl)-2H-1,2,3-triazol-4-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride (Compound YI): 4-(5- Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-3,4- dihydro-2H-1,4-thiazine hydrochloride was prepared by deprotection of Boc-group using condition-E. Off white solid.35.0 mg, Yield: 84%.1H NMR (400 MHz, DMSO-d6): į 12.14 (s, 1H), 9.24 - 9.22 (m, 1H), 8.95 - 8.92 (m, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.66 (s, 1H), 7.29 (s, 1H), 4.97 - 4.70 (m, 1H), 4.25 - 4.22 (m, 2H), 3.37 - 3.33 (m, 4H), 3.14 - 3.06 (m, 2H), 2.29 (s, 3H), 2.26 - 2.14 (m, 4H); MS (ESI) m / z 383 [C18H23ClN8S + H]+; UPLC Purity: 97.8% (Method-A).

[0385] Compound YP comprising Scaffold-C was prepared by the synthetic protocol set forth in Scheme 21. Scheme 21: Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(2-(piperidin-3- yl)-2H-1,2,3-triazol-4-yl)-3,4-dihydro-2H-1,4-thiazine h

[0386] Preparation of tert-butyl 3-(4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazin-6-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (1): tert-Butyl 3- (4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2H- 1,2,3-triazol-2-yl)piperidine-1-carboxylate was prepared by a Suzuki reaction with tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1- carboxylate following condition-C (45.0 mg, 12%).

[0387] Preparation of 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(2-(piperidin-3- yl)-2H-1,2,3-triazol-4-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride (Compound YP): 4-(5- Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(2-(piperidin-3-yl)-2H-1,2,3-triazol-4-yl)-3,4- dihydro-2H-1,4-thiazine hydrochloride was prepared by deprotection of Boc-group using condition-E. Off white solid.9.00 mg, Yield: 23%.1H NMR (400 MHz, DMSO-d6): į 11.95 (s, 1H), 9.30 - 9.07 (m, 2H), 8.38 (s, 1H), 8.07 - 7.95 (m, 1H), 7.69 (s, 1H), 7.25 (s, 1H), 4.90 - 4.83 (m, 1H), 4.24 - 4.22 (m, 2H), 4.07 - 4.04 (m, 1H), 3.63 - 3.23 (m, 4H), 3.17 - 2.96 (m, 1H), 2.29 - 2.22 (m, 4H), 2.11 - 1.94 (m, 1H), 1.88 - 1.72 (m, 2H); MS (ESI) m / z 383.35 [C18H23ClN8S + H]+; UPLC Purity: 98.8% (Method-A). EXAMPLE 4

[0388] This example provides an exemplary synthesis for Compounds YC and YQ.

[0389] Compound YC was prepared by the synthetic protocol set forth in Scheme 22. Scheme 22: Preparation of 6-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine hydrochloride (Compound YC):

[0390] Preparation of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2): To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.0 g, 49.7 mmol) in dichloromethane (100 mL) was added triethylamine (13.85 mL, 99.36 mmol) and methane sulfonyl chloride (4.61 mL, 59.6 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h, and then the progress of the reaction was monitored by thin layer chromatography. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (2 × 50 mL) and brine solution (2 × 50 mL), dried over from sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. The crude material was purified by flash chromatography using silica gel, and eluting with 9% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (12.5 g, 90%) as an off-white solid.1H NMR (400 MHz, CDCl3): į 4.91 - 4.86 (m, 1H), 3.74 - 3.67 (m, 2H), 3.33 - 3.27 (m, 2H), 3.04 (s, 3H), 2.00 - 1.93 (m, 2H), 1.86 - 1.77 (m, 2H), 1.46 (s, 9H).

[0391] Preparation of tert-butyl 4-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1- carboxylate (4): To a stirred solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1- carboxylate (2.00 g, 7.14 mmol) in dimethyl formamide (20.0 mL) was added cesium carbonate (2.32 g, 7.14 mmol) and 4,5-dibromo-2H-1,2,3-triazole (1.28 g, 5.72 mmol) at room temperature. The reaction was heated to 100 °C and stirred for 16 h. The reaction mixture was poured into ice-cold water (40.0 mL) and extracted with methyl tert-butyl ether (2 × 60.0 mL). The combined organic extracts were washed with ice cold water (60.0 mL), brine (60.0 mL), dried over from sodium sulfate, filtered and concentrated under reducedpressure. The crude material was purified by flash silica gel column chromatography, eluting with 11% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford tert-butyl 4-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1- carboxylate (1.75 g, 59%) as colorless viscous liquid.1H NMR (400 MHz, CDCl3): į 4.58 - 4.51 (m, 1H), 4.42 - 4.13 (m, 2H), 2.97 (t, J = 11.60 Hz, 2H), 2.17 - 2.01 (m, 4H), 1.47 (s, 9H).

[0392] Preparation of tert-butyl 4-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1- carboxylate (5): To a stirred solution of tert-butyl 4-(4,5-dibromo-2H-1,2,3-triazol-2- yl)piperidine-1-carboxylate (1.75 g, 4.27 mmol) in tetrahydrofuran (35 mL) was added n- butyl lithium (1.87 mL, 4.69 mmol, 1.6 M in hexane) at ^78 °C. The resulting solution was stirred at same temperature for 30 min. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (30.0 mL) and extracted ethyl acetate (2 × 60.0 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography, eluting with 11% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford tert-butyl 4-(4-bromo-2H-1,2,3- triazol-2-yl)piperidine-1-carboxylate (0.88 g, 62%) as pale yellow solid.1H NMR (400 MHz, CDCl3): į 7.55 (s, 1H), 4.58 (s, 1H), 4.41 (br s, 2H), 2.98 (t, J = 11.60 Hz, 2H), 2.17-2.03 (m, 4H), 1.47 (s, 9H).

[0393] Preparation of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H- 1,2,3-triazol-2-yl)piperidine-1-carboxylate (BA-30): To a stirred solution of tert-butyl 4-(4- bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (0.88 g, 2.7 mmol) in tetrahydrofuran (10.0 mL) was added n-butyl lithium (2.49 mL, 1.18 mmol, 1.6 M in hexane) at ^78 °C. After stirring for 10 mins at same temperature, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.08 mL, 5.31 mmol) was added to the reaction mixture. The resulting solution was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (30.0 mL) and extracted with ethyl acetate (2 × 30.0 mL). The combined organic extracts were dried over from sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (1.20 g, crude) as pale yellow liquid. The crude product was used in the next step without further purification.

[0394] Preparation of tert-butyl 4-(4-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6- yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (7): tert-Butyl 4-(4-(4-(9H-purin-6-yl)- 3,4-dihydro-2H-1,4-thiazin-6-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate was prepared using a Suzuki reaction with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (BA-30) following condition-C (26.0 mg, 13%).

[0395] Preparation of 6-(2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine hydrochloride (Compound YC): 6-(2-(Piperidin-4-yl)-2H-1,2,3- triazol-4-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride was prepared by deprotection of Boc group using condition-E. Off-white solid.13.0 mg, Yield: 60%,1H NMR (400 MHz, DMSO-d6): į 13.47 (br s, 1H), 9.18 (br s, 2H), 8.87 - 8.84 (m, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 7.90 (s, 1H), 4.91 - 4.85 (m, 1H), 4.79 - 4.49 (m, 2H), 3.39 - 3.36 (m, 2H), 3.31 - 3.30 (m, 2H), 3.17 - 3.11 (m, 2H), 2.31 - 2.18 (m, 4H); MS (ESI) m / z 370 [C16H20ClN9S + H]+; UPLC Purity: 95.7% (Method-A).

[0396] Compound YQ was prepared by the synthetic protocol set forth in Scheme 23. Scheme 23: Preparation of 6-(2-(piperidin-3-yl)-2H-1,2,3-triazol-4-yl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine hydrochloride (Compound YQ): [To a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (5.00 g, 24.9 mmol) in dichloromethane (50.0 mL) was added triethylamine (6.86 mL, 49.7 mmol) and methane sulfonyl chloride (2.30 mL, 29.8 mmol) at 0 °C. The reaction mixture was stirred at roomtemperature for 2 h. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (2 × 50 mL), brine solution (2 × 50 mL), dried over from sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. The crude material was purified by flash chromatography using silica gel, eluting with 6% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford tert-butyl 3- ((methylsulfonyl)oxy)piperidine-1-carboxylate (6.70 g, 97%) as an off-white solid.1H NMR (400 MHz, CDCl3): į 4.72 (br s, 1H), 3.67-3.62 (m, 2H), 3.58 - 3.42 (m, 1H), 3.36 - 3.30 (m, 1H), 3.05 (s, 3H), 2.07 - 1.89 (m, 2H), 1.86 - 1.77 (m, 1H), 1.56 - 1.51 (m, 1H), 1.46 (s, 9H).

[0398] Preparation of tert-butyl 3-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1- carboxylate (4): To a stirred solution of tert-butyl 3-((methylsulfonyl)oxy)piperidine-1- carboxylate (3.00 g, 10.7 mmol) in N,N-dimethyl formamide (30.0 mL) was added cesium carbonate (3.50 g, 10.7 mmol), 4,5-dibromo-2H-1,2,3-triazole (1.95 g, 8.59 mmol) at room temperature. The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was cooled to room temperature poured into ice-cold water (60.0 mL). This mixture was extracted with methyl tert-butyl ether (2 × 60.0 mL). The combined organic extracts were washed with ice cold water (100.0 mL), brine (100.0 mL), dried over from sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography, eluting with 8% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford tert-butyl 3-(4,5- dibromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (1.75 g, 38%) as colorless viscous liquid.

[0399] Preparation of tert-butyl 3-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1- carboxylate (5): To a stirred solution of tert-butyl 3-(4,5-dibromo-2H-1,2,3-triazol-2- yl)piperidine-1-carboxylate (1.65 g, 4.02 mmol) in tetrahydrofuran (35.0 mL) was added n- butyl lithium (1.77 mL, 4.43 mmol, 1.6 M in hexanes) at ^78 °C. The reaction mixture was stirred at same temperature for 30 min. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (30.0 mL) and extracted with ethyl acetate (2 × 30.0 mL). The combined organic extracts were washed with brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography, eluting with 9% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford tert-butyl 3-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (0.88 g, 66) as pale yellow solid.1H NMR (400 MHz, CDCl3): į 7.55 (s, 1H), 4.53 - 4.48 (m, 1H), 4.25 (br s, 1H), 3.99 - 3.93 (m, 1H), 3.50 - 3.36 (m, 1H), 2.96 - 2.90 (m, 1H), 2.29 - 2.25 (m, 1H), 2.13 - 2.05 (m, 1H), 1.91 - 1.87 (m, 1H), 1.61 - 1.50 (m, 1H), 1.45 (s, 9H).

[0400] Preparation of tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H- 1,2,3-triazol-2-yl)piperidine-1-carboxylate (BA-29): To a stirred solution of tert-butyl 3-(4- bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (0.88 g, 2.7 mmol) in tetrahydrofuran (5.00 mL) was added n-butyl lithium (0.47 mL, 4.0 mmol, 1.6 M in hexane) at ^78 °C. After stirring for 10 minutes, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.08 mL, 5.31 mmol) was added to the reaction at same temperature. The resulting mixture was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50.0 mL) and extracted with ethyl acetate (2 × 30.0 mL). The combined organic extracts were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (1.10 g, crude) as pale yellow liquid. The crude product was used for the next step without purification.

[0401] Preparation of tert-butyl 3-(4-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6- yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (7): tert-Butyl 3-(4-(4-(9H-purin-6-yl)- 3,4-dihydro-2H-1,4-thiazin-6-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate was prepared using a Suzuki reaction with tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate following condition-C (18.0 mg, 9%).

[0402] Preparation of 6-(2-(piperidin-3-yl)-2H-1,2,3-triazol-4-yl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine hydrochloride (Compound YQ): 6-(2-(Piperidin-3-yl)-2H-1,2,3- triazol-4-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine hydrochloride was prepared by deprotection of Boc-group using condition-E. Off-white solid.6.00 mg, Yield: 38%.1H NMR (400 MHz, DMSO-d6): į 13.41 (br s, 1H), 9.20 - 8.98 (m, 3H), 8.44 (s, 1H), 8.36 (, 1H), 7.94 (s, 1H), 4.92 - 4.85 (m, 1H), 4.68 (br s, 2H), 3.71 - 3.62 (m, 1H), 3.44 - 3.33 (m, 1H), 3.31 - 3.25 (m, 3H), 3.17 - 2.94 (m, 1H), 2.28 - 2.15 (m, 1H), 2.14 - 2.06 (m, 1H), 1.94 - 1.79 (m, 2H) ; MS (ESI) m / z 370.31 [C16H20ClN9S + H]+; UPLC Purity: 96.3% (Method-A). EXAMPLE 5

[0403] This example provides an exemplary synthesis for Compounds BJ-BW, DM, and YV.

[0404] Synthesis of Acid Scaffold-A. Acid Scaffold-A was synthesized from the commercially available H-1 and H-2. In particular, H-1 was reacted with H-2 in presence of Xantphos Pd G3 and Cs2CO3to afford H-3, which was reacted with KOH to afford Acid Scaffold-A, as set forth in Scheme 24. Scheme 24: Preparation of Acid Scaffold-A of Example 5thiazine-6-carboxylate (H-3): To the mixture of ethyl 3,4-dihydro-2H-1,4-thiazine-6- carboxylate (H-1, 1 equiv., 100 mg) and 4-bromo-7H-pyrrolo[2,3-d]pyrimidine (H-2, 1.1 equiv., 125 mg) was added Xantphos Pd G3 (10 mol%, 55 mg), Cs2CO3 (3 equiv., 560 mg), and DMF (5 mL). The reaction vial was filled with N2and capped tightly. The reaction mixture was then stirred vigorously at 110 °C overnight before it was dried down under vacuum. The residue was re-dissolved in DMSO followed by preparative HPLC purification using a Gemini 5 ^m NX-C18 column (110 Å, 250 × 21.2 mm) with a flow rate of 10 mL / min (eluted with 10% to 100% MeCN in 0.1% TFA) to yield H-3 (109 mg, 65% yield) as a pale white solid.1H NMR (600 MHz, DMSO-d6): į 12.21 (s, 1H), 8.84 (s, 1H), 8.44 (s, 1H), 7.49 (s, 1H), 6.67 (s, 1H), 4.35 (br s, 2H), 4.20 (br s, 2H), 3.13 (br s, 2H), 1.24 (br s, 3H);13C NMR (150 MHz, DMSO-d6): į 164.7, 152.8, 152.6, 149.9, 133.3, 125.0, 104.5, 100.7, 100.1, 60.4, 45.3, 23.9, 14.3; HRESIMS m / z 291.0910, [M+H]+(calcd for C13H15N4O2S, 291.0916).

[0406] Preparation of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine- 6-carboxylic acid (Acid Scaffold-A): H-3 (109 mg) was reacted with KOH (3 equiv., 62 mg) in MeOH (5 mL) and H2O (5 mL) and stirred at 95 °C for 2 h. The reaction solution was acidified with 2M HCl (1.4 mL) and then dried down under vacuum. The crude product was then washed and desalted with H2O (1 mL x 3 times) to yield Acid Scaffold-A (80 mg, 81% yield) as a pale white solid.1H NMR (600 MHz, DMSO-d6): į 12.18 (s, 1H), 8.79 (s, 1H), 8.43 (s, 1H), 7.47 (s, 1H), 6.65 (s, 1H), 4.33 (br s, 2H), 3.12 (br s, 2H);13C NMR (150 MHz,DMSO-d6): į 166.2, 152.7, 152.6, 149.9, 132.9, 124.8, 104.4, 101.7, 100.1, 44.9, 24.0; HRESIMS m / z 263.0608, [M+H]+(calcd for C11H11N4O2S, 263.0603).

[0407] Synthesis of Acid Scaffold-B. Acid Scaffold-B was synthesized from the commercially available H-1 and H-4. In particular, H-1 was reacted with H-4 in presence of Xantphos Pd G3 and Cs2CO3to afford H-5 which was reacted with KOH to afford Acid Scaffold-B, as set forth in Scheme 25. Scheme 25: Preparation of Acid Scaffold-B of Example 5thiazine-6-carboxylate (H-5): To the mixture of ethyl 3,4-dihydro-2H-1,4-thiazine-6- carboxylate (H-1, 1 equiv., 100 mg) and 4-bromo-7-azaindole (H-4, 1 equiv., 95 mg) was added Xantphos Pd G3 (10 mol%, 55 mg), Cs2CO3 (3 equiv., 560 mg), and DMF (5 mL). The reaction vial was filled with N2 and capped tightly. The reaction mixture was then stirred vigorously at 110 °C overnight before it was dried down under vacuum. The residue was re- dissolved in DMSO followed by preparative HPLC purification using a Gemini 5 ^m NX- C18 column (110 Å, 250 × 21.2 mm) with a flow rate of 10 mL / min (eluted with 10% to 100% MeCN in 0.1% TFA) to yield H-5 (78 mg, 47% yield) as a pale white solid.1H NMR (600 MHz, DMSO-d6): į 12.42 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 8.21 (s, 1H), 7.59 (d, J = 3.5 Hz,1H), 6.97 (d, J = 6.0 Hz,1H), 6.69 (d, J = 3.5 Hz,1H), 4.18 (q, J = 7.1 Hz, 2H), 4.17 (m, 2H), 3.18 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H);13C NMR (150 MHz, DMSO-d6): į 164.5, 147.7, 145.1, 139.2, 135.1, 126.3, 111.6, 104.5, 100.8, 100.1, 60.5, 47.1, 23.9, 14.3; HRESIMS m / z 290.0977, [M+H]+(calcd for C14H16N3O2S, 290.0963).

[0409] Preparation of 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxylic acid (Acid Scaffold-B): H-5 (78 mg) was reacted with KOH (3 equiv., 45 mg) in MeOH (3 mL) and H2O (3 mL) and stirred at 95 °C for 2 h. The reaction solution was acidified with 2M HCl (0.99 mL) and then dried down under vacuum. The crude product was then washed and desalted with H2O (1 mL x 3 times) to yield Acid Scaffold-B (48 mg, 68% yield) as a pale white solid.1H NMR (600 MHz, DMSO-d6): į 12.30 (s, 1H), 8.23 (d, J = 6.0 Hz, 1H), 8.18 (s, 1H), 7.57 (d, J = 3.5 Hz,1H), 6.93 (d, J = 6.0 Hz,1H), 6.67 (d, J = 3.5Hz,1H), 4.15 (m, 2H), 3.17 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 166.0, 147.5, 145.2, 139.4, 134.6, 126.0, 111.3, 104.3, 102.1, 100.1, 46.8, 23.9; HRESIMS m / z 262.0650, [M+H]+(calcd for C12H12N3O2S, 262.0650).

[0410] Synthesis of Bromo Scaffold-A. Bromo Scaffold-A was synthesized from Acid Scaffold-A, as set forth in Scheme 26. Scheme 26: Preparation of Bromo Scaffold-A of Example 5

[0411] Preparation o in-4-yl)-3,4-dihydro-2H-1,4-thiazine (Bromo Scaffold-A): A reaction vial containing a DMF (8 mL) solution of Acid scaffold-A (1 equiv., 40 mg) and K2CO3 (2 equiv., 40 mg) was filled with N2 and cooled down in an ice bath. A 40 mg / mL MeCN solution of N-bromosuccinimide (1.2 equiv., 800 ^L) was added dropwise into the reaction vial. The reaction mixture was stirred at 0 °C for 2 h and then warmed up to room temperature with continued stirring overnight. The reaction mixture was dried down under vacuum. The residue was re-dissolved in DMSO followed by preparative HPLC purification using a Gemini 5 ^m NX-C18 column (110 Å, 250 × 21.2 mm) with a flow rate of 10 mL / min (eluted with 10-100% MeCN in 0.1% TFA) to yield Bromo scaffold-A (13 mg, 29% yield) as a pale orange solid.1H NMR (600 MHz, DMSO- d6): į 12.12 (s, 1H), 8.32 (s, 1H), 7.96 (s, 1H), 7.39 (br s, 1H), 6.64 (br s, 1H), 4.37 (m, 2H), 3.32 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 152.1, 151.8, 149.6, 125.0, 123.9, 103.4, 100.8, 43.8, 28.7; ESIMS m / z 296.98, [M+H]+.

[0412] Synthesis of Bromo Scaffold-B. Bromo Scaffold-B was synthesized from Acid Scaffold-B, as set forth in Scheme 27. Scheme 27: Preparation of Bromo Scaffold-B of Example 5

[0413] Preparation ofpy , py n-4-yl)-3,4-dihydro-2H-1,4- thiazine (Bromo scaffold-B): A reaction vial containing a DMF (6 mL) solution of Acidscaffold-B (1 equiv., 30 mg)) was filled with N2and cooled down in an ice bath. Et3N (1.2 equiv., 36 ^L) and a 40 mg / mL MeCN solution of N-bromosuccinimide (1 equiv., 510 ^L) was added dropwise into the reaction vial. The reaction mixture was stirred at 0 °C for 2 h and then warmed up to room temperature with continued stirring overnight. The reaction mixture was dried down under vacuum. The residue was re-dissolved in DMSO followed by preparative HPLC purification using a Gemini 5 ^m NX-C18 column (110 Å, 250 × 21.2 mm) with a flow rate of 10 mL / min (eluted with 10-100% MeCN in 0.1% TFA) to yield Bromo scaffold-B (17 mg, 29% yield) as a pale orange solid.1H NMR (600 MHz, DMSO- d6): į 12.12 (s, 1H), 8.32 (s, 1H), 7.96 (s, 1H), 7.39 (br s, 1H), 6.64 (br s, 1H), 4.37 (m, 2H), 3.32 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 152.1, 151.8, 149.6, 125.0, 123.9, 103.4, 100.8, 43.8, 28.7; ESIMS m / z 296.98, [M+H]+.

[0414] Synthesis of Suzuki Coupling Products. Each of the following compounds was synthesized by the general procedure for Suzuki Coupling set forth in Scheme 28. Scheme 28: General Procedure for Suzuki Coupling of Example 5) and boronic acid pinacol (BPin) esters (4 equiv.) was added Xantphos Pd G3 (20 mol%), Cs2CO3 (3 equiv.), and DMF / H2O (2 : 1). The reaction vial was filled with N2and capped tightly. The reaction mixture was then stirred vigorously at 95 °C overnight before it was dried down under vacuum. The residue was re-dissolved in DMSO followed by successive preparative HPLC purifications using a Gemini 5 ^m NX-C18 column (110 Å, 250 × 21.2 mm) with a flow rate of 10 mL / min (eluted with 10% to 100% MeCN in 0.1% TFA) and a Synergi 5 ^m Hydro-RP column (110 Å, 250 × 21.2 mm) with a flow rate of 10 mL / min (eluted with 10-100% MeCN in 0.1% TFA) to yield the Suzuki product.

[0415] Preparation of 6-(1-methyl-1H-imidazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 3,4-dihydro-2H-1,4-thiazine (Compound BJ):6-(1-methyl-1H-imidazol-5-yl)-4-(1H-p ]pyridin-4-yl)-3,4-dihydro-2H-1,4-thiazine was obtained (1% yield) as an off white solid.1H NMR (600 MHz, DMSO-d6): į 12.21 (s, 1H), 9.06 (br s, 1H), 8.19 (br s, 1H), 7.75 (br s, 1H), 7.47 (s, 1H), 7.35 (s, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 4.27 (m, 2H), 3.83 (s, 3H), 3.36 (m, 2H);13C NMR (150 MHz, DMSO- d6): į 147.4, 144.8, 139.7, 136.5, 131.8, 129.7, 125.1, 119.0, 110.8, 103.8, 100.6, 90.6, 46.8, 33.9, 25.5; HRESIMS m / z 298.1132, [M+H]+(calcd for C15H16N5S, 298.1126).

[0416] Preparation of 6-(1-methyl-1H-imidazol-5-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3,4-dihydro-2H-1,4-thiazine (Compound BK): 6-(1-methyl-1H-imidazol-5-yl)-4-(7H-ppyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazine was obtained (63% yield) as an off white solid.1H NMR (600 MHz, DMSO-d6): į 12.14 (s, 1H), 9.11 (s, 1H), 8.35 (s, 1H), 7.93 (s, 1H), 78 (s, 1H), 7.41 (dd, J = 2.2, 3.5 Hz, 1H), 6.73 (dd, J = 1.8, 3.5 Hz, 1H), 4.45 (m, 2H), 3.84 (s, 3H), 3.35 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 152.7, 152.5, 149.9, 136.6, 132.1, 128.0, 124.2, 118.7, 103.9, 100.7, 94.2, 44.8, 34.0, 25.7; HRESIMS m / z 299.1073, [M+H]+(calcd for C15H16N5S, 299.1079).

[0417] Preparation of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1-(tetrahydro-2H-pyran- 2-yl)-1H-imidazol-5-yl)-3,4-dihydro-2H-1,4-thiazine (Compound BL):4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl)-3,4- dihydro-2H-1,4-thiazine was obtained (13% yield) as an off white solid.1H NMR (600 MHz, methanol-d4): į 9.23 (br s, 1H), 8.42 (br s, 1H), 8.15 (s, 1H), 7.66 (br s, 1H), 7.34 (d, J = 3.6 Hz, 1H), 6.77(d, J = 3.6 Hz, 1H), 5.65 (d, J = 10.5 Hz, 1H), 4.68 (m, 1H), 4.48 (m, 1H), 4.11 (dd, J = 1.9, 11.7 Hz, 1H), 3.71(dt, J = 2.5, 11.7 Hz, 1H), 3.39 (m, 2H), 2.20 (m, 1H), 2.05 (m, 2H), 1.77 (m, 1H), 1.77 (m, 1H), 1.61 (m, 1H); HRESIMS m / z 369.1498, [M+H]+(calcd for C18H21N6OS, 369.1498).

[0418] Preparation of 6-(2-chloro-1-methyl-1H-imidazol-5-yl)-4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound BM): pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine was obtained (53% yield) as an off white solid;1H NMR (600 MHz, methanol-d4): į 8.49 (s, 1H), 7.45 (s, 1H), 7.42 (d, J = 3.6 Hz, 1H), 7.16 (br s, 1H), 6.89 (d, J = 3.6 Hz, 1H), 4.57 (m, 2H), 3.74 (s, 3H), 3.40 (m, 2H);13C NMR (150 MHz, methanol-d4): į 154.2, 148.1, 146.8, 134.8, 133.2, 127.8, 126.3, 126.0, 107.2, 106.5, 103.8, 46.4, 32.8, 27.3; HRESIMS m / z 333.0692, [M+H]+(calcd for C14H14ClN6S, 333.0689).

[0419] Preparation of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)pyridin-3-amine (Compound BN): 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-ylH-1,4-thiazin-6-yl)pyridin-3-amine was obtained (3.4% yield) as a yellow solid.1H NMR (600 MHz, DMSO-d6): į 12.14 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.17 (br s, 1H), 7.85 (br s, 1H), 7.63 (s, 1H), 7.43 (t, J = 3.0 Hz, 1H), 6.72 (m, 1H), 4.44 (m, 2H), 3.32 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 152.5, 152.2, 149.6, 147.2, 137.6, 124.6, 124.3, 123.8, 123.4, 121.3, 104.1, 103.8, 100.1, 44.6, 24.7; HRESIMS m / z 311.1081, [M+H]+(calcd for C15H15N6S, 311.1079).

[0420] Preparation of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-6-(1,2,3,6-tetrahydropyridin- 4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound BO): ropyridin-4-yl)-3,4-dihydro-2H-1,4-thiazine (TFA salt) was obtained (11% yield) as a pale orange solid.1H NMR (600 MHz, DMSO-d6): į 12.09 (s, 1H), 8.82 (s, 2H), 8.36 (s, 1H), 7.92 (s, 1H), 7.40 (br s, 1H), 6.66 (br s, 1H), 5.76 (t, J = 3.6 Hz, 1H), 4.34 (m, 2H), 3.98 (br s, 2H), 3.29 (m, 2H), 3.16 (m, 2H), 2.60 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 153.1, 152.5, 150.1, 132.1, 123.9, 121.9, 114.1, 110.3, 104.0, 100.6, 45.0, 41.8, 40.2, 24.7, 22.2; HRESIMS m / z 300.1281, [M+H]+(calcd for C15H18N5S, 300.1277).

[0421] Preparation of 6-(6-methylpyridazin-4-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,4-dihydro-2H-1,4-thiazine (Compound BP): 6-(6-methylpyridazin-4-yl)-4-(7H-pyrrmidin-4-yl)-3,4-dihydro-2H-1,4-thiazine was obtained (32% yield) as a red solid.1H NMR (600 MHz, DMSO-d6): į 12.33 (s, 1H), 9.44 (br s, 1H), 8.98 (s, 1H), 8.53 (s, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 2.4, 3.6 Hz, 1H), 6.80 (dd, J = 1.8, 3.6 Hz, 1H), 4.52 (m, 2H), 3.34 (m, 2H), 2.70 (s, 3H);13C NMR (150 MHz, DMSO-d6): į 157.6, 153.2, 152.8, 150.0, 145.2, 142.9, 133.2, 125.8, 122.7, 105.7, 102.4, 100.3, 46.4, 24.2, 19.0; HRESIMS m / z 311.1083, [M+H]+(calcd for C15H15N6S, 311.1079).

[0422] Preparation of 6-(3-chloropyridin-4-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine (Compound BQ):6-(3-chloropyridin-4-yl)-4-(7H-pyrrolo[ idin-4-yl)-3,4-dihydro-2H-1,4-thiazine was obtained (17% yield) as an off whitesolid. H NMR (600 MHz, DMSO-d6): į 12.14 (s, 1H), 8.75 (br s, 1H), 8.60 (br s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 7.42 (t, J = 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 4.46 (m, 2H), 3.30 (m, 2H); HRESIMS m / z 330.0586, [M+H]+(calcd for C15H13ClN5S, 330.0580).

[0423] Preparation of (4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)phenyl)methanamine (TFA salt) (Compound BR):4-thiazin-6- yl)phenyl)methanamine (TFA salt) was obtained (5.4% yield) as an off white solid.1H NMR (600 MHz, DMSO-d6): į 12.06 (s, 1H), 8.35 (s, 1H), 8.15 (br s, 3H), 8.10 (s, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 3.5 Hz, 1H), 6.18 (dd, J = 1.8, 3.5 Hz, 1H), 4.41 (m, 2H), 4.04 (m, 2H), 3.29 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 153.1, 152.4, 150.2, 138.6, 132.5, 129.4 (2C), 125.0 (2C), 123.8, 122.0, 110.6, 103.9, 100.6, 44.2, 42.0, 25.6; HRESIMS m / z 324.1281, [M+H]+(calcd for C17H18N5S, 324.1277).

[0424] Preparation of 1-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)pyridin-2-yl)ethan-1-one (Compound BS):, , ro-2H-1,4-thiazin-6-yl)pyridin-2- yl)ethan-1-one was obtained (20% yield) as a light orange solid.1H NMR (600 MHz, DMSO-d6): į 12.20 (s, 1H), 8.64 (br s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 8.02 (s, 1H), 7.74 (dd,J = 2.2, 5.2 Hz, 1H), 7.47 (t, J = 2.9 Hz, 2H), 6.72 (dd, J = 1.8, 3.6 Hz, 1H), 4.46 (m, 2H), 3.32 (m, 2H), 2.65 (s, 3H);13C NMR (150 MHz, DMSO-d6): į 199.2, 152.9, 152.6, 152.5, 149.9, 149.2, 147.2, 125.9, 124.6, 121.8, 115.7, 106.8, 104.5, 100.6, 45.4, 25.9, 24.8; HRESIMS m / z 338.1073, [M+H]+(calcd for C17H16N5OS, 338.1076).

[0425] Preparation of 2-(5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)pyridin-3-yl)propan-2-ol (Compound BT): 2-(5-(4-(7H-pyrrolo[2,3-d]pyrimidin -2H-1,4-thiazin-6-yl)pyridin-3-yl)propan-2-ol was obtained (19% yield) as a yellow solid.1H NMR (600 MHz, methanol- d4): į 8.79 (br s, 1H), 8.69 (br s, 1H), 8.86 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 7.35 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 4.57 (m, 2H), 3.37 (m, 2H), 1.63 (s, 6H);13C NMR (150 MHz, methanol-d4): į 155.0, 153.0, 150.6, 150.3, 139.6 (2C), 139.1, 136.4, 126.4, 125.3, 108.5, 106.3, 102.2, 71.6, 47.0, 31.5 (2C), 26.8; HRESIMS m / z 354.1393, [M+H]+(calcd for C18H20N5OS, 354.1389).

[0426] Preparation of 5-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)pyrimidin-2-amine (Compound BU):H-1,4-thiazin-6-yl)pyrimidin-2-amine was obtained (47% yield) as an off white solid.1H NMR (600 MHz, DMSO-d6): į 12.22 (s, 1H), 8.49 (s, 2H), 8.40 (s, 1H), 7.82 (s, 1H), 7.40 (dd, J = 2.0, 3.6 Hz, 1H), 6.67 (dd, J = 1.4, 3.6 Hz, 1H), 4.40 (m, 2H), 3.31 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 160.5, 154.5 (2C), 152.5, 151.0, 148.8, 123.9, 121.0, 120.6, 107.3, 103.8, 101.3, 44.0, 25.9; HRESIMS m / z 312.1028, [M+H]+(calcd for C14H14N7S, 312.1031).

[0427] Preparation of 4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazin-6-yl)picolinonitrile (Compound BV):4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y H-1,4-thiazin-6-yl)picolinonitrile wasobtained (19% yield) as a yellow solid.1H NMR (600 MHz, DMSO-d6): į 12.17 (s, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.59 (s, 1H), 8.44 (s, 1H), 8.11 (s, 1H), 7.71 (d, J = 5.3 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 4.44 (m, 2H), 3.30 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 153.0, 152.8, 151.4, 150.0, 147.3, 133.0, 127.1, 124.7, 123.4, 121.8, 117.8, 105.3, 104.7, 100.6, 45.3, 24.8; HRESIMS m / z 321.0924, [M+H]+(calcd for C16H13N6S, 321.0922).

[0428] Preparation of 6-(3-(pyridin-3-yl)phenyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,4-dihydro-2H-1,4-thiazine (Compound BW):in-4-yl)-3,4-dihydro-2H-1,4-thiazine was obtained (39% yield) as an off white solid.1H NMR (600 MHz, DMSO-d6): į 12.22 (s, 1H), 9.30 (br s, 1H), 8.91 (br s, 1H), 8.69 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 7.98 (br s, 1H), 7.91 (s, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.60 (t, J = 1.8 Hz, 1H), 7.40 (br s, 1H), 6.69 (d, J = 3.6 Hz, 1H), 4.43 (m, 2H), 3.33 (m, 2H); HRESIMS m / z 372.1284, [M+H]+(calcd for C21H18N5S, 372.1283).

[0429] Preparation of 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3,4-dihydro-2H-1,4-thiazine (Compound DM):6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4-( ]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine (183A071B): 23% yield; light yellow solid;1H NMR (600 MHz, DMSO-d6): į 12.25 (s, 1H), 11.81 (s, 1H), 8.42 (d, J = 11.0 Hz, 1H), 8.40 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.53 (t, J = 2.9 Hz, 1H), 7.41 (dd, J = 2.2, 3.5 Hz, 1H), 6.72 (dd, J = 1.7, 3.6 Hz, 1H), 6.52 (dd, J = 1.7, 3.4 Hz, 1H), 4.44 (m, 2H), 3.36 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 152.4, 150.6, 148.6, 147.4, 140.0, 127.4, 126.4, 125.7, 123.9, 120.6, 120.0, 112.4, 103.7, 101.4, 100.3, 44.0, 26.1; HRESIMS m / z 335.1084, [M+H]+(calcd for C17H15N6S, 335.1079).

[0430] Preparation of 6-(pyrimidin-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3,4-dihydro- 2H-1,4-thiazine (Compound YV): 6-(pyrimidin-4-yl)-4-(1H-pyrrolo[2,3-b]pyl)-3,4-dihydro-2H-1,4-thiazine (183A081D): 8.7% yield; light yellow solid;1H NMR (600 MHz, DMSO-d6): į 12.50 (s, 1H), 9.10 (s, 1H), 8.96 (s, 2H), 8.24 (br s, 1H), 7.71 (s, 1H), 7.54 (br s, 1H), 7.10 (d, J = 6.2 Hz, 1H), 6.87 (s, 1H), 4.34 (m, 2H), 3.38 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 156.8, 153.0 (2C), 149.5, 141.9, 136.6, 125.5, 125.2, 111.4, 107.0, 103.8, 102.1, 46.8, 25.4; HRESIMS m / z 296.0973, [M+H]+(calcd for C15H14N5S, 296.0970). EXAMPLE 6

[0431] This example provides an exemplary synthesis for Compounds BX-DL. Compounds BX-DL are synthesized using the methods described in Examples 1-5. EXAMPLE 7

[0432] This example provides an exemplary synthesis for Compounds EA-EJ.

[0433] Synthesis of Thiazine Amide Products. Each of the following compounds was synthesized by the general procedure for Amide Coupling set forth in Scheme 29.Scheme 29: General Procedure for Amide Coupling of Example 7diamines (1.5 equiv.) was added HATU (1.5 equiv.), DIPEA (10 equiv.), and DMF. The reaction mixture was then stirred vigorously at room temperature overnight before it was dried down under vacuum. The residue was re-dissolved in DMSO followed by preparative HPLC purification using a Gemini 5 ^m NX-C18 column (110 Å, 250 × 21.2 mm) with a flow rate of 10 mL / min (eluted with 10% to 100% MeCN in 0.1% TFA). The purified Boc- protected amide product was deprotected in DCM : TFA (2 : 1) followed by HPLC purification using a Synergi 5 ^m Hydro-RP column (110 Å, 250 × 21.2 mm) with a flow rate of 10 mL / min (eluted with 10-100% MeCN in 0.1% TFA) to yield the deprotected amide product and in some cases, the sulfoxide side product.

[0434] Preparation of N-(2-aminoethyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxamide (TFA salt) (Compound EA): N-(2-aminoethyl)-4-(1H-pyrroloydro-2H-1,4-thiazine-6- carboxamide (TFA salt) was obtained (62% yield) as a colorless solid.1H NMR (600 MHz, DMSO-d6): į 12.65 (s, 1H), 8.28 (br s, 1H), 8.12 (t, J = 5.6 Hz, 1H),1H), 7.88 (br s, 3H), 7.58 (br s, 1H), 7.05 (t, J = 6.3 Hz,1H), 6.83 (s, 1H), 4.22 (m, 2H), 3.41 (m, 2H), 3.18 (m, 2H), 2.93 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 165.0, 149.0, 142.7, 137.2, 130.2, 125.9, 111.6, 107.4, 103.9, 101.5, 47.2, 38.7, 37.2, 24.3; HRESIMS m / z 304.1227, [M+H]+(calcd for C14H18N5OS, 304.1227).

[0435] Preparation of N-(2-aminoethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide (TFA salt) (Compound EB):N-(2-aminoethyl)-4-(7H-pyrrolo[ -dihydro-2H-1,4-thiazine-6- carboxamide (TFA salt) was obtained (70% yield) as a colorless solid.1H NMR (600 MHz, DMSO-d6): į 12.18 (s, 1H), 8.67 (s, 1H), 8.42 (s, 1H), 7.90 (t, J = 5.7 Hz, 1H), 7.82 (br s, 3H), 7.46 (br s, 1H), 6.71 (br s, 1H), 4.36 (m, 2H), 3.41 (m, 2H), 3.13 (m, 2H), 2.93 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 165.3, 153.0, 152.5, 149.9, 129.7, 124.6, 104.6, 104.4, 100.5, 45.4, 38.9, 37.3, 24.4; HRESIMS m / z 305.1182, [M+H]+(calcd for C13H17N6OS, 305.1179).

[0436] Preparation of N-(3-aminopropyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide (TFA salt) (Compound EC):ro-2H-1,4-thiazine-6- carboxamide (TFA salt) was obtained (30% yield) as a colorless solid.1H NMR (600 MHz, DMSO-d6): į 12.14 (s, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 7.88 (t, J = 5.7 Hz, 1H), 7.73 (br s, 3H), 7.45 (dd, J = 2.3, 9.6 Hz, 1H), 6.67 (dd, J = 1.8, 9.6 Hz, 1H), 4.35 (m, 2H), 3.24 (m, 2H), 3.13 (m, 2H), 2.78 (m, 2H), 1.75 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 165.0, 152.9, 152.7, 150.0, 129.4, 124.4, 104.5, 104.2, 100.3, 45.2, 36.8, 36.2, 27.5, 24.3; HRESIMS m / z 319.1335, [M+H]+(calcd for C14H19N6OS, 319.1336).

[0437] Preparation of N-(3-aminopropyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide 1-oxide (TFA salt) (Compound ED): N-(3-aminopropyl)-4-(7H-pyrro, , dihydro-2H-1,4-thiazine-6- carboxamide 1-oxide (TFA salt) was obtained (36% yield) as a colorless solid.1H NMR (600MHz, DMSO-d6): į 12.39 (s, 1H), 8.87 (s, 1H), 8.57 (s, 1H), 8.20 (t, J = 5.7 Hz, 1H), 7.74 (br s, 3H), 7.60 (dd, J = 2.3, 9.6 Hz, 1H), 6.81 (dd, J = 1.8, 9.6 Hz, 1H), 4.84 (m, 1H), 4.03 (m, 1H), 3.28 (m, 1H), 3.24 (m, 2H), 2.81 (m, 2H), 2.74 (m, 1H), 1.77 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 164.4, 153.5, 152.3, 150.0, 137.9, 126.2, 112.5, 105.3, 99.7, 41.9, 36.9, 36.2, 34.3, 27.6; HRESIMS m / z 335.1287, [M+H]+(calcd for C14H19N6O2S, 335.1285).

[0438] Preparation of N-(4-aminobutyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide (TFA salt) (Compound EE): N-(4-aminobutyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide (TFA salt) was obtained (44% yield) as a colorless solid.1H NMR (600 MHz, DMSO-d6): į 12.15 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 7.75 (t, J = 5.7 Hz, 1H), 7.73 (br s, 3H), 7.44 (dd, J = 2.3, 9.6 Hz, 1H), 6.67 (dd, J = 1.8, 9.6 Hz, 1H), 4.34 (m, 2H), 3.18 (m, 2H), 3.12 (m, 2H), 2.79 (m, 2H), 1.53 (m, 2H), 1.52 (m, 2H);13C NMR (150 MHz, DMSO- d6): į 164.5, 153.0, 152.6, 149.9, 129.1, 124.4, 105.1, 104.2, 100.4, 45.1, 38.7, 38.5, 26.3, 24.5, 24.4; HRESIMS m / z 333.1498, [M+H]+(calcd for C15H21N6OS, 333.1492).

[0439] Preparation of N-(3-aminopropyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide 1-oxide (TFA salt) (Compound EF): N-(3-aminopropyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide 1-oxide (TFA salt) was obtained (29% yield) as a colorless solid.1H NMR (600 MHz, DMSO-d6): į 12.39 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 8.10 (t, J = 5.7 Hz, 1H), 7.72 (br s, 3H), 7.60 (dd, J = 2.3, 9.6 Hz, 1H), 6.80 (dd, J = 1.8, 9.6 Hz, 1H), 4.84 (m, 1H), 4.03 (m, 1H), 3.26 (m, 1H), 3.22 (m, 2H), 2.82 (m, 2H), 2.74 (m, 1H), 1.56 (m, 2H), 1.52 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 164.0, 153.4, 152.3, 149.9, 137.6, 126.1, 112.8, 105.3, 99.7, 41.9, 38.7, 38.5, 34.3, 26.3, 24.6; HRESIMS m / z 349.1447, [M+H]+(calcd for C15H21N6O2S, 349.1441).

[0440] Preparation of N-(5-aminopentyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide (TFA salt) (Compound EG): N-(5-aminopentyl)-4-(7H-py hydro-2H-1,4-thiazine-6-carboxamide (TFA salt) was obtained (63% yield) as a colorless solid.1H NMR (600 MHz, DMSO-d6): į 12.15 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 7.76 (br s, 3H), 7.71 (t, J = 5.7 Hz, 1H), 7.44 (dd, J = 2.3, 9.6 Hz, 1H), 6.67 (dd, J = 1.8, 9.6 Hz, 1H), 4.34 (m, 2H), 3.18 (m, 2H), 3.12 (m, 2H), 2.79 (m, 2H), 1.56 (m, 2H), 1.47 (m, 2H), 1.31 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 164.4, 153.0, 152.6, 150.0, 129.0, 124.4, 105.4, 104.2, 100.4, 45.0, 38.9, 38.8, 28.7, 26.7, 24.4, 23.2; HRESIMS m / z 347.1652, [M+H]+(calcd for C16H23N6OS, 347.1649).

[0441] Preparation of N-(5-aminopentyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide 1-oxide (TFA salt) (Compound EH): N-(5-aminopentyl)-4-(7H-pyrrdihydro-2H-1,4-thiazine-6- carboxamide 1-oxide (TFA salt) was obtained (25% yield) as a colorless solid.1H NMR (600 MHz, DMSO-d6): į 12.39 (s, 1H), 8.83 (s, 1H), 8.56 (s, 1H), 8.04 (t, J = 5.7 Hz, 1H), 7.72 (br s, 3H), 7.60 (dd, J = 2.3, 9.6 Hz, 1H), 6.80 (dd, J = 1.8, 9.6 Hz, 1H), 4.83 (m, 1H), 4.01 (m, 1H), 3.24 (m, 1H), 3.19 (m, 2H), 2.80 (m, 2H), 2.74 (m, 1H), 1.56 (m, 2H), 1.50 (m, 2H), 1.32 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 163.9, 153.4, 152.3, 149.9, 137.5, 126.1, 112.9, 105.3, 99.7, 41.9, 38.9, 38.8, 34.3, 28.7, 26.7, 23.2; HRESIMS m / z 363.1602, [M+H]+(calcd for C16H23N6O2S, 363.1598).

[0442] Preparation of N-(6-aminohexyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide (TFA salt) (Compound EI):N-(6-aminohexyl)-4-(7H-pyr ydro-2H-1,4-thiazine-6- carboxamide (TFA salt) wasobtained (49% yield) as a colorless solid.1H NMR (600 MHz, DMSO-d6): į 12.15 (s, 1H), 8.59 (s, 1H), 8.40 (s, 1H), 7.72 (br s, 3H), 7.70 (t, J = 5.7 Hz, 1H), 7.44 (dd, J = 2.3, 9.6 Hz, 1H), 6.66 (dd, J = 1.8, 9.6 Hz, 1H), 4.33 (m, 2H), 3.16 (m, 2H), 3.12 (m, 2H), 2.78 (m, 2H), 1.53 (m, 2H), 1.46 (m, 2H), 1.32 (m, 2H), 1.27 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 164.3, 153.0, 152.6, 150.0, 128.9, 124.3, 105.4, 104.2, 100.4, 45.0, 39.1, 38.8, 29.0, 26.7, 25.9, 25.5, 24.4; HRESIMS m / z 361.1812, [M+H]+(calcd for C17H25N6OS, 361.1805).

[0443] Preparation of N-(6-aminohexyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide 1-oxide (TFA salt) (Compound EJ):,4-thiazine-6- carboxamide 1-oxide (TFA salt) was obtained (24% yield) as a colorless solid.1H NMR (600 MHz, DMSO-d6): į 12.39 (s, 1H), 8.82 (s, 1H), 8.56 (s, 1H), 8.04 (t, J = 5.7 H7.71 (br s, 3H), 7.60 (dd, J = 2.3, 9.6 Hz, 1H), 6.80 (dd, J = 1.8, 9.6 Hz, 1H), 4.83 (m, 1H), 4.00 (m, 1H), 3.24 (m, 1H), 3.19 (m, 2H), 2.78 (m, 2H), 2.75 (m, 1H), 1.55 (m, 2H), 1.47 (m, 2H), 1.33 (m, 2H), 1.30 (m, 2H);13C NMR (150 MHz, DMSO-d6): į 163.9, 153.4, 152.3, 150.0, 137.5, 126.1, 113.0, 105.3, 99.7, 41.9, 39.7, 38.8, 34.3, 29.0, 27.0, 25.9, 25.5; HRESIMS m / z 377.1758, [M+H]+(calcd for C17H25N6O2S, 377.1754). EXAMPLE 8

[0444] This example provides an exemplary synthesis for Compounds EK-GO, OT-OY, QJ-QL, and QN.

[0445] Starting material Acid Scaffold-A was prepared using the synthetic protocol set forth in Scheme 30.Scheme 30: Preparation of 4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid (Acid Scaffold-A) of Example 8Potassium carbonate (40.20 g, 291.2 mmol) was added to a stirred solution of 6-chloro-9H- purine (15.0 g, 97.1 mmol) in anhydrous dimethylformamide (400 mL) at room temperature. The reaction mixture was cooled to below 10 °C and 2-(trimethylsilyl)ethoxymethyl chloride (26.20 mL, 145.6 mmol) was added dropwise over a period of 15 min. The reaction mixture was warmed to room temperature and stirring was continued for 24 h. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was poured into ice-cold water (1.50 L) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with a brine solution (3 × 50 mL), dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude material as a pale-yellow solid. The material was purified by flash chromatography by using silica gel (230-400 mesh). The desired product was eluted with 20-25% ethyl acetate / hexanes. The pure fractions were collected and concentrated under reduced pressure to afford 6-chloro-9- ((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (14.70 g, 53%) as colourless oil which solidified upon standing overnight.1H NMR (400 MHz, CDCl3): į 8.78 (s, 1H), 8.27 (s, 1H), 5.67 (s, 2H), 3.64 – 3.60 (m, 2H), 0.96 – 0.92 (m, 2H), -0.03 (s, 9H); MS (ESI) m / z 285.10 [C11H17ClN4OSi + H]+.

[0447] Preparation of ethyl 4-(9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxylate (3): Cesium carbonate (22.88 g, 70.42 mmol) and ethyl 3,4-dihydro-2H-1,4-thiazine-6-carboxylate (7.30 g, 42.3 mmol) were added to a stirred solution of 6-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (10.0 g, 35.2 mmol) in dry dimethylformamide (150 mL) under argon atmosphere at room temperature. The reaction mixture was stirred at 120 °C for 3 h. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was cooled to room temperature and diluted with cold water (1.0 L). The solid that formed was collected by filtration and washed with excess cold water (500 mL). The solids were dried under vacuum to afford ethyl 4-(9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylate [13.48 g (crude)] as an off-white solid.1H NMR (400 MHz, CDCl3): į 9.80 (br s,1H), 8.57 (s, 1H), 8.08 (s, 1H), 5.63 (s, 2H), 4.66 (br s, 2H), 4.33 (q, J = 7.20 Hz, 2H), 3.61 – 3.57 (m, 2H), 3.15 – 3.13 (m, 2H), 1.37 (t, J = 7.20 Hz, 3H), 0.95 – 0.91 (m, 2H), -0.03 (s, 9H); MS (ESI) m / z 422.2 [C18H27N5O3SSi + H]+.

[0448] Preparation of ethyl 4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylate (4): Trimethylsilyl chloride (13.0 mL, 102.35 mmol) was added to a stirred solution of ethyl 4-(9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxylate (13.0 g, 30.9 mmol) in trifluoroethanol (130 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to afford ethyl 4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylate [9.70 g (crude HCl salt)] as yellow solid; MS (ESI) m / z 292.1 [C12H13N5O2S + H]+.

[0449] Preparation of 4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid (Acid Scaffold-A): Lithium hydroxide hydrate (3.42 g, 81.6 mmol) was added to a stirred solution of ethyl 4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylate (9.50 g, 32.6 mmol) in ethanol: tetrahydrofuran: water (2:2:1, 100 mL) at room temperature. The resulting reaction mixture was stirred at 90 °C for 18 h. The progress of the reaction was monitored by thin layer chromatography which showed complete consumption of starting material. The mixture was concentrated under reduced pressure to obtain crude material which was diluted with water (100 mL) and acidified with 10% aqueous citric acid solution (pH~5). The obtained solid material was collected by filtration and the solid cake was washed with excess cold water and dried to afford 4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid [7.50 g (crude)] as an off-white solid.1H NMR (400 MHz, DMSO-d6): į 13.52 (s,1H), 12.53 (br s, 1H), 9.78 (s, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 4.53 (br s, 2H), 3.15 (m, 2H); MS (ESI) m / z 264.0 [C10H9N5O2S + H]+.

[0450] Acid Scaffold-A was transformed into Compounds EK-GO, OT-OY, QJ, QL, and QN using the general synthetic protocol for amide targets set forth in Scheme 31. Scheme 31: General Synthetic Protocol for Amide Targets of Example 8

[0451] Preparation of (S)-N-(2-aminopropyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride (Compound EK): (S)-N-(2-aminopropyl)-4-(9H-puri -1,4-thiazine-6-carboxamidehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (52.0 mg; 34%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 61%; MS (ESI) m / z 320.0 [C13H17N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0452] Preparation of N-(2-aminoethyl)-N-methyl-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride (Compound EL): N-(2-aminoethyl)-N-methyl-4-(9-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (59.0 mg; 37%). The Boc derivative was deprotected using condition-D. Colorless gum. Yield: 66%; MS (ESI) m / z 320.0 [C13H17N7OS + H]+; UPLC Purity: 98.0% (Method-A).

[0453] Preparation of (R)-N-(2-aminopropyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride (Compound EM): (R)-N-(2-aminopropyl)-4-(9H-puri-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A(60.0 mg; 38%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 96%; MS (ESI) m / z 320.0 [C13H17N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0454] Preparation of (R)-N-(piperidin-3-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride (Compound EN): ,4-thiazine-6-carboxamidehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (57.0 mg; 34%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 98%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 97.0% (Method-A).

[0455] Preparation of (R)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3- aminopiperidin-1-yl)methanone hydrochloride (Compound EO): (R)-(4-(9H-purin-6-yl)-3,4-dihydaminopiperidin-1-yl)methanone hydro chloride was prepared with the appropriate Boc-protected amine by using condition-A (60.0 mg; 34%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 95%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0456] Preparation of (S)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(2- (aminomethyl)piperidin-1-yl)methanone hydrochloride (Compound EP):(S)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(2-(aminomethyl)piperidin-1- yl)methanone hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (31.0 mg; 18%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 82%; MS (ESI) m / z 360 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0457] Preparation of (S)-N-(piperidin-2-ylmethyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound EQ): (S)-N-(piperidin-2-ylmethyl)-4-(9H dro-2H-1,4-thiazine-6-carboxamidehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (44.0 mg; 25%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 92%; MS (ESI) m / z 360 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0458] Preparation of (R)-N-(piperidin-2-ylmethyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound ER): (R)-N-(piperidin-2-ylmethyl)-4-(9Hdro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (56.0 mg; 32%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 81%; MS (ESI) m / z 360 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0459] Preparation of (R)-N-(azepan-3-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride (Compound ES):(R)-N-(azepan-3-yl)-4-(9H-purin- 4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (54.0 mg; 31%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 88%; MS (ESI) m / z 360 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0460] Preparation of N-(2-aminoethyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine- 6-carboxamide hydrochloride (Compound ET): N-(2-aminoethyl)-4-(9H-purin-6- iazine-6-carboxamidehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (40.0 mg; 26%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 81%; MS (ESI) m / z 306 [C12H15N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0461] Preparation of N-((1R,2R)-2-aminocyclopentyl)-4-(9H-purin-6-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxamide hydrochloride (Compound EU): N-((1R,2R)-2-aminocyclopentyl)-44-dihydro-2H-1,4-thiazine-6- carboxamidehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (55.0 mg; 32%). The Boc derivative was deprotected using condition-D. Lightyellow solid. Yield: 98%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0462] Preparation of (S)-N-(1-aminopropan-2-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound EV): (S)-N-(1-aminopropan-2-yl)-4-( o-2H-1,4-thiazine-6-carboxamidehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (53.0 mg; 29%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 67%; MS (ESI) m / z 320.0 [C13H17N7OS + H]+; UPLC Purity: 98.0% (Method-A).

[0463] Preparation of (R)-N-(1-aminopropan-2-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound EW): (R)-N-(1-aminopropan-2-yl)-4-(9-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (70.0 mg; 44%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 93%; MS (ESI) m / z 320.0 [C13H17N7OS + H]+; UPLC Purity: 98.0% (Method-A).

[0464] Preparation of (S)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3- aminopiperidin-1-yl)methanone hydrochloride (Compound EX):(S)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3-aminopiperidin-1-yl)methanone hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (70.0 mg; 44%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 86%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0465] Preparation of N-((1-aminocyclobutyl) methyl)-4-(9H-purin-6-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxamide hydrochloride (Compound EY): N-((1-aminocyclobutyl) methyl)-4- -dihydro-2H-1,4-thiazine-6-carboxamidehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (81.0 mg; 47%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 86%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0466] Preparation of (S)-4-(9H-purin-6-yl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound EZ): (S)-4-(9H-purin-6-yl)-N-(pyrrolidihydro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (87.0 mg; 52%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 94%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0467] Preparation of (R)-4-(9H-purin-6-yl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound FA):(R)-4-(9H-purin-6-yl)-N-(pyrrolid hydro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (72.0 mg; 43%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 97%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0468] Preparation of (S)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3- aminoazepan-1-yl)methanone hydrochloride (Compound FB): (S)-(4-(9H-purin-6-yl)-3,4-dihyd -aminoazepan-1-yl)methanonehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (74.0 mg; 43%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 94%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0469] Preparation of (R)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3- aminoazepan-1-yl)methanone hydrochloride (Compound FC): (R)-(4-(9H-purin-6-yl)-3,4-dihy-aminoazepan-1-yl)methanone hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (86.0 mg; 49%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 61%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0470] Preparation of N-(2-amino-2-methylpropyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound FD): N-(2-amino-2-methylpropyl)-4-( ro-2H-1,4-thiazine-6-carboxamidehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (55.0 mg; 33%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 85%; MS (ESI) m / z 334.0 [C14H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0471] Preparation of N-((1S,2S)-2-aminocyclopentyl)-4-(9H-purin-6-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FE): N-((1S,2S)-2-aminocyclopentyl)-4--dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (45.0 mg; 24%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 90%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0472] Preparation of (S)-N-(piperidin-3-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride (Compound FF):(S)-N-(piperidin-3-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (58.0 mg; 34%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 92%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0473] Preparation of Rel-N-((1S,3R)-3-aminocyclohexyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FG): -1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (27.0 mg; 15%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 95%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0474] Preparation of (4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3-amino-3- methylpiperidin-1-yl)methanone hydrochloride (Compound FH): (4-(9H-purin-6-yl)-3,4-dihydro-ino-3-methylpiperidin-1- yl)methanone hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (57.0 mg; 33%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 12%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 91.0% (Method-A).

[0475] Preparation of N-((1R,2R)-2-aminocyclohexyl)-4-(9H-purin-6-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FI):N-((1R,2R)-2-aminocyclohexyl)-4-( -dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (48.0 mg; 28%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 91%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0476] Preparation of (R)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(2- (aminomethyl)piperidin-1-yl)methanone hydrochloride (Compound FJ): (R)-(4-(9H-purin-6-yl)-3,4-dihydr(2-(aminomethyl)piperidin-1- yl)methanone was prepared with the appropriate Boc-protected amine by using condition-A (19.0 mg; 11%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 92%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0477] Preparation of N-((1S,2R)-2-aminocyclopentyl)-4-(9H-purin-6-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FK): N-((1S,2R)-2-aminocyclopentyl)-4--dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (58.0 mg; 33%). The Boc derivative was deprotected using condition-D. Lightyellow solid. Yield: 94%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 97.0% (Method-A).

[0478] Preparation of N-((1R,2S)-2-aminocyclopentyl)-4-(9H-purin-6-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FL): N-((1R,2S)-2-aminocyclopentyl)-4- -dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (62.0 mg; 37%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 94%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 97.0% (Method-A).

[0479] Preparation of (S)-N-(azepan-3-yl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride (Compound FM): Cl4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (28.0 mg; 16%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 91%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0480] Preparation of (R)-4-(9H-purin-6-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound FN):(R)-4-(9H-purin-6-yl)-N-(pyrroli ro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared withthe appropriate Boc-protected amine by using condition-A (45.0 mg; 27%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 90%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0481] Preparation of (S)-4-(9H-purin-6-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound FO): (S)-4-(9H-purin-6-yl)-N-(pyrrolid ro-2H-1,4-thiazine-6-carboxamidehydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (39.0 mg; 23%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 90%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0482] Preparation of N-((1R,3R)-3-aminocyclohexyl)-4-(9H-purin-6-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FP):o-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (7.5 mg; 5%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 62%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 97.0% (Method-A).

[0483] Preparation of N-(1-(amino methyl) cyclobutyl)-4-(9H-purin-6-yl)-3,4-dihydro- 2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FQ): N-(1-(amino methyl) cyclobutyl)-4- 4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (22.0 mg; 13%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 80%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0484] Preparation of N-(piperazin-2-ylmethyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide dihydrochloride (Compound FR): N-(piperazin-2-ylmethyl)-4-(9HH-1,4-thiazine-6-carboxamide dihydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (55.0 mg; 26%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 84%; MS (ESI) m / z 361.0 [C15H20N8OS + H]+; UPLC Purity: 96.0% (Method-A).

[0485] Preparation of (S)-4-(9H-purin-6-yl)-N-(pyrrolidin-3-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride (Compound FS):, -1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A(32.0 mg; 19%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 92%; MS (ESI) m / z 332.0 [C14H17N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0486] Preparation of Rel-N-((1S,2R)-2-aminocyclohexyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FT): Rel-N-((1S,2R)-2-aminocyclohexyl)- 3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (43.0 mg; 25%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 54%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0487] Preparation of Rel-N-((1S,3S)-3-hydroxy-2,3-dihydro-1H-inden-1-yl)-4-(9H- purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide (Compound FU): Rel-N-((1S,3S)-3-hydroxy-2,3-dihy-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide was prepared with the appropriate benzoyl protected amine by using condition-C (43.0 mg; 25%). The benzoyl derivative was deprotected using condition- G. Off white solid. Yield: 11%; MS (ESI) m / z 395.0 [C19H18N6O2S + H]+; UPLC Purity: 99.0% (Method-A).

[0488] Preparation of (S)-N-methyl-N-(piperidin-2-ylmethyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FV):(S)-N-methyl-N-(piperidin-2-ylmet l)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (36.0 mg; 20%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 35%; MS (ESI) m / z 374.0 [C17H23N7OS + H]+; UPLC Purity: 97.0% (Method-A).

[0489] Preparation of Rel-N-((1R,3S)-3-hydroxy-2,3-dihydro-1H-inden-1-yl)-4-(9H- purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide (Compound FW): Rel-N-((1R,3S)-3-hydroxy-2,3-dihy-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide was prepared with the appropriate benzoyl protected amine by using condition-C (36.0 mg; 20%). The benzoyl derivative was deprotected using condition- G. Off white solid. Yield: 4%; MS (ESI) m / z 395.0 [C19H18N6O2S + H]+; UPLC Purity: 99.0% (Method-A).

[0490] Preparation of (R)-4-(9H-purin-6-yl)-N-(pyrrolidin-3-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride (Compound FX):(R)-4-(9H-purin-6-yl)-N-(pyrrolidin-3-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (31.0 mg; 9%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 76%; MS (ESI) m / z 332.0 [C14H17N7OS + H]+; UPLC Purity: 98.0% (Method-A).

[0491] Preparation of Rel-N-(((1S,2S)-2-aminocyclobutyl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-carboxamide hydrochloride (Compound FY): Rel-N-(((1S,2S)-2-aminocyclobutyl) n-6-yl)-3,4-dihydro-2H-1,4-thiazine-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (34.0 mg; 20%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 62%; MS (ESI) m / z 346.0 [C15H19N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0492] Preparation of N-(((1R,2S)-2-aminocyclopentyl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound FZ): O S (R) N-(((1R,2S)-2-aminocyclopentyl)m-yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (42.0 mg; 24%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 56%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 98.0% (Method-E).

[0493] Preparation of N-(((1S,2S)-2-aminocyclopentyl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GA):N-(((1S,2S)-2-aminocyclopentyl)m -yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (60.0 mg; 34%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 48%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 97.0% (Method-E).

[0494] Preparation of (R)-N-methyl-N-(piperidin-2-ylmethyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GB): (R)-N-methyl-N-(piperidin-2-ylmet)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (50.0 mg; 27%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 76%; MS (ESI) m / z 374.0 [C17H23N7OS + H]+; UPLC Purity: 96.0% (Method-E).

[0495] Preparation of N-(((1S,2R)-2-aminocyclopentyl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GC): N-(((1S,2R)-2-aminocyclopentyl)m-yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by usingcondition-A (70.0 mg; 40%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 30%; MS (ESI) m / z 362.0 [C15H19N7OS + H]+; UPLC Purity: 95.0% (Method-E).

[0496] Preparation of N-((4-methylpiperazin-2-yl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide dihydrochloride (Compound GD): N-((4-methylpiperazin-2-yl)meth 4-dihydro-2H-1,4-thiazine-6-carboxamide dihydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (59.0 mg; 33%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 35%; MS (ESI) m / z 375.0 [C16H22N8OS + H]+; UPLC Purity: 98.0% (Method-E).

[0497] Preparation of N-(((1R,2R)-2-aminocyclopentyl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GE): N-(((1R,2R)-2-aminocyclopentyl)m6-yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (6.0 mg; 3%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 87%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 98.0% (Method-E).

[0498] Preparation of N-(((1S,2R)-2-aminocyclopentyl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GF):N-(((1S,2R)-2-aminocyclopentyl)m -yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (35.0 mg; 20%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 13%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 96.0% (Method-E).

[0499] Preparation of N-((1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl)-4-(9H-purin-6- yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GG):ro-2H-1,4- thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (4.0 mg; 2%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 86%; MS (ESI) m / z 394.0 [C19H19N7OS + H]+; UPLC Purity: 97.0% (Method-E).

[0500] Preparation of N-((1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl)-4-(9H-purin-6- yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GH):, , , o-2H-1,4- thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protectedamine by using condition-A (5.0 mg; 2%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 92%; MS (ESI) m / z 394.0 [C19H19N7OS + H]+; UPLC Purity: 98.0% (Method-E).

[0501] Preparation of N-((1S,2R)-1-amino-2,3-dihydro-1H-inden-2-yl)-4-(9H-purin-6- yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GI): dro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (5.0 mg; 2%). The Boc derivative was deprotected using condition-D. Light yellow solid. Yield: 46%; MS (ESI) m / z 394.0 [C19H19N7OS + H]+; UPLC Purity: 97.0% (Method-E).

[0502] Preparation of N-((1R,2S)-2-aminocyclohexyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide hydrochloride (Compound GJ): N-((1R,2S)-2-aminocyclohexyl)-4-(-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (27.0 mg; 15%). The Boc derivative was deprotected using condition-E. Light yellow solid. Yield: 56%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 98.0% (Method-A).

[0503] Preparation of N-(phenyl((S)-pyrrolidin-2-yl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GK):N-(phenyl((S)-pyrrolidin-2-yl) meth )-3,4-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (30.0 mg; 15%). The Boc derivative was deprotected using condition-E. Light yellow solid. Yield: 91%; MS (ESI) m / z 422.0 [C21H23N7OS + H]+; UPLC Purity: 95.0% (Method-A).

[0504] Preparation of N-(phenyl((R)-pyrrolidin-2-yl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GL):-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (40.0 mg; 21%). The Boc derivative was deprotected using condition-E. Light yellow solid. Yield: 60%; MS (ESI) m / z 422.0 [C21H23N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0505] Preparation of N-((1S,2R)-2-aminocyclohexyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamidehydrochloride (Compound GM):N-((1S,2R)-2-aminocyclohexyl)-4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (55.0 mg; 31%). The Boc derivative was deprotected using condition-E. Light yellow solid. Yield: 84%; MS (ESI) m / z 360.0 [C16H21N7OS + H]+; UPLC Purity: 98.0% (Method-A).

[0506] Preparation of N-(phenyl((S)-pyrrolidin-2-yl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GN): 2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine by using condition-A (50.0 mg; 33%). The Boc derivative was deprotected using condition-E. Light yellow solid. Yield: 63%; MS (ESI) m / z 360.0 [C21H23N7OS + H]+; UPLC Purity: 99.0% (Method-A).

[0507] Preparation of N-(phenyl((R)-pyrrolidin-2-yl)methyl)-4-(9H-purin-6-yl)-3,4- dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound GO):2H-1,4-thiazine-6- carboxamide hydrochloride was prepared appropriate Boc-protected amine by using condition-A (41.0 mg; 21%). The Boc derivative was deprotected using condition-E. Light yellow solid. Yield: 83%; MS (ESI) m / z 360.0 [C21H23N7OS + H]+; UPLC Purity: 96.6% (Method-A).

[0508] Preparation of N-(((2R,4R)-4-hydroxypyrrolidin-2-yl)methyl)-4-(9H-purin-6-yl)- 3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound OT):N-(((2R,4R)-4-Hydroxypyrrolidi in-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine using condition-A (25.0 mg; 18%). The Boc derivative was deprotected using condition-E. Light yellow solid.20.0 mg, Yield: 93%; MS (ESI) m / z 362 [C15H19N7O2S + H]+; UPLC Purity: 98.1% (Method-A).

[0509] Preparation of (S)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3-amino- 3-methylpiperidin-1-yl)methanone hydrochloride (Compound OU): (S)-(4-(9H-Purin-6-yl)-3,4-dihydr(3-amino-3-methylpiperidin-1- yl)methanone hydrochloride was prepared with the appropriate Boc-protected amine using condition-A (43.0 mg; 32%). The Boc derivative was deprotected using condition-E. Light yellow solid.35.0 mg, Yield: 95%; MS (ESI) m / z 360 [C16H21N7OS + H]+; UPLC Purity: 99.1% (Method-A).

[0510] Preparation of (R)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3-amino- 3-methylpiperidin-1-yl)methanone hydrochloride (Compound OV): (R)-(4-(9H-Purin-6-yl)-3,4-dihydro, (3-amino-3-methylpiperidin-1- yl)methanone hydrochloride was prepared with the appropriate Boc-protected amine using condition-A (45.0 mg; 26%). The Boc derivative was deprotected using condition-E. Lightyellow solid.25.0 mg, Yield: 64%; MS (ESI) m / z 360 [C16H21N7OS + H]+; UPLC Purity: 97.6% (Method-A).

[0511] Preparation of N-(((2S,4S)-4-hydroxypyrrolidin-2-yl)methyl)-4-(9H-purin-6-yl)- 3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound OW): N-(((2S,4S)-4-Hydroxypyrrolidin n-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine using condition-A (28.0 mg; 20%). The Boc derivative was deprotected using condition-E. Light yellow solid.20.0 mg, Yield: 83%; MS (ESI) m / z 362 [C15H19N7O2S + H]+; UPLC Purity: 96.6% (Method-A).

[0512] Preparation of (S)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3- aminopyrrolidin-1-yl)methanone hydrochloride (Compound OX): (S)-(4-(9H-Purin-6-yl)-3,4-dihydro(3-aminopyrrolidin-1-yl)methanone hydrochloride was prepared with the appropriate Boc-protected amine using condition-A (50.0 mg; 40%). The Boc derivative was deprotected using condition-E. Light yellow solid.35.0 mg, Yield: 83%; MS (ESI) m / z 332 [C14H18ClN7OS + H]+; UPLC Purity: 99.1% (Method-A).

[0513] Preparation of (R)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3- aminopyrrolidin-1-yl)methanone hydrochloride (Compound OY):(R)-(4-(9H-Purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3-aminopyrrolidin-1-yl)methanone hydrochloride was prepared with the appropriate Boc-protected amine using condition-A (55.0 mg; 44%). The Boc derivative was deprotected using condition-E. Light yellow solid.45.0 mg, Yield: 95%; MS (ESI) m / z 332 [C14H17N7OS + H]+; UPLC Purity: 99.1% (Method-A).

[0514] Preparation of (R)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3- (methylamino)piperidin-1-yl)methanone hydrochloride (Compound QJ): O H S N N(R)(R)-(4-(9H-Purin-6-yl)-3,4-dihydro (3-(methylamino)piperidin-1-yl)methanone hydrochloride was prepared with the appropriate Boc-protected amine using condition-B (80.0 mg; 46%). The Boc derivative was deprotected using condition-E. Light yellow solid.57.0 mg, Yield: 83%; MS (ESI) m / z 360 [C16H21N7OS + H]+; UPLC Purity: 99% (Method-A).

[0515] Preparation of (4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3,4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone (Compound QK): O S H N N N (4-(9H-Purin-6-yl)-3,4-dihydro-2H,6,7-tetrahydro-5H-imidazo[4,5- c]pyridin-5-yl)methanone was prepared with the appropriate amine using condition-A. off- white solid.18.0 mg, Yield: 13%.1H-NMR (400 MHz, DMSO-d6): į 13.43 (br s, 1H), 11.96 – 11.78 (m, 1H), 9.14 (br s, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 7.51 (s, 1H), 4.65 – 4.44 (m, 4H), 3.83 (t, J = 5.6 Hz, 2H), 3.25 – 3.22 (m, 2H), 2.83 – 2.68 (m, 2H). MS (ESI) m / z 369 [C16H16N8OS + H]+; UPLC Purity: 97.5% (Method-A).

[0516] Preparation of (S)-(4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)(3- (methylamino)piperidin-1-yl)methanone (Compound QL):(S)-(4-(9H-Purin-6-yl)-3,4-dihydro (3-(methylamino)piperidin-1-yl)methanone was prepared with the appropriate Boc-protected amine using condition-A (60.0 mg; 60%). The Boc derivative was deprotected using condition-E. Off-white solid.34.0 mg, Yield: 87%; MS (ESI) m / z 360 [C16H21N7OS + H]+; UPLC Purity: 95.0% (Method-A).

[0517] Preparation of N-(((2S,4R)-4-hydroxypyrrolidin-2-yl)methyl)-4-(9H-purin-6-yl)- 3,4-dihydro-2H-1,4-thiazine-6-carboxamide hydrochloride (Compound QN): N-(((2S,4R)-4-Hydroxypyrrolidin-6-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxamide hydrochloride was prepared with the appropriate Boc-protected amine using condition-A (9.00 mg; 5.0%). The Boc derivative was deprotected using condition-E. Light yellow solid.3.00 mg, Yield: 50%; MS (ESI) m / z 362 [C15H19N7O2S + H]+; UPLC Purity: 99% (Method-A). EXAMPLE 9

[0518] This example provides an exemplary synthesis for Compounds GP-IU, OZ-PB, PE, PF, PH, PJ, PK, QM, QO-QR, RR-RT, RV, RW, RZ, SA, SC, SK, SM-SO, TA, TD-TF, TL, TM, TO-TR, TV, TY, UQ-UW, VF-VL, VN, VO, VS-WP.

[0519] Starting material Acid Scaffold-B was prepared using the synthetic protocol set forth in Scheme 32. Scheme 32: Preparation of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine- 6-carboxylic acid (Acid Scaffold-B) of Example 9d]pyrimidine (2): To a stirred suspension of sodium hydride (60% in paraffin oil, 2.10 g, 54.69 mmol) in dimethylformamide (140 mL) was added 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (7.0 g, 45.58 mmol) in dimethylformamide (70.0 mL) followed by 2-(Trimethylsilyl)ethoxymethyl chloride (9.60 mL, 53.69 mmol) dropwise at 0 °C under argon atmosphere. The reaction mixture was stirred at room temperature for 30 min, the progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (100 mL) and diluted with ice-water (100 mL). The resulted solution was extracted with methyl tert-butyl ether (2 × 100 mL). The combined organic layers were washed with brine solution (3 × 50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The obtained crude material was purified by flash chromatography by using silica gel (230- 400 mesh). The desired product was eluted with 20-25% ethyl acetate in hexanes, the pure fractions were collected and concentrated under reduced pressure to afford 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (11.20 g, 87%) as colour less liquid.1H NMR (400 MHz, CDCl3): į 8.66 (s, 1H), 8.39 (d, J = 3.60 Hz, 1H),6.67 (d, J = 3.60 Hz, 1H), 5.65 (s, 2H), 3.54 – 3.50 (m, 2H), 0.91 (t, J = 8.00 Hz, 2H), -0.05 (s, 9H); MS (ESI) m / z 284.1 [C12H18ClN3OSi + H]+.

[0521] Preparation of ethyl 4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylate (3): Cesium carbonate (25.30 g, 77.72 mmol) and ethyl 3,4-dihydro-2H-1,4-thiazine-6-carboxylate (7.40 g, 42.75 mmol) were added to a stirred solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (11.0 g, 38.86 mmol) in dry dimethylformamide (110 mL) under argon atmosphere at room temperature. Upon the reaction mixture was stirred at 120 °C for 1 h, progress of the reaction was monitored by thin layer chromatography & UPLC-MS. The reaction mixture was cooled to room temperature and diluted with cold water (400 mL). The obtained solid was filtered and washed the solid cake with excess cold water (100 mL), dried under vacuum to afford ethyl 4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylate [15.10 g (crude)] as pale brownsolid.1H NMR (400 MHz, DMSO-d6): į 8.92 (s, 1H), 8.59 (s, 1H), 7.76 (d, J = 3.60 Hz, 1H), 6.85 (d, J = 3.60 Hz, 1H), 5.68 (s, 2H), 4.51 – 4.39 (m, 2H), 4.27 (q, J = 7.20 Hz, 2H), 3.59 (t, J = 7.60 Hz, 2H), 3.23 – 3.17 (m, 2H), 1.33 (t, J = 7.20 Hz, 3H), 0.91 (t, J = 8.00 Hz, 2H), -0.03 (s, 9H); MS (ESI) m / z 421.2 [: C19H28N4O3SSi + H]+.

[0522] Preparation of ethyl 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4- thiazine-6-carboxylate (4): Trimethylsilyl chloride (22.5 mL, 177.28 mmol) was added to a stirred solution of ethyl 4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylate (15.0 g, 35.71 mmol) in trifluoroethanol (90.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give the crude product which was dissolved in methanol (30.0 mL) and added 25% aqueous ammonia solution (30.0 mL) at 0 °C. The precipitation was observed in the reaction and it was stirred at room temperature for 2 h. The progress of the reaction was monitored by UPLC-MS. The resulting solid was filtered, washed with cold me...

Claims

CLAIM(S):

1. A compound of formula (I)wherein is a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3 alkyl; R3is an aryl; R4is C1-C3alkyl; A is –NR5((CHR7)mR6); R5, R6, and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, C8-C10 bicycloalkyl, C4-C10 biheterocycloalkyl, aryl,heteroaryl, or R5and R6combine to form a C3-C8heterocycloalkyl, C4-C10biheterocycloalkyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C1-C6 alkoxy, -C(O)OH, -C(O)O-(C1-C6 alkyl), -C(O)-(C1-C6alkyl), -(C1-C3alkyl)-C(O)OH, -(C1-C3alkyl)-C(O)O-(C1-C6alkyl), - (C1-C3 alkyl)-C(O)-(C1-C6 alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6 alkyl), -NH-C(O)-(C1- C6alkyl), -(C1-C3alkyl)-NH-C(O)OH, -(C1-C3alkyl)-NH-C(O)O-(C1-C6alkyl), -(C1-C3alkyl)-NH-C(O)-(C1-C6 alkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)- C(O)O-(C1-C6alkyl), -(C1-C6alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6 alkyl)-(C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)-heterocycloalkyl, - (C1-C6alkyl)-heterocycloalkyl-(C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl-(C1-C6 alkyl), halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6alkyl-amino; -NH-aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, spiro C3- C8cycloalkyl, fused C3-C8heterocycloalkyl, spiro C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, provided that R5and R6are not both hydrogen; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein is a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3 alkyl; R3is an aryl;R4is C1-C3alkyl; A is –NR5((CHR7)mR6); R5, R6, and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (C1-C6alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, aryl, heteroaryl, or R5 and R6 combine to form a C3-C8 heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, provided that R5 and R6 are not both hydrogen; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein wherein is a single or double bond,X and X are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl; R4is C1-C3 alkyl; A is –NR5R6; andR5and R6are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -(C1- C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, C3-C8 cycloalkyl, C3-C8heterocycloalkyl, aryl, heteroaryl, or R5and R6combine to form a C3-C8heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, and a combination thereof, provided that R5and R6are not both hydrogen; or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein is a double bond.

5. The compound of any one of claims 1-4, wherein the compound of formula (I) is of formula (Ia): ,or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, wherein A is a nitrogen bound C3-C8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one ormore substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, - (C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, wherein the compound of formula (I) is of formula (Ib), (Ic), (Id), or (Ie): ,(Id) (Ie) or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, wherein R1is H.

9. The compound of any one of claims 1-8, wherein A comprises a C3-C8heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, - (C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein the compound of formula (I) is selected from Compounds EA, EC-ES, and EU-WP or a pharmaceutically acceptable salt thereof.

11. A compound of formula (II)X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl; R4is C1-C3 alkyl; and E is C3-C8 heterocycloalkyl, C8-C10 bicycloalkyl, C4-C10 biheterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C1-C6alkoxy, -C(O)OH, -C(O)O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), -(C1-C3 alkyl)-C(O)OH, -(C1-C3 alkyl)-C(O)O-(C1-C6 alkyl), -(C1-C3 alkyl)-C(O)-(C1- C6alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -(C1-C3alkyl)- NH-C(O)OH, -(C1-C3 alkyl)-NH-C(O)O-(C1-C6 alkyl), -(C1-C3 alkyl)-NH-C(O)-(C1-C6 alkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -O-(C1-C6alkyl)-O-(C1-C6alkyl), -(C1-C6alkyl)-OH, - (C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-C(O)O-(C1-C6 alkyl), -(C1-C6 alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)-heterocycloalkyl, -(C1-C6 alkyl)-heterocycloalkyl- (C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-heterocycloalkyl, -(C1-C6 alkyl)-C(O)-heterocycloalkyl- (C1-C6alkyl), halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6 alkyl), -C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8cycloalkyl, spiro C3-C8cycloalkyl, fused C3- C8 heterocycloalkyl, spiro C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11, whereinis a single or double bond, X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl; R4is C1-C3 alkyl; and E is C3-C8 heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)- NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 11 or 12, wherein wherein is a single or double bond,X1and X2are each independently CH, CR4, or N; X3is S, S=O, or S(=O)2; R1is H or –NR2R3; R2is H or C1-C3alkyl; R3is an aryl;R4is C1-C3alkyl; and E is a carbon bound C3-C8 heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)- COOH, -(C1-C6alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6alkylamino, di-C1-C6alkyl- amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, - (C1-C3 alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 11-13, wherein is a double bond.

15. The compound of any one of claims 11-14, wherein the compound of formula (II) is of formula (IIa): ,or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 11-15, wherein the compound of formula (II) is of formula (IIb), (IIc), (IId), or (IIe):, ,or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 11-16, wherein E is selected from: ,, ,alkyl, C2-C6alkenyl, C2-C6alkynyl, trifluoromethyl, C1-C6alkoxy, arylated C1-C6alkoxy, trifluoromethylated C1-C6 alkoxy, -C(O)OH, -C(O)O-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), - (C1-C3 alkyl)-C(O)OH, -(C1-C3 alkyl)-C(O)O-(C1-C6 alkyl), -(C1-C3 alkyl)-C(O)-(C1-C6 alkyl), -NH-C(O)OH, -NH-C(O)O-(C1-C6 alkyl), -NH-C(O)-(C1-C6 alkyl), -(C1-C3 alkyl)- NH-C(O)OH, -(C1-C3 alkyl)-NH-C(O)O-(C1-C6 alkyl), -(C1-C3 alkyl)-NH-C(O)-(C1-C6 alkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-OH, - (C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-C(O)O-(C1-C6 alkyl), -(C1-C6 alkyl)-(C1-C6cycloalkyl)-OH, -(C1-C6alkyl)-NH2, -(C1-C6cycloalkyl)-NH2, -(C1-C6alkyl)- (C1-C6 cycloalkyl)-NH2, -(C1-C6 alkyl)-heterocycloalkyl, -(C1-C6 alkyl)-heterocycloalkyl- (C1-C6alkyl), -(C1-C6alkyl)-C(O)-heterocycloalkyl, -(C1-C6alkyl)-C(O)-heterocycloalkyl- (C1-C6 alkyl), halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl-amino; -NH- aryl, -NH-heterocycloalkyl, -NH-heterocycloalkyl-(C1-C6alkyl), -C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8 heterocycloalkyl, fused C3-C8 cycloalkyl, spiro C3-C8 cycloalkyl, fused C3- C8heterocycloalkyl, spiro C3-C8heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3 alkyl)-CN, carbonyl, amino acid, amino acid methyl ester, and a combination thereof, or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 11-17, wherein E is selected from:, , , , , , , , , ,C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(C1-C6alkyl)-OH, -(C1-C6cycloalkyl)- OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6alkyl-amino; –NH-aryl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, fused C3-C8 cycloalkyl, fused C3-C8 heterocycloalkyl, aryl, heteroaryl, fused aryl, fused heteroaryl, -CN, -(C1-C3alkyl)-CN, carbonyl, and a combination thereof, or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 11-18, wherein R1is H.

20. The compound of claim 11, wherein the compound of formula (II) is selected from Compounds A-Z, AA-AE, AG-DZ, and YA-YV or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound of any one of claims 1-20 and a pharmaceutical carrier.

22. A method of inhibiting kinase activity in a subject, the method comprising administering to the subject a compound of any one of claims 1-20 or the pharmaceutical composition of claim 21 to the subject.

23. The method of claim 22, wherein the kinase is PKA, PKA / DNAJ, cAMP- PKA, PKG1a, PKG1b, PKG2, PfPKG, PKC-^, PKC-nu, PKC-d, PKC-eta, PKC-g, STK39, CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, LATS1, or LATS2.

24. The method of claim 22, wherein the kinase is PKA, PKA / DNAJ, or cAMP- PKA.

25. The method of claim 22, wherein the kinase is PKG1a, PKG1b, PKG2, or PfPKG.

26. The method of claim 22, wherein the kinase is DYRK1A, DYRK1B, DYRK2, DYRK3, or DYRK4.

27. The method of claim 22, wherein the kinase is CLK1, CLK2, CLK3, or CLK4.

28. A method of suppressing the immune system in a subject, the method comprising administering to the subject a compound of any one of claims 1-20 or the pharmaceutical composition of claim 21 to the subject.

29. A method of preventing organ rejection in a subject, the method comprising administering to the subject a compound of any one of claims 1-20 or the pharmaceutical composition of claim 21 to the subject.

30. A method of treating cancer in a subject, the method comprising administering to the subject a compound of any one of claims 1-20 or the pharmaceutical composition of claim 21 to the subject.

31. The method of claim 30, wherein the cancer is fibrolamellar carcinoma (FLC).

32. The method of claim 30, wherein the cancer is fibrolamellar hepatocellular carcinoma (FL-HCC).

33. The method of claim 30, wherein the cancer is gastric cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer, lung cancer, or gliomas.

34. A method of modulating mRNA splicing in a subject, the method comprising administering to the subject a compound of any one of claims 1-20 or the pharmaceutical composition of claim 21 to the subject.

35. A method of treating diabetic neuropathic pain in a subject, the method comprising administering to the subject a compound of any one of claims 1-20 or the pharmaceutical composition of claim 21 to the subject.

36. A method of treating malaria in a subject, the method comprising administering to the subject a compound of any one of claims 1-20 or the pharmaceutical composition of claim 21 to the subject.

37. A method of treating an infection associated with a protozoa in a subject, the method comprising administering to the subject a compound of any one of claims 1-21 or the pharmaceutical composition of claim 20 to the subject.

38. The method of any one of claims 22-37, wherein the subject is human.

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